Monthly Archives: September 2021

iECURE is emerging from stealth with $50 million and a mission to go after the "holy grail" of gene editing with an in vivo approach that is mutation agnostic.

The biotech will use the funds for a slate of gene insertion programs for liver disorders out of the lab of gene therapy pioneerJim Wilson, M.D., Ph.D. at the University of Pennsylvania.

Versant Ventures, which has backed gene-editing companiesCRISPR Therapeutics and Graphite Bio,is launching iECURE alongside OrbiMed Advisors. The series A gives the biotech access to up to 13 programs out of Wilson's Gene Therapy Program at Penn.

Wilson's lab will conduct the preclinical, toxicology and manufacturing supportand then iECURE will sign the regulatory filings and move the assets through the clinic and onto the market, CEO JosephTruitt told Fierce Biotech.

Its a much more mature company than you would typically start off with if you were just licensing some technology from an academic center," Truitt said. By getting access to Wilson's team, iECURE doesn't have to recruit dozens of employees, the CEO said.

RELATED:FDA committee takes on complex gene therapy safety questions with Novartis' Zolgensma providing lessons learned

Wilson's lab has already shown long-term evidence of genome editing in non-human primates, which is important because translating into species larger than mice is often difficult, said Tom Woiwode, Ph.D., iECURE chairman and Versant managing director, in a joint interview with Truitt and Wilson.

Wilson has thought of the liver as a great target for gene therapy since the late-1980's, when he was in the lab as a post-doc, because "so many diseases have their root in the liver [and] it's accessible to biologics." Wilson is also director of the Orphan Disease Center and a professor in medicine and pediatrics at Penn's School of Medicine.

iECURE and Wilson's lab are approaching the "holy grail of genome editing" by using an in vivo approach that inserts genes inside organs, inside the human body, Woiwode said. In another adventurous analogy,Woiwode said the company is also going after the "untapped frontier of gene editing" by using a mutation agnostic approach. This is critical given many genetic diseases have multiple, "sometimes hundreds," of individual mutations. That many targets would not lend well to creating therapies at scale, the chairman added.

The series A will help iECURE bankroll the first three indications in the program of up to 13, Truitt said. More indications down the pipeline are still under evaluation. The financing is slated to take iECURE through the early part of 2023, the CEO said.

The first program goes after familial hypercholesterolemia, or high cholesterol caused by abnormalities in the gene PCSK9. The treatment reduced PCSK9 protein levels by 85% and LDL cholesterol by 56% in nonhuman primates for three years, Wilson's lab reported in Molecular Therapy in February.

RELATED:Moderna donates ultra-rare disease therapy to nonprofit founded by late Takeda R&D chief

The lab has been working with Precision Biosciences on that asset, which is ready to enter the clinic.As part of iECURE's deal with Wilson's lab, iECURE will conduct the phase 1 study and then return the program to Precision, Truitt said.

The next two indications in the pipeline are the rare metabolic disorders phenylketonuria and ornithine transcarbamylase deficiency, Truitt said.

The gene-editing technology used by iECURE and Wilson's lab is delivered viaadeno-associated virus, or AAV. Toxicity and safety issues have arisen with AAV gene therapies, which resulted in an FDA advisory committee meeting last week to discuss and make recommendations on animal and human testing with these therapies.

Wilson took part in two panels during thetwo-day meeting and said he doesn't see the results of that meeting having an impact on iECURE.

"In terms of the work with IECURE, there really isnt anything that I heard at the committee that impacts on our preclinical plan, our clinical plan or our discussions with health authorities," Wilson said.

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iECURE emerges with $50M to search for 'holy grail' and 'untapped frontier' of gene editing - FierceBiotech

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Researchers have discovered a specific gene that drives much of the development of the stripes, blotches, and spots that decorate cat fur with patterns.

Color patterns are one of these unsolved biological mysteries; theres no go-to model organism to study itmice dont have stripes or spots, says Gregory Barsh, professor emeritus of genetics at Stanford University School of Medicine.

The color patterns and variability that you see in animals like tigers, cheetahs, and zebras prompted some central questions for us: What are the developmental genetic mechanisms and the cellular mechanisms that give rise to these patterns and how have they been altered during mammalian evolution to give rise to the amazing diversity of shape and form we see today?

Barsh and his team have answered part of that question: They have identified a gene, DKK4, that helps regulate the early development of the different fur patterns in domestic cats. DKK4, the team suspects, is likely involved in color patterns in all cats and perhaps other mammals, too.

The researchers findings appear in Nature Communications. Barsh is the senior author. Research scientists Christopher Kaelin and Kelly McGowan are co-lead authors.

The researchers previously identified a different gene that controls coat color variation in tabby cats. Its the same gene that accounts for the difference between cheetahs and king cheetahs, which have thicker, more prominent fur patterns.

We knew from studying domestic cats that there were other genes that contributed to color pattern formation; we just didnt know what they were, Barsh says.

They found a clue in fetal cat tissue that seemed to foreshadow fur color: a thickening of the skin tissue in certain areas. These thickened regions constitute a prepattern that mimics the eventual color patterns in an adult cats fur. The thick area marks the patches of fur that will later be darker; the thin area marks the patches that will be lighter.

We call this step establishment, and it happens long before color appears and long before hair follicles are mature, Barsh says.

The prepattern provided a map of sorts for the researchers, indicating cells involved in creating the pattern and the time when the pattern formed. The researchers then inspected the genetic makeup of individual cells in the thick and thin regions of skin. DKK4 was particularly active in the thickened skin, but not in skin that had remained relatively thin.

But to really lock in the connection between DKK4 and early pattern formation, the team turned to the Abyssinian cat. Abyssinians are known for sporting a blur of colors in their coat, with tiny, darker markings squished together, as if someone used a pencil to lightly shade a layer of gray on top of their orangish-brown coat. Barsh and his team identified disrupting mutations in the DKK4 gene responsible for the Abyssinian cats apparent lack of tabby markings, a look thats called ticked.

If you remove DKK4, the dark areas dont go away entirely, but they become smaller and more packed together, Barsh says.

You may be wondering, what about all-white cats? Or all-black cats? They, too, are patterned underneath their monochrome swath of fur. There are two distinct processes that make a color pattern: One that forms the pattern during embryonic development and one that translates the pattern into pigment produced in hair follicles. In solid-colored cats, the pattern is essentially overridden by instructions to produce dark pigment everywhere. In white cats, the pigment is lacking.

Scientists dont know exactly how DKK4 paints the array of color patterns domestic cats sport, but they do know DKK4 interacts with a class of proteins called WNTs, which are crucial in early development. WNTs and DKK4 help to form a prepattern when embryos are only two or three millimeters in length, weeks before pigment is produced in hairs. DKK4 is involved in marking areas that will eventually have darkly pigmented hairs, Barsh says, but how these skin areas remember their fate to induce target pigment is unclear.

This is one of the big unanswered questions in our workhow to connect the process of prepattern formation to the process that implements the pattern later in development, he says. Thats something that were actively trying to figure out.

On top of that, DKK4 is only part of the answer to the mysterious genetics dictating fur patterns. There are still other genes that are behind why, for instance, some cats have spots and why some cats have stripes, Barsh says. Looking into that is on their list, too.

Funding for the work came from the HudsonAlpha Institute for Biotechnology and the National Institutes of Health. Stanfords genetics department also supported the work.

Source: Stanford University

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Gene helps put stripes and blotches on cats of all sizes - Futurity: Research News

Gene therapy experts Fulvio Mavilio, Ph.D., and Nicoletta Loggia, Ph.D., join as chief scientific officer and chief technical officer, respectively

Neuroscience and rare disease leader Leslie Meltzer, Ph.D., promoted to chief medical officer

Appointments reinforce companys strategic focus on innovation in the areas of discovery, clinical development and manufacturing

BOSTONandLONDON, Sept. 09, 2021 (GLOBE NEWSWIRE) -- Orchard Therapeutics (Nasdaq: ORTX), a global gene therapy leader, today announced the appointment of two gene therapy and industry experts, Fulvio Mavilio, Ph.D., and Nicoletta Loggia, Ph.D., to serve as chief scientific officer and chief technical officer, respectively. The company also announced the promotion of Leslie Meltzer, Ph.D., who has been serving as senior vice president of medical affairs, clinical operations and diagnostics, to chief medical officer. Together, Drs. Mavilio, Loggia and Meltzer will oversee strategically important functions as Orchard continues to advance its later-stage portfolio and expand its hematopoietic stem cell (HSC) gene therapy pipeline into larger indications. We have seen the potentially transformative impact of our HSC gene therapy approach in devastating rare diseases and are now extending our focus on more prevalent conditions where there is a compelling rationale, said Bobby Gaspar, M.D., Ph.D., chief executive officer of Orchard Therapeutics. Fulvio, Nicoletta and Leslie all have proven track records in their respective areas of expertise, and their leadership in building our next-generation R&D and technical operations capabilities will be instrumental in accelerating our progress, advancing our pipeline and scaling our commercial infrastructure.

I have worked with many types of genetic medicine technology during my career and believe HSC gene therapy offers immense and distinct promise to correct the underlying cause of many severe diseases with a single treatment, said Dr. Mavilio. I am eager to begin working with this exceptional team to unlock the full potential of HSC gene therapy in new and larger indications.

I am excited to join Orchard at this vital juncture as we continue to invest in and scale our technical operations on a global level, said Dr. Loggia. "I look forward to working closely with our CMC teams and CDMO network to put in place innovative and efficient manufacturing solutions that will meet the needs of patients and our organization now and into the future.

Since joining Orchard more than three years ago, I have been proud to help cultivate the clinical, medical and operational capabilities that support our deep pipeline of investigational and approved HSC gene therapies, including five clinical-stage programs, said Dr. Meltzer. I look forward to partnering with our development and commercial teams to ensure a seamless integration and advance our portfolio through key anticipated milestones.

Drs. Loggias and Meltzers appointments are effective immediately. Dr. Mavilio has initially joined the company in a consulting capacity and will start full-time in January 2022.

About Fulvio Mavilio, Ph.D., chief scientific officer Dr. Mavilio will lead the companys discovery and translational research activities. In this capacity he will be responsible for expanding the companys pipeline into larger indications.

He joins Orchard Therapeutics from Smart Immune where he serves as chief scientific officer. Previously, Dr. Mavilio was senior vice president of translational science at Audentes Therapeutics in San Francisco, where he was responsible for advancing the companys pipeline from discovery to clinical development overseeing molecular biology, in vivo pharmacology, bioinformatics, and bioanalytics. Prior to joining Audentes, Dr. Mavilio was chief scientific officer of Genethon in vry, France from 2012 to 2017 where he led the development of a robust pipeline of gene therapy programs for blood, liver, and neuromuscular diseases. Earlier in his career, he held various positions at the Center for Regenerative Medicine of the University of Modena, Molmed SpA, Genera SpA, and the San Raffaele-Telethon Institute of Gene Therapy in Milan, Italy.

Dr. Mavilio is a member of the European Molecular Biology Association, past member of the Board of the American Society of Gene and Cell Therapy and a member of the editorial board of many international journals in the fields of genetics, molecular biology and gene therapy. Dr. Mavilio earned a Ph.D. in medical genetics at the University of Rome School of Medicine and has published more than 200 articles in major international journals. He also serves as Professor of Molecular Biology at the University of Modena and Reggio Emilia in Modena, Italy.

About Nicoletta Loggia, Ph.D., chief technical officer In her role, Dr. Loggia will be responsible for leading all aspects of technical operations, including process and analytical development, manufacturing, supply chain, engineering and CMC lifecycle management.

She joins Orchard Therapeutics from Novartis, where she held positions of increasing responsibility since 2004, most recently serving as global head of cell and gene therapies. In this role, Dr. Loggia led multidisciplinary international teams responsible for the end-to-end technical development, manufacturing and project management of several gene and cell therapies modalities, including lentiviral, adeno-associated virus (AAV), stem and CAR-T cell processes, from concept to commercialization. She also oversaw the integration of the CAR-T teams and AveXis AAV technical capabilities into Novartis technical R&D. Previously, Dr. Loggia was global head of technical development novel biologic entities and cell and gene therapies where she was responsible for the early phase development of biologics and gene therapies. Her broad industry experience encompasses global leadership in the development and manufacturing of sterile drug products and devices and approvals of several commercial assets.

A medicinal chemist by training, Dr. Loggia began her career in the biopharmaceutical industry as a formulation scientist at Pfizer. She earned her Ph.D. in pharmaceutical technologies from the University of Pavia in Italy. She is a registered pharmacist and member of the UK Royal and Italian Pharmaceutical societies. About Leslie Meltzer, Ph.D., chief medical officer Dr. Meltzer joined Orchard Therapeutics in June 2018 bringing extensive experience leading medical affairs for several premier biopharmaceutical companies. Throughout her career, Dr. Meltzer led integration of medical functions across brands including publication planning, field team training, advisory boards, patient registry and identification efforts, investigator-initiated trial prioritization and post-marketing planning. A neuroscientist by training, Dr. Meltzer has dedicated much of her career to advancing new therapies for difficult-to-treat brain diseases. During her tenure at the company, Dr. Meltzer has held positions of increasing responsibility, most recently serving as senior vice president of global medical affairs, diagnostics, clinical operations and data management.

She joined Orchard Therapeutics from Keryx Biopharmaceuticals (prior to its merger with Akebia Therapeutics) where she was the vice president of medical affairs supporting Auryxia (ferric citrate) for the treatment of chronic kidney disease. She previously served in various positions of increasing seniority in medical affairs at Biogen, where she led key elements of the U.S. launch and post-launch plan for Tecfidera (dimethyl fumarate) for the treatment of relapsing forms of multiple sclerosis. In recognition of her success and contributions, Dr. Meltzer was promoted to leadership roles in Biogens multiple sclerosis and then its hemophilia franchises, comprising the companys approved and investigational therapies. Dr. Meltzer began her career at Actelion (now part of Janssen) where she supported four approved and eight investigational therapies in a variety of therapeutic areas, including respiratory, cardiovascular, rheumatology, neurology and rare disease.

Dr. Meltzer earned her Ph.D. in neuroscience from Stanford University School of Medicine. About Orchard Therapeutics At Orchard Therapeutics, our vision is to end the devastation caused by genetic and other severe diseases. We aim to do this by discovering, developing and commercializing new treatments that tap into the curative potential of hematopoietic stem cell (HSC) gene therapy. In this approach, a patients own blood stem cells are genetically modified outside of the body and then reinserted, with the goal of correcting the underlying cause of disease in a single treatment.

In 2018, the company acquired GSKs rare disease gene therapy portfolio, which originated from a pioneering collaboration between GSK and the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy. Today, Orchard has a deep pipeline spanning pre-clinical, clinical and commercial stage HSC gene therapies designed to address serious diseases where the burden is immense for patients, families and society and current treatment options are limited or do not exist.

Orchard has its global headquarters inLondonandU.S.headquarters inBoston. For more information, please visit http://www.orchard-tx.com, and follow us on Twitter and LinkedIn.

Availability of Other Information About Orchard Investors and others should note that Orchard communicates with its investors and the public using the company website ( http://www.orchard-tx.com ), the investor relations website ( ir.orchard-tx.com ), and on social media ( Twitter and LinkedIn ), including but not limited to investor presentations and investor fact sheets,U.S. Securities and Exchange Commissionfilings, press releases, public conference calls and webcasts. The information that Orchard posts on these channels and websites could be deemed to be material information. As a result, Orchard encourages investors, the media, and others interested in Orchard to review the information that is posted on these channels, including the investor relations website, on a regular basis. This list of channels may be updated from time to time on Orchards investor relations website and may include additional social media channels. The contents of Orchards website or these channels, or any other website that may be accessed from its website or these channels, shall not be deemed incorporated by reference in any filing under the Securities Act of 1933.

Forward-looking Statements This press release contains certain forward-looking statements about Orchards strategy, future plans and prospects, which are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include express or implied statements relating to, among other things, Orchards business strategy and goals, including its plans and expectations for the commercialization of Libmeldy, the therapeutic potential of Libmeldy (OTL-200) and Orchards product candidates, including the product candidates referred to in this release, Orchards expectations regarding its ongoing preclinical and clinical trials, including the timing of enrollment for clinical trials and release of additional preclinical and clinical data, the likelihood that data from clinical trials will be positive and support further clinical development and regulatory approval of Orchard's product candidates, and Orchards financial condition and cash runway into the first half of 2023. These statements are neither promises nor guarantees and are subject to a variety of risks and uncertainties, many of which are beyond Orchards control, which could cause actual results to differ materially from those contemplated in these forward-looking statements. In particular, these risks and uncertainties include, without limitation: the risk that prior results, such as signals of safety, activity or durability of effect, observed from clinical trials of Libmeldy will not continue or be repeated in our ongoing or planned clinical trials of Libmeldy, will be insufficient to support regulatory submissions or marketing approval in the US or to maintain marketing approval in the EU, or that long-term adverse safety findings may be discovered; the risk that any one or more of Orchards product candidates, including the product candidates referred to in this release, will not be approved, successfully developed or commercialized; the risk of cessation or delay of any of Orchards ongoing or planned clinical trials; the risk that Orchard may not successfully recruit or enroll a sufficient number of patients for its clinical trials; the risk that prior results, such as signals of safety, activity or durability of effect, observed from preclinical studies or clinical trials will not be replicated or will not continue in ongoing or future studies or trials involving Orchards product candidates; the delay of any of Orchards regulatory submissions; the failure to obtain marketing approval from the applicable regulatory authorities for any of Orchards product candidates or the receipt of restricted marketing approvals; the inability or risk of delays in Orchards ability to commercialize its product candidates, if approved, or Libmeldy, including the risk that Orchard may not secure adequate pricing or reimbursement to support continued development or commercialization of Libmeldy; the risk that the market opportunity for Libmeldy, or any of Orchards product candidates, may be lower than estimated; and the severity of the impact of the COVID-19 pandemic on Orchards business, including on clinical development, its supply chain and commercial programs. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements.

Other risks and uncertainties faced by Orchard include those identified under the heading "Risk Factors" in Orchards quarterly report on Form 10-Q for the quarter endedJune 30, 2021, as filed with theU.S. Securities and Exchange Commission(SEC), as well as subsequent filings and reports filed with theSEC. The forward-looking statements contained in this press release reflect Orchards views as of the date hereof, and Orchard does not assume and specifically disclaims any obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as may be required by law.

Editors note: Auryxia and Tecfidera are registered trademarks of Akebia Therapeutics, Inc. and Biogen Inc., respectively.

Contacts

Investors Renee Leck Director, Investor Relations +1 862-242-0764 Renee.Leck@orchard-tx.com

Media Benjamin Navon Director, Corporate Communications +1 857-248-9454 Benjamin.Navon@orchard-tx.com

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Orchard Therapeutics Bolsters R&D and Technical Operations Leadership with New Executive ... - The Bakersfield Californian

For the first time, doctors have partially restored the vision of a completely blind French man using light-sensing algae proteins. The breakthrough marks a significant milestone in genetic blindness treatment.

The man was diagnosed with the rare, genetic eye condition retinitis pigmentosa (RP) which causes the death of light-sensing cells on the retina forty years ago. The condition affects over two million people worldwide, and while complete blindness is rare, the man has had no vision for the past twenty years.

The French man, whose identity has not been revealed, was treated with optogenetics therapy, which uses the algae proteins to control cells at the back of his eye. He first realized the treatment was working when he could see the painted stripes of a crosswalk. Impressively, he can now count and grab objects too!

According to the study published on May 24 in Nature Medicine, this is the first reported case of partial functional recovery in a neurodegenerative condition after optogenetic therapy.

Optogenetics is a standard tool in fundamental neuroscience research, but its new to the world of medicine. It works by using light to activate specific brain cells and was used by the doctors in France to restore one of the mans eyes to detect light.

In his case, the light-detecting cells in his retina had died off a long time ago; therefore, the doctors inserted an algae gene into the surviving cells of the retina at the back of his eye. This caused them to produce channelrhodopsins, a protein found in algae that helps the photosynthetic microbes move toward light sources. In other words, now, when they are hit with light, they will send an electrical signal directly to the brain.

Since theres a big difference between photosynthetic algae and the human eye, the new therapy has limitations. It didnt restore the mans vision to normal levels and didnt allow him to see in color. However, they would respond to amber-colored light.

To solve this problem, the patient wore special goggles with a video camera and projector to capture the real world and translate a version in the correct wavelength onto the back of his eye, allowing him to see.

After months of training and building up high enough levels of the rhodopsins in the eye, the mans brain finally learned how to see again, starting with the white stripes of a pedestrian crossing.

Dr. Jos-Alain Sahel, who treated the patient at Pariss Institute of Vision, said:

This patient initially was a bit frustrated because it took a long time between the injection and when he started to see something. But when he started to report spontaneously that he could see the white stripes across the street, you can imagine he was very excited. We were all excited.

Not only did the patient report identifying the crosswalk, but that he could count the number of white stripes too! After more training, the patient displayed a significant improvement in daily visual activities, including detecting a mug, plate, phone, furniture in a room, or a door in a corridor, but only while using the goggles. Therefore, treatment by combining an optogenetic route with light-stimulating goggles led to a decent level of visual recovery.

While the mans eyesight isnt perfect, the difference between no vision and limited is a life-changer. The findings provide proof-of-concept that using optogenetic therapy to partially restore vision is possible, concluded Prof. Botond Roska from the University of Basel.

James Bainbridge, a retinal studies professor at the UKs UCL, said:

This exciting new technology might help people whose eyesight is very severely impaired.

Researchers are also exploring optogenetic therapy for conditions like Parkinsons disease to see whether it can improve recovery from a stroke.

In recent years, scientists have developed several approaches to restore sight. One includes correcting the genetic defects that cause RP, a challenging task since the disease has a significant number of mutations in over 71 different genes. In 2018, scientists at Oxford University in the UK completed a first gene therapy trial, improving patients vision for Choroideremia (one of the many forms of RP) by injecting a single healthy gene into their eyes. Their results were published in Nature Medicine.

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Algae Gene Therapy Partially Restored Completely Blind Man's Vision - Intelligent Living

PHILADELPHIA, Sept. 09, 2021 (GLOBE NEWSWIRE) -- Scout Bio today announced the successful completion of a CKD-associated anemia study in client owned cats treated with SB-001, an AAV expressing feline erythropoietin (fEPO). The study demonstrated a prolonged therapeutic effect with statistically significant increases in red blood cells after a single injection. SB-001 is the first gene therapy to successfully treat feline patients with an acquired non-monogenic disease. These results pave the way for Scout Bios portfolio of AAV delivered therapeutic proteins for companion animal diseases.

Clinical Study Highlights:

In this study we have successfully shown that SB-001 has the ability to increase PCV into the normal range, thereby reducing or eliminating the clinical effects of anemia associated with CKD, said Mark Heffernan, Ph.D., CEO of Scout Bio. These exciting results reinforce the potential for Scout Bios gene therapy platform to advance treatments for other acquired chronic diseases such as diabetes, chronic pain and atopic dermatitis.

There are no FDA-approved treatments available for CKD-associated anemia in cats. The single injection treatment of SB-001 presents an enormous advantage in convenience, improved compliance, and potentially allows owners more quality time with their pets. A new option for cats with kidney disease and anemia is urgently needed. These cats come into the veterinary clinic with weakness, lethargy, breathing difficulties, and overall feeling very unwell. SB-001s ability to increase the PCV can make a huge difference for many of these cats that would otherwise face euthanasia, said Anne Traas, DVM, MS, DACT, Chief Development Officer for Scout Bio and head of the clinical team leading the study. It was very rewarding to hear from owners participating in the study who expressed their deep gratitude for the additional time SB-001 was able to provide their beloved pets.

James M. Wilson, MD, PhD, Director of the Gene Therapy Program at the University of Pennsylvaniaand a co-founder of Scout Bio, commented, Scout Bios focus in companion animals with chronic diseases has resulted in this successful demonstration that AAV gene therapy can be an effective alternative to frequent injections with therapeutic proteins and result in the improvement of feline patient lives. These results provide validation that Scout Bios platform can be used to successfully deliver therapeutic proteins to treat chronic diseases in companion animals.

Scout Bio intends to progress key manufacturing activities and safety studies that will be necessary to apply for Expanded Conditional Approval under FDA guidelines.

About SB-001 SB-001 has a unique and innovative adeno-associated viral (AAV) vector, containing the gene for feline EPO, for delivery into the muscle cell nucleus which will continually produce therapeutic levels of the hormone. The expressed feline EPO stimulates erythropoiesis, or red blood cell production. The U.S. Food and Drug Administration (FDA) CVM has confirmed that SB-001 is eligible for Expanded Conditional Approval, potentially shortening the time until this product could be approved and made available.

About Chronic Kidney Disease (CKD)-Associated AnemiaAnemia associated with chronic kidney disease (CKD) in cats is a disease of high unmet medical need, with no FDA-approved therapies currently available. CKD is one of the most common diseases in senior cats and is an end-of-life disease that creates quality of life issues for cats and their owners. Up to 21% of cats with CKD have anemia and the only currently available therapeutic options are multiple blood transfusions or repeated injections of off-label human drugs. Compared to the off-label use of human EPO drugs, SB-001 is expected to have a superior safety profile with respect to immune reactions and incidence of pure red cell aplasia (PRCA), a serious life-threatening condition.

About Scout BioScout Bio is a biotechnology company revolutionizing pet medicine by delivering a pipeline of one-time gene therapies for major chronic pet health conditions. Scout Bios therapeutics are designed to induce long-term expression of therapeutic proteins in pet patients using AAV vector technology. Scout Bio has a research and development collaboration with the University of Pennsylvanias Gene Therapy Program, a leader in the field of genetic medicine research. Scout Bio is a private company headquartered in Philadelphia, Pennsylvania. For more information, seewww.scoutbio.co

University of Pennsylvania Financial DisclosureDr. Wilson is a Penn faculty member, scientific collaborator, key advisor, and co-founder of Scout Bio. As such, he holds an equity stake in the Company, his laboratory at Penn receives sponsored research funding from Scout Bio, and as an inventor of the licensed technology he may receive additional future financial benefits under licenses granted by Penn to Scout Bio. The University of Pennsylvania also holds equity and licensing interests in Scout Bio.

For further information, please contact:Fran GaconnierScout Bio214.417.4142 Fran.gaconnier@scoutbio.co

Link:
Scout Bio Successfully Completes Pilot Clinical Study of SB-001, a Single-Injection AAV Gene Therapy - GlobeNewswire

On September 1, 1971, unknowingly to most, the world changed for the fields of behavioral genetics and circadian clocks. Ronald Konopka, a graduate student with Seymour Benzer at Caltech, published a paper (1) that I would argue is the most important discovery ultimately leading to our current molecular understanding of the circadian clock in animals. In this classic paper, Ron and Seymour reported the isolation of three single-gene mutants in Drosophila that dramatically altered circadian rhythms in pupal eclosion and locomotor activity. One mutant exhibited no rhythmicity, another had a short 19-h period, and a third had a long 28-h period. Remarkably, all three mutants mapped to the same locus on the X chromosome. They named this gene period.

Seymour Benzer had recently joined the faculty at Caltech in 1967, after two previously successful careers in physics and molecular biology, and spurred on by Max Delbruck to do something more interesting, launched his third career in behavioral biology (25). Having done a sabbatical at Caltech with Roger Sperry, Seymour interacted with Ed Lewis, a giant in Drosophila genetics who trained with Alfred Sturtevant (descendent of Thomas Hunt Morgan) (6). Seymour chose Drosophila as a model system because its nervous system was intermediate in complexity between a single neuron and the human brain yet exhibited complex behavior and was amenable to genetic analysis (7). That same year, Seymour published his first paper (8) using mutagenesis and countercurrent technology to isolate phototaxis mutants in Drosophila. The opening sentence of this paper reads, Complex as it is, much of the vast network of cellular functions has been successfully dissected, on a microscopic scale, by the use

1Email: joseph.takahashi{at}utsouthwestern.edu.

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The 50th anniversary of the Konopka and Benzer 1971 paper in PNAS: Clock Mutants of Drosophila melanogaster - pnas.org

In many ways, Shang-Chi and the Legend of the Ten Rings, Marvels latest mega-blockbuster, is following in the footsteps of Black Panther. The 2018 installment of the MCU opened the door for Black representation in blockbuster cinema, and walked all the way to the Oscars. It took an even longer time for Marvel to get to a point where Shang-Chi could fill that role for Asian audiences.

The history of the character is far more complicated and messy than the movies production timeline. Originally, Shang-Chi was an extension of Marvels licensing deal for the problematic British literary villain Fu Manchu created by white author Sax Rohmer. Stereotypes abounded in the original Shang-Chi comic books, which had to be resolved in order for Marvel to bring this character into the 21st century. One of the people responsible for that transformation is this weeks guest on Galaxy Brains, Gene Luen Yang. Yangs credits include the graphic novel American Born Chinese, several Avatar: The Last Airbender comics, DCs Superman Smashes the Klan, and most recently, an ongoing Shang-Chi book for Marvel Comics.

To rethink Shang-Chi for the modern Marvel universe, Yang brought traditional Chinese mysticism and cultural heritage to the characters backstory. For our Shang-Chi episode of Galaxy Brains, we asked the cartoonist and writer to dig into the history of Shang-Chi, his familial relationship to Fu Manchu, and how he was able to reclaim this character for Asian communities around the world. Heres an excerpt:

What were the origins of this character and why was it not a character that was in regular rotation in the Marvel Comics universe?

Gene: I began reading Marvel Comics in the 1980s back when I was in fifth grade. I bought my very first comic from a spinner rack at my local bookstore. And back then there were some Shang-Chi comics that were around. I think his monthly series had recently ended at issue 125. So they were in back-issue bins. But as a Chinese-American kid, I was going through this thing where I just didnt want to be Asian.

So I actively avoided picking up those Shang-Chi comics. So I didnt know a ton about the character. I didnt read any Shang-Chi comics until I was an adult. But from doing research in order to write the ongoing series, he began with ... not-so-awesome origins. In the original run, he was the son of Fu Manchu. My understanding was that Marvel wanted to do a comic based on Kung Fu, the television series, but were unable to acquire the license. So getting the Fu Manchu license was the next best thing. And they created this character who was the son of Fu Manchu. If you read those early comics, there are really fun things about them the way they do action is amazing. But then the character himself, Shang-Chi himself, doesnt totally fit the Marvel mold. Like when you think of Marvel, at least when I was a kid, one of the things that I loved the most about Marvel was that the characters were meant to be relatable. Like you got to see Spider-Man go to his local laundromat to do his laundry and you identify with him. But those early Shang-Chi comics were structured that way. They werent structured in a way where youre meant to identify with.

I think about Black Panther, and how it played a similar role in the MCU to what Shang-Chi is playing now, but the Black Panther comic books were very unique in that period of the Marvel Golden Age because he wasnt a Peter Parker, a kid whos trying to scrape by and make something of himself. This character of Black Panther is a king. You know, hes very regal; TChala is not like us. Hes not relatable in that way. They found a way to make him relatable in the films, but it wasnt quite as connected and grounded to the real world as some of the other Marvel comics. Im interested to hear you say that about Shang-Chi, that it was similar in that it was, I wouldnt say othering because that seems like a negative word, but its certainly different from how grounded the Marvel superheroes were.

Gene: Yeah, thats right. For TChalla, it took awhile for them to kind of Marvel-ize him, to make them fit into what makes Marvel unique. To build in those identification pieces.

I want to drill down into Fu Manchu. For those who dont know what Fu Manchu was, or the reason why its offensive to a lot of Asian people, can you explain kind of what this character was and what his place in the popular culture was at that time?

Gene: Fu Manchu is what we would recognize as the prototypical Yellow Peril villain. Yellow Peril villains were a trend in the late 1800s, early 1900s of Western media portraying these Chinese characters, predominantly Chinese characters, as pretty inhuman. Like Fu Manchu was a Chinese super genius whos bent on taking over the Western world. He had bright yellow skin, he had really exaggerated facial features, hair, pointed ears. An early Asian stereotype was that Asians had pointy ears. I have no idea where this came from! Like, Ive never met an Asian person with remotely pointy ears. But in any case, Fu Manchu starred in these early novels written by an author named Sax Rohmer. The way I see Fu Manchu now is that I think of him as almost like a ghost. Hes not actually a ghost in the stories, but often ghost stories are a supernatural way of talking about people wrestling with their sins. The ghost in a ghost story often represents an embodiment of the repercussions of sin.

Fu Manchu became really popular towards the end. Like, I think he debuted right after what the Chinese call their century of humiliation. So during the 1800s, China as a nation just went through hell. They lost war after war and one of the one of the big wars that they lost was the Opium War against the British. And the Opium War was about Britain fighting for their right to sell drugs to the Chinese populace, which the Chinese government didnt want. And they were doing that in order to even out a trade deficit. So I think deep down inside, the Brits knew that this was a bad thing. I think deep down inside the new right, theyre sinning against this other nation. In a lot of ways, the way I read Fu Manchu is that he kind of represents the repercussions of Britains actions towards the Chinese in the 1800s. And when Fu Manchu gets defeated in those early Fu Manchu stories, its sort of like the Brits writing the story about how theyre able to put off the repercussions of their own sins.

Right now youre personally responsible for revamping the origin story of Shang-Chi. And I was wondering if you could talk us through how you approach this new story and what new details you added to the characters backstory?

Gene: Yeah, its been a ton of fun to work on. Ive gotten to work with some amazing artists. Dike Ruan and I are now doing the monthly ongoing series for the limited series that came out about a year ago. Dike did part of the art and Phillip Tan did another part. The whole things being edited by Darren Shan, an amazing editor with amazing instincts. Were all of Chinese descent and, early on, we talked about what this character meant to us. And all of us had that weird relationship that I talked about earlier, where we didnt fully embrace Shang-Chi as kids. So ultimately, what we wanted to do was bring more Marvel into this character. We wanted to make him more of a character that we could all relate to regardless of our readers cultural background. We wanted them to be able to relate to Shang-Chi.

The Marvel Universe is different from DC. Like with DC, you sometimes have these hard resets of the entire universe that happened with Crisis on Infinite Earths in the 80s, and its happened again more recently with New 52. But Marvels never gone through something like that. Marvels never had a hard reset. So it means that all the stuff in the Marvel past, like the Marvel history, is still in play, which means we have to kind of figure out how to talk about all the problematic pieces of Shang-Chi without doing a hard reset. We kept the fact that Shang-Chis dad is a supervillain. Hes no longer Fu Manchu, but hes the super villain. We tried to make his supervillain dad more sympathetic, but we wanted to lean into a family drama. Everybody can relate to family drama. So we wanted to lean into the tension between him and his dad, and we also wanted to give them a bunch of siblings that he could both support and squabble with.

That family dynamic and the idea of squabbling, I think, is probably the most unifying aspect of the Marvel Universe, both on the page and on the screen. How are you going to improve upon your parents or how are you going to overcome the obstacles presented by your parents? Theres just so much that is there in these stories. Was that something that when you were reading the comics as a kid you related to or was it something that was more just like subtext that you got later on when you grew up?

Gene: Oh, yeah, absolutely. I dont know if I would have been able to articulate it as a kid, but that was definitely something that I was drawn to. My favorite Marvel book when I was little, like when I was in elementary school, was Fantastic Four. The whole thing was about how these people love each other, but kind of hate each other sometimes, too. Thats almost all of us, the way we feel about our families. We love them. But sometimes, you know, sometimes maybe not.

Theres a big plot point in your comics about the spirit of Shang-Chis father and a jiangshi, which is a vampiric ghost-like creature from Chinese mythology and folklore. Im wondering what other elements of Chinese mythology that you worked into these comics and why did you choose to tie in those specific characters, creatures and themes?

Gene: In a lot of ways, all of the work that Ive done in comics has been about connecting with my own cultural heritage. I was born and raised in the United States, so I really only knew about Chinese culture through my parents. I remember visiting China for the very first time as an adult when I was in my 20s, and it was just weird. It was like seeing all the stuff for the first time that I had only known through echoes. So in a lot of ways my work on Shang-Chi is like trying to figure out all of this stuff. Its kind of like a selfish reason! But I just want to figure out these parts of myself.

So one of the big pieces that we used from traditional Chinese culture is this idea from traditional Chinese medicine called the five elements. You know how there are four elements of Western culture air, water, earth and fire but in Chinese culture, there are five elements: fire, earth, metal, water and wood. And what we did was we had Shang-Chi come from ... his family runs this organization called the Five Weapons Society, and the five weapons correlate with the five elements of traditional Chinese medicine.

So what was that experience like? Did you go to a theater? Did you try to make it an event for yourself?

Gene: Yeah, it was amazing. I went with a friend of mine who is also a cartoonist and we sat in that theater for a whole two hours when I watched the trailer after it dropped a few months ago, I had this feeling. I dont even know how to describe it. But basically the movie was that same feeling. For two hours, it was amazing. All the expectations that I had going in were exceeded. My friend, hes just like the prototypical nerd, before we went into the movie was like If this is good, Im going to go by all the action figures. And the first thing he did after we exited the theater was he went to GameStop and bought all the action figures..

Thats awesome. I can think back to how I felt seeing Black Panther and how a lot of people of African descent felt seeing that for the first time. And it was like, Oh, my God, I cant believe they made this thing. And I had to go out and buy all the toys.

In addition to your writing, your comics writing, you are a teacher in the Bay Area and youve merged these two careers with an online comic book for teaching math called Factoring with Mr. Yang and Mosley the Alien. How effective do you find comic books to be is teaching tools?

Gene: I think comics are an amazing tool for education. I was a high school teacher for 17 years at a high school in Oakland, and I also got my masters in education. So for a final masters project,I did that online interactive comic teaching factorials, the topic from algebra.

Dont make me remember algebra two. Im breaking out in hives.

Gene: Youre breaking out in hives because the teacher didnt use comics to teach you! For a really long time, the educational establishment avoided comics. There was this book that came out in the 1950s called Seduction of the Innocent that argued that comics cause juvenile delinquency. So even though that book was wrong, it had a huge cultural impact. And educators just avoided comics for decades. Thats changed recently, but in my research for my masters program, what I found was that, out of all of the visual storytelling media like film and television and animation comics is the only one where it puts control over time in the hands of the reader. A comic can go as fast or slow in the readers mind as the reader desires. That is an incredibly effective tool. And I think thats one of the most powerful things about comics. Theres no other visual media that allows you to do that. Its only comics.

Dive into more Galaxy Brains with our latest episodes on Candyman, Suicide Squad, and Idiocracy, featuring future MCU star Kumail Nanjiani!

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Rethinking Shang-Chis problematic origins in the Marvel universe - Polygon

Doctors regard amyloid plaque lodged between the brains nerve cells and tangled tau protein fibers forming within the cells as the hallmark of Alzheimers disease.

However, amyloid plaque consisting of broken pieces of protein that clump together is also present in the brains of older adults who do not develop Alzheimers, suggesting another factor is triggering the disease.

A new study finds that inflammation in the brain drives the progression from the presence of amyloid plaque and tau tangles to the onset of dementia and Alzheimers disease.

Lead author of the study, Dr. Tharick Pascoal, Ph.D., assistant professor of psychiatry and neurology at the University of Pittsburgh School of Medicine, PA, explains:

Many [older adults] have amyloid plaques in their brains but never progress to developing Alzheimers disease. We know that amyloid accumulation on its own is not enough to cause dementia our results suggest that it is the interaction between neuroinflammation and amyloid pathology that unleashes tau propagation and eventually leads to widespread brain damage and cognitive impairment.

The study appears in Nature Medicine.

While scientists have observed neuroinflammation in people with Alzheimers before, the new study reveals for the first time its critical role in the development of the disease.

The research finds that activating the brains immune cells its microglial cells promotes the spread of tangled tau proteins that comprise amyloid plaque.

Heather M. Snyder, Ph.D., Alzheimers Association vice president of medical and scientific relations, who was not involved in the study, explained the purpose of neuroinflammation to Medical News Today. The Alzheimers Association contributed funding to the research.

Inflammation has an important role in fighting off infection and other pathogens in the body, including in the brain and central nervous system, said Snyder. Microglia help clear debris (damaged neurons, infections) from the brain.

However, adds Dr. Snyder, a sustained inflammatory response, or a change from acute to chronic neuroinflammation, may contribute to the underlying biology of several neurodegenerative disorders.

Inflammation is not by itself associated with cognitive impairment, Dr. Pascoal told MNT. However, he said, when neuroinflammation converges with amyloid pathology, the interaction potentiates tau pathology. As a consequence, the coexistence of these three processes in the brain amyloid, neuroinflammation, and tau pathology determines cognitive deterioration.

While experiments using cultured cells and laboratory animals have previously implicated microglial activation in the spread of tau fibers, the new study is the first to document their relationship in living people.

The researchers used MRI and PET scans to study 130 people across the age and Alzheimers disease spectra, observing the presence and extent of microglial activation, amyloid plaque, and tau tangles.

Successfully controlling neuroinflammation as a means of treating Alzheimers disease remains a challenge. Dr. Pascoal told MNT: Several different anti-inflammatory drugs can potentially reduce neuroinflammation. However, some of them have already been tested in clinical trials aiming to mitigate cognitive decline but failed.

However, he suggested, the issue may be the timing of treatment.

Our study indicates these anti-inflammatory drugs would present optimal efficacy at a specific moment in the course of the disease when the patients have tau pathology confined to the medial temporal brain cortex, he says.

Thus, says Dr. Pascoal, our results suggest that the combination of anti-amyloid with anti-inflammatory therapies in the early stages of the disease, when the pathology of tau is still confined to the temporal cortex, would maximize the efficacy of these drugs.

Snyder noted, The Alzheimers Association, through its Part the Cloud initiative, is focused on accelerating findings from the laboratory, through trials, into possible therapies filling the gap in Alzheimers drug development by supporting early phase clinical studies.

She reported, Scientists around the world were invited to submit proposals that could translate into human trials of treatments targeting neuroinflammation, with the goal of improving cognition in individuals with neurodegenerative diseases. The initiative selected four projects.

For Dr. Pascoal, the research is personal, he tells UPMC:

As a young resident neurologist in my home country of Brazil, I noticed that many patients with Alzheimers disease are left neglected and without access to appropriate care.

The studys finding gives him hope for those people. He says, Our research suggests that combination therapy aimed to reduce amyloid plaque formation and limit neuroinflammation might be more effective than addressing each pathology individually.

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Alzheimer's: Is inflammation the key? - Medical News Today

Even with the plethora of studies that have occurred in the field, unanswered questions remain and until certain questions are answered, HCC remains a challenge for oncologists to treat.

We get new question every time we get new answers, so it's a never-ending process, Lujambio, an associate professor of Oncological Sciences and Medicine in Liver Disease at the Icahn School of medicine at Mount Sinai, told Targeted Oncology.

Building upon research around the molecular makeup of HCC, resistance mechanisms, and individualized options for treatment is ongoing in the field.

In an interview, Lujambio, discussed the diversity of genomic alterations in HCC and advanced in molecular testing that could shape future understanding of the disease.

TARGETED ONCOLOGY: Can you explain the diverse molecular makeup of HCC?

So, every tumor is very diverse and every tumor type, but HCC, it's in particular, very diverse if we compare it to other tumor types. That means that tumors from different patients have very different mutations, and very different combinations of mutations. The gene that is most frequently mutated is the promoter of a telomerase of TERT, which confers the cancer cells with unlimited replication potential. There are also other genes such as p53, and beta catenin, that are also frequently mutated. However, the way these genes are mutated, they are not mutated together, they are mutated in different patients. So, that makes it more difficult to treat, because right now, there are not selective therapies for HCC patients. All the patients receive the same treatment. There are different therapies, but there is not a way of selecting the best therapy for each patient.

The hope for the future is that we can identify which mutations confer sensitivity to a specific therapy, so that we compare each patient with each a specific therapy. And in addition to this great genetic heterogeneity that is present among the different HCC patients, something to consider is that HCC in most of the cases appears in a liver that has been damaged, and the way of damaging the liver can also be very diverse. So, that adds an additional layer of complexity to the problem because you can have 2 patients with maybe the same driver mutation, but 1 patient has a liver with hepatitis B and the other one has a liver with a non-alcoholic state of hepatitis. That is going to completely change how that patient responds to therapy. For an oncologist and their patients, this can be a very challenging disease.

From a pathologists perspective, how would you advise oncologists on how to order genetic testing for HCC?

I think the main idea in the whole liver cancer field is that we need to keep studying liver tumors as much as possible. One challenge with that is that patients with liver cancer, they are very sick, not only because they have cancer, but also because their liver is damaged. So, they receive a treatment, and in many cases, is not recommended that the treating physician takes a sample from the tumor so that it can be studied. So, it's tough to ask a patient that is in very bad shape to undergo a procedure that can represent a risk for their health. So ideally, we would like to study, like the genetic makeup of the tumors of every patient and how they respond to each therapy that that patient is receiving, so that we have a more complete picture. This is all very challenging because of this fact.

There are other strategies that people are developing such as liquid biopsies, which basically means that you can detect the mutations from the tumor cells in the blood of the patient. And it may offer a similar level of information in terms of choosing the best therapy. So, whenever possible, we need to study as much as we can, every single aspect of the tumors. And if that's not possible, then implementing liquid biopsies could be a great strategy as well. Then we need to combine basic and translational research, so that we come up with the best therapy options for each genetic alteration.

What are the unanswered questions in this field right now?

We get new question every time we get new answers, so it's a never-ending process. But a, 1 of the biggest questions is which therapy is appropriate for each patient? And even if there are challenges in trying to address that question, there are also advances. There was an interesting study this year, where they found out that those patients that have a liver associated with nonalcoholic steatohepatitis, those patients in general respond worse to monotherapy. So that was a great discovery this year, but then that begs the question of, what therapy should we use with those patients and definitely combining research with a mouse model with knowledge from patient samples again will be critical to address this question.

Another interesting question is the heterogeneity among different patients, which is critical, but also a liver tumor within a single patient, they can also be very diverse. So not all the tumor cells within a tumor are identical. That means that you may have some cells that respond to therapy, but or others that don't, and the tumor will develop resistance to the therapy. So that's going to be another important challenge and a question to address in the next few years. Luckily, now we have technologies based on single-cell analysis of either DNA or mRNA, or proteins that are going to enable us to study this a little bit more.

Another important research question in HCC is how tumor cells escape the immune system. Can you discuss your research in this area?

The immune system in is going to always try to attack the tumor, but the tumor is very smart and basically has different ways of hiding from the immune system. And there are many different ways of hiding. So, we have found that tumors that present genetic alteration, which is overexpression of NOTCH, which can be an oncogene in hepatocellular carcinoma, they are very good at hiding from the immune system. That makes the tumors with a NOTCH overexpression be resistant to immunotherapy. I keep coming and repeating the word in immunotherapy because this is one of the therapies that is most promising right now in HCC. So, we are trying to decipher the mechanism by which NOTCH on oncogene is inducing immune escape. So, we have found that there are the tumors that have a lower ability to attract T cells, which are cells of the immune system that can recognize specifically the tumor cells and a basically kill them. There is a definitely a defect in the ability of those cells to recreate the immune T cells, but also we are seeing that those T cells that actually managed to get to the tumor, they are not able to kill the tumor cells.

If we are successful with our research, which is conducted mainly in models, and we find a similar mechanism in HCC patients, then that the therapies that we are testing in models could be a used in patients. That's the ultimate goal.

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Studying the Tumor Microenvironment of Hepatocellular Carcinoma - Targeted Oncology