Category Archives: Gene Medicine

At first glance, two 50-something women with breast cancer appear to have similar cases. But an article by Wilmot Cancer Institute experts points out that technically, only one woman is eligible for a newer, potentially lifesaving treatment due to slight differences in tumor markers.

The article raises questions about rules around using the latest therapies and illustrates how nuances in tumor biology can have a major influence on treatment choices. It also speaks to the critical need for consistent, high standards for pathology testing across the U.S.

Ruth O'Regan, MD

Co-author Ruth ORegan, M.D., a national thought-leader in breast cancer and executive at Wilmot, would like to see the U.S. follow Europe and loosen the limitations for the breast cancer treatment in question, known as CDK inhibitors.

We believe that restricting the use of these drugs is controversial and deserves more discussion, she said.

ORegan and David Hicks, M.D., a professor of Pathology and Laboratory Medicine who has devoted his career to innovations in breast tumor analysis, described two cases of breast cancer in postmenopausal women in a Grand Rounds article in the Journal of Clinical Oncology.

Both women were diagnosed with stage 2 breast cancer, which had begun to spread to the lymph nodes. Each woman faced a high risk of the cancer recurring after initial treatment was completed. Testing also showed that the hormones estrogen and progesterone were largely fueling each persons disease.

A key fact separated these Wilmot patients, however: Only one waseligible for CDK therapy, which has a proven survival advantage.

The reason? Her tumor had a higher level of a cancer-related gene known as Ki-67, indicating rapid reproduction of cancer cells.

A mixed bag of clinical trial data has shown that certain levels of Ki-67 in breast tumors support better outcomes for patients who are treated with CDK inhibitors. The FDA approved the use of CDK inhibitors for individuals whose tumors have Ki-67 levels of 20 percent or higher.

But, ORegan said, this leaves out women whose tumors have Ki-67 markers at 15-to-19 percent, for example, even though other factors in their cases may indicate that treatment with the drug would help.

One clinical trial in the U.S. does, in fact, support the use of the newer drug for tumors with lower levels of Ki-67, and Europes equivalent of the FDA approved the CDK treatment without limitations, ORegan noted.

David Hicks, MD

The lynchpin in the U.S. is that measurement of Ki-67 is notoriously inconsistent across hospital systems and clinical laboratories. Many institutions do not routinely check for this tumor marker although all breast cancer patients at Wilmot receive Ki-67 testing in optimal, standardized laboratory conditions, ORegan said.

It will take time to overcome the testing hurdle nationwide, Hicks and ORegan wrote, due to variability among practices and materials available.

Meanwhile, ORegan continues to assess cases on an individual basis, often in collaboration with Wilmots tumor board, and has achieved insurance approval for CDK therapy for a few patients that fell outside of current FDA eligibility requirements, she said.

CDK inhibitors are also available to women with stage 4 breast cancer; limitations only exist for earlier-stage disease. Breast cancer patients should ask their doctors about this newer form of treatment, O'Regan said.

ORegan is the Charles A. Dewey Professor and Chair of Medicine at the University of Rochester Medical Center, as well as the Associate Director of Wilmots education and mentoring program. Hicks has studied tumor markers in breast cancer for several years at URMC and helped to develop national guidelines on estrogen-receptor and HER2 gene testing.

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What is Ki-67 in Breast Cancer? It Can Spell the Difference in Treatment Options - URMC

The clinical trial of an old antibiotic for a new purpose is offering hope to thousands of patients with drug-resistant breast cancer whose early remissions have given way to resurgent tumors.

Novobiocin was once used in humans but today is largely limited to animal applications, such as treating mastitis in dairy cows. Its trial as a cancer drug is expected to begin this spring at the Dana-Farber Cancer Institute. If it proves effective, the fact that its still manufactured and already approved in people should allow it to become rapidly available to patients, trial organizers say.

While the discovery of a potentially powerful anti-cancer agent in a veterinary niche may seem serendipitous, it sits at the end of a long chain of discovery. That chain has already deepened our understanding of a group of well-known cancers breast, ovarian, pancreatic, and prostate that together afflict more than 600,000 people and kill about 140,000 each year. Research in recent decades has revealed that half of ovarian cancers, 15 percent of breast and prostate, and 10 percent of pancreatic cancers share a flaw in their DNA repair mechanism that make them susceptible to drugs like novobiocin. The work has also shown that they are related to a rare, often fatal childhood disease called Fanconi anemia.

In fact, the discoveries trace back to the suffering of Fanconi anemia families, hinging on a key moment two decades ago at a Maine summer camp where children suffering Fanconi anemia offered their blood for science. The distressing irony is that the resulting treatments, which now offer hope to thousands of cancer sufferers, are not only ineffective for Fanconi children, theyre potentially fatal.

This is a terrible disease, said Alan DAndrea, who heads Dana-Farbers Susan F. Smith Center for Womens Cancers and who has worked on Fanconi anemia since the early 1990s. The children have birth defects. They have a strong disposition to developing anemia and then leukemia. And their cells are super-sensitive to DNA damaging agents.

The condition is rare and genetic. As a recessive disease, a child must inherit two copies of a Fanconi gene one from each parent for the condition to develop. It affects just one in 130,000 U.S. births each year, which translates to about 28 children, many of whom are afflicted with short stature, microcephaly, abnormal facial features, or other birth defects. Anemia tends to emerge around age 7, often followed by acute myeloid leukemia and eventually bone marrow failure. Many patients dont live to adulthood, and the average age of death in 2000 was 30.

Sometimes the most important discoveries in science are obvious when you hit them.

DAndrea, who also directs Dana-Farbers Center for DNA Damage and Repair, became interested in Fanconi anemia in a roundabout fashion. While he was an undergraduate in Quincy House at Harvard College in the late 1970s, his mother developed breast cancer. She recovered, but the episode sparked an interest that led DAndrea to the lab of William Haseltine at Dana-Farber, then called the Sidney Farber Cancer Institute. Haseltine was studying DNA repair, a subject that grabbed DAndreas interest. The pair pioneered using new tools of gene sequencing to investigate DNA damage and repair. Later, while studying at Harvard Medical School, DAndrea became interested in leukemia and then, as an assistant professor at the Medical School and Dana-Farber in the early 1990s, in Fanconi anemia. DAndrea thought that a better understanding of the condition might not only help those afflicted with it, but also produce insights broadly applicable to leukemias, which affect 61,000 Americans and kill 24,000 per year.

DAndreas efforts were met with enthusiasm. Families of Fanconi sufferers often struggle alone, trying to manage a condition frequently unrecognized by physicians and ignored by researchers. The Fanconi Anemia Research Fund was just a year old when DAndrea got involved in 1990, but it was already beginning to support research on the condition.

I first met Alan in the year 1990; our daughter Katie died in 1991, said Lynn Frohnmayer, one of the funds founders. We were advised to consult with a DNA expert at Harvard about her condition, so we talked to him for a long time. Its hard to remember a time when he hasnt been part of what we were doing.

Community was no less important than research to Fanconi families, who gathered annually at a summer camp on Maines Sebago Lake.

Id go to this camp every summer and teach the families what we knew about the disease, said DAndrea, the Alvan T. and Viola D. Fuller American Cancer Society Professor of Radiation Oncology. At the same time, we would collect blood samples from the children or the parents, and sometimes skin biopsies. We assumed at this point that if we could clone the genes that were involved for Fanconi anemia, we might discover something very fundamental about why these children get leukemia, and also discover some kind of DNA repair pathway.

DAndreas method identifying defective Fanconi genes and using them to understand the function of the normal gene took time, but slowly revealed the diseases genetic underpinnings. As Fanconi genes were discovered scientists have so far identified 23 DAndreas lab demonstrated how the proteins they encode work together in a biochemical pathway required for DNA repair.

We figured out that these genes probably work together in some kind of a genetic DNA repair pathway and that was exciting, DAndrea said. But it was a backwater field of cancer research. I would give talks on Fanconi anemia at big meetings and thered be 12 people in the audience, and theyd be reading the newspaper, not paying attention.

In the early 2000s, DAndrea was at the camp drawing blood from an 11-year-old girl who had recently developed leukemia. He was talking with her mother, who was in her 30s, and noticed that her arm was in a sling. When she said shed had a mastectomy after a breast cancer diagnosis, his interest was piqued.

In the mid-1990s, researchers had identified mutations in two genes, BRCA1 and BRCA2, that increase the risk of early breast cancer. The BRCA genes are tumor suppressors that play a role in DNA repair. In most women, healthy BRCA genes prevent tumors by keeping DNA functioning properly. In women who inherit mutated genes, faulty DNA repair opens the door to tumor growth.

Suddenly, this rare disease, Fanconi anemia, and this rare pathway that we have been studying crashed into breast cancer and ovarian cancer research.

DAndreas work over the prior decade had pointed to faulty DNA repair as a cause of Fanconi anemia, so when he heard the young mothers story, something clicked. He tracked down the girls father and asked about his family history. The man said he had been healthy, but that his mother had died of ovarian cancer.

After DAndrea raced back to the lab, he and colleagues examined DNA from the girls samples. They found that she had two copies of a faulty breast cancer gene BRCA2 one inherited from each parent.

Suddenly, this rare disease, Fanconi anemia, and this rare pathway that we have been studying crashed into breast cancer and ovarian cancer research, DAndrea said. And not only those cancers in the general population, but BRCA2 and, subsequently, BRCA1, extremely important cancer-susceptibility genes. We call it today the Fanconi anemia/BRCA pathway.

In hindsight, the connection seems obvious, DAndrea said.

We had been studying all these other Fanconi anemia genes and we knew that process had something to do with DNA repair. It made sense. Sometimes the most important discoveries in science are obvious when you hit them. You realize this child with Fanconi anemia had mutations in the BRCA gene thats why this child got cancer. When you get cancer as a child, you get leukemia, you dont get breast cancer, you dont get ovarian cancer. Leukemia that was a very severe form of BRCA deficiency.

Subsequent research found that the Fanconi anemia/BRCA pathway was disrupted not only in some breast and ovarian cancers, but also in a significant number of prostate and pancreatic cancers.

Not only did these children have Fanconi anemia, but their parents and grandparents have other cancers: breast, ovarian, and we now know prostate cancer and pancreatic cancer, DAndrea said. These poor families, they have children with Fanconi anemia, a fatal childhood disease, and their older siblings, parents, older family members who have a mutation in one of the genes, they get breast, ovarian, prostate, pancreatic cancer.

The discovery of a common DNA repair pathway linking Fanconi anemia to deadly cancers brought immediate attention to the condition and to DNA repair as a common feature of some cancers. It also provided a new way to treat them. Subsequent research showed that cancers caused by BRCA mutations become more dependent on other DNA repair pathways. Drugs called PARP inhibitors were developed to attack a key protein in a backup DNA repair pathway used by BRCA-deficient tumors. PARP inhibitors rapidly disrupt tumor growth, leading to dramatic remissions, but only for a time.

A year to 18 months after PARP treatment begins, tumors often recur as the cancer mutates to use a third DNA repair pathway, which relies on a protein called polymerase theta. To counter that move, DAndrea turned to modern drug-screening techniques, examining thousands of compounds effectiveness against polymerase theta. Novobiocin rose to the top. Subsequent trials in mouse models confirmed its effectiveness, which led to plans for the spring trial.

Should novobiocin prove an effective tool, researchers will shift to examining how tumors respond over time and whether they can eventually evade the drugs effects by using one of the bodys other DNA repair pathways, according to Geoffrey Shapiro, Dana-Farbers senior vice president for developmental therapeutics and a professor of medicine who is collaborating with DAndrea on the novobiocin trial. Having an additional drug will also let researchers explore combination therapies that might be harder for tumors to overcome. Such therapies are already extending the lives of many patients and, in some cases, reducing cancer to a chronic disease.

Ultimately, we will be combining all these DNA repair inhibitors to try to maximize response up front if its safe enough to do that, Shapiro said. This is our next decade of work.

Fanconi anemia remains a target for DAndrea and other researchers. Thanks to recent advances, including improved survival rates for bone-marrow transplants, more patients are living into their 30s or later. This is good news for families, but the threat of cancer is ever-present, and comes with a cruel twist. While treatments such as PARP and novobiocin grew out of Fanconi-related science, the key difference between Fanconi patients and others with cancer makes those treatments not only useless but potentially deadly for people with the condition.

For most cancer patients, the DNA repair defect that is vulnerable to PARP inhibitors and, potentially, novobiocin is in their tumor cells, which creates targets for treatment. In Fanconi patients, the defect is present throughout their bodies, meaning that the inhibitors would attack all their cells, not just cancerous ones. Frohnmayer said chemotherapy and radiation therapy are also dangerous for Fanconi patients, whichlimits cancer-fighting optionstoa heavy emphasis on early detection and surgery while the search for other treatments continues.

The first gene was discovered in 1992, so we were in the dark. All we had were these horrible statistics, Frohnmayer said. Today its much more hopeful. People know that getting through the bone-marrow-failure part of the problem is at least a possibility, maybe even a likelihood. Were working really hard on the cancer problem. And you can at least have the hope that, by the time your child is in danger, theres going to be a better answer than we have today.

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Hope for breast cancer patients, but with a cruel caveat - Harvard Gazette

FRIDAY, March 11, 2022 (HealthDay News) -- A one-time infusion of betibeglogene autotemcel (beti-cel) gene therapy yields high levels of transfusion independence in children and adults with transfusion-dependent -thalassemia and a non-0/0 genotype, according to a study published in the Feb. 3 issue of the New England Journal of Medicine.

Franco Locatelli, M.D., Ph.D., from the University of Rome, and colleagues conducted an open-label phase 3 study to examine the efficacy and safety of beti-cel in adult and pediatric populations with transfusion-dependent -thalassemia and a non-0/0 genotype. Twenty-three patients were enrolled, underwent myeloablation with busulfan, and then received intravenous beti-cel. Patients were followed for a median of 29.5 months.

The researchers found that 20 of the 22 patients (91 percent) who could be evaluated had transfusion independence, including six of seven (86 percent) who were younger than 12 years. During transfusion independence, the average hemoglobin level was 11.7 g/dL. In patients with transfusion independence, the median level of gene therapy-derived adult hemoglobin with a T87Q amino acid substitution was 8.7 g/dL at 12 months after beti-cel infusion. Four patients had at least one adverse event considered to be related or possibly related to beti-cel; all except one were nonserious. There were no cases of cancer.

"These data suggest that in most patients with transfusion-dependent -thalassemia and a non-0/0 genotype, one-time infusion of beti-cel is potentially curative through transfusion independence and the attainment of near normal hemoglobin levels," the authors write.

Several authors disclosed financial ties to biopharmaceutical companies, including Bluebird Bio, which funded the study.

Abstract/Full Text (subscription or payment may be required)

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Gene Therapy Potentially Curative for -Thalassemia - Consumer Health News | HealthDay - HealthDay News

Specific comorbidities and conditions have been associated with severe COVID-19, including diabetes, obesity, and, of course, older age. But researchers have now identified 16 new genetic variants associated with severe COVID-19. For that and more research stories, continue reading.

16 Genetic Variants Associated with Severe COVID-19

Investigators with theUniversity of Edinburghanalyzedthe genomes of 57,000 people, part of the GenOMICC consortium, a global collaboration to study genetics in critical diseases. They identified 16 new genetic variants associated with severe COVID-19 and sequenced the genomes of 7,491 patients from 224 intensive care units in the U.K. That DNA was compared with 48,400 other people who did not have COVID-19. They were participants inGenomics Englands 100,000 Genomes Project and another 1,630 people who had mild COVID-19. The findings are published inNature.

Our latest findings point to specific molecular targets in critical COVID-19, said Professor Kenneth Baillie, the projects chief investigator and a Consultant in Critical Care Medicine at the University of Edinburgh. These results explain why some people develop life-threatening COVID-19, while others get no symptoms at all. But more importantly, this gives us a deep understanding of the process of disease and is a big step forward in finding more effective treatments.

In addition to the 16 new gene variations, they confirmed seven other genetic variations that were already linked with severe COVID-19. Part of their findings was a single gene variant that can disrupt interferon alpha-10, a key messenger molecule in immune system signaling. This variant alone was enough to increase a patients severe disease risk. Another variation is Factor 8, which is important to blood clotting, and was connected to critical COVID-19.

Nanoparticle decreases Scleroderma Skin and Lung Scarring

Researchers withMichigan Medicine University of Michiganidentifieda unique macrophage, a type of immune cell, that plays a significant role in the chronic inflammation and scarring seen in the lungs and skin of scleroderma patients. The macrophage, dubbed MARCO+, was isolated in people with the disease, which is rare and affects about 70,000 people in the U.S. They then, working with laboratory mice, injected the animals with biodegradable PLG (lactic-co-glycolic acid) nanoparticles that targeted MARCO+ inflammatory cells. This appeared to prevent the skin and lung fibrosis in the mice associated with the disease. The team theorizes that the MARCO+ cells are activated in scleroderma, circulate in the bloodstream, move to tissues, and cause scar formation.

A Predictive Model for Rheumatoid Arthritis

Scientists fromTokyo Medical and Dental Universitydevelopeda genomic model to predict the progression of rheumatoid arthritis. They utilized data from a genome-wide association study (GWAS) of R.A. susceptibility. They then developed a polygenic risk score (PRS) and tested it to predict radiographic progression in people with rheumatoid arthritis. Earlier studies identified specific genetic factors for R.A. progression, including anti-citrullinated protein antibodies (ACPAs) and variants in the human leukocyte antigen (HLA) region of the chromosome that regulates the immune system. Those are useful but not considered robust. Their new analysis found that patients with a higher PRS had a higher risk of severe progression, particularly in people who were younger at the onset.

microRNAs Unique to Human Beings

Student researchers atJohn Jay College of Criminal Justiceidentifiedhuman microRNA genes that are not found in any other primate species. They believe they may have had a significant role in the evolution of human beings. They found at least three families of microRNA genes on chromosome 21. They leveraged genome alignment tools and compared the most recent versions of human and chimpanzee genomes, working to find genetic elements unique to humans.

On chromosome 21, they found a large region of unique DNA called 21p11, which harbors several orphan microRNA genes. The long arm of human chromosome 21 matches up well with other ape species, but the short arm aligns poorly. The microRNAs in that region, specifically miR3648 and miR6724, probably evolved since the chimpanzee and human lineages split probably in the last seven million years.

Organs Age at Different Rates

Youre only as old as you feel, right? Well, maybe. Butnew researchout of theBeijing Genomics InstituteandChina National GeneBankin Shenzhen, China, found that different organs and systems have different ages from a biological perspective.

Using biomarkers, statistical modeling, and other tools, they analyzed the aging in 4,066 volunteers who supplied blood and stool samples, facial skin images, and to undergo physical fitness examinations. They were between the ages of 20 and 45 years. They measured 403 features: 74 metabolomic features, 34 clinical biomarkers, 10 electroencephalography features, 16 facial skin features, and 210 gut microbiome features. They then classified them into nine categories, including cardiovascular-related, renal-related, liver-related, sex hormone, facial skin, nutrition and metabolism, immune system, physical fitness-related and gut microbiome features. They found that the biological ages of different organs and bodily systems had diverse correlations. They also examined single nucleotide polymorphisms (SNPs) and identified certain genetic changes associated with aging-related pathways.

FDA-Approved Drug Halts RAS-Based Tumor Growth

Researchers with theUniversity of California, San Franciscousedan FDA-approved drug to stop tumor growth in cancers driven by mutations in the RAS gene. RAS mutations are typically difficult to treat and make up about one in four cancer deaths. They found that cancer cells require a reactive form of iron called ferrous iron. They then modified an anticancer drug to work only on these iron-rich cells, allowing other cells to function normally. They focused their research on RAS-mutated pancreatic and gastrointestinal cancers. Cobimetinib and similar drugs are effective at blocking the excessive growth stimulated by RAS mutations and do the same thing in non-cancer tissue, which causes serious side effects that lead many patients to discontinue treatment. They modified cobimetinib to have a small molecule that senses ferrous iron, which essentially shuts cobimetinib off until it meets up with ferrous iron in the cancer cells.

By removing toxicity from the equation, youre talking not just about one new drug, but 10 new combinations that you can now think about exploring in the clinic, said Adam Renslo, a pharmaceutical chemist at UCSF and co-author of the study. That would be the home run for this approach.

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Research Roundup: Genetic Variants Associated with Severe COVID-19 and More - BioSpace

NEW YORK

U.S. regulators on Monday cleared the way for the sale of beef from gene-edited cattle in coming years after the Food and Drug Administration concluded the animals do not raise any safety concerns.

The cattle by Recombinetics are the third genetically altered animals given the green light for human consumption in the U.S., after salmon and pigs. Many other foods already are made with genetically modified ingredients from crops like soybeans and corn.

The cattle reviewed by the FDA had genes altered with a technology called CRISPR to have short, slick coats that let them more easily withstand hot weather. Cattle that arent stressed by heat might pack on weight more easily, making for more efficient meat production.

The company did not say when home cooks or restaurants might be able to buy the beef, but the FDA said it could reach the market in as early as two years.

Unlike the salmon and pigs, the cattle did not have to go through a years-long approval process. The FDA said the cattle were exempt from that because their genetic makeup is similar to that of other existing cattle and the trait can be found naturally in some breeds.

Dr. Steven Solomon, director of the FDAs Center for Veterinary Medicine, said the agencys review of Recombinetics cattle took several months. He said theres no reason that meat from the animals or their offspring would need to be labeled differently.

Solomon said a genetically altered animal marketed as having a special advantage such a higher than normal ability to withstand heat might need to go through the full approval process.

This opens up a completely different pathway, he said, noting the decision could be encouraging for other biotech companies, many of which are small startups.

The gene-edited trait in the Recombinetics cattle can be passed down so semen and embryos from them could be used to produce offspring with the same shorter coats.

The trait will make beef production more sustainable and could improve animal welfare in warmer climates, Recombinetics said in a statement without providing further details.

Greg Jaffe, who specializes in biotechnology at the Center for Science in the Public Interest, said the FDAs announcement made clear it wasnt exempting all gene-edited animals from the longer approval process.

They reinforce the idea that this is a case-by-case review, Jaffe said.

He said the agency should be more transparent about the review process so people know whats in the works. That could lead to better public acceptance and minimize any potential economic disruptions from global trade, since other countries might consider the animals genetically modified foods that need to be labeled, he said.

Jaydee Hanson, of the Center for Food Safety, said the agency should keep track of the animals for several generations to ensure there arent any unintended issues.

The genetically modified pig is intended mainly for medical purposes, not meat, according to the company that developed it. The firm recently provided a pig heart that was transplanted into a dying man in an experimental surgery.

The company behind the modified salmon said the fish are being sold to distributors in the Midwest and Northeast.

Alison Van Eenennaam, an animal geneticist at UC Davis who has worked with Recombinetics, said requiring all companies to go through the lengthy approval process could end the possibility of commercializing gene-edited animals in the U.S.

For the gene-edited cattle cleared by the FDA, she said it could take about two years for beef from the offspring to reach the market.

Once the semen is used to create embryos, she said gestation would take about nine months and the resulting calves might be slaughtered after about 10 months. She noted the market isnt limited to the U.S., given the way cattle are bred.

Lets face it, bull semen goes all over the world, she said.

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Gene-edited beef cattle receive regulatory clearance in U.S. - Los Angeles Times

Image of the female mouse that gave birth via asexual reproduction.PNAS

Chinese scientists have managed to get a female mouse to produce live viable offspring from an unfertilized egg thanks to gene editing. This is in theory the first case of a mammal that has achieved asexual reproduction, technically known as parthenogenesis or virgin creation, which is common in many insects and reptiles, and even in some bird species. But until very recently, it was believed that mammals could not reproduce without male genetic material.

In 2004, the world learned about Kaguya, a mouse born without the need for sperm or sexual reproduction. Mammals have two copies of each gene in their genome one from their mother and one from their father. When a sperm cell penetrates an egg, something called genomic imprinting happens, meaning that some genes behave differently depending on whether they were inherited from the father or the mother.

Many of the genes involved in the process have to do with growth, which may mean, for evolutionary reasons, that the fathers imprint favors growth in order to have larger offspring, while the mothers may do the opposite to ensure that the pregnancy can be brought to term. Some of these genes are also associated with a greater risk of suffering cancer, among other diseases. The Japanese scientists who created Kaguya used two eggs: one worked as the real egg while the other one imitated the sperms contribution. The result was a baby that was born to two females.

The new study, led by Yanchang Wei, a reproductive medicine researcher at Ren Ji Hospital in Shanghai, took the concept a step further, creating a pregnancy from a single, unfertilized egg. Chinese scientists used a gene-editing technique very similar to CRISPR, which is used in medicine and biotechnology. The authors of the study used the tool to imitate the genomic imprint in seven different points of the genome of an egg that already had two copies of each gene. This triggered a biochemical process that was the equivalent of fertilization: the egg grew from one single cell to a 140-cell blastocyst.

Theyve managed something fascinating but terribly inefficient

The scientists implanted 192 embryos made with this technique in as many female mice, but only one of them gave birth to a healthy pup that survived, although it weighed less than average. Two others died shortly after birth. The survivor reached adulthood and was able to reproduce normally.

In their study, published in the scientific journal PNAS, researchers noted that parthenogenesis can be achieved by targeted epigenetic rewriting of multiple critical imprinting control regions. The team believes that the technique could be perfected to achieve a higher live birth success rate. The success of parthenogenesis in mammals opens many opportunities in agriculture, research, and medicine, says the study.

It is a groundbreaking study, agrees Lluis Montoliu, a researcher at Spains National Research Council (CSIC), who underscored that the eggs had a copy of their genes and another copy taken from another egg that came from a different species of mouse, allowing scientists to check the effects of the editing. In theory at least, further perfecting this technique might allow a woman to have children on her own, admits Montoliu. But the researcher adds that its use on humans is a very long way off. The main thing now is to follow the lives of these mice born through these techniques, and see whether they have problems with their lives and reproduction. There are still a lot of unanswered questions.

Theyve managed something fascinating but terribly inefficient, adds David Haig, a researcher at Harvard University who developed a theory about genomic imprinting several years ago.

English version by Susana Urra.

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Female mouse gives birth without sex or sperm - EL PAS in English

The first person to have his failing heart replaced with that of a genetically altered pig in a groundbreaking operation died Tuesday afternoon at the University of Maryland Medical Center, two months after the transplant surgery.

David Bennett Sr., who lived in Maryland, was 57. He had severe heart disease, and had agreed to receive the experimental pigs heart after he was rejected from several waiting lists to receive a human heart.

It was unclear whether his body had rejected the foreign organ. There was no obvious cause identified at the time of his death, a hospital spokeswoman said.

Hospital officials said they could not comment further on the cause of death, because his physicians had yet to conduct a thorough examination. They plan to publish the results in a peer-reviewed medical journal.

Dr. Bartley Griffith, the surgeon who performed the transplant, said the hospitals staff was devastated by the loss of Mr. Bennett.

He proved to be a brave and noble patient who fought all the way to the end, Dr. Griffith said. Mr. Bennett became known by millions of people around the world for his courage and steadfast will to live.

The heart transplant was one of a number of pioneering procedures in recent months in which organs from genetically altered pigs were used to replace organs in humans. The process, called xenotransplantation, offers new hope for tens of thousands of patients with ailing kidneys, hearts and other organs, as there is an acute shortage of donated organs.

Mr. Bennetts transplant was initially deemed successful. It is still considered a significant step forward, because the pigs heart was not immediately rejected and continued to function for well over a month, passing a critical milestone for transplant patients.

Some 41,354 Americans received a transplanted organ last year, more than half of them kidneys, according to the United Network for Organ Sharing, a nonprofit that coordinates the nations organ procurement efforts.

But there is a dire shortage of organs, and a dozen or more people on waiting lists die each day. About 3,800 Americans received human donor hearts last year as replacements, more than ever before, but demand remains high.

Scientists have been trying to produce pigs whose organs would not be rejected by the human body, a research effort that has picked up steam over the past decade because of new gene editing and cloning technologies.

New York surgeons announced in October that they had successfully attached a kidney grown in a genetically altered pig to a brain-dead human patient, finding that the organ worked normally and produced urine for 54 hours.

In January, surgeons at the University of Alabama at Birmingham reported that they had for the first time successfully transplanted kidneys from a genetically modified pig into the abdomen of a 57-year-old brain-dead man. The kidneys functioned and produced urine for three days.

U.A.B. surgeons said they hoped to launch a small clinical trial with live human patients by the end of the year.

Shortly after Mr. Bennetts heart surgery in January, The Washington Post reported that he had a criminal record stemming from an assault 34 years ago, in which he repeatedly stabbed a young man in a fit of jealousy, leaving him paralyzed.

The victim, Edward Shumaker, spent two decades in a wheelchair, paralyzed from the waist down, and suffered numerous medical complications including a stroke that left him cognitively impaired before he died in 2007 at age 40, according to his sister, Leslie Shumaker Downey, of Frederick, Md.

Mr. Bennetts son, David Bennett Jr., who was a child at the time of the stabbing, has said that he does not want to discuss his fathers past, and emphasized that his father was contributing to medical science by undergoing the experimental transplant and hoped to potentially save patient lives in the future.

The heart given to Mr. Bennett came from a genetically altered pig provided by Revivicor, a regenerative medicine company based in Blacksburg, Va.

The pig carried 10 genetic modifications. Four genes were knocked out, or inactivated, including one that encodes a molecule that causes an aggressive human rejection response.

Another gene was also inactivated to prevent the pigs heart from continuing to grow after it was implanted. In addition, six human genes were inserted into the genome of the donor pig modifications designed to make the pigs organs more tolerable to the human immune system.

On New Years Eve, the Food and Drug Administration granted an emergency authorization for the experimental surgery, which was done a week later.

The transplanted heart performed well initially, and there were no signs of rejection for several weeks. Mr. Bennett spent time with his family, did physical therapy and watched the Super Bowl, hospital officials said.

But he was not discharged, and several days ago his condition started to deteriorate, hospital officials said.

His son issued a statement thanking the hospital and staff for their exhaustive efforts on behalf of his father.

We hope this story can be the beginning of hope and not the end, Mr. Bennett said. We also hope that what was learned from his surgery will benefit future patients and hopefully one day, end the organ shortage that costs so many lives each year.

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Patient Who Recieved Groundbreaking Pig Heart Transplant Dies - The New York Times

LONDON--(BUSINESS WIRE)--Ixaka Ltd, an integrated cell and gene therapy company, announces that Advanced Therapy Medicinal Product (ATMP) classification has been granted by the European Medicines Agency (EMA) for its Chemically Encapsulated Lentiviral vector for Targeted In Vivo CAR T-cell therapy (CELTIC-19) targeted nanoparticle (TNP) product.

ATMP status was granted to CELTIC-19 due to its potential as a gene therapy medicinal product that targets specific cells and expression of the gene of interest directly within the patients body. Such an approach makes it possible to eliminate all the ex vivo stages of genetic modification, that are required for the production of currently marketed cell therapy products.

CELTIC-19 is Ixakas lead TNP program for CD19 haematological malignancies. It consists of a polymer nanoparticle encapsulating a bald lentiviral vector encoding for a T-cell specific promoter and the chimeric antigen receptor (CAR). The nanoparticle is coated with a CD3 binding molecule allowing in vivo targeting and transduction of the T-cells. The construct can then be infused systemically into the bloodstream to target and genetically modify T-cells within the body. This approach allows the generation of CAR T-cells which are potentially more efficacious, safer, and considerably less expensive to produce than established CAR T-cell therapies, which have been shown to be effective and have been approved for use in CD19-malignancies.

CELTIC-19s numerous advantages over established ex vivo CAR T-cells therapies, include but are not limited to its high specificity and transduction efficiency, retreatment possibility, no cytokine requirement and persistent expression.

Gilbert Wagener, Senior Vice President, Chief Medical Officer at Ixaka commented:

TNP-based in vivo CAR T-cell therapies such as Ixakas represent a significant advance over recently approved ex vivo CAR T-cell therapies, and hold the promise of delivering more effective, universal, and safer treatment option for patients. It is great to see this potential recognized by the Europeans Medicine Agency.

Joe Dupere, CEO at Ixaka commented:

Our nanoparticle-based in vivo gene delivery technology is ideally positioned to deliver on the promise of in vivo CAR-T therapies to transform cancer treatment without the need for costly dedicated manufacturing sites for T-cell modification. The designation of CELTIC-19 as an Advanced Therapy Medicinal Product further signifies its potential as a ground-breaking new treatment option and is an important step on our continued journey.

About Ixaka

Ixaka is a cell and gene therapy company focused on using the natural powers of the body to cure disease.

Ixakas proprietary technologies enhance the naturally therapeutic power of cells by increasing the presence of curative cells at the site of disease, or by directly modifying cells within the body to improve disease targeting and boost their restorative effect.

Ixakas technologies concentrated multi-cell therapies and nanoparticle therapeutics demonstrate potential for the treatment of a broad range of serious diseases across oncology, cardiovascular, neurological and ocular diseases, and genetic disorders.

Ixaka has offices in London, UK with R&D and manufacturing operations in Seville, Spain and Paris, France and additional manufacturing capability in Frankfurt, Germany.

For more information, please visit http://www.ixaka.com

Connect with us: Twitter: https://twitter.com/ixaka_Ltd; LinkedIn: https://www.linkedin.com/company/ixaka-limited/

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CELTIC-19 Granted Advanced Therapy Medicinal Product Classification by European Medicines Agency - Business Wire

In the United States, 1 in 10 people has type 2 diabetes. Someone dies every 36 seconds from cardiovascular disease (CVD) in the U.S., and CVD causes one-third of all deaths worldwide.

Both conditions may develop slowly, and the symptoms are not always evident. Doctors assess a persons risk of developing them by taking a patient history and observing current lifestyle factors.

Now, a study led by Prof. Dr. Chris Lauber, of Twincore in Germany, has shown that lipids in blood plasma can predict future risk of type 2 diabetes and CVD.

The method known as lipidomic profiling can provide a quantitative measurement of risk long before symptoms develop.

The authors of this study have added to the growing evidence that lipidomics profiling could very well usher in the next generation of detection of cardiovascular diseases as well as diabetes.

Dr. Suneet Singh, Medical Director of CareHive.

The longitudinal study included just over 4,000 healthy, middle-aged Swedish people from the Malm Diet and Cancer-Cardiovascular Cohort.

Participants ranged from 4668 years at the start of the study. Around 10% had a body mass index (BMI) of more than 30.

The researchers took one baseline blood sample from each participant. They then centrifuged these blood samples to separate out the plasma for analysis.

Researchers measured concentrations of 184 different lipids in the blood plasma using mass spectrometry. They used these lipidomic profiles to calculate risk scores and assign participants into one of six risk groups.

Dr. Singh told Medical News Today the study could add to previous methods of assessing risk:

This new approach allows for a novel framework of risk stratification which also allows for enhancement when used in conjunction with the measurement of standard clinical variables.

He did, however, note that there was little diversity in the study population: It is advisable to continue to expand upon this research by increasing the patient population to include several more variables. This includes different patient ages, racial groups, ethnicities, and physical activity levels.

The researchers followed up participants for more than 20 years from baseline assessments made between 1991 and 1994. In that time, 13.8% of the cohort developed type 2 diabetes, and 22% developed CVD.

For those in the highest risk groups, these values rise to 37% for developing type 2 diabetes and 40.5% for developing CVD as compared to the group averages above.

People in the lowest risk groups had a decreased risk of developing both conditions.

The researchers also found that people with high lipid risk scores had a much greater likelihood of developing obesity during the follow-up period. Obesity is a risk factor for both type 2 diabetes and CVD.

The authors suggest that this risk-score-based approach could indicate the risk of both type 2 diabetes and CVD many years before disease onset.

[T]his earlier disease detection occurs at a time where the disease has not become clinically evident. As a result, researchers and clinicians can now take on diseases from a more proactive preventive lens and not simply one that starts at the treatment stage, Dr. Singh commented.

Using mass spectrometry to measure blood plasma lipids is quick, relatively inexpensive, and gives quantitative results.

The authors of this study suggest that it could identify lipids that contribute most to the risk of developing subsequent health conditions and, potentially, lead to new drug treatments.

Dr. Singh told MNT: Research [] demonstrated in this paper helps to advance the field of clinical mass spectrometry as a whole by continuing to demonstrate the potential for earlier disease detection in advance of conventional means.

The authors stress that further research is needed to verify their hypothesis and demonstrate how informative the plasma lipidome is for health and disease.

The lipidome may provide insights much beyond diabetes and cardiovascular disease risk.

Prof. Chris Lauber, lead author of the study.

So, this simple test could tell people their risk of developing both type 2 diabetes and CVD. By making diet and lifestyle changes, they may then be able to decrease that risk.

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Blood test may predict long-term risk of diabetes and heart disease - Medical News Today

IRVINE, Calif. & BASEL, Switzerland--(BUSINESS WIRE)--Urovant Sciences, a wholly-owned subsidiary of Sumitovant Biopharma Ltd., today announced positive topline results from its Phase 2a, double-blind, placebo-controlled exploratory study of URO-902, an investigational, novel, locally injected gene therapy product (plasmid human cDNA encoding maxi-K channel), in patients with overactive bladder (OAB), who were not well managed by oral therapies.

URO-902 showed a clinically meaningful and statistically significant effect on a number of relevant outcome measures in OAB including number of micturitions, urgency episodes, and quality of life indicators compared to placebo, 12 weeks post-administration, said Cornelia Haag-Molkenteller, MD, PhD, executive vice president and chief medical officer of Urovant Sciences. URO-902 was well tolerated, compared to placebo. The most common adverse event was urinary tract infection, in both treatment groups. We are encouraged by these positive results and pending the completion of the study in Fall 2022 and we look forward to discussing next steps for the URO-902 clinical development plan.

The Phase 2a study included 80 female patients and was designed to evaluate the efficacy, safety, and tolerability of a single, physician administered dose of URO-902 of 24 milligrams (mg) and 48 mg, compared with placebo with a primary timepoint at week 12 post-administration. Patients were followed for up to 48 weeks post-administration. URO-902 has the potential to be the first gene therapy for patients with OAB.

These promising results suggest that URO-902 could potentially offer a new treatment option for patients with overactive bladder who have been inadequately managed by oral pharmacologic therapy, said Kenneth Peters, MD, principal investigator, and chief of the department of urology at Beaumont Hospital, Royal Oak; Medical director of the Beaumont Womens Urology and Pelvic Health Center and professor and chair of urology of the Oakland University William Beaumont School of Medicine in Rochester, Michigan.

The company plans to present the topline results of the study at the American Urological Association annual meeting being held May 13-16, 2022 in New Orleans, LA.

About the Phase 2a Study

The study was a randomized, double blind, placebo-controlled trial to evaluate the efficacy, safety, and tolerability of a single physician administered dose of URO-902, a novel gene therapy being developed for patients with OAB who have not been adequately managed with oral or transdermal pharmacologic therapy for OAB. URO-902 is administered via direct intradetrusor injections into the bladder wall under local anesthesia in patients who are experiencing OAB symptoms and urge urinary incontinence (UUI).

The Phase 2a trial enrolled 80 female patients in two cohorts: the first cohort received either a single administration of 24 mg of URO-902 or matching placebo, and the second cohort received 48 mg of URO-902 or matching placebo into the bladder wall. Multiple outcome measures were explored, including the effect on the number of micturitions, urgency episodes, and quality of life indicators compared to placebo, 12 weeks post-administration, as well as an assessment of the safety and tolerability of this potential new therapy. Patients were followed for up to 48 weeks after initial administration.

About URO-902

URO-902 has the potential to be the first gene therapy for patients with OAB. If approved, this innovative treatment may address an unmet need for patients who have not been adequately managed by oral or transdermal pharmacologic OAB therapies and are concerned with potential urinary retention with other minimally invasive therapies or surgical interventions related to existing third-line OAB treatments.

About Urovant Sciences

Urovant Sciences is a biopharmaceutical company focused on developing and commercializing innovative therapies for areas of unmet need, with a dedicated focus in Urology. The Companys lead product, GEMTSA(vibegron), is an oral, once-daily (75 mg) small molecule beta-3 agonist for the treatment of adult patients with overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency. GEMTESA was approved by the U.S. FDA in December 2020 and launched in the U.S. in April 2021. GEMTESA is also being evaluated for the treatment of OAB in men with benign prostatic hyperplasia. The Companys second product candidate, URO-902, is a novel gene therapy being developed for patients with OAB who have failed oral pharmacologic therapy. Urovant Sciences, a wholly owned subsidiary of Sumitovant Biopharma Ltd., intends to bring innovation to patients in need in urology and other areas of unmet need. Learn more about us at http://www.urovant.com or follow us on Twitter or LinkedIn.

About Sumitovant Biopharma Ltd.

Sumitovant is a global biopharmaceutical company leveraging data-driven insights to rapidly accelerate development of new potential therapies for unmet patient conditions. Through our unique portfolio of wholly-owned Vant subsidiariesUrovant, Enzyvant, Spirovant, Altavantand use of embedded computational technology platforms to generate business and scientific insights, Sumitovant has supported the development of FDA-approved products and advanced a promising pipeline of early-through late-stage investigational assets for other serious conditions. Sumitovant, a wholly-owned subsidiary of Sumitomo Dainippon Pharma, is also the majority-shareholder of Myovant (NYSE: MYOV). For more information, please visit our website at http://www.sumitovant.com or follow us on Twitter and LinkedIn.

About Sumitomo Dainippon Pharma Co., Ltd.

Sumitomo Dainippon Pharma is among the top-ten listed pharmaceutical companies in Japan, operating globally in major pharmaceutical markets, including Japan, the U.S., China, and other Asian countries. Sumitomo Dainippon Pharma is based on the 2005 merger between Dainippon Pharmaceutical Co., Ltd., and Sumitomo Pharmaceuticals Co., Ltd. Today, Sumitomo Dainippon Pharma has more than 7,000 employees worldwide. Additional information about Sumitomo Dainippon Pharma is available through its corporate website at https://www.ds-pharma.com.

About GEMTESA

GEMTESA is a prescription medicine for adults used to treat the following symptoms due to a condition called overactive bladder:

It is not known if GEMTESA is safe and effective in children.

IMPORTANT SAFETY INFORMATION

Do not take GEMTESA if you are allergic to vibegron or any of the ingredients in GEMTESA.

Before you take GEMTESA, tell your doctor about all your medical conditions, including if you have liver problems; have kidney problems; have trouble emptying your bladder or you have a weak urine stream; take medicines that contain digoxin; are pregnant or plan to become pregnant (it is not known if GEMTESA will harm your unborn baby; talk to your doctor if you are pregnant or plan to become pregnant); are breastfeeding or plan to breastfeed (it is not known if GEMTESA passes into your breast milk; talk to your doctor about the best way to feed your baby if you take GEMTESA).

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

What are the possible side effects of GEMTESA?

GEMTESA may cause serious side effects including the inability to empty your bladder (urinary retention). GEMTESA may increase your chances of not being able to empty your bladder, especially if you have bladder outlet obstruction or take other medicines for treatment of overactive bladder. Tell your doctor right away if you are unable to empty your bladder.

The most common side effects of GEMTESA include headache, urinary tract infection, nasal congestion, sore throat or runny nose, diarrhea, nausea and upper respiratory tract infection. These are not all the possible side effects of GEMTESA. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Please click here for full Product Information for GEMTESA.

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Urovant Sciences Announces Positive Topline Results of Phase 2a Trial of its Potential Novel Gene Therapy, URO-902 - Business Wire