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The one Republican Senate candidate willing to call out Donald Trump – POLITICO

Posted on May 11, 2020 by Danzig

Plenty, plenty of issues, James responded. Everything from cutting Great Lakes funding to shithole countries to speaking ill of the dead," apparently referring to Trump's disparagement of the late Sen. John McCain. "I mean, where do you want to start?

"And so yes, there's gonna be places that I disagree with the president and those are just a couple," he added.

James, a 38-year-old Iraq War veteran, also pushed back against what he described as a Democratic talking point that he was bankrolled by the president and Education Secretary Betsy DeVos, who hails from one of the states wealthiest political families.

I havent gotten any money from Donald Trump. I haven't gotten any money from Betsy DeVos. I havent gotten any money thats political talking points. Very little of that is true, James said during the appearance, a video of which was obtained by POLITICO.

(While James hasn't received funding from the education secretary, her family has contributed heavily to a super PAC supporting his candidacy.)

James faces the hurdle of running in Michigan, a swing state where the presidents popularity has ebbed. A recent Fox News poll showed Trump trailing Joe Biden by 8 percentage points and James lagging behind Democratic Sen. Gary Peters by 10 percentage points.

The candidate made the case that he is taking a balanced approach toward the president and wasnt afraid to disagree with him. He said he wasnt focusing his campaign on Trump, though he acknowledged that many would see the race through the prism of the president.

I do recognize that it's human to disagree with people and like I've said millions of times, I can agree with the president without worshiping him. I can disagree without attacking him, James said.

Trump, James said at one point, "has his own campaign to run."

While the presidents poll numbers are sagging across the country amid the coronavirus pandemic, Trump advisers regard Michigan as a particular trouble spot. Of all the states the president won in 2016, they say, Michigan will be the hardest to carry again. Republicans have also struggled to recruit candidates in a pair of Michigan congressional seats that Democrats flipped in the 2018 midterm elections.

James has made clear throughout the 2020 race that hes willing to distinguish himself from Trump in certain areas and has stressed that he intends to run on local, not national issues.

This race isnt about President Trump, James was quoted as saying during the Mackinac Republican Leadership Conference in September. This race is about people in the state of Michigan whove been failed by their leaders for generations. This race is about people who are hurting in this state, and Im going to make this race about Michigan.

Gail Gitcho, a James spokeswoman, said, John James is willing to have these tough conversations with voters. John James is his own man, and he will point out when he agrees with the president and respectfully point out when he disagrees with him.

"I do recognize that it's human to disagree with people and like I've said millions of times, I can agree with the president without worshiping him."

John James

Trump has heavily promoted James, tweeting last month that James will be a GREAT Senator for Michigan!

Trump also endorsed James in his unsuccessful 2018 Senate bid. At one point, he tweeted a picture of him with James in the Oval Office.

James has publicly touted his support from the White House and recently said that Trump has done everything that he has thought was best in his managing of the pandemic.

Democrats say they are eager to paint James as a Trump puppet and frequently highlight his comment during the 2018 race that he was "2,000 percent" with the president's agenda.

During the late April conference, James was peppered with an array of skeptical questions about the president. James, who is African American, was reminded reminded that many in the black community don't trust Trump. James was asked whether he would publicly speak out against the administration and advocate for the needs of African Americans.

James responded that his access to Trump as a Republican senator would be an asset to African Americans in the state.

Look, Donald Trump doesnt need less black folks around him, he needs more, said James.

He added: Hopefully youll see through my actions that I am for you, that I am for black people, and that we share the same destiny. And hopefully as the result of that, you give me the benefit of the doubt.

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James challenged Sen. Debbie Stabenow (D-Mich.) in 2018 and lost by 6 percentage points. Afterward, Senate Majority Leader Mitch McConnell pushed for James to run again. GOP leaders regard the Michigan seat as one of their top pickup opportunities, and the National Republican Senatorial Committee has booked nearly $3 million for ads this fall.

Trump's campaign advisers were less enthusiastic about his second bid. Last year, the presidents political team wrote a memo to the Senate GOP campaign arm making the case that a James statewide candidacy would further amp up Democratic energy and involvement and potentially hurt Trumps prospects in the battleground state. Trump advisers instead pushed for James to run for a House seat.

Trump aides, who are constantly on the lookout for signs of Republican dissent, are suspicious that James is trying to have it both ways.

They were rankled when James, after announcing his Senate bid in June, tweeted, We are heading in the wrong direction as a country and our leaders in Washington are failing to lead us toward a better and brighter future.

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The one Republican Senate candidate willing to call out Donald Trump - POLITICO

The crude and callous coronavirus calculation of Chris Christie and Donald Trump | TheHill – The Hill

Posted on May 11, 2020 by Danzig

Last week Chris Christie, the former governor of New Jersey, declared that the United States should push ahead to reopen the economy because there are going to be deaths no matter what. Christie compared the coronavirus crisis to World War I and World War II, when Americans sent young men abroad knowing many of them would not come home alive. As in 1918-1919 and the 1940s, he declared, we have to stand up for the American way of life.

Christies comments coincided with attempts by the Trump administration to distance itself from the murderous math of COVID-19 in the United States. At the end of April, Jared KushnerJared Corey KushnerThe crude and callous coronavirus calculation of Chris Christie and Donald Trump Ivanka Trump's personal assistant tests positive for coronavirus FDA chief to self-quarantine after exposure to person with coronavirus MORE, who, as Bess Levin points out, has spent a lifetime failing upward, declared Were on the other side of the medical aspect of this and I think weve achieved all of the different milestones that are needed, so the federal government rose to the challenge and this is a great success story. A few days ago, President TrumpDonald John TrumpTrump says Chuck Todd should be fired over edited clip of Barr Trump lashes out at Obama in Mother's Day tweetstorm Georgia officials: Arrest made over online threat against Ahmaud Arbery protesters MORE confirmed that the Coronavirus Task Force would be wrapping up its work at the end of the month, then changed his mind, all the while emphasizing that the administration was moving on to implement Phase One of its guidelines for reopening the economy.

Along with the presidents encouragement of protesters seeking to liberate their (blue) states, these statements present a false choice: reopen the economy right now, or as Christie claimed stay locked in our own houses for another year, a recommendation no one has made. And Christie implied, falsely, that the number of fatalities in the United States is fixed and inevitable.

In World War I and World War II, the United States did not send its soldiers into battle without protective gear and weapons. Moreover, military strategy was or should have been designed to minimize casualties. Whats done is done, of course, but we must not lose sight of the impact of the failure of the United States despite dire warnings from public health officials to prepare for the pandemic.

The United States and South Korea reported their first cases of COVID-19 on the same day, Jan. 20, 2020. During the early stages of an outbreak, epidemiologists have found, an infected person passes the virus to 2-3 other people. The spread accelerates when, as with the coronavirus, asymptomatic individuals are infectious. During the month of February, while President Trump claimed when you have 15 people, and the 15 within a couple of days is going to be down to close to zero, thats a pretty good job weve done, South Korea conducted 80,000 tests; the United States conducted fewer than 1,000. South Korea quarantined individuals who tested positive, tracked down people with whom they had had contact, and quarantined them as well. As a result, South Korea has experienced five deaths for every 1 million of its citizens, while the United States has 237 (a number that is certain to grow). Other countries that tested, quarantined, contact traced, mandated social distancing and kept all but essential workers at home early in the pandemic also avoided the murderous math: Germany has had 90 fatalities per 1 million in its population; Japan 4; Australia 4; Taiwan 0.3. With robust testing and contact tracing in place, these countries are now opening up their economies.

And now, despite projections that fatalities are likely to spike, perhaps to 135,000 by August, as stay-at-home mandates are lifted and some states permit hair salons, restaurants, gymnasiums, and retail outlets to open in violation of the administrations own guidelines, and in the absence of robust testing (conducted randomly to identify hotspots as well as on those who present symptoms) and contact tracing capacity Chris Christie, President Trump, and Mr. Kushner insist that we have to get the economy open very soon.

Every American wants the economy to reopen. Every American embraces the American way of life. With good reason, however, the vast majority of Americans are more concerned about opening up too quickly than they are about a more cautious approach, informed by public health realities and recommendations.

Lets put a sock in the crude and callous calculations and the false choices.

We need to balance two vitally important priorities and learn from the experiences of other countries who are getting it right.

Glenn C. Altschuler is the Thomas and Dorothy Litwin Professor of American Studies at Cornell University. He is the co-author (with Stuart Blumin) ofRude Republic: Americans and Their Politics in the Nineteenth Century.

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The crude and callous coronavirus calculation of Chris Christie and Donald Trump | TheHill - The Hill

The Best Thing That Happened This Week: No, the Phillies Didnt Scout Donald Trump in High School – Philadelphia magazine

Posted on May 11, 2020 by Danzig

The Best Thing This Week

"There's no chance," says a scouting expert. Thank God somebody finally stood up for the integrity of our baseball team.

Did the Phillies scout Donald Trump? The presidents baseball prowess as a New York high-schooler appears to have been surprise! overstated. (Photo by Andrew Harrer-Pool/Getty Images)

Were not saying the President of the United States is a liar. We prefer the term embellisher, particularly when it comes to the truth. Hey, we understand how easy it can be to get carried away when youre chitchatting about, you know, your IQ,or your penchant for science, or your great good looks, or even your mental stability. Who among us doesnt do that every now and again, right? Right?

But when rumors get spread around that our very own Phillies were so impressed with your athletic ability that they scouted you when you were in high school, well, thats just a bridge too far. And back in 2013, Donald Trump proudly tweeted that he was said to be the best bball player in N.Y. State when he attended New York Military Academy in the 1960s. He was backed up by one of his former coaches there, the now, alas, deceased Theodore Dobias, who told both Rolling Stone and the Daily Mail that the Phils were interested in signing the schools supposed standout first baseman. The President has reminisced fondly about winning games with thunderous home runs but ultimately choosing a career in real estate because there just wasnt enough money in baseball back then.

Well, this week an enterprising reporter with the unlikely name of Leander Schaerlaeckens decided to look into the Presidents record on his high-school team. Slate published the result, and its delightful. Turns out Trumps memories of his prowess on the diamond are, oh, just a tad larger than life. His batting average, as Schaerlaecken determined by poring through regional newspaper accounts of NYMAs games, hovered at around .138. Dobias, according to the Washington Post, would say anything that his former protg told him to say. Schaerlaecken took the stats he found to the Athletics senior baseball writer, Keith Law, and asked point-blank: Would this guy have been recruited by the pros? Theres no chance, Law responded. You dont hit .138 for some podunk cold-weather high school playing the worst competition you can possibly imagine. You wouldnt even get recruited by Division I baseball programs, let alone by pro teams. Law declared the idea absolutely laughable. So, the evidence seems pretty conclusive. The Phillies, at least, have had their dignity restored.

The Best Thing That Happened This Week: No, the Phillies Didnt Scout Donald Trump in High School - Philadelphia magazine

Teenagers reveal what they really think of Donald Trump – The Conversation US

Posted on May 11, 2020 by Danzig

Teenagers in the United States are informed about their political world and capable of effectively evaluating political leaders, including President Donald Trump.

This statement runs counter to stereotypes that adults tend to hold about teens. Ask most adults to describe the political abilities of the typical American adolescent and you may hear words like apathetic, uninformed and immature.

But a study I conducted in 2017 with Laura-Wray Lake of UCLA, Amy Syvertsen of the Search Institute and two of my graduate students, Lauren Alvis and Katelyn Romm, indicates that high school students are much more knowledgeable and have stronger feelings about their political world than they are usually given credit for.

We asked more than 1,400 high school students in grades 9 to 12 to evaluate President Trump and provide reasons for their approval or disapproval of the president. The teenagers came from Southern California near Los Angeles, suburban Minnesota and rural West Virginia. They were diverse 43% identified as Latino, 34% as white, 13% as African American and 6% as Asian American and lived in communities that support and oppose Trump.

Several key themes emerged from the responses.

One was enthusiasm. Teens had a lot to say about Trump. Both youth who approved of Trump and those who did not provided thoughtful reasons for their views of the president. Many youth wrote sophisticated responses that counter stereotypes of adolescents as indifferent to their political world.

Another theme was knowledge. Teens supported their views by pointing to specific policies or statements by the president. Many of them justified their opinions by mentioning Trumps policies on social and political issues such as economic policy, abortion and relationships with foreign countries.

A large percentage of teens mentioned immigration, pointing to specific Trump statements or policy proposals, like the construction of a border wall between the United States and Mexico.

An 18-year-old female, for example, expressed her approval of Trumps immigration policies: Regarding issues with immigrants and stuff, I am not completely against it. I think we should be more aware of who and what kind of people we are allowing into our country, to keep everyone safe.

A 15-year-old white female had this to say about Trumps border policies: I just dont understand how that would make us great again. Because America is made up of immigrants, so it wouldnt be America if he didnt allow immigrants.

Teenagers also demonstrated knowledge of the presidents leadership style and background. Many of them mentioned Trumps business portfolio or his extensive Twitter use as a communication tool.

I feel that [Trump] will bring more jobs to the economy since he is a businessman, said a 17-year-old Latina.

On the other hand, youth who disapproved of Trump pointed to his lack of political experience.

Political beliefs varied greatly among adolescents, with many teens expressing strong approval or disapproval of the president in a way that echoed the range of views we see among adult voters.

Trump is going to do many things such as lower taxes, repeal Obamacare and try to institute the travel ban, wrote an 18-year-old white male. He also is not going to be a gun control freak.

A 17-year-old African American female said: I give [Trump] some credit because he is against abortion and gay marriage.

By contrast, a 15-year-old white female from Minnesota wrote: President Trump is a climate change denier. He also is in support of defending the Second Amendment, which I also believe in. However, I also understand that gun violence is rampant in the United States and needs to be regulated more heavily.

The responses we gathered help counter another stereotype about American adolescents: that they are overwhelmingly liberal and likely to vote for Democratic candidates.

Yes, younger generations lean more liberal on some social and political issues compared to older generations. But our study indicates that its inaccurate to generalize about teens political inclinations, because they hold a full range of views.

Teen views of Trump, like those of adults, were strongly related to where they live. Overwhelming majorities of adolescents in Southern California (85%) and Minnesota (84%) disapproved of Trump, but a majority of youth in West Virginia held positive views (66%). Adolescents with more conservative parents were more likely to approve of Trump, while youth from more liberal homes more strongly disapproved of the president. White youth generally held more favorable views of Trump, while females and black and Latino youth tended to reject him.

Our study also helps counter the notion that adolescents are not directly affected by political activity, that they have no skin in the game.

Adolescents in rural West Virginia underlined how Trumps energy policies could directly affect family members employed by power plants or coal mines. This is how one 14-year-old white female put it: I am happy Donald Trump is our president because my dad works for a power company, and that is how we made the majority of our money. Without his job we would have a hard time buying medicines and taking care of everyone in my family.

Many teen Trump skeptics from Southern California noted how his proposed immigration policies could threaten their families or neighborhoods. A 15-year-old Latina, for instance, noted: I am very scared [Trump] will harm my family. My parents are not from this country, but they do the best they can to be here with us and have us live the American dream.

One final theme present in our study highlights issues that will weigh on younger voters in the 2020 election and beyond. A large percentage of responses were framed around issues of racism, sexism and homophobia. Over half of the youth who dismiss Trump viewed his policies as potentially biased or loaded with discriminatory rhetoric, which is consistent with data indicating that younger generations are more attuned to issues of equity.

These concerns were not limited to any one group of teens. For example, an 18-year-old white male from West Virginia said, [Trump] is misogynistic and sexually offensive as audio clips of Donald Trump would prove more than once going as far to make fun of a disabled man in front of national television.

As this response shows, teenagers are more politically informed and opinionated than is usually assumed. This should encourage parents and teachers to engage teens in political discussion and anticipate that they will be able to effectively share informed views.

Additionally, our findings may be interesting to several U.S. districts mulling whether to lower the voting age from 18 to 16.

At very least, this study may help to counter concerns that youth dont care or will arrive at polls uninformed.

[Youre too busy to read everything. We get it. Thats why weve got a weekly newsletter. Sign up for good Sunday reading. ]

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Teenagers reveal what they really think of Donald Trump - The Conversation US

Trump, Biden gear up for battle in Florida, where coronavirus isn’t the only thing on voters’ minds – NBCNews.com

Posted on May 11, 2020 by Danzig

Miami resident Elisaul Herrera, who became a U.S. citizen along with his wife earlier this year, will cast his first presidential ballot this November for Donald Trump.

Elisa Mora, a high school counselor from Orlando who is a registered independent voter, says she'll support Joe Biden.

Neither sees the coronavirus crisis which has killed at least 1,700 people in the state and wreaked havoc on parts of the economy as a factor in their decision. Herrera said his choice would be motivated by the administrations policies toward his native Venezuela, while Mora said she was motivated by Bidens approach to immigration and his message of inclusiveness.

Interviews with Floridians as well as numerous current and former lawmakers, political strategists, politics watchers and academics in Florida paint a picture of a battleground state largely unmoved by the Trump administrations disjointed pandemic response and Bidens myriad proposals to handle things differently.

Unlike in Pennsylvania, a swing state where Trump's re-election hopes seem more closely tied to the fallout of the pandemic, the electoral picture in Florida heading into the fall appears to resemble any other presidential election year: a diverse, 50-50 state that will be won at the margins, driven largely by the economic picture and by how well each campaign is able to reach independent and undecided voters.

Because the economic toll in Florida, by some metrics, has not been as devastating as in other states and because the Biden campaign has struggled with its efforts to reach voters virtually the president may end up being spared from major pandemic-specific political consequences, sources told NBC News.

The election here, more than any one in recent memory, is going to be an us versus them on both sides," Alan Clendenin, the Southern caucus chair for the Democratic National Committee and a resident of Tampa, said. "I dont know whos left as a persuadable voter. Folks have their minds made up, regardless of what happens with the pandemic, and its going to be a get-out-the-vote campaign."

Rick Wilson, a Florida-based veteran Republican strategist, added, You might say that Trumps head is on the chopping block, but that hes nowhere near being executed.

Florida the country's third-most-populous state and, as of October, the president's official permanent residence has hardly been spared the devastation of the coronavirus. As of Saturday night, the state hadthe eighth-most confirmed cases of COVID-19 and the 10th-most deaths from the virus in the U.S.

But its COVID-19 per capita death rate of 8 people per 100,000 is better than about half of other states and is well below therates of other states its size. Statewide, the curve of new cases appears to have flattened in recent weeks, even as the state reopened its economy on Monday.

In addition, about 60 percent of all cases in the state have occurred in the solidly blue trifecta of southern Florida counties Miami-Dade, Broward and Palm Beach a concentration that could blunt electoral damage for Trump, sources told NBC News.

Meanwhile, the economic data can tell different stories depending on the interpretation. Since March 14, about 1.7 million workers in the state have lost their jobs.

That total is the third-highest number in the country, behind only California and New York. But how the figures break down as a percentage of the states workforce who have filed for unemployment actually puts Florida squarely in the middle of the pack: 16.2 percent, or a little less than 1 in 6 workers, have sought unemployment.

Because the pandemic is more likely to be painted as an economic issue in Florida, and not a public health matter, Trump may actually have an easier time recalibrating his general election message, strategists said.

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He had a very simple message to run on before, which was that he created a great economy and that the country was booming under his leadership, said Alex Conant, a Republican strategist who worked on Florida GOP Sen. Marco Rubios 2016 presidential campaign.

Now, it's a nuanced message, which is that he grew the economy before and that he can do it again, he added. The question again becomes who do voters trust more to create jobs, which favors Trump.

On the other hand, Florida has been beset by extraordinary problems relating to its state unemployment benefits system, for which voters may end up assigning blame to Trump, strategists and lawmakers said.

They will punish Trump for that in the fall, said Florida Democratic state Rep. Shev Jones, a Biden surrogate. People will not forget how Florida Republicans treated them.

At the moment, polls reflect a close race in the state fueled by modestly negative approval ratings for Trump, who narrowly won Florida in 2016 by 1.2 percentage points.

The latest RealClearPolitics polling average shows Biden leading Trump 46.5 percent to 43.3 percent inside all the comprising polls margin of error. An April 22 Quinnipiac poll showed 51 percent of registered Florida voters disapprove of the way the president was handling his pandemic response, with 46 percent saying they approve. On the other hand, 45 percent of respondents said they approve of the overall job he is doing as president his highest-ever mark in a Quinnipiac survey.

Political strategists from both parties, however, said Florida polling has often underreported GOP enthusiasm on models in previous elections due to a robust state party that is particularly skilled at turning out voters late in the race.

If youre a Democrat in a Florida poll and youre ahead, it means youre tied. Im not bullish on Biden until I see him up eight, 10 points here in a poll, Wilson said.

Only twice since 1928 Bill Clinton in 1992 and John F. Kennedy in 1960 has the winner of the general election not carried Florida's crucial 29 electoral votes, making it, arguably, the most critical battleground state.

Subsequently, the Biden campaign, mired in a virtual campaign that has seen the apparent nominee forced to relyon television appearances from his home studio in Delaware, has made Florida the genesis of its first state-specific virtual campaign events. He held a virtual roundtable with local lawmakers Thursday afternoon in Jacksonville and a virtual rally later in the day in Tampa.

But if the events were designed to show that Biden meant business in Florida, they fell short.

The afternoon roundtable was not broadcast. The evening rally featured several long-winded and awkward introductions from Florida lawmakers and a 65-year-old DJ named Jack Henriquez plagued by technical glitches, including audio delays and a total blackout that lasted several minutes.

When Biden finally came on 35 minutes after the event began, he appeared unprepared, saying, Did they introduce me?

Biden only spoke for about 10 minutes, giving a brief spiel that included a nod to the shrinking economy as well as an apology for the events flaws and a closing message drowned out by loudly chirping birds.

The campaign, however, has recently held other Florida-specific virtual events, including a virtual climate roundtable geared toward the state and a virtual town hall with gun control activist Fred Guttenberg, whose 14-year-old daughter was killed in the 2018 Parkland, Florida, high school shooting.

A campaign spokesperson told NBC News that Biden planned to hammer the economic troubles in Florida that have resulted from the pandemic and his campaign would continue, and expand, our aggressive outreach in Florida to turn that vision into votes."

Democratic lawmakers in south Florida, however, told NBC News they had, so far, not been satisfied with the Biden virtual campaigns outreach, especially to one key bloc of Florida voters: Latinos.

He is not reaching them at all at the moment, said Florida Democratic state Sen. Annette Taddeo, who represents a Miami-area district.

Meanwhile, Trump Victory, the joint operation between the Trump re-election campaign and the Republican National Committee, told NBC News since the campaign went digital-only on March 13, it has hosted at least 480 virtual trainings for campaign volunteers in Florida and made about 4 million voter contacts online in Florida.

Our campaign efforts in the state have not missed a beat, said Trump Victory spokesperson Rick Gorka.

Political strategists told NBC News that, assuming that Biden carries the reliably blue counties in the southeastern part of the state and Trump carries much of northern and central Florida, the likeliest path to victory in November would go through the so-called I-4 corridor, the area of the state running along the interstate between Tampa and Orlando that Floridians say is loaded with undecided and independent voters.

Among voters in those key counties is Christopher Talley, a 36-year-old resident of St. Petersburg, a city in Pinellas County, which Trump won in 2016 by 5,500 votes and Barack Obama won in 2012 by about 26,000.

Talley, a registered Democrat who has voted Republican in state races previously, said hell vote for Biden, citing the balance of the Supreme Court as his motivating issue.

Seeing how Trump can fill seats is terrifying, Talley said.

Not on his mind, however, is the pandemic. Talley didnt even mention it.

Adam Edelman reported from New York. Carmen Sesin reported from Miami.

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Trump, Biden gear up for battle in Florida, where coronavirus isn't the only thing on voters' minds - NBCNews.com

How Donald Trump, Joe Biden, and America Get Away With It – The Intercept

Posted on May 11, 2020 by Danzig

Photo illustration: Elise Swain/ The Intercept, Getty Images

Americas accountability problem is being laid bare. Once a global superpower, today jeers of failed state better describe our geriatric empire. Having survived impeachment, Americas acquitted president poorly navigates an unclear future as a pandemic rages and a recession looms, leaving hundreds of thousands dead in its global wake. An embattled population barrels toward a national election between two accused rapists and known liars: President Donald Trump and former Vice President Joseph Biden.

Biden, accused of sexual assault by one woman, has all but secured the Democratic nomination, gearing up for a general election against Trump, who faces at least 25 sexual misconduct allegations that range in criminal severity. Both men deny all the allegations.

Bidens accuser, Tara Reade, was one of eight women who registered complaints of inappropriate touching in April of last year before Biden ever jumped into the presidential race. As Biden appeared likely to be the Democratic nominee, Reade came forward in late March and told her story about her former boss. In an interview with podcast host Katie Halper, Reade said Biden penetrated her vagina with his fingers. She alleges the incident occurred in 1993, while she was an aide in his Senate office. What Reade describes is rape, according to the Department of Justices own definition. In an interview with Megyn Kelly, Reade has called on Biden to end his presidential bid and step forward and be held accountable.

Now Reade, not Biden, is on trial in the American media landscape. Democrats, the party of believe women, are changing their tune, terrified at the prospect of another four years of a Trump presidency. After all, 2016 proved that lugging a litany of sexual assault and harassment accusations does not guarantee an electoral loss. Before the election, at least four women were on record accusing Trump of sexual misconduct. American flags aloft, his fanatical base laughed along with the presidential candidate as he called his accusers liars and implied that they werent attractive enough for him to assault. When youre a star, they let you do it, Trump said on the infamous Access Hollywood recording. Grab em by the pussy. You can do anything.This unearthed admission did not cost him the election either.

If Democrats continue to do nothing, Reades accusation should prove that sexual misconduct allegations in either party are nothing more than a mild political inconvenience.

Protestors demonstrating against torture stand in front of the White House in Washington, D.C., February 18, 2015.

Photo: Saul Loeb/AFP via Getty Images

The lack of impetus to replace Biden speaks to how Washington, D.C., has long neglected creating a culture of accountability. Some of the darkest chapters of U.S. history have been classified away. Our villainous past remains unprosecuted as bipartisan bombs continue falling. Americas lack of understanding wrongdoing enables figures who should have atoned in order for the country to progress to instead linger in political relevance.

If you supervised torture and destroyed evidence, like Gina Haspel, you can still get promoted. If youre a war criminal, like George W. Bush, you can be rehabilitated. If youre a judge, credibly accused of sexual conduct, like Clarence Thomas and Brett Kavanaugh, you, too, can become a Supreme Court justice.

Now, high-profile Democratic endorsements for Biden signal that a quest for the truth and a reckoning for the allegations against him will never come.

I think thats really whats corrosive about this moment, is this idea that you can try to shred Tara Reades credibility and stick up for Joe Biden and still say that you have any kind of commitment to ending sexual violence, that you have any kind of commitment to womens rights, Melissa Gira Grant, a staff writer at the New Republic, explained on Intercepted. I dont think you get to have it both ways.

The name Lucy Flores may be all but forgotten in an exhausting year of political reporting. Flores was the first to come forward and register publicly that an encounter with Biden made her deeply uncomfortable. In a viral essay, Flores described how, in 2015, then-Vice President Biden made her feel uneasy, gross, and confused as she campaigned for lieutenant governor in Nevada.

I feel him come up close behind me, and thats when he leans in and he lingers around my head, Flores recounted on Intercepted. I hear him kind of inhale. And then he proceeds to plant this low kiss on the top of my head. (Biden denied that he had acted inappropriately toward Flores.)

Seven more women came forward with similar stories of Bidens manner of unwanted, inappropriate touching. Descriptions told of how his hands intimately lingered on everything from the womens necks, shoulders, backs, or thighs. Some say his forehead pressed against theirs. Noses so close that they rubbed together. Breathing in the smell of hair. Kissing the back of the head.

The bottom line with that kind of behavior is entitlement.

The bottom line with that kind of behavior is entitlement, Gira Grant explained. Both entitlement to someones physical body, but then also entitlement to characterize what happened through whatever lens you have that allows you to continue that behavior.

Flores was precise in calling out the inequality inherent in how womens bodies were assumed to be touchable, especially by powerful men. Most people acknowledge that men dont usually kiss, smell, rub noses with, place their hands on the thighs of, or touch foreheads with random women they dont know, Flores opined in the New York Times. Yet some men do, especially powerful men, who are protected by privilege and a crew of self-interested enablers who dont want to lose their access to power by calling out the obvious.

Lucy Flores in the lobby of the office building where she works in downtown Los Angeles, on May 25, 2019.

Photo: Jenna Schoenefeld for The Washington Post via Getty Images

When allegations of inappropriate kissing and touching surfaced against Sen. Al Franken, D-Minn., from seven accusers, dozens of his Democratic Senate colleagues quickly called for his resignation. With a professed zero-tolerance position for any sexual misconduct, Sen. Kirsten Gillibrand, D-N.Y., led the charge. Within weeks, Franken took the incredibly rare step of resigning from his Senate seat.

Biden, apparently lacking a particularly damning enough photograph of misconduct, has been given a pass. And Gillibrand, despite Reades allegation, has maintained her support and endorsement of Biden. Democratic National Committee Chair Tom Perez has dismissed the accusations. House Speaker Nancy Pelosi, D-Calif., also supports Biden. A day after Business Insiders investigation further corroborated Reades story, Hillary Clinton, too, threw in her high-profile endorsement of Biden.

For Flores, Bidens conduct that day was disqualifying. But, for the Democratic establishment, perhaps fearing both more years of Trump and a Bernie Sanders presidency, Bidens conduct has been accepted. His character has been troublingly defended by colleagues especially by women eyeing a vice presidential nomination.

As complaints from women mounted, Biden told reporterslast year, Im not sorry for any of my intentions. Im not sorry for anything that I have ever done. Ive never been disrespectful intentionally to a man or a woman. With this, Biden revealed an inability to comprehend culpability.

This is what hes known for, Flores told Intercepted. He is not known for voluntarily or willingly acknowledging that he has made mistakes in the past, whether its around his position on the Hyde Amendment, whether it was around how he mishandled the Clarence Thomas hearings, school busing and segregationist policies I mean, the list is pretty long.

Bidens record is long and troubling. Some voters, myself included, are struggling with a moral debate in response to the electoral options before us. We face an impossible choice and feel disgust at being put in this position.

Its a mind-fuck. Gira Grant said, about the inevitable choice between Trump and Biden. I want to appreciate how that feels and how uncomfortable that is. I think its just, like, ripping something back about our culture and our politics and revealing it to us. I dont think its necessarily new.

I think its just, like, ripping something back about our culture and our politics and revealing it to us. I dont think its necessarily new.

Yet it isnt surprising. Bidens inability to admit fault he has said, I am not sorry for anything I have ever done simply shows that he is a byproduct of an institution of impunity. America, too, doesnt do apologies. Reparations for black people and native people are nowhere in sight. We didnt prosecute torture and we wont prosecute war crimes. The cancer at the core of this nation is one of fundamental injustice, hidden beneath platitudes of freedom, liberty, and equality for all. To remove Biden would be to indict American exceptionalism itself.

Liberals like Biden, who believe that Americas divisions can be healed by a new president, dont see this country as built on exploitation. To understand how we heal, we have to view America through the painful lens of wrongs committed. Accountability must be viewed as a feminist issue, especially in a nationthatwove oppression into every fiber of its flag.

America should live in shame until we admit fault, recognize hurt, and ask for forgiveness. Joe Biden can go first.

11 US Secret Service agents test positive for the coronavirus – Business Insider – Business Insider

Posted on May 11, 2020 by Danzig

Eleven members of the US Secret Service have tested positive for the coronavirus as of Thursday evening, according to Yahoo News.

Documents from the Department of Homeland Security (DHS) seen by Yahoo News, revealed that the agency has 11 active coronavirus cases and an additional 60 employees who are reportedly self-quarantining. On top of this, another 23 members have already recovered from COVID-19, the diseases caused by the coronavirus.

It is not known whether the employees who tested positive for the coronavirus worked at the White House or if they had recent close contact with President Donald Trump or Vice President Mike Pence.

Both Trump and Pence get tested for the disease regularly but have not tested positive so far. However, Trump said this week that he would switch from having weekly to daily tests following the new cases, according to The Hill.

Justin Whelan, a spokesperson for the Secret Service told Yahoo News that the agency is following guidelines from the Centers for Disease Control (CDC).

"To protect the privacy of our employee's health information and for operational security, the Secret Service is not releasing how many of its employees have tested positive for COVID-19, nor how many of its employees were, or currently are, quarantined," Whelan added.

FILE - In this Sept. 20, 2019, file photo President Donald Trump's White House Senior Adviser Stephen Miller, left, and Katie Waldman, now Miller, arrive for a State Dinner with Australian Prime Minister Scott Morrison and President Donald Trump at the White House. (AP Photo/Patrick Semansky, File) Associated Press

The news comes as President Donald Trump revealed on Friday that Mike Pence's press secretary, Katie Miller, tested positive for the coronavirus. Miller, who is the wife of Stephen Miller Trump's senior adviser, and primary speechwriter confirmed her diagnosis with NBC News, adding that she was asymptomatic.

Ivanka Trump's personal assistant has also tested positive for the coronavirus, CNN's Kaitlan Collins reported.

This follows a US Navy member who serves as one of Trump's valets who tested positive for the coronavirus on Thursday, according to CNN.

The string of recent diagnoses in the White House raises concerns about the president's possible exposure to the virus, which has since infected more than 1.3 million people in the US, according to Worldometer.

Trump has previously said that he's "not worried" about getting infected and has notably been seen not wearing a face mask at recent meetings and public appearances, despite the advice on face coverings by the CDC.

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11 US Secret Service agents test positive for the coronavirus - Business Insider - Business Insider

Passage Bio Announces Expansion of Gene Therapy Collaboration with University of Pennsylvania – GlobeNewswire

Posted on May 11, 2020 by Danzig

PHILADELPHIA, May 07, 2020 (GLOBE NEWSWIRE) -- Passage Bio, Inc. (NASDAQ: PASG), a genetic medicines company focused on developing transformative therapies for rare, monogenic central nervous system (CNS) disorders and the Gene Therapy Program (GTP) at the University of Pennsylvania (UPenn) today announced the expansion of their collaboration agreement to include an additional five programs and extending Passage Bios period to exercise new programs for an additional three years (through 2025). Additionally, Passage Bio will fund discovery research at GTP and will receive exclusive rights, subject to certain limitations, to technologies resulting from the discovery program for Passage Bio products developed with GTP, such as novel capsids, toxicity reduction technologies and delivery and formulation improvements.

Our collaboration with the GTP gives us access not only to the best discovery, technology, and research available but also to pioneering expertise in the field of gene therapy, including pre-clinical development and manufacturing experience that will help guide our programs as we move into clinical development, said Bruce Goldsmith, Ph.D., president and chief executive officer of Passage Bio. Expanding this collaboration provides us with the opportunity to not only deepen our pipeline but also strengthen our own expertise and capabilities as we strive to develop transformative gene therapies for patients. We are tremendously proud of the progress we have accomplished to date through this partnership and look forward to continuing this momentum in the years to come.

This expansion builds upon the original collaboration, which successfully established a strong partnership between Passage and GTP. Under the expanded agreement, Passage will pay $5 million annually to Penn to fund research across numerous technology applications for gene therapy. In addition to five additional program options and an extension of the relationship through 2025, Passage will receive exclusive rights, subject to certain limitations, to IP arising from this research and related indications that are applicable to the products it develops with GTP.

The partnership between GTP and Passage Bio continues to be extremely strong and productive as we collaborate to bring our gene therapy products to patients. We are extremely excited to expand the reach of our CNS products and discovery research through this continued collaboration, said James Wilson, M.D., Ph.D. director of the Gene Therapy Program at the University of Pennsylvania and chief scientific advisor of Passage Bio. As a co-founder of the company, I am also deeply committed to the growth and success of Passage. I believe that the expansion of this strong collaboration further establishes Passage Bios leadership in gene therapy and I look forward to continuing to work with our dedicated teams to reach these shared goals of helping patients with rare, monogenic CNS disorders.

About Passage Bio Passage Bio is a genetic medicines company focused on developing transformative therapies for rare, monogenic central nervous system disorders with limited or no approved treatment options. The company is based in Philadelphia, PA and has a research, collaboration and license agreement with the University of Pennsylvania and its Gene Therapy Program (GTP). The GTP conducts discovery and IND-enabling preclinical work and Passage Bio conducts all clinical development, regulatory strategy and commercialization activities under the agreement. The company has a development portfolio of six product candidates, with the option to license eleven more, with lead programs in GM1 gangliosidosis, frontotemporal dementia and Krabbe disease.

Forward Looking StatementThis press release contains forward-looking statements within the meaning of, and made pursuant to the safe harbor provisions of, the Private Securities Litigation Reform Act of 1995, including, but not limited to: our expectations about our collaborators and partners ability to execute key initiatives and the benefits and obligations associated with our arrangements with our collaborators and partners; and the ability of our lead product candidates to treat the underlying causes of their respective target monogenic CNS disorders. These forward-looking statements may be accompanied by such words as aim, anticipate, believe, could, estimate, expect, forecast, goal, intend, may, might, plan, potential, possible, will, would, and other words and terms of similar meaning. These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements, including: our ability to develop, obtain regulatory approval for and commercialize our product candidates; the timing and results of preclinical studies and clinical trials; the risk that positive results in a preclinical study or clinical trial may not be replicated in subsequent trials or success in early stage clinical trials may not be predictive of results in later stage clinical trials; risks associated with clinical trials, including our ability to adequately manage clinical activities, unexpected concerns that may arise from additional data or analysis obtained during clinical trials, regulatory authorities may require additional information or further studies, or may fail to approve or may delay approval of our drug candidates; the occurrence of adverse safety events; failure to protect and enforce our intellectual property, and other proprietary rights; failure to successfully execute or realize the anticipated benefits of our strategic and growth initiatives; risks relating to technology failures or breaches; our dependence on collaborators and other third parties for the development of product candidates and other aspects of our business, which are outside of our full control; risks associated with current and potential delays, work stoppages, or supply chain disruptions caused by the coronavirus pandemic; risks associated with current and potential future healthcare reforms; risks relating to attracting and retaining key personnel; failure to comply with legal and regulatory requirements; risks relating to access to capital and credit markets; and the other risks and uncertainties that are described in the Risk Factors section in documents the company files from time to time with theSecurities and Exchange Commission(SEC), and other reports as filed with theSEC. Passage Bio undertakes no obligation to publicly update any forward-looking statement, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise.

For further information, please contact:

Investors:Sarah McCabeStern Investor Relations, Inc.212-362-1200sarah.mccabe@sternir.com

Media:Emily MaxwellHDMZ312-506-5220emily.maxwell@hdmz.com

Financial Disclosure: The University of Pennsylvania and Dr. James Wilson are both co-founders of Passage Bio and hold equity interests in the company. Dr. Wilson is also the chief scientific advisor of the Company. Penn and GTP are the recipients of significant sponsored research support from the Company under research programs directed by Dr. Wilson. Penn has licensed or optioned numerous technologies to Passage Bio under an existing license and these ongoing sponsored research activities, and both Penn and Dr. Wilson stand to receive additional financial gains in the future under these licensing arrangements.

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Passage Bio Announces Expansion of Gene Therapy Collaboration with University of Pennsylvania - GlobeNewswire

Orgenesis sees 1Q revenue rocket driven by its Cell and Gene Therapy Biotech platform – Proactive Investors USA & Canada

Posted on May 11, 2020 by Danzig

For its first quarter ended March 31, 2020, the Maryland-based company, reported revenue of $1.9 million, compared to $0.4 million a year earlier

Inc (), a global biotech company focused on accelerating and transforming the delivery of cell and gene therapies, posted first-quarter results on Monday that saw its revenue soar 348% year-over-year driven by its Cell and Gene Therapy (CGT) Biotech platform.

For its first quarter ended March 31, 2020, the Germantown, Maryland-based company, reported revenue of $1.9 million, compared to $0.4 million in the first quarter of 2019.

Orgenesis achieved net income of $75.6 million, or $4.23 per share, reflecting the sale of subsidiary Masthercell Global Inc, a contract development manufacturing organization (CDMO).

READ:Orgenesis boss Vered Caplan makes top 20 list of inspirational leaders in advanced medicine

On February 11, Orgenesis completed the successful sale of its CDMO business to Somerset, New Jersey-based Catalent Pharma Solutions, for around $127 million.

As a result, Orgenesis reported cash and equivalents of $107.1 million as of March 31, 2020.

In a statement accompanying the numbers, Orgenesis CEO Vered Caplan said: Step by step, our CGT Biotech Platform is gaining traction within the market, as illustrated by the year-over-year growth.

In the first quarter of 2020, revenue increased to $1.9 million, or nearly an $8 million revenue run rate compared to $3.1 million for all of 2019. We believe our CGT Biotech Platform is poised for growth this year through industry partnerships that are currently underway with leading research institutes and hospitals around the world, she added.

The companys CGT Biotech platform consists of three core elements:point-of care Therapeutics, point-of care Technologies, and point-of care Network.

Caplan also noted that earlier this year, the company struck collaboration agreements with two leading healthcare research institutes in the US.

We plan to utilize our point-of-care Network to support their growing development and processing needs in order to advance and accelerate cell and gene-based clinical therapeutic research, said Caplan.

Orgenesis is using the Masthercell sale proceeds to expand the companys point-of-care cell therapy business. The biotech is currently focused on therapies which span a wide range of treatments.

In addition to our POCare Network, we are building our pipeline of POCare Therapeutics and Technologies, with an ultimate goal of providing life-changing treatments to large numbers of patients at reduced costs within the point-of-care setting, said Caplan.

Specifically, we are focusing on immune-oncology, metabolic and autoimmune diseases, as well as anti-viral therapies.

Orgenesis also recently completed the acquisition of Tamir Biotechnology and its broad-spectrum antiviral platform, ranpirnase in a cash and stock deal for roughly $21 million. The company will use ranpirnase to target human papillomavirus (HPV), which causes genital warts.

Ranpirnase has demonstrated clinical efficacy against HPV and other hard to target viruses based on its unique mechanism of action of killing the virus and modulating the immune system, said Caplan.

Going forward, Orgenesis plans to move the program through a Phase 2b trial in the US.

Meanwhile, the Orgenesis boss said the company has received a nod from regulators to keep research alive at its labs during the coronavirus (COVID-19) pandemic.

We are leveraging all our knowledge and expertise in the field of cell and gene therapy, including anti-viral technologies, in an attempt to find potential COVID-19 cures and therapies, said Caplan.

Importantly, we have a strong balance sheet and are strategically positioned to bring a variety of therapies to market in a cost-effective, high-quality and scalable manner.

At the start of April, Orgenesis teamed up with regenerative medicine and cell therapy firm RevaTis on a new joint venture to produce certain stem cells. The two firms plan to leverage Orgenesiss autologous CGT Biotech platform to advance clinical trials.

Under the deal, RevaTis and Orgenesis will use the formers patented technique to obtain muscle-derived mesenchymal stem cells (mdMSC) as a source of exosomes and various other cellular products.

Our plan is to combine RevaTis patented technique to obtain mdMSCs through a minimally invasive muscle micro-biopsy with our own automated/closed-systems, 3D printing, and bioreactor technologies, said Caplan.

The goal of this JV is to lower the costs and accelerate the timeline of bringing these innovative therapies through the clinic and into commercialization.

Contact the author Uttara Choudhury at [emailprotected]

Follow her on Twitter: @UttaraProactive

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Orgenesis sees 1Q revenue rocket driven by its Cell and Gene Therapy Biotech platform - Proactive Investors USA & Canada

Gene therapy for follistatin mitigates systemic metabolic inflammation and post-traumatic arthritis in high-fat dietinduced obesity – Science Advances

Posted on May 11, 2020 by Danzig

Abstract

Obesity-associated inflammation and loss of muscle function play critical roles in the development of osteoarthritis (OA); thus, therapies that target muscle tissue may provide novel approaches to restoring metabolic and biomechanical dysfunction associated with obesity. Follistatin (FST), a protein that binds myostatin and activin, may have the potential to enhance muscle formation while inhibiting inflammation. Here, we hypothesized that adeno-associated virus 9 (AAV9) delivery of FST enhances muscle formation and mitigates metabolic inflammation and knee OA caused by a high-fat diet in mice. AAV-mediated FST delivery exhibited decreased obesity-induced inflammatory adipokines and cytokines systemically and in the joint synovial fluid. Regardless of diet, mice receiving FST gene therapy were protected from post-traumatic OA and bone remodeling induced by joint injury. Together, these findings suggest that FST gene therapy may provide a multifactorial therapeutic approach for injury-induced OA and metabolic inflammation in obesity.

Osteoarthritis (OA) is a multifactorial family of diseases, characterized by cartilage degeneration, joint inflammation, and bone remodeling. Despite the broad impact of this condition, there are currently no disease-modifying drugs available for OA. Previous studies demonstrate that obesity and dietary fatty acids (FAs) play a critical role in the development of OA, and metabolic dysfunction secondary to obesity is likely to be a primary risk factor for OA (1), particularly following joint injury (2, 3). Furthermore, both obesity and OA are associated with a rapid loss of muscle integrity and strength (4), which may contribute directly and indirectly to the onset and progression of OA (5). However, the mechanisms linking obesity, muscle, and OA are not fully understood and appear to involve interactions among biomechanical, inflammatory, and metabolic factors (6). Therefore, strategies that focus on protecting muscle and mitigating metabolic inflammation may provide an attractive target for OA therapies in this context.

A few potential interventions, such as weight loss and exercise, have been proposed to reverse the metabolic dysfunction associated with obesity by improving the quantity or quality of skeletal muscle (7). Skeletal muscle mass is modulated by myostatin, a member of the transforming growth factor (TGF-) superfamily and a potent negative regulator of muscle growth (8), and myostatin is up-regulated in obesity and down-regulated by exercise (9). While exercise and weight loss are the first line of therapy for obesity and OA, several studies have shown difficulty in achieving long-term maintenance of weight loss or strength gain, particularly in frail or aging populations (10). Thus, targeted pharmacologic or genetic inhibition of muscle-regulatory molecules such as myostatin provides a promising approach to improving muscle metabolic health by increasing glucose tolerance and enhancing muscle mass in rodents and humans (8).

Follistatin (FST), a myostatin- and activin-binding protein, has been used as a therapy for several degenerative muscle diseases (11, 12), and loss of FST is associated with reduced muscle mass and prenatal death (13). In the context of OA, we hypothesize that FST delivery using a gene therapy approach has multifactorial therapeutic potential through its influence on muscle growth via inhibition of myostatin activity (14) as well as other members of the TGF- family. Moreover, FST has been reported to reduce the infiltration of inflammatory cells in the synovial membrane (15) and affect bone development (16), and pretreatment with FST has been shown to reduce the severity of carrageenan-induced arthritis (15). However, the potential for FST as an OA therapy has not been investigated, especially in exacerbating pathological conditions such as obesity. We hypothesized that overexpression of FST using a gene therapy approach will increase muscle mass and mitigate obesity-associated metabolic inflammation, as well as the progression of OA, in high-fat diet (HFD)induced obese mice. Mice fed an HFD were treated with a single dose of adeno-associated virus 9 (AAV9) to deliver FST or a green fluorescent protein (GFP) control, and the effects on systemic metabolic inflammation and post-traumatic OA were studied (fig. S1).

Dual-energy x-ray absorptiometry (DXA) imaging of mice at 26 weeks of age (Fig. 1A) showed significant effects of FST treatment on body composition. Control-diet, FST-treated mice (i.e., Control-FST mice) exhibited significantly lower body fat percentages, but were significantly heavier than mice treated with a GFP control vector (Control-GFP mice) (Fig. 1B), indicating that increased muscle mass rather than fat was developed with FST. With an HFD, control mice (HFD-GFP mice) showed significant increases in weight and body fat percentage that were ameliorated by FST overexpression (HFD-FST mice).

(A) DXA images of mice at 26 weeks of age. (B) DXA measurements of body fat percentage and bone mineral density (BMD; 26 weeks) and body weight measurements over time. (C) Serum levels for adipokines (insulin, leptin, resistin, and C-peptide) at 28 weeks. (D) Metabolite levels for glucose, triglycerides, cholesterol, and FFAs at 28 weeks. (E) Serum levels for cytokines (IL-1, IL-1, MCP-1, and VEGF) at 28 weeks. (F) Fluorescence microscopy images of visceral adipose tissue with CD11b:Alexa Fluor 488 (green), CD11c:phycoerythrin (PE) (red), and 4,6-diamidino-2-phenylindole (DAPI; blue). Scale bars, 100 m. Data are presented as mean SEM; n = 8 to 10; two-way analysis of variance (ANOVA), P < 0.05. Groups not sharing the same letter are significantly different with Tukey post hoc analysis. For IL-1 and VEGF, P < 0.05 for diet effect and AAV effect. For MCP-1, P < 0.05 for diet effect.

In the HFD group, overexpression of FST significantly decreased serum levels of several adipokines including insulin, leptin, resistin, and C-peptide as compared to GFP-treated mice (Fig. 1C). HFD-FST mice also had significantly lower serum levels of glucose, triglycerides, cholesterol, and free FAs (FFAs) (Fig. 1D), as well as the inflammatory cytokine interleukin-1 (IL-1) (Fig. 1E) when compared to HFD-GFP mice. For both dietary groups, AAV-FST delivery significantly increased circulating levels of vascular endothelial growth factor (VEGF) while significantly decreasing IL-1 levels. Furthermore, obesity-induced inflammation in adipose tissue was verified by the presence of CD11b+CD11c+ M1 pro-inflammatory macrophages or dendritic cells (Fig. 1F).

To determine whether FST gene therapy can mitigate injury-induced OA, mice underwent surgery for destabilization of the medial meniscus (DMM) and were sacrificed 12 weeks after surgery. Cartilage degeneration was significantly reduced in DMM joints of the mice receiving FST gene therapy in both dietary groups (Fig. 2, A and C) when compared to GFP controls. FST overexpression also significantly decreased joint synovitis (Fig. 2, B and D) when compared to GFP controls. To evaluate the local influence of pro-inflammatory cytokines to joint degeneration and inflammation, synovial fluid (SF) was harvested from surgical and ipsilateral nonsurgical limbs and analyzed using a multiplexed array. The DMM joints from mice with FST overexpression exhibited a trend toward lower levels of pro-inflammatory cytokines, including IL-1, IL-1, and IL-6, and a higher level of interferon- (IFN-)induced protein (IP-10) in the SF of DMM joints as compared to contralateral controls (Fig. 2E).

(A) Histologic analysis of OA severity via Safranin O (glycosaminoglycans) and fast green (bone and tendon) staining of DMM-operated joints. (B) Histology [hematoxylin and eosin (H&E) staining] of the medial femoral condyle of DMM-operated joints. Thickened synovium (S) from HFD mice with a high density of infiltrated cells was observed (arrows). (C) Modified Mankin scores compared within the diet. (D) Synovitis scores compared within the diet. (E) Levels of proinflammatory cytokines in the SF compared within the diet. (F) Hot plate latency time and sensitivity to cold plate exposure, as measured using the number of jumps in 30 s, both for non-operated algometry measurements of pain sensitivity compared within the diet. Data are presented as mean SEM; n = 5 to 10 mice per group; two-way ANOVA, P < 0.05. Groups not sharing the same letter are significantly different with Tukey post hoc analysis.

To investigate the effect of FST on pain sensitivity in OA, animals were subjected to a variety of pain measurements including hot plate, cold plate, and algometry. Obesity increased heat withdrawal latency, which was rescued by FST overexpression (Fig. 2F). Cold sensitivity trended lower with obesity, and because no significant differences in heat withdrawal latency were found with surgery (fig. S2), no cold sensitivity was measured after surgery. We found that FST treatment protected HFD animals from mechanical algesia at the knee receiving DMM surgery, while Control-diet DMM groups demonstrated increased pain sensitivity following joint injury.

A bilinear regression model was used to elucidate the relationship among OA severity, biomechanical factors, and metabolic factors (table S1). Factors significantly correlated with OA were then selected for multivariate regression (Table 1). Both multivariate regression models revealed serum tumor necrosis factor- (TNF-) levels as a major predictor of OA severity.

, standardized coefficient. ***P < 0.001.

We analyzed the effects of FST treatment on muscle structure and mass, and performance measures were conducted on mice in both dietary groups. Both Control-FST and HFD-FST limbs exhibited visibly larger muscles compared to both AAV-GFP groups (Fig. 3A). In addition, the muscle masses of tibialis anterior (TA), gastrocnemius, and quadriceps increased significantly with FST treatment (Fig. 3B). Western blot analysis confirmed an increase in FST expression in the muscle at the protein level in FST-treated groups compared to GFP-treated animals in Control and HFD groups (Fig. 3C). Immunofluorescence labeling showed increased expression of FST in muscle (Fig. 3D) and adipose tissue (Fig. 3E) of the AAV-FST mice, with little or no expression of FST in control groups.

(A) Photographic images and (B) measured mass of tibialis anterior (TA), gastrocnemius (GAS), and quadriceps (QUAD) muscles; n = 8, diet and AAV effects both P < 0.05. (C) Western blot showing positive bands of FST protein only in FST-treated muscles, with -actin as a loading control. Immunolabeling of (D) GAS muscle and (E) adipose tissue showing increased expression of FST, particularly in skeletal muscle. (F) H&E-stained sections of GAS muscles were measured for (G) mean myofiber diameter; n = 100 from four mice per group, diet, and AAV effects; both P < 0.05. (H) Oil Red O staining was analyzed for (I) optical density values of FAs; n = 6. (J) Second-harmonic generation imaging of collagen in TA sections was quantified for intensity; n = 6. (K) Western blotting showing the level of phosphorylation markers of protein synthesis in GAS muscle. (L) Functional analysis of grip strength and treadmill time to exhaustion; n = 10. Data are presented as mean SEM; two-way ANOVA, P < 0.05. Groups not sharing the same letter are significantly different with Tukey post hoc analysis. Photo credit: Ruhang Tang, Washington University.

To determine whether the increases in muscle mass reflected muscle hypertrophy, gastrocnemius muscle fiber diameter was measured in H&E-stained sections (Fig. 3F) at 28 weeks of age. Mice with FST overexpression exhibited increased fiber diameter (i.e., increased muscle hypertrophy) relative to the GFP-expressing mice in both diet treatments (Fig. 3G). Oil Red O staining was used to determine the accumulation of neutral lipids in muscle (Fig. 3H). We found that HFD-FST mice were protected from lipid accumulation in muscles compared to HFD-GFP mice (Fig. 3I). Second-harmonic generation imaging confirmed the presence of increased collagen content in the muscles of HFD mice, which was prevented by FST gene therapy (Fig. 3J). We also examined the expression and phosphorylation levels of the key proteins responsible for insulin signaling in muscles. We observed increased phosphorylation of AktS473, S6KT389, and S6RP-S235/2369 and higher expression of peroxisome proliferatoractivated receptor coactivator 1- (Pgc1-) in muscles from FST mice compared to GFP mice, regardless of diet (Fig. 3K). In addition to the improvements in muscle structure with HFD, FST-overexpressing mice also showed improved function, including higher grip strength and increased treadmill running endurance (Fig. 3L), compared to GFP mice.

Because FST has the potential to influence cardiac muscle and skeletal muscle, we performed a detailed evaluation on the effect of FST overexpression on cardiac function. Echocardiography and short-axis images were collected to visualize the left ventricle (LV) movement during diastole and systole (fig. S3A). While the Control-FST mice had comparable LV mass (LVM) and left ventricular posterior wall dimensions (LVPWD) with Control-GFP mice (fig. S3, B and C), the HFD-FST mice have significantly decreased LVM and trend toward decreased LVPWD compared to HFD-GFP. Regardless of the diet treatments, FST overexpression enhanced the rate of heart weight/body weight (fig. S3D). Although Control-FST mice had slightly increased dimensions of the interventricular septum at diastole (IVSd) compared to Control-GFP (fig. S3E), there was significantly lower IVSd in HFD-FST compared to HFD-GFP. In addition, we found no difference in fractional shortening among all groups (fig. S3F). Last, transmitral blood flow was investigated using pulse Doppler. While there was no difference in iso-volumetric relaxation time (IVRT) in Control groups, HFD-FST mice had a moderate decrease in IVRT compared to HFD-GFP (fig. S3G). Overall, FST treatment mitigated the changes in diastolic dysfunction and improved the cardiac relaxation caused by HFD.

DXA demonstrated that FST gene therapy improved bone mineral density (BMD) in HFD compared to other groups (Fig. 1B). To determine the effects of injury, diet intervention, and overexpression of FST on bone morphology, knee joints were evaluated by microcomputed tomography (microCT) (Fig. 4A). The presence of heterotopic ossification was observed throughout the GFP knee joints, whereas FST groups demonstrated a reduction or an absence of heterotopic ossification. FST overexpression significantly increased the ratio of bone volume to total volume (BV/TV), BMD, and trabecular number (Tb.N) of the tibial plateau in animals, regardless of diet treatment (Fig. 4B). Joint injury generally decreased bone parameters in the tibial plateau, particularly in Control-diet mice. In the femoral condyle, BV/TV and Tb.N were significantly increased in mice with FST overexpression in both diet types, while BMD was significantly higher in HFD-FST compared to HFD-GFP mice (Fig. 4B). Furthermore, AAV-FST delivery significantly increased trabecular thickness (Tb.Th) and decreased trabecular space (Tb.Sp) in the femoral condyle of HFD-FST compared to HFD-GFP animals (fig. S4).

(A) Three-dimensional (3D) reconstruction of microCT images of non-operated and DMM-operated knees. (B) Tibial plateau (TP) and femoral condyle (FC) regional analyses of trabecular bone fraction bone volume (BV/TV), BMD, and trabecular number (Tb.N). Data are presented as mean SEM; n = 8 to 19 mice per group; two-way ANOVA. (C) 3D microCT reconstruction of metaphysis region of DMM-operated joints. (D) Analysis of metaphysis BV/TV, Tb.N, and BMD. (E) 3D microCT reconstruction of cortical region of DMM-operated joints. (F) Analysis of cortical cross-sectional thickness (Ct.Cs.Th), polar moment of inertia (MMI), and tissue mineral density (TMD). (D and F) Data are presented as mean SEM; n = 8 to 19 mice per group; Mann-Whitney U test, *P < 0.05.

Further microCT analysis was conducted on the trabecular (Fig. 4C) and cortical (Fig. 4E) areas of the metaphyses. FST gene therapy significantly increased BV/TV, Tb.N, and BMD in the metaphyses regardless of the diet (Fig. 4D). Furthermore, FST delivery significantly increased the cortical cross-sectional thickness (Ct.Cs.Th) and polar moment of inertia (MMI) of mice on both diet types, as well as tissue mineral density (TMD) of cortical bones of mice fed control diet (Fig. 4F).

To elucidate the possible mechanisms by which FST mitigates inflammation, we examined the browning/beiging process in subcutaneous adipose tissue (SAT) with immunohistochemistry (Fig. 5A). Here, we found that key proteins expressed mainly in brown adipose tissue (BAT) (PGC-1, PRDM16, thermogenesis marker UCP-1, and beige adipocyte marker CD137) were up-regulated in SAT of the mice with FST overexpression (Fig. 5B). Increasing evidence suggests that an impaired mitochondrial oxidative phosphorylation (OXPHOS) system in white adipocytes is a hallmark of obesity-associated inflammation (17). Therefore, we further examined the mitochondrial respiratory system in SAT. HFD reduced the amount of OXPHOS complex subunits (Fig. 5C). We found that proteins involved in OXPHOS, including subunits of complexes I, II, and III of mitochondria OXPHOS complex, were significantly up-regulated in AAV-FSToverexpressing animals compared to AAV-GFP mice (Fig. 5D).

(A) Immunohistochemistry of UCP-1 expression in SAT. Scale bar, 50 m. (B) Western blotting of SAT for key proteins expressed in BAT, with -actin as a loading control. (C) Western blot analysis of mitochondria lysates from SAT for OXPHOS proteins using antibodies against subunits of complexes I, II, III, and IV and adenosine triphosphate (ATP) synthase. (D) Change of densitometry quantification normalized to the average FST level of each OXPHOS subunit. Data are presented as mean SEM; n = 3. *P < 0.05, t test comparison within each pair.

Our findings demonstrate that a single injection of AAV-mediated FST gene therapy ameliorated systemic metabolic dysfunction and mitigated OA-associated cartilage degeneration, synovial inflammation, and bone remodeling occurring with joint injury and an HFD. Of note, the beneficial effects were observed across multiple tissues of the joint organ system, underscoring the value of this potential treatment strategy. The mechanisms by which obesity and an HFD increase OA severity are complex and multifactorial, involving increased systemic metabolic inflammation, joint instability and loss of muscle strength, and synergistic interactions between local and systemic cytokines (4, 6). In this regard, the therapeutic consequences of FST gene therapy also appear to be multifactorial, involving both direct and indirect effects such as increased muscle mass and metabolic activity to counter caloric intake and metabolic dysfunction resulting from an HFD while also promoting adipose tissue browning. Furthermore, FST may also serve as a direct inhibitor of growth factors in the TGF- family that may be involved in joint degeneration (18).

FST gene therapy showed a myriad of notable beneficial effects on joint degeneration following joint injury while mitigating HFD-induced obesity. These data also indirectly implicate the critical role of muscle integrity in the onset and progression of post-traumatic OA in this model. It is important to note that FST gene therapy mitigated many of the key negative phenotypic changes previously associated with obesity and OA, including cartilage structural changes as well as bone remodeling, synovitis, muscle fibrosis, and increased pain, as compared to GFP controls. To minimize the number of animals used, we did not perform additional controls with no AAV delivery; however, our GFP controls showed similar OA changes as observed in our previous studies, which did not involve any gene delivery (2). Mechanistically, FST restored to control levels a number of OA-associated cytokines and adipokines in the serum and the SF. While the direct effects of FST on chondrocytes remains to be determined, FST has been shown to serve as a regulator of the endochondral ossification process during development (19), which may also play a role in OA (20). Furthermore, previous studies have shown that a 2-week FST treatment of mouse joints is beneficial in reducing infiltration of inflammatory cells into the synovial membrane (15). Our findings suggest that FST delivery in skeletally mature mice, preceding obesity-induced OA changes, substantially reduces the probability of tissue damage.

It is well recognized that FST can inhibit the activity of myostatin and activin, both of which are up-regulated in obesity-related modalities and are involved in muscle atrophy, tissue fibrosis, and inflammation (21). Consistent with previous studies, our results show that FST antagonizes the negative regulation of myostatin in muscle growth, reducing adipose tissue content in animals. Our observation that FST overexpression decreased inflammation at both serum systemic and local joint inflammation may provide mechanistic insights into our findings of mitigated OA severity in HFD-fed mice. Our statistical analysis implicated serum TNF- levels as a major factor in OA severity, consistent with previous studies linking obesity and OA in mice (22). Although the precise molecular mechanisms of FST in modulating inflammation remain unclear, some studies postulate that FST may act like acute-phase protein in lipopolysaccharide-induced inflammation (23).

In addition to these effects of skeletal muscle, we found that FST gene therapy normalized many of the deleterious changes of an HFD on cardiac function without causing hypertrophy. These findings are consistent with previous studies showing that, during the process of aging, mice with myostatin knockout had an enhanced cardiac stress response (24). Furthermore, FST has been shown to regulate activin-induced cardiomyocyte apoptosis (1). In the context of this study, it is also important to note that OA has been shown to be a serious risk factor for progression of cardiovascular disease (25), and severity of OA disability is associated with significant increases in all-cause mortality and cardiovascular events (26).

FST gene therapy also rescued diet- and injury-induced bone remodeling in the femoral condyle, as well as the tibial plateau, metaphysis, and cortical bone of the tibia, suggesting a protective effect of FST on bone homeostasis of mice receiving an HFD. FST is a known inhibitor of bone morphogenetic proteins (BMPs), and thus, the interaction between the two proteins plays an essential role during bone development and remodeling. For example, mice grown with FST overexpression via global knock-in exhibited an impaired bone structure (27). However, in adult diabetic mice, FST was shown to accelerate bone regeneration by inhibiting myostatin-induced osteoclastogenesis (28). Furthermore, it has been reported that FST down-regulates BMP2-driven osteoclast activation (29). Therefore, the protective role of FST on obesity-associated bone remodeling, at least in part, may result from the neutralizing capacity of FST on myostatin in obesity. In addition, improvement in bone quality in FST mice may be explained by their enhanced muscle mass and strength, as muscle mass can dominate the process of skeletal adaptation, and conversely, muscle loss correlates with reduced bone quality (30).

Our results show that FST delivery mitigated pain sensitivity in OA joints, a critical aspect of clinical OA. Obesity and OA are associated with both chronic pain and pain sensitization (31), but it is important to note that structure and pain can be uncoupled in OA (32), necessitating the measurement of both behavioral and structural outcomes. Of note, FST treatment protected only HFD animals from mechanical algesia at the knee post-DMM surgery and also rescued animals from pain sensitization induced by HFD in both the DMM and nonsurgical limb. The mitigation in pain sensitivity observed here with FST treatment may also be partially attributed to the antagonistic effect of FST on activin signaling. In addition to its role in promoting tissue fibrosis, activin A has been shown to regulate nociception in a manner dependent on the route of injection (33, 34). It has been shown that activin can sensitize the transient receptor potential vanilloid 1 (TRPV1) channel, leading to acute thermal hyperalgesia (33). However, it is also possible that activin may induce pain indirectly, for example, by triggering neuroinflammation (35), which could lead to sensitization of nociceptors.

The earliest detectable abnormalities in subjects at risk for developing obesity and type 2 diabetes are muscle loss and accumulation of excess lipids in skeletal muscles (4, 36), accompanied by impairments in nuclear-encoded mitochondrial gene expression and OXPHOS capacity of muscle and adipose tissues (17). PGC-1 activates mitochondrial biogenesis and increases OXPHOS by increasing the expression of the transcription factors necessary for mitochondrial DNA replication (37). We demonstrated that FST delivery can rescue low levels of OXPHOS in HFD mice by increasing expression PGC-1 (Fig. 3H). It has been reported that high-fat feeding results in decreased PGC-1 and mitochondrial gene expression in skeletal muscles, while exercise increases the expression of PGC-1 in both human and rodent muscles (38, 39). Although the precise molecular mechanism by which FST promotes PGC-1 expression has not been established, the infusion of lipids decreases expression of PGC-1 and nuclear-encoded mitochondrial genes in muscles (40). Thus, decreased lipid accumulation in muscle by FST overexpression may provide a plausible explanation for the restored PGC-1 in the FST mice. These findings were further confirmed by the metabolic profile, showing reduced serum levels of triglycerides, glucose, FFAs, and cholesterol (Fig. 1D), and are consistent with previous studies, demonstrating that muscles with high numbers of mitochondria and oxidative capacity (i.e., type 1 muscles with high levels of PGC-1 expression) are protected from damage due to an HFD (4).

In addition, we found increased phosphorylation of protein kinase B (Akt) on Ser473 in the skeletal muscle of FST-treated mice as compared to untreated HFD counterparts (Fig. 3K), consistent with restoration of a normal insulin response. A number of studies have demonstrated that the serine-threonine protein kinase Akt1 is a critical regulator of cellular hypertrophy, organ size, and insulin signaling (41). Muscle hypertrophy is stimulated both in vitro and in vivo by the expression of constitutively active Akt1 (42, 43). Furthermore, it has been demonstrated that constitutively active Akt1 also promotes the production of VEGF (44).

BAT is thought to be involved in thermogenesis rather than energy storage. BAT is characterized by a number of small multilocular adipocytes containing a large number of mitochondria. The process in which white adipose tissue (WAT) becomes BAT, called beiging or browning, is postulated to be protective in obesity-related inflammation, as an increase in BAT content positively correlates with increased triglyceride clearance, normalized glucose level, and reduced inflammation. Our study shows that AAV-mediated FST delivery serves as a very promising approach to induce beiging of WAT in obesity. A recent study demonstrated that transgenic mice overexpressing FST exhibited an increasing amount of BAT and beiging in subcutaneous WAT with increased expression of key BAT-related markers including UCP-1 and PRDM16 (45). In agreement with previous reports, our data show that Ucp1, Prdm16, Pgc1a, and Cd167 are significantly up-regulated in SAT of mice overexpressing FST in both dietary interventions. FST has been recently demonstrated to play a crucial role in modulating obesity-induced WAT expansion by inhibiting TGF-/myostatin signaling and thus promoting overexpression of these key thermogenesis-related genes. Together, these findings suggest that the observed reduction in systemic inflammation in our model may be partially explained by FST-mediated increased process of browning/beiging.

In conclusion, we show that a single injection of AAV-mediated FST, administered after several weeks of HFD feeding, mitigated the severity of OA following joint injury, and improved muscle performance as well as induced beiging of WAT, which together appeared to decrease obesity-associated metabolic inflammation. These findings provide a controlled model for further examining the differential contributions of biomechanical and metabolic factors to the progression of OA with obesity or HFD. As AAV gene therapy shows an excellent safety profile and is currently in clinical trials for a number of conditions, such an approach may allow the development of therapeutic strategies not only for OA but also, more broadly, for obesity and associated metabolic conditions, including diseases of muscle wasting.

All experimental procedures were approved by and conducted in accordance with the Institutional Animal Care and Use Committee guidelines of Washington University in Saint Louis. The overall timeline of the study is shown in fig. S1A. Beginning at 5 weeks of age, C57BL/6J mice (The Jackson Laboratory) were fed either Control or 60% HFD (Research Diets, D12492). At 9 week of age, mice received AAV9-mediated FST or GFP gene delivery via tail vein injection. A total of 64 mice with 16 mice per dietary group per AAV group were used. DMM was used to induce knee OA in the left hind limbs of the mice at the age of 16 weeks. The non-operated right knees were used as contralateral controls. Several behavioral activities were measured during the course of the study. Mice were sacrificed at 28 weeks of age to evaluate OA severity, joint inflammation, and joint bone remodeling.

Mice were weighed biweekly. The body fat content and BMD of the mice were measured using a DXA (Lunar PIXImus) at 14 and 26 weeks of age, respectively.

Complementary DNA synthesis for mouse FST was performed by reverse transcriptase in a reverse transcription quantitative polymerase chain reaction (RT-qPCR) ( Invitrogen) mixed with mRNAs isolated from the ovary tissues of C57BL/6J mouse. The PCR product was cloned into the AAV9-vector plasmid (pTR-UF-12.1) under the transcriptional control of the chicken -actin (CAG) promoter including cytomegalovirus (CMV) enhancers and a large synthetic intron (fig. S1B). Recombinant viral vector stocks were produced at Hope Center Viral Vectors Core (Washington University, St. Louis) according to the plasmid cotransfection method and suspension culture. Viral particles were purified and concentrated. The purity of AAV-FST and AAV-GFP was evaluated by SDSpolyacrylamide gel electrophoresis (PAGE) and stained by Coomassie blue. The results showed that the AAV protein components in 5 1011 vector genomes (vg) are only stained in three major protein bands: VR1, 82 kDa; VR2, 72 kDa; and VR3, 62 kDa. Vector titers were determined by the DNA dot-blot and PCR methods and were in the range of 5 1012 to 1.5 1013 vector copies/ml. AAV was delivered at a final dose of 5 1011 vg per mouse by intravenous tail injection under red light illumination at 9 weeks of age. This dose was determined on the basis of our previous studies showing that AAV9-FST gene delivery by this route resulted in a doubling of muscle mass at a dose of 2.5 1011 vg in 4-week-old mice or at 5 1011 vg in 8-week-old mice (46).

At 16 weeks of age, mice underwent surgery for the DMM to induce knee OA in the left hindlimb as previously described (2). Briefly, anesthetized mice were placed on a custom-designed device, which positioned their hindlimbs in 90 flexion. The medial side of the joint capsule was opened, and the medial meniscotibial ligament was transected. The joint capsule and subcutaneous layer of the skin were closed with resorbable sutures.

Mice were sacrificed at 28 weeks of age, and changes in joint structure and morphology were assessed using histology. Both hindlimbs were harvested and fixed in 10% neutral-buffered formalin (NBF). Limbs were then decalcified in Cal-Ex solution (Fisher Scientific, Pittsburgh, PA, USA), dehydrated, and embedded in paraffin. The joint was sectioned in the coronal plane at a thickness of 8 m. Joint sections were stained with hematoxylin, fast green, and Safranin O to determine OA severity. Three blinded graders then assessed sections for degenerative changes of the joint using a modified Mankin scoring system (2). Briefly, this scoring system measures several aspects of OA progression (cartilage structure, cell distribution, integrity of tidemark, and subchondral bone) in four joint compartments (medial tibial plateau, medial femoral condyle, lateral tibial plateau, and lateral femoral condyle), which are summed to provide a semiquantitative measure of the severity of joint damage. To assess the extent of synovitis, sections were stained with H&E to analyze infiltrated cells and synovial structure. Three independent blinded graders scored joint sections for synovitis by evaluating synovial cell hyperplasia, thickness of synovial membrane, and inflammation in subsynovial regions in four joint compartments, which were summed to provide a semiquantitative measure of the severity of joint synovitis (2). Scores for the whole joint were averaged among graders.

Serum and SF from the DMM and contralateral control limbs were collected, as described previously (2). For cytokine and adipokine levels in the serum and SF fluid, a multiplexed bead assay (Discovery Luminex 31-Plex, Eve Technologies, Calgary, AB, Canada) was used to determine the concentration of Eotaxin, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), IFN-, IL-1, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17A, IP-10, keratinocyte chemoattractant (KC), leukemia inhibitory factor (LIF), liposaccharide-induced (LIX), monocyte chemoattractant protein-1 (MCP-1), M-CSF, monokine induced by gamma interferon (MIG), macrophage inflammatory protein1 (MIP-1), MIP-1, MIP-2, RANTES, TNF-, and VEGF. A different kit (Mouse Metabolic Array) was used to measure levels for amylin, C-peptide, insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), ghrelin, glucagon, insulin, leptin, protein phosphatase (PP), peptide yy (PYY), and resistin. Missing values were imputed using the lowest detectable value for each analyte.

Muscles were cryopreserved by incubation with 2-methylbutane in a steel beaker using liquid nitrogen for 30 s, cryoembedded, and cryosectioned at 8 m thickness. Tissue sections were stained following standard H&E protocol. Photomicrographs of skeletal muscle fiber were imaged under brightfield (VS120, Olympus). Muscle slides fixed in 3.7% formaldehyde were stained with 0.3% Oil Red O (in 36% triethyl phosphate) for 30 min. Images were taken in brightfield (VS120, Olympus). The relative concentration of lipid was determined by extracting the Oil Red O with isopropanol in equally sized muscle sections and quantifying the OD500 (optical density at 500 nm) in a 96-well plate.

To determine spatial expression of FST in different tissues, cryosections of gastrocnemius muscles and adipose tissue were immunolabeled for FST. Tissue sections were fixed in 1.5% paraformaldehyde solution, and primary anti-FST antibody (R&D Systems, AF-669, 1:50) was incubated overnight at 4C after blocking with 2.5% horse serum (Vector Laboratories), followed by labeling with a secondary antibody (Alexa Fluor 488, Invitrogen, A11055) and with 4,6-diamidino-2-phenylindole (DAPI) for cell nuclei. Sections were imaged using fluorescence microscopy.

Second-harmonic generation images of TA were obtained from unstained slices using backscatter signal from an LSM 880 confocal microscope (Zeiss) with Ti:sapphire laser tuned to 820 nm (Coherent). The resulting image intensity was analyzed using ImageJ software.

To measure bone structural and morphological changes, intact hindlimbs were scanned by microCT (SkyScan 1176, Bruker) with an 18-m isotropic voxel resolution (455 A, 700-ms integration time, and four-frame averaging). A 0.5-mm aluminum filter was used to reduce the effects of beam hardening. Images were reconstructed using NRecon software (with 10% beam hardening and 20 ring artifact corrections). Subchondral/trabecular and cortical bone regions were segmented using CTAn automatic thresholding software. Tibial epiphysis was selected using the subchondral plate and growth plate as references. Tibial metaphysis was defined as the 1-mm region directly below the growth plate. The cortical bone analysis was performed in the mid-shaft (4 mm below the growth plate with a height of 1 mm). Hydroxyapatite calibration phantoms were used to calibrate bone density values (mg/cm3).

Fresh visceral adipose tissues were collected, frozen in optimal cutting temperature compound (OCT), and cryosectioned at 5-m thickness. Tissue slides were then acetone-fixed followed by incubation with Fc receptor blocking in 2.5% goat serum (Vector Laboratories) and incubation with primary antibodies cocktail containing anti-CD11b:Alexa Fluor 488 and CD11c:phycoerythrin (PE) (BioLegend). Nuclei were stained with DAPI. Samples were imaged using fluorescence microscopy (VS120, Olympus).

Adipose tissues were fixed in 10% NBF, paraffin-embedded, and cut into 5-m sections. Sections were deparaffinized, rehydrated, and stained with H&E. Immunohistochemistry was performed by incubating sections (n = 5 per each group) with the primary antibody (antimUCP-1, U6382, Sigma), followed by a secondary antibody conjugated with horseradish peroxidase (HRP). Chromogenic substrate 3,3-diaminobenzidine (DAB) was used to develop color. Counterstaining was performed with Harris hematoxylin. Sections were examined under brightfield (VS120, Olympus).

Proteins of the muscle or fat tissue were extracted using lysis buffer containing 1% Triton X-100, 20 mM tris-HCl (pH 7.5), 150 mM NaCl, 1 mm EDTA, 5 mM NaF, 2.5 mM sodium pyrophosphate, 1 mM -glycerophosphate, 1 mM Na3VO4, leupeptin (1 g ml1), 0.1 mM phenylmethylsulfonyl fluoride, and a cocktail of protease inhibitors (Sigma, St. Louis, MO, USA, catalog no. P0044). Protein concentrations were measured with Quick Start Bradford Dye Reagent (Bio-Rad). Twenty micrograms of each sample was separated in SDS-PAGE gels with prestained molecular weight markers (Bio-Rad). Proteins were wet-transferred to polyvinylidene fluoride membranes. After incubating for 1.5 hours with a buffer containing 5% nonfat milk (Bio-Rad #170-6404) at room temperature in 10 mM tris-HCl (pH 7.5), 100 mM NaCl, and 0.1% Tween 20 (TBST), membranes were further incubated overnight at 4C with antiUCP-1 rabbit polyclonal antibody (1:500, Sigma, U6382), anti-PRDM16 rabbit antibody (Abcam, ab106410), anti-CD137 rabbit polyclonal antibody (1:1000, Abcam, ab203391), total OXPHOS rodent western blot (WB) antibodies (Abcam, ab110413), anti-actin (Cell Signaling Technology, 13E5) rabbit monoclonal antibody (Cell Signaling Technology, 4970), followed by HRP-conjugated secondary antibody incubation for 30 min. A chemiluminescent detection substrate (Clarity, Western ECL) was applied, and the membranes were developed (iBrightCL1000).

The effects of HFD and FST gene therapy on thermal hyperalgesia were examined at 15 weeks of age. Mice were acclimatized to all equipment 1 day before the onset of testing, as well as a minimum of 30 min before conducting each test. Thermal pain tests were measured in a room set to 25C. Peripheral thermal sensitivity was determined using a hot/cold analgesia meter (Harvard Apparatus, Holliston, MA, USA). For hot plate testing, the analgesia meter was set to 55C. To prevent tissue damage, a maximum cutoff time of 20 s was established a priori, at which time an animal would be removed from the plate in the absence of pain response, defined as paw withdrawal or licking. Animals were tested in the same order three times, allowing each animal to have a minimum of 30 min between tests. The analgesia meter was cleaned with 70% ethanol between trials. The average of the three tests was reported per animal. To evaluate tolerance to cold, the analgesia meter was set to 0C. After 1-hour rest, animals were tested for sensitivity to cold over a single 30-s exposure. The number of jumps counted per animal was averaged within each group and compared between groups.

Pressure-pain tests were conducted at the knee using a Small Animal Algometer (SMALGO, Bioseb, Pinellas Park, FL, USA). Surgical and nonsurgical animals were evaluated over serial trials on the lateral aspect of the experimental and contralateral knee joints. The average of three trials per limb was calculated for each limb. Within each group, the pain threshold of the DMM limb versus non-operated limb was compared using a t test run on absolute values of mechanical pain sensitivity for each limb, P 0.05.

To assess the effect of HFD and AAV-FST treatments on neuromuscular function, treadmill running to exhaustion (EXER3, Columbus Instruments) was performed at 15 m/min, with 5 inclination angle on the mice 4 months after gene delivery. Treadmill times were averaged within groups and compared between groups.

Forelimb grip strength was measured using Chatillon DFE Digital Force Gauge (Johnson Scale Co.) for front limb strength of the animals. Each mouse was tested five times, with a resting period of 90 s between each test. Grip strength measurements were averaged within groups and compared between groups.

Cardiac function of the mice was examined at 6 months of age (n = 3) using echocardiography (Vevo 2100 High-Resolution In Vivo Imaging System, VisualSonics). Short-axis images were taken to view the LV movement during diastole and systole. Transmitral blood flow was observed with pulse Doppler. All data and images were performed by a blinded examiner and analyzed with an Advanced Cardiovascular Package Software (VisualSonics).

Detailed statistical analyses are described in methods of each measurement and its corresponding figure captions. Analyses were performed using GraphPad Prism, with significance reported at the 95% confidence level.

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

Acknowledgments: Funding: This study was supported, in part, by NIH grants AR50245, AR48852, AG15768, AR48182, AG46927, AR073752, OD10707, AR060719, AR074992, and AR75899; the Arthritis Foundation; and the Nancy Taylor Foundation for Chronic Diseases. Author contributions: R.T. and F.G. developed the concept of the study; R.T., N.S.H., C.-L.W., K.H.C., and Y.-R.C. collected and analyzed data; S.J.O. analyzed data; and all authors contributed to the writing of the manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Gene therapy for follistatin mitigates systemic metabolic inflammation and post-traumatic arthritis in high-fat dietinduced obesity - Science Advances

BioMarin broadens its gene therapy horizons with a new R&D alliance in rare cardio cases – Endpoints News

Posted on May 11, 2020 by Danzig

BioMarin has just struck a deal to back a Swiss biotech startup with some deep ties to top research institution UCL in London as it beefs up the swelling gene therapy portion of the pipeline.

We dont have any terms to deal with, just the knowledge that BioMarin CEO JJ Bienaim saw enough of DiNAQORs work to invest in the company as it licenses their lead preclinical program, DiNA-001 for MYBPC3 hypertrophic cardiomyopathy, while collaborating on the rest of the pipeline.

DiNAQOR barely rippled the pond with its launch a year ago with its base in Pfffikon, Switzerland and operations in London and Boston. Part of those ties belong to UCL, where CMO Valeria Ricotti is an MD in pediatrics with experience running gene therapy studies. It set up a manufacturing pact with Lonzas cell and gene therapy unit in Houston last fall as it looked to jump into the clinic with treatments for monogenic cardiomyopathies.

The pact marks a significant expansion in the gene therapy portion of the pipeline at BioMarin. Just days ago the biotech reported that the FDA is providing an accelerated review for the hemophilia A drug valrox, which will likely speed the arrival of a new drug that will test the limits of pricing in the field.

Bienaim has said the company is considering a price range of $2 million to $3 million for valrox, even though there are lingering doubts on just how long it can remain effective.

BioMarin built its rep on rare diseases, and clearly sees a much bigger future in gene therapy.

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BioMarin broadens its gene therapy horizons with a new R&D alliance in rare cardio cases - Endpoints News

BioLife Solutions to Report First Quarter 2020 Financial Results and Provide Business Update on May 14th, 2020 – Chinook Observer

Posted on May 11, 2020 by Danzig

BOTHELL, Wash., May 11, 2020 /PRNewswire/ --BioLife Solutions, Inc. (NASDAQ: BLFS)("BioLife" or the "Company"), a leading developer and supplier of a portfolio of best-in-class bioproduction tools for cell and gene therapies, today announced that the Company's first quarter 2020 financial results will be released after market close on Thursday, May 14th, 2020, and that the Company will host a conference call and live webcast at 4:30 p.m. ET (1:30 p.m. PT) that afternoon. Management will provide an overview of the Company's financial results and a general business update.

To access the webcast, log onto the Investor Relations page of the BioLife Solutions website athttp://www.biolifesolutions.com/earnings. Alternatively, you may access the live conference call by dialing (844) 825-0512 (U.S. &Canada) or (315) 625-6880 (International) with the following Conference ID: 2085346. A webcast replay will be available approximately two hours after the call and will be archived onhttp://www.biolifesolutions.com/for 90 days.

About BioLife Solutions

BioLife Solutions is a leading supplier of cell and gene therapy bioproduction tools. Our tools portfolio includes our proprietaryCryoStorfreeze media,HypoThermosolshipping and storage media,ThawSTARfamily of automated, water-free thawing products,evocold chain management system, and Custom Biogenic Systemshigh capacity storage freezers.For more information, please visitwww.biolifesolutions.com,and follow BioLife onTwitter.

Media & Investor RelationsRoderick de GreefChief Financial and Chief Operating Officer(425) 686-6002rdegreef@biolifesolutions.com

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BioLife Solutions to Report First Quarter 2020 Financial Results and Provide Business Update on May 14th, 2020 - Chinook Observer

Neurophth Therapeutics Announces Presentations at ASGCT and ARVO Annual Meetings – PRNewswire

Posted on May 11, 2020 by Danzig

BOSTON and WUHAN, China, May 11, 2020 /PRNewswire/ -- Neurophth Therapeutics, Inc., a clinical-stage biotechnology company discovering and developing innovative therapies for ocular and other genetic disease, today announced that the results of two clinical studies utilizing NFS-01 (rAAV2-ND4) in the treatment of Leber's Hereditary Optic Neuropathy (LHON) will be presented in May 2020 at the American Society of Gene and Cell Therapy (ASGCT) 23rd Annual Meeting and the Association for Vision and Ophthalmology (ARVO) Annual Meeting.

Founder Bin Li, M.D., Ph.D., professor of ophthalmology at the Tongji Medical College of Huazhong University of Science and Technology (HUST), initiated the first China gene therapy clinical trial in 2011, evaluating an adeno-associated virus serotype 2 (AAV2)-based gene therapy in nine Leber's Hereditary Optic Neuropathy (LHON) patients with the G11778A (ND4) mutation. Patients have been followed for over 7 years, several demonstrating significant visual acuity improvement and none reporting severe adverse events.

"The exciting results of the first study (NCT01267422) have been instrumental in developing the largest international clinical study (NCT03153293) in 159 LHON patients, who have been followed for 12 months," said Alvin Luk, Ph.D., M.B.A., C.C.R.A., Chief Executive Officer of Neurophth. "Our results from NFS-01 demonstrate the potential of gene therapy to be both effective and safe for the treatment of LHON and further validate Neurophth's platform which is being applied across a growing pipeline of pre-clinical and clinical programs in gene therapy to treat a wide range of inherited diseases."

ASGCT: American Society of Gene and Cell Therapy Virtual Annual Meeting 2020Presentations can be accessed through ASGCT's website at http://www.asgct.org on May 12, 2020.

First China International Gene Therapy Study in Leber's Hereditary Optic Neuropathy (Abstract #1307)Oral presentation by Alvin Luk, Ph.D., M.B.A., C.C.R.A., Chief Executive Officer, Neurophth Session Date/Time: Friday, May 15, 10:45AM EDTSession Title:AAV Vectors - Clinical Studies I

Multiyear Follow-up of AAV2-ND4 Gene Therapy for Leber's Hereditary Optic Neuropathy (Abstract #621)Poster presentation by Su Xiao, Ph.D., Co-Founder and Chief Technical Operations Officer, NeurophthSession Date/Time: Wednesday, May 13, 5:30PM EDTSession Title:AAV Vectors - Clinical Studies

ARVO: Association for Vision and Ophthalmology The ARVO 2020 Annual Meeting has been modified to a virtual format and presentations have been published online on May 6, 2020.

First China International Gene Therapy Study in Leber's Hereditary Optic Neuropathy (Abstract #5182)Oral Presentation by Alvin Luk, Ph.D., M.B.A., C.C.R.A., Chief Executive Officer, NeurophthNarrated presentation will be available onlineScientific Section: Eye Movements/Strabismus/Amblyopia/Neuro-Ophthalmology

About Neurophth Therapeutics, Inc.

Neurophth Therapeutics, Inc. ("Neurophth") is China's first gene therapy company for ophthalmic diseases. Founded in 2016 by Professor Bin Li, M.D., Ph.D., the clinical-stage biotechnology company is dedicated to discovering and developing gene therapies for ocular and other genetic diseases. Currently, Neurophth is advancing several clinical-stage and pre-clinical programs in ophthalmology. In April 2020, Neurophth successfully raised $18.4 million USD in a Series A round led by Fosun's InnoStar Venture and Sequoia Capital China. The company plans to bring the lead assets to patients globally and build a GMP gene therapy manufacturing facility for global supply.

About NFS-01

NFS-01 is an AAV construct comprising with promoter, mitochondrial targeting sequence (MTS), correct ND4 gene sequence, and an untranslated region flanked by two inverted terminal repeats (ITRs). In 2011, Neurophth initiated the world's first investigational NFS-01 (AAV2-ND4) gene therapy study (NCT01267422) of a single intravitreal injection into one of the eyes of patient with ND4 mutation associated with Leber's Hereditary Optic Neuropathy (LHON). The corrected ND4 gene is transferred into the cell to be expressed and eventually produces the missing functional protein to restore mitochondrial function of the respiratory chain. After nearly 8 years of long-term follow-up, the treatment displayed good safety profiles and patients have maintained significant visual acuity improvement to-date. These results demonstrated long-term safety and durability of clinical application of gene therapy technology and were published in Ophthalmology 2020. Encouraged by these results, Professor Li's team has completed an international gene therapy clinical trial (NCT03153293) during 2017-2018 in 159 LHON patients in China and Argentina, which is the world's largest clinical trial for LHON gene therapy.

About Leber's Hereditary Optic Neuropathy (LHON)

Leber's Hereditary Optic Neuropathy (LHON) is a maternally inherited mitochondrial disorder which often manifests as bilateral visual loss. The most common mutation is the mitochondrial DNA at nucleotide position of 11778G>A, which is located within the NADH ubiquinone oxidoreductase subunit-4 (ND4) gene. This mutation causes impairment of the respiratory chain, adenosine triphosphate deficiency, and oxidative stress in retinal ganglion cells, leading to apoptosis. There is currently no effective treatment or cure for LHON.

SOURCE Neurophth Therapeutics, Inc.

Neurophth Therapeutics Announces Presentations at ASGCT and ARVO Annual Meetings - PRNewswire

Adverum soars on early gene therapy data; BerGenBio raises 45.4M on the heels of Covid-19 move – Endpoints News

Posted on May 11, 2020 by Danzig

Another cut of positive interim data have lifted expectations that Adverums gene therapy that could give the anti-VEGF developers a run for their money in wet AMD. In a Phase I trial, investigators reported that the first two cohorts continue to respond to treatment, with the majority still free of rescue injections, while the third cohort experienced fewer side effects, presumably because they were given topical steroids rather than oral steroids.

Norways BerGenBio raised 45.4 million in a private placement. The biotech has been working on AXL kinase inhibitors and the UK government recently opted to add bemcentinib in the ACCORD study for Covid-19 patients.

Cancer Research UK has jumped in to fund clinical development of Crescendo Biologics bispecific CB213, which targets PD-1 and LAG-3 simultaneously. The research group will take charge of Phase I while the biotech retains a right to license the results.

Seattle-based Kineta has closed a $5 million round to back its work on immunotherapies. Our team is thrilled to quickly close this round with significant investments from the Schlaepfer Family Foundation as well as current investors, said CEO Shawn Iadonato in a statement.

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Adverum soars on early gene therapy data; BerGenBio raises 45.4M on the heels of Covid-19 move - Endpoints News

Study suggests effective fat-reducing therapy – Tech Explorist

Posted on May 11, 2020 by Danzig

Scientists at the Washington University School of Medicine in St. Louis, believe that gene therapy could one day be used as fat reducing therapy.

In a new study conducted on mice, scientists found that gene therapy helped build significant muscle mass quickly and reduced the severity of osteoarthritis in the mice without exercising more. Surprisingly, the therapy also staved off obesity, even when the mice ate an extremely high-fat diet.

Senior investigator Farshid Guilak, Ph.D., the Mildred B. Simon Research Professor of Orthopaedic Surgery and director of research at Shriners Hospitals for ChildrenSt. Louis said,Obesity is the most common risk factor for osteoarthritis. Being overweight can hinder a persons ability to exercise and benefit fully from physical therapy. Weve identified here a way to use gene therapy to build muscle quickly. It had a profound effect on the mice and kept their weight in check, suggesting a similar approach may be effective against arthritis, particularly in cases of morbid obesity.

Scientists gave 8-week-old mice a single injection of a virus conveying a gene called follistatin. The gene works to obstruct the action of a protein in muscle that keeps muscle growth in check. This empowered the mice to gain significant muscle mass without exercising more than usual.

Even without additional exercise, and while continuing to eat a high-fat diet, the muscle mass of these super mice more than doubled, and their strength nearly doubled, too. The mice also had less cartilage damage related to osteoarthritis, lower numbers of inflammatory cells and proteins in their joints, fewer metabolic problems, and healthier hearts and blood vessels than littermates that did not receive the gene therapy. The mice also were significantly less sensitive to pain.

During the study, scientists were concerned that some of the muscle growth might lead to being harmful. But, they found that heart function improved, as did cardiovascular health in general.

Although scientists think that long-term studies are required to determine the safety of this type of gene therapy, but, if safe, the strategy could be particularly beneficial for patients with conditions such as muscular dystrophy that make it challenging to build new muscle.

Guilak said,More traditional methods of muscle strengthening, such as lifting weights or physical therapy, remain the first line of treatment for patients with osteoarthritis. Something like this could take years to develop. Still, were excited about its prospects for reducing joint damage related to osteoarthritis, as well as possibly being useful in extreme cases of obesity.

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Study suggests effective fat-reducing therapy - Tech Explorist

Senti Biosciences to Present on Gene Circuit-Based Therapies at the 2020 ASGCT Annual Meeting – Business Wire

Posted on May 11, 2020 by Danzig

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Senti Biosciences, Inc., the gene circuit company focused on outsmarting complex diseases with intelligent medicines, today announced upcoming oral and poster presentations at the 23rd Annual Meeting of the American Society for Gene and Cell Therapies (ASGCT), being held May 12-15, 2020 in a virtual format.

We are excited about this opportunity to further showcase the potential of our gene circuit platform in oncology, said Tim Lu, M.D., Ph.D., CEO and cofounder of Senti Biosciences. At ASGCT, we are presenting data on in vivo gene therapies, which are equipped with computer-like logic to target tumors in a highly specific manner. Additionally, we will highlight new preclinical data on SENTI-101, an allogeneic cell therapy genetically modified to express a potent combination of cytokines, which give us confidence in its therapeutic potential as we progress towards IND submission.

Details of the presentations are listed below:

ASGCT Annual Meeting, May 12-15, 2020

Title: Tumor-Selective Gene Circuits Enable Highly Specific Localized Cancer ImmunotherapyAbstract Number: 17Oral Presentation Session: Cancer Targeted Gene and Cell TherapyPresentation Date and Time: May 12, 10:45 a.m. - 11:00 a.m. EDTPresenter: Russell Gordley, Ph.D.

Title: Phenotypic and Functional Characterization of Gene Circuit Modified Allogeneic Mesenchymal Stromal Cells (MSCs) for Solid Tumor ImmunotherapyAbstract Number: 783Poster Session: Cancer Targeted Gene and Cell TherapyPresentation Date and Time: May 13, 5:30 p.m. - 6:30 p.m. EDTPresenter: Dharini Iyer, Ph.D.

Title: SENTI-101, an Allogeneic Cell Product Expressing a Combination of Cytokines, Promotes Anti-Tumor Immunity in a Syngeneic Orthotopic Model of Pancreatic Ductal AdenocarcinomaAbstract Number: 1180Poster Session: Cancer Targeted Gene and Cell TherapyPresentation Date and Time: May 14, 5:30 p.m. - 6:30 p.m. EDTPresenter: Ori Maller, Ph.D.

About Senti Biosciences

Senti Biosciences is a next-generation therapeutics company that is developing gene circuits and programming cells for tremendous therapeutic value. Sentis mission is to outsmart complex diseases with more intelligent medicines that will transform peoples lives. By programming cells to respond, adapt and make decisions, Senti is creating smarter therapies with computer-like logic, enhanced functionality and greater therapeutic control.

Sentis product candidates address major challenges in cancer treatment. To overcome cancer immune evasion, Senti is building cell therapies equipped with combinatorial arming gene circuits to elicit broad and sustained anti-tumor immune responses. Senti is also developing next-generation cell therapies that more precisely target and eliminate cancer cells while sparing healthy tissue.

Senti Biosciences is based in South San Francisco and was founded in 2016 by Drs. Tim Lu, Philip Lee, Jim Collins and Wilson Wong. Senti is proud to count NEA, 8VC, Amgen Ventures, Lux Capital, Menlo Ventures, Pear Ventures, Allen & Company, Nest.Bio, Omega Funds, and LifeForce Capital among its investors.

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Senti Biosciences to Present on Gene Circuit-Based Therapies at the 2020 ASGCT Annual Meeting - Business Wire

Genprex Enters Into Exclusive Worldwide Patent and Technology License Agreement for Combination of its TUSC2 Gene Therapy with Immunotherapies -…

Posted on May 11, 2020 by Danzig

AUSTIN, Texas--(BUSINESS WIRE)--Genprex, Inc. (Genprex or the Company) (Nasdaq: GNPX), a clinical-stage gene therapy company developing potentially life-changing technologies for patients with cancer and diabetes, today announced that it has entered into a Patent and Technology License Agreement (License Agreement) with The University of Texas MD Anderson Cancer Center (MD Anderson) in which MD Anderson granted to Genprex an exclusive worldwide license to a portfolio of 16 patent applications and related technology (Licensed IP) for the treatment of cancer using Genprexs lead drug candidate and TUSC2 gene therapy, known as Oncoprex or GEN-001, in combination with immunotherapies. This is a distinct therapeutic approach from that of combining Oncoprex with targeted therapies such as osimertinib (marketed as Tagrisso by AstraZeneca).

Genprex was recently awarded U.S. FDA Fast Track designation for use of Oncoprex combined with Tagrisso for the treatment of non-small cell lung cancer (NSCLC) patients with EGFR mutations whose tumors progressed after treatment with Tagrisso alone. The Company is now preparing to file an Investigational New Drug application to initiate a clinical trial of Oncoprex in combination with pembrolizumab (marketed as Keytruda by Merck) in NSCLC.

We are pleased to advance the intellectual property that is covered by this License Agreement, said Rodney Varner, Genprexs Chairman and Chief Executive Officer. We are excited to be developing two distinct therapeutic approaches to lung cancer utilizing the combination of our gene therapy with successful targeted therapies, such as Tagrisso, and immunotherapies, such as Keytruda, to potentially improve patient outcomes and increase the number of patients who may benefit from these important therapies.

Immunotherapy or immunotherapy combined with chemotherapy is now the first-line standard of care for the majority of lung cancer patients. Published preclinical data indicate that when Oncoprex is combined with immunotherapies such as Keytruda, Oncoprex is synergistic with those drugs, meaning that the combination is more effective than either drug alone. The combination of Oncoprex and Keytruda may lead to better outcomes for many lung cancer patients.

The Licensed IP covers the use of Oncoprex in combination with one or more immunotherapies, including anti-PD1 antibodies, anti-PDL1 antibodies, anti-PDL2 antibodies, anti-CTLA-4 antibodies and/or anti-KIR antibodies for the treatment of cancer. These immunotherapies include pembrolizumab (Mercks largest selling drug Keytruda), nivolumab (Bristol-Myers Squibbs Opdivo), ipilimumab (Bristol-Myers Squibbs Yervoy), and others. Use of chemotherapy in combination with Oncoprex and immunotherapy is also covered by the Licensed IP. While the initial disease indication for Oncoprex is NSCLC, the Licensed IP claims patent protection for combination use of Oncoprex in all types of cancers.

The License Agreement also provides for payment to MD Anderson of an up-front license fee and annual maintenance fees, with the potential for milestone payments, sublicensing fees, and product royalties.

About Genprex, Inc.

Genprex, Inc. is a clinical-stage gene therapy company developing potentially life-changing technologies for patients with cancer and diabetes. Genprexs technologies are designed to administer disease-fighting genes to provide new treatment options for large patient populations with cancer and diabetes who currently have limited treatment options. Genprex works with world-class institutions and collaborators to in-license and develop drug candidates to further its pipeline of gene therapies in order to provide novel treatment approaches. The Companys lead product candidate, Oncoprex, is being evaluated as a treatment for non-small cell lung cancer (NSCLC). Oncoprex has a multimodal mechanism of action that has been shown to interrupt cell signaling pathways that cause replication and proliferation of cancer cells; re-establish pathways for apoptosis, or programmed cell death, in cancer cells; and modulate the immune response against cancer cells. Oncoprex has also been shown to block mechanisms that create drug resistance. In January 2020, the U.S. Food and Drug Administration granted Fast Track Designation for Oncoprex immunogene therapy for NSCLC in combination therapy with osimertinib (AstraZenecas Tagrisso). For more information, please visit the Companys web site at http://www.genprex.com or follow Genprex on Twitter, Facebook and LinkedIn.

Forward-Looking Statements

Statements contained in this press release regarding matters that are not historical facts are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Such statements include, but are not limited to, statements regarding the effect of Genprexs product candidates, alone and in combination with other therapies, on cancer and diabetes, regarding potential, current and planned clinical trials and regarding our commercial partnerships and intellectual property licenses. Risks that contribute to the uncertain nature of the forward-looking statements include the presence and level of the effect of our product candidates, alone and in combination with other therapies, on cancer; the timing and success of our clinical trials and planned clinical trials of Oncoprex, alone and in combination with targeted therapies and/or immunotherapies, and whether our other potential product candidates, including our gene therapy in diabetes, advance into clinical trials; the success of our strategic partnerships; the timing and success of obtaining FDA approval of Oncoprex and our other potential product candidates including whether we receive fast track or similar regulatory designations; and whether patents will ever be issued under patent applications that are the subject of our license agreements. These and other risks and uncertainties are described more fully under the caption Risk Factors and elsewhere in our filings and reports with the United States Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made. We undertake no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.

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Genprex Enters Into Exclusive Worldwide Patent and Technology License Agreement for Combination of its TUSC2 Gene Therapy with Immunotherapies -...

Hitachi Chemical Advanced Therapeutics Solutions and apceth Biopharma GmbH Enter into Strategic Clinical and Commercial Manufacturing Agreements with…

Posted on May 11, 2020 by Danzig

ALLENDALE, NJ., USA and MUNICH, Germany, May 11, 2020 / B3C newswire / -- Hitachi Chemical Advanced Therapeutics Solutions, LLC (HCATS) and apceth Biopharma GmbH (apceth), both subsidiaries of Hitachi Chemical Co., Ltd. (Hitachi Chemical) today announced that they have expanded their relationship with bluebird bio (NASDAQ: BLUE) with long-term development and manufacturing services agreements for clinical and commercial supply for multiple therapies, including:

These agreements are the latest in a long-standing partnership between bluebird bio and Hitachi Chemical. In 2011, HCATS, which represents the North America region of Hitachi Chemicals global regenerative medicine business, and bluebird bio entered into their first clinical services agreement. A commercial drug product manufacturing service agreement was also established between bluebird bio and apceth (which represents the Europe region of Hitachi Chemicals global regenerative medicine business) in 2016. In January 2020, apceth announced its readiness to begin commercial manufacturing of ZYNTEGLO with bluebirds announcement of the launch in Germany.

"With three products in our severe genetic disease franchise to potentially launch between now and 2022, securing long-term commercial drug product manufacturing capacity is critical to our ability to deliver for patients, " said Nick Leschly, chief bluebird. "Our partnership with Hitachi Chemical is a significant example of our continued progress on this front and we believe Hitachi Chemicals recent expansion will help support our growing commercial needs. We are pleased to benefit from their expertise as well as their footprint in both the US and Europe as we work to bring transformative therapies to patients in need."

We are excited to partner with bluebird bio through our new U.S. facility, utilizing our state-of-the-art capabilities and systems for late-stage clinical testing and ultimately commercial production once all applicable regulatory approvals are granted, said Robert Preti, Ph.D., Chief Strategy Officer, Hitachi Chemical Life Science Business Headquarters. It is our honor to support bluebird bio in the manufacture of their potentially transformative gene therapies, to the benefit of patients in both the United States and Europe, as the foundation for our collaboration to address this devastating disease

We are very happy to deepen our trustful and productive strategic partnership with bluebird bio, commented Dr. Christine Guenther, Deputy General Manager of the Hitachi Chemical Regenerative Medicine Business Sector and CEO of apceth Biopharma GmbH. The apceth team is proud to be part of bluebird bios most exciting pioneering work for the advancement of cell and gene therapies and to supply patients suffering from severe genetic illnesses with potentially life-changing treatments.

This medicinal product is subject to additional monitoring.

About Hitachi Chemicals Regenerative Medicine BusinessHitachi Chemical provides cell and gene therapy contract development and manufacturing organization (CDMO) services at current Good Manufacturing Practices (cGMP) standards, including clinical manufacturing, commercial manufacturing, and manufacturing development. The global footprint of the business is over 200,000 square feet and includes operations in North America (Allendale, New Jersey and Mountain View, California), Europe (Munich, Germany), and Japan (Yokohama). The business leverages two decades of experience exclusively focused on the cell therapy industry.

For more information on North America services, please visit http://www.pctcelltherapy.comFor more information on Europe services, please visit http://www.apceth.comFor more information on Japan services, please visit http://www.hitachi-chem.co.jp/english

Contacts

Hitachi Chemical Advanced Therapeutics SolutionsEric PowersDirector, Marketing and CommunicationsThis email address is being protected from spambots. You need JavaScript enabled to view it.

apceth Biopharma GmbHAlmut WindhagerManager, Business Development and CommunicationsThis email address is being protected from spambots. You need JavaScript enabled to view it.

Keywords: Humans; Regenerative Medicine; Thalassemia; HLA Antigens; Hematopoietic Stem Cell Transplantation; Anemia, Sickle Cell; Hematopoietic Stem Cells; Genetic Therapy

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Hitachi Chemical Advanced Therapeutics Solutions and apceth Biopharma GmbH Enter into Strategic Clinical and Commercial Manufacturing Agreements with...

Flexion Therapeutics Announces Virtual Poster Presentations for FX201, an Intra-Articular Gene Therapy Candidate for the Treatment of Osteoarthritis,…

Posted on May 11, 2020 by Danzig

BURLINGTON, Mass., May 05, 2020 (GLOBE NEWSWIRE) -- Flexion Therapeutics, Inc. (Nasdaq:FLXN) will present positive data from two studies of FX201, an investigational gene therapy for osteoarthritis (OA), at the American Society of Gene and Cell Therapy (ASGCT) Annual Meeting taking place virtually May 12-15, 2020. The abstracts were published in the May supplement of Molecular Therapy.

The data from the rodent model served as a basis for the FX201 IND and reinforce our belief that FX201 holds the potential to become a transformative therapy for OA, saidMichael Clayman, M.D., President and Chief Executive Officer of Flexion. Further, we are delighted to be presenting manufacturing studies at ASGCT which demonstrate a capable Good Manufacturing Process (GMP) to support the production of FX201 for our clinical trials.

Establishing the Efficacy, Safety, and Biodistribution of FX201, a Helper-Dependent Adenoviral Gene Therapy for the Treatment of Osteoarthritis, in a Rat Model (Abstract 747)

Flexion assessed the efficacy of HDAd-rat-IL-1Ra, the rat surrogate of FX201, in a rodent surgical model of OA. Efficacy was assessed after a single intra-articular administration one week post-surgery via histopathology at Week 12 using a semi-quantitative microscopic grading system (Osteoarthritis Research Society International [OARSI] score) for OA-related cartilage, synovium, and bone changes. In addition, two Good Laboratory Practice (GLP) studies were performed in a rodent model of OA to evaluate the safety and biodistribution of FX201 and the rat surrogate (a helper-dependent adenovirus vector with a transgene encoding rat variant of IL-1Ra) administered four weeks post-surgery. Key study findings include:

Development of a Highly Productive and Reproducible Manufacturing Process for FX201, a Novel Helper-Dependent Adenovirus-Based Gene Therapy for Osteoarthritis (Abstract 1273)

Using a fit-for-purpose manufacturing process suitable for early development, Flexion successfully produced four batches of drug substance, which will enable GLP toxicology, pharmacology, and GMP clinical studies. Key findings include:

About FX201FX201 is a locally administered gene therapy product candidate which utilizes a helper-dependent adenovirus (HDAd) vector, designed to stimulate the production of an anti-inflammatory protein, interleukin-1 receptor antagonist (IL-1Ra), whenever inflammation is present within the joint. Inflammation is a known cause of pain, and chronic inflammation is thought to play a major role in the progression of osteoarthritis (OA). By persistently suppressing inflammation, Flexion believes FX201 holds the potential to both reduce OA pain and modify the disease.

About Osteoarthritis (OA) of the KneeOA, also known as degenerative joint disease, affects more than 30 million Americans and accounts for more than $185 billion in annual expenditures. In 2017, approximately 15 million Americans were diagnosed with OA of the knee and the average age of physician-diagnosed knee OA has fallen by 16 years, from 72 in the 1990s to 56 in the 2010s. The prevalence of OA is expected to continue to increase as a result of aging, obesity and sports injuries. Each year, approximately five million OA patients receive either a corticosteroid (immediate-release or extended-release) or hyaluronic acid intra-articular injection to manage their knee pain.

About Flexion TherapeuticsFlexion Therapeutics(Nasdaq:FLXN) is a biopharmaceutical company focused on the development and commercialization of novel, local therapies for the treatment of patients with musculoskeletal conditions, beginning with osteoarthritis, the most common form of arthritis. The company's core values are focus, ingenuity, tenacity, transparency and fun. Visitflexiontherapeutics.com.

Forward-Looking Statements This release contains forward-looking statements that are based on the current expectations and beliefs of Flexion. Statements in this press release regarding matters that are not historical facts, including, but not limited to, statements relating to the future of Flexion; expected increases in the rate of individuals with OA of the knee; and the potential therapeutic and other benefits of FX201, are forward looking statements. These forward-looking statements are based on management's expectations and assumptions as of the date of this press release and are subject to numerous risks and uncertainties, which could cause actual results to differ materially from those expressed or implied by such statements. These risks and uncertainties include, without limitation, risks related to clinical trials, including potential delays, safety issues or negative results; risks related to key employees, markets, economic conditions, and health care reform; and other risks and uncertainties described in our filings with theSecurities and Exchange Commission(SEC), including under the heading "Risk Factors" in our Annual Report on Form 10-Kfiled with theSEConMarch 12, 2020and subsequent filings with theSEC. The forward-looking statements in this press release speak only as of the date of this press release, and we undertake no obligation to update or revise any of the statements. We caution investors not to place considerable reliance on the forward-looking statements contained in this press release.

Contacts:

Scott YoungVice President, Corporate Communications & Investor RelationsFlexion Therapeutics, Inc.T: 781-305-7194syoung@flexiontherapeutics.com

Julie DownsAssociate Director, Corporate Communications & Investor Relations Flexion Therapeutics, Inc.T: 781-305-7137jdowns@flexiontherapeutics.com

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Flexion Therapeutics Announces Virtual Poster Presentations for FX201, an Intra-Articular Gene Therapy Candidate for the Treatment of Osteoarthritis,...

UPDATE Amicus Therapeutics Announces Upcoming Presentations at the American Society of Gene & Cell Therapy 23rd Annual Meeting – GlobeNewswire

Posted on May 11, 2020 by Danzig

CRANBURY, N.J., May 06, 2020 (GLOBE NEWSWIRE) -- Amicus Therapeutics (Nasdaq: FOLD) a global, patient-dedicated biotechnology company focused on discovering, developing and delivering novel medicines for rare diseases today announced the acceptance of several abstracts for presentation at the American Society of Gene & Cell Therapy 23rd Annual Meeting being held virtually on May 12 15. Preclinical data from its Pompe gene therapy program, which Amicus is developing with the Gene Therapy Program of the Perelman School of Medicine at the University of Pennsylvania, will be presented as an oral presentation. Preclinical data related to the CLN6 and CLN8 Batten disease programs, with our partners at Sanford Research and Nationwide Childrens Hospital, will be presented in respective posters.

Oral Platform Presentation: Thursday, May 14, 2020,4:45-5:00p.m. ET

Pompe Disease:

Poster Session: Tuesday, May 12, 2020, 5:30-6:30 p.m. ET

CLN6 Batten Disease:

Poster Session: Wednesday, May 13, 2020, 5:30-6:30 p.m. ET

CLN8 Batten Disease:

All abstracts for the American Society of Gene & Cell Therapy 23rd Annual Meeting are now available online.

About Pompe DiseasePompe disease is an inherited lysosomal disorder caused by deficiency of the enzyme acid alpha-glucosidase (GAA). Reduced or absent levels of GAA leads to accumulation of glycogen in cells, which results in the clinical manifestations of Pompe disease. The disease can be debilitating and is characterized by severe muscle weakness that worsens over time. Pompe disease ranges from a rapidly fatal infantile form with significant impacts to heart function to a more slowly progressive, late-onset form primarily affecting skeletal muscle. It is estimated that Pompe disease affects approximately 5,000 to 10,000 people worldwide.

About Batten DiseaseBatten disease is the common name for a broad class of rare, fatal, inherited disorders of the nervous system also known as neuronal ceroid lipofuscinoses, or NCLs. In these diseases, a defect in a specific gene triggers a cascade of problems that interferes with a cells ability to recycle certain molecules. Each gene is called CLN (ceroid lipofuscinosis, neuronal) and given a different number designation as its subtype. There are 13 known forms of Batten disease often referred to as CLN1-8; 10-14. The various types of Batten disease have similar features and symptoms but vary in severity and age of onset.

Most forms of Batten disease/NCLs usually begin during childhood. The clinical course often involves progressive loss of independent adaptive skills such as mobility, feeding, and communication. Patients may also experience vision loss, personality changes, behavioral problems, learning impairment, and seizures. Patients typically experience progressive loss of motor function and eventually become wheelchair-bound, are then bedridden, and die prematurely.

About Amicus Therapeutics Amicus Therapeutics (Nasdaq: FOLD) is a global, patient-dedicated biotechnology company focused on discovering, developing and delivering novel high-quality medicines for people living with rare metabolic diseases. With extraordinary patient focus, Amicus Therapeutics is committed to advancing and expanding a robust pipeline of cutting-edge, first- or best-in-class medicines for rare metabolic diseases. For more information please visit the companys website at http://www.amicusrx.com, and follow us on Twitter and LinkedIn.

Forward-Looking StatementsThis press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995 relating to preclinical and clinical development of our product candidates. The inclusion of forward-looking statements should not be regarded as a representation by us that any of our plans or projections will be achieved. Any or all of the forward-looking statements in this press release may turn out to be wrong and can be affected by inaccurate assumptions we might make or by known or unknown risks and uncertainties. For example, with respect to statements regarding results of preclinical studies and clinical trials, actual results may differ materially from those set forth in this release due to the risks and uncertainties inherent in our business, including, without limitation: the potential that results of clinical or preclinical studies indicate that the product candidates are unsafe or ineffective; the potential that preclinical and clinical studies could be delayed because we identify serious side effects or other safety issues; the potential that we may not be able to manufacture or supply sufficient clinical products; and the potential that we will need additional funding to complete all of our studies and manufacturing. Further, the results of earlier preclinical studies and/or clinical trials may not be predictive of future results. In addition, all forward-looking statements are subject to other risks detailed in our Annual Report on Form 10-K for the year ended December 31, 2019. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, and we undertake no obligation to revise or update this press release to reflect events or circumstances after the date hereof.

CONTACTS:

Investors/Media:Amicus TherapeuticsAndrew FaughnanDirector, Investor Relationsafaughnan@amicusrx.com(609) 662-3809

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