"We are excited to have reached this important milestone in the clinical evaluation of INXN-4001 for treatment of end-stage heart failure," stated Amit Patel, MD, MS, Co-Founder and Medical Director of TripleGene. "Heart failure rarely results from a single genetic defect, and while single gene therapy approaches have been studied, these treatments may not fully address the causes of the disease. Our unique multigenic approach is designed to stimulate biological activity targeting multiple points in the disease progression pathway."

Triple-Gene's investigational therapy uses non-viral delivery of a constitutively expressed multigenic plasmid designed to express human S100A1, SDF-1, and VEGF165 gene products, which affect progenitor cell recruitment, angiogenesis, and calcium handling, respectively, and target the underlying molecular mechanisms of pathological myocardial remodeling. The plasmid therapy is delivered via RCSI which allows for cardiac-specific delivery to the ventricle.

"Heart failure is the leading cause of death worldwide and represents a significant and growing global health problem. Aside from heart transplant and LVAD, current treatment options for those patients with end-stage disease are limited," commented Timothy Henry, MD, FACC, MSCAI, Medical Director of the Carl and Edyth Lindner Center for Research and Education at The Christ Hospital and a member of the Triple-Gene Medical Advisory Board. "The INXN4001 investigational therapy represents a biologically-based method focused on repairing the multiple malfunctions of cardiomyocytes, and I look forward to seeing the results of this initial safety study and further exploring the promise of this innovative treatment approach."

Triple-Gene will present preliminary data from the Phase 1 study at theAmerican Heart Association Scientific Sessionsat the Pennsylvania Convention Center in Philadelphia. A poster titled "Safety of First in Human Triple-Gene Therapy Candidate for Heart Failure Patients" will be presented on Sunday, November 17thfrom 3:00 pm - 3:30 pm ETin Zone 4 of the Science and Technology Hall.

About the Phase 1 Trial of INXN-4001INXN-4001 is being evaluated in a Phase I open label study in adult patients with implanted Left Ventricular Assist Device (LVAD). The study is designed to investigate the safety and feasibility of supplemental cardiac expression of S100A1, SDF-1 and VEGF-165 from a single, multigenic plasmid delivered via Retrograde Coronary Sinus Infusion (RCSI) in stable patients implanted with a LVAD for mechanical support of end-stage heart failure. Twelve stable patients with an implanted LVAD were allocated into 2 cohorts (6 subjects each) to evaluate the safety and feasibility of infusing 80mg of INXN4001 in either a 40mL (Cohort 1) or 80mL (Cohort 2) volume. The primary endpoint of safety and feasibility is assessed at the 6-month endpoint. Daily activity data are also collected throughout the study using a wearable biosensor. Dosing on both Cohorts 1 and 2 has been completed, and patients continue follow-up per protocol.

About Triple-GeneTriple-Gene LLC is a clinical stage gene therapy company focused on advancing targeted, controllable, and multigenic gene therapies for the treatment of complex cardiovascular diseases. The Company's lead product is a non-viral investigational gene therapy candidate that drives expression of three candidate effector genes involved in heart failure. Triple-Gene is a majority owned subsidiary ofIntrexon Corporation(NASDAQ: XON) co-founded by Amit Patel, MD, MS, and Thomas D. Reed, PhD, Founder and Chief Science Officer of Intrexon. Learn more about Triple-Gene atwww.3GTx.com.

About Intrexon CorporationIntrexon Corporation (NASDAQ: XON) is Powering the Bioindustrial Revolution with Better DNAto create biologically-based products that improve the quality of life and the health of the planet through two operating units Intrexon Health and Intrexon Bioengineering. Intrexon Health is focused on addressing unmet medical needs through a diverse spectrum of therapeutic modalities, including gene and cell therapies, microbial bioproduction, and regenerative medicine. Intrexon Bioengineering seeks to address global challenges across food, agriculture, environmental, energy, and industrial fields by advancing biologically engineered solutions to improve sustainability and efficiency. Our integrated technology suite provides industrial-scale design and development of complex biological systems delivering unprecedented control, quality, function, and performance of living cells. We call our synthetic biology approach Better DNA, and we invite you to discover more atwww.dna.comor follow us on Twitter at@Intrexon, onFacebook, andLinkedIn.

TrademarksIntrexon, Powering the Bioindustrial Revolution with Better DNA,and Better DNA are trademarks of Intrexon and/or its affiliates. Other names may be trademarks of their respective owners.

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Triple-Gene Announces Completion of Enrollment and Dosing in Phase 1 Trial of INXN4001, First Multigenic Investigational Therapeutic Candidate for...

GENES are the building blocks of life but like all things, they can sometimes go wrong, resulting in a range of conditions and diseases.

Repairing or replacing these genes with good ones, however, could solve or at the very least treat the problem, and this is what the emerging science of gene therapy is all about.

It was first suggested in the early-1970s that using good DNA (genes are short sections of DNA) to replace defective DNA could treat inherited diseases, and since then scientists have been trying to work out how to do it, both for inherited conditions and many others.

The British Society for Gene and Cell Therapy (bsgct.org) says the first approved human gene therapy took place in 1990, on four-year-old Ashanti DeSilva who had ADA-SCID an inherited disease that prevents normal development of the immune system. The therapy made a huge difference, meaning the little girl no longer needed to be kept in isolation and could go to school.

When the human genome was mapped nearly 20 years ago, the notion that it could potentially unlock therapies capable of fixing genes responsible for some of the worlds most devastating diseases was an idea of the future, says gene therapy expert Professor Bobby Gaspar, speaking on behalf of Jeans for Genes Day, the annual campaign for Genetic Disorders UK (geneticdisordersuk.org).

We are at the forefront of a new era of treatment for genetic diseases using gene and cell therapies. Some of these are one-time, potentially curative investigational therapies that could provide life-changing benefits to patients and their families.

Gaspar says there are currently more than 10 cell and gene therapy products approved in the European Union, ranging from products that treat cancer to rare immune deficiencies. A number of these are approved in the UK and available on its National Health Service in specialised centres.

And with nearly 3,000 clinical gene therapy trials underway worldwide, the number of available treatments is expected to grow significantly over the next few years.

Here, Gaspar a professor of paediatrics and immunology at the UCL Great Ormond Street Institute of Child Health and chief scientific officer at Orchard Therapeutics, a gene therapy company that seeks to permanently correct rare, often-fatal diseases outlines five of the ways gene therapy can cure, stop, or slow a disease...

A variety of efforts are underway to use gene therapy to treat cancer. Some types of gene therapy aim to boost the bodys immune cells to attack cancer cells, while others are designed to attack the cancer cells directly.

One way the body protects itself from cancer is through T-cells, a main component of the immune system. But some cancers are good at avoiding these protection mechanisms, says Gaspar.

Chimeric antigen receptor, or CAR T-cell therapy, is a new form of immunotherapy that uses specially altered T-cells to more specifically target cancer cells.

Some of the patients T-cells are collected from their blood, then genetically modified to produce special CAR proteins on the surface.

When these CAR T-cells are reinfused into the patient, the new receptors help the T-cells identify and attack cancer cells specifically and kill them.

There are more than 250 genetic mutations that can lead to a type of blindness called inherited retinal diseases, or IRD. People with a defect in the RPE65 gene start losing their vision in childhood.

As the disease progresses, patients experience gradual loss of peripheral and central vision, which can eventually lead to blindness.

Gene therapy for some IRD patients became available in 2017, delivering a normal copy of the RPE65 gene directly to the retinal cells at the back of the eye using a naturally-occurring virus as a delivery vehicle.

For children with the genetic disorder spinal muscular atrophy, or SMA, a rare muscular dystrophy, motor nerve cells in the spinal cord are damaged, causing patients to lose muscle strength and the ability to walk, eat or even breathe, says Gaspar.

SMA is caused by a mutation in a gene called SMN which is critical to the function of the nerves that control muscle movement. Without this gene, those nerve cells cant properly function and eventually die, leading to debilitating and often fatal muscle weakness.

Researchers recently developed the first US-approved gene therapy to treat children less than two years of age with SMA.

The therapy is designed to target the cause of SMA by replacing the missing or nonworking gene with a new, working copy of a human SMN gene, helping motor neuron cells work properly.

Researchers believe targeted gene therapy and gene editing may have widespread application for a range of infectious diseases that arent amenable to standard clinical management, including HIV.

Although HIV isnt a hereditary disease, the virus does live and replicate in DNA, Gaspar explains.

Another early but encouraging approach uses a gene editing technology combined with a new long-acting, antiretroviral treatment to suppress HIV replication and eliminate HIV from cells and organs of infected animals.

Gene editing is an approach that precisely and efficiently modifies the DNA within a cell. In this approach, gene editing can knock out a receptor called CCR5 on immune cells used by HIV to enter and invade cells. Without CCR5, HIV may no longer invade and cause disease.

One approach being investigated for a number of rare, often-fatal diseases uses gene-modified blood stem cells with a goal of permanently correcting the underlying cause of disease.

Blood stem cells are taken from the patient, and corrected outside the body by introducing a working copy of the gene into the cells. The gene-corrected cells are then put back into the patient to potentially cure the disease.

Gene-modified blood stem cells have the capacity to self-renew and, once taken up in the bone marrow, can potentially provide a lifelong supply of corrected cells. Because of their ability to become many different types of cells in the body, this approach has the potential to provide a lasting treatment for many different severe and often life-limiting inherited disorders, many of which have no approved treatment options available, says Gaspar.

For instance, ADA-SCID, sometimes referred to as bubble baby syndrome, is a disease where babies lack almost all immune protection, leading to frequent and devastating infections. Left untreated, babies rarely live past two years of age. Standard treatment options are not always effective or can carry significant risks. In 2016, the European Medicines Agency approved Strimvelis, a blood stem cell gene therapy for the treatment of ADA-SCID. Strimvelis was the first approved ex vivo gene therapy product in Europe.

Jeans for Genes Day helped fund some of the earliest work using this type of gene therapy at Great Ormond Street Hospital in 2002, when Rhys Evans, a little boy with SCID, became one of the first children worldwide to be treated by gene therapy.

Jeans for Genes Day aims to raise money for children with life-altering genetic disorders by asking people to donate money for wearing jeans to work, school or wherever they like, on any day between September 16-20. Visit jeansforgenesday.org.

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Five benefits of gene therapies - Echo Live

How will Cell and Gene Therapy Usher in a New Industrial Revolution?

Cell and gene therapy companies are on the verge of transforming how we treat unmet medical needs such as cancer, rare diseases, genetic disorders and diabetes, to name only a few. By using a patients own cells and genes to fight disease, cell and gene therapy treatments deliver highly-targeted therapies and cures for unserved and underserved patients in need of solutions to a wide variety of intractable diseases.

What was once relegated to science fictionlike the miniaturized heroes sent into a human body in the Fantastic Voyage sci-fi movie of 1966has, to a large degree, become reality with modified cells being put into patients to act as virtual bots capable of clearing diseaseseven cancersfrom the body. New technologies are empowering science to do what would never have been thought possible years ago.

Understanding the complexities of how these novel personalized medicines actually work can be daunting and confusing for many people, especially for the patients who are in need of these new medicines and those who are non-scientific minded.

Jeff Galvin, CEO of American Gene Technologies (AGT), has helped a wide variety of audiences understand this new technology by explaining the similarities between the human cell and an organic computer. He explains that DNA is the operating system of the human cell. It contains commands for the cellular machinery called genes, which are coded in four symbols: A, G, T, and C (for the nucleotides adenine, guanine, thymine, and cytosine). The order of these nucleotides determines the instruction that a gene provides to the machine just like the order of 1s and 0s in your personal computer or cell phone determine the commands to be executed by the device. Galvin coined this human computer analogy to describe the work that his company is doing and what is actually taking place with cell and gene therapies to make new solutions for formerly unaddressable human diseases.

Galvin describes gene and cell therapy as the software revolution for the next 100 years: reprogramming DNA in cells to improve health. Scientists have long understood that viruses infect cells and hijack them with new instructions (viral DNA) to cause disease. Over the last few decades, methods have been developed to crack open viruses, scoop out their bad instructions that make cells sick, and replace them with new good instructions that improve the operation of the cell. In a way, the gene and cell therapy industry is hijacking the hijacker, says Galvin. We are taking viruses and converting them to updates to fix bugs or improve the operating system (DNA) of human cells. Just like viruses and updates on your computer work. The possibilities are endless. We can use these updates to repair a broken gene that is the root cause of a disease, insert new instructions into cells to improve their operation allowing them to do their jobs better, clear or protect the body from disease, or even change the operation of cells to make them little bots that can carry out functions that they would not normally do in your body, like clearing cancer. All of these things are within the scope of reprogramming the human computer.

American Gene Technologies (AGT), a biotech company located in Rockville, Maryland, is a company where Silicon Valley tech innovation and the human computer mindset is converging to rethink the approach to developing medicine.

AGTs CEO Jeff Galvin has shared that he and other cell and gene therapy leaders are on a mission to reprogram the human computer to save lives and improve outcomes for patients fighting infectious diseases, monogenic disorders, cancer and other devastating illnesses.

A serial tech innovator, Galvin made his mark as a Silicon Valley entrepreneur. He retired in his early 40s in 2002. His retirement was short-lived. When Galvin discovered the groundbreaking viral vector work of the National Institute of Healths (NIH) Dr. Roscoe Brady, he exited retirement to do what he always does: Vigorously pursue what he loves.

Galvin leapt out of retirementin 2007 to start AGT, and to continue developing Bradys technology.

I was very lucky to meet Roscoe Brady. When he showed me viral vectors and I realized we now had the ability to modify DNA with viruses, I immediately felt that this is the future of pharmaceuticals, stated Galvin. I could see the inherent power in this approach and how viral vectors could bring opportunities to new biotech companies to cure diseases that were formerly untreatable or incurable.

Bradys commitment to solving diseases and improving lives was also infectious. Dr. Brady was retiring, and it looked like this brilliant work was going to be shelved. explains Galvin. I saw it as too valuable and potentially world-changing to ignore. Dr. Brady agreed to stay on as a scientific advisor and I founded AGT with the mission to find the most efficient, effective, and fastest ways to bring this cutting edge technology to patients in need.

A lot of what I imagined as a computer programmer and software/IT specialist coming from the West Coast is actually coming true for this technology. This vision has fortunately attracted a lot of great scientists to our company and they are doing all of the rocket science. The concept is correct: We can use viral vectors to hijack the viruses that have been hijacking our cells for 1.5 billion years, using the inherent ability of viruses to infect cells and carry malevolent genetic code to deliver benevolent code instead,. Galvin stated.

What I am witnessing in our part of this industry is that high tech has come to drug development. The capabilities of everything we are doing is doubling every yearits like the computer revolution; every year youre getting more power while the price of the technology is going down, so youre getting exponential growth in power and value, Galvin commented.

Our approach is a major shift from old-style drug development, which relies on the random generation of thousands or tens of thousands of molecules. And then you try to screen them down via a cell model that gives you the effect youre looking for. And generally after two years and $10 million of investment, you have a few (drug programs) you can test in a mouse, and then one in 19 get into the clinic, stated Galvin.

What were doing at AGT and in the cell and gene therapy field is just different. Gene and cell therapy is about directed development. You can create highly targeted drugs that hit a specific cellular pathway and you can even narrow that down using specific promoters or chimeric envelopes so you can direct that drug to a certain cell type or even to a certain disease indicator, stated Galvin. By narrowing the drug to the particular tissue or particular disease indicator you are sparing all the healthy tissue, which is the main reason drugs drop out of clinical development, the side effects. Gene and cell therapy largely avoids this issue.

We can test some of these in cell models at the bench, then in animal models and be able to get to a go-no-go decision after $100K in investment. We might be able to characterize it so well at the bench that the clinical development becomes highly predictable. This turned out to be true with our HIV therapy, stated Galvin.

Galvin believes that AGTs cell and gene therapy platform will help contributeas part of a wider cell and gene therapy revolutionto the eradication of the $2 to $4 trillion in palliative care treatment costs replaced with one-and-done cures. Viral-vector based drug development platforms like the one AGT deploys will help find new gene and cell therapy treatments and cures for the approximately 7,000 rare diseases that impact approximately one in ten people across the globe.

The future of drug development, in my mind, is that the toolset will keep evolving like computers and software. Software developers used creativity to leverage a limited toolset to create value in the market. At AGT, were thinking about correcting DNA to improve human health and mitigate disease. Everything about technology is playing in our favor. If you were in computers a while ago and you saw mainframes turn into mini-computers and then micro computers you would have said, Eventually we will have these things in our pocket and you would have been right. The same is now true about drug development, stated Galvin, Nearly anything will be possible in the future as this technology continues to exponentially improve. In this high-tech revolution of gene and cell therapy, if you can dream it, you will eventually be able to do it!

AGT is part of an evolving, growing and groundbreaking cell and gene therapy cluster thriving in the BioHealth Capital Region.

Maryland is at the epicenter of the gene and cell therapy technological explosion Its all about the resources. They are starting to hit a critical mass here, added Galvin.

Steve has over 20 years experience in copywriting, developing brand messaging and creating marketing strategies across a wide range of industries, including the biopharmaceutical, senior living, commercial real estate, IT and renewable energy sectors, among others. He is currently the Principal/Owner of StoryCore, a Frederick, Maryland-based content creation and execution consultancy focused on telling the unique stories of Maryland organizations.

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Reprogramming the Human Computer: Silicon Valley Meets Cell and Gene Therapy - BioBuzz

DURHAM Precision BioSciences, a genome-editing company based in Durham, has received authorization from the U.S. Food and Drug Administrationto advance its second genome-edited cancer therapy to clinical trials.

The FDA has accepted Precisions Investigational New Drug application for PBCAR20A to treat non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CCL), and small lymphocytic lymphoma (SSL).

Precisions technology is part of a new approach to fighting cancer using T cells a type of immune system cell that recognizes invading germs or cancer cells. T cells are engineered to carry a cancer bullet called a tumor-targetingchimericantigenreceptor (CAR). These engineered cells have the potential to save the lives of many patients unresponsive to traditional chemotherapy and radiation regimens.

Precision Biosciences

Autologous CAR T therapies currently on the market rely on patient-derived T cells, which are extracted and individually manufactured for each patient using that patients own cells. They require a complex and lengthy process.

Precisions allogeneic CAR T product candidates use T cells derived from qualified donors. The T cells are manufactured in large batches and are cryopreserved (safely preserved, intact, at extremely low temperatures) for shipment, storage and off-the-shelf use.

These allogeneic CAR T product candidates rely on Precisions ARCUS genome-editing platform to remove the T cell receptor to prevent graft versus host disease without the need for donor-patient matching. ARCUS editing also enables targeted insertion of the CAR gene into a single, specific location in the T cell genome for more controlled, consistent expression.

Pfizers 300 new jobs, $500M investment symbolize Triangles growth as gene therapy hub

The company said it will begin a Phase1/2a clinical trial later this year in non-Hodgkin lymphoma patients, including a subset of patients with a cancer called mantle cell lymphoma, for which Precision has received the FDAs Orphan Drug designation.

PBCAR20A is Precisions second off-the-shelf cell therapy. The company is also studying the precursor to PBCAR20A PBCAR0191 in adult patients who are not responding to other therapies. Technically, these are designated as patients with relapsed or refractory (R/R) NHL or R/R B-cell precursor acute lymphoblastic leukemia (B-ALL).

Both of Precisions treatments use the companys ARCUS genome editing technology to produce CAR T cells derived from healthy donors, rather than relying on cancer patients own blood. The development of these allogeneic CAR Ts is designed to overcome the manufacturing limitations of traditional autologous CAR T therapies, to target a broader range of malignancies, and to increase the number of patients who can potentially benefit.

FDA clearance to begin clinical trials with our anti-CD20 off-the-shelf therapy candidate is a significant milestone for Precision, said Matt Kane, the companys CEO and co-founder. Todays announcement demonstrates our ability to advance multiple product candidates in parallel into the clinic, leveraging the unique capabilities of our ARCUS genome editing platform, CAR T development approach and highly differentiated manufacturing process developed in-house.

Precision uses ARCUS to remove T cell receptors to prevent graft versus host disease, thus avoiding the need for donor-patient matching that is required in traditional tissue donation procedures. And the ARCUS technology also provides for the targeted insertion of the CAR gene into a single, specific location in the T cell genome for controlled, consistent expression. Precisions product candidates can be made in advance, manufactured in large batches and then cryopreserved for shipment, storage and off-the-shelf use.

AskBio gets $235 million in gene therapy support

PBCAR20A, if approved, will fill an important gap in current cancer treatments. In the United States, B-cell malignancies account for 85 percent of all non-Hodgkin lymphoma. And CLL and SLL represent 25 to 30 percent of leukemia cases. Precision said that, while front-line treatments benefit more than half of newly diagnosed NHL patients, at least a third of those achieve only partial remission or relapse after remission.And patients with CLL have limited success with autologous CAR T therapies. An allogeneic CAR T like PBCAR20A may overcome treatment resistance and offer the possibility of combination treatments.

It is our hope that PBCAR20A will provide a new allogeneic CAR T therapy option with the benefits of reliable, off-the-shelf access and optimized cellular activity to patients living with NHL or CLL/SLL, where a significant need for new treatment options remains, said David Thomson, Precisions chief development officer.

Precision Biosciences is a 2006 Duke University spin-out dedicated to improving life by using its ARCUS gene editing technology to treat human diseases and create healthy and sustainable food and agriculture solutions.

In 2018 the company created a new name and brand identity for its food and agriculture business,Elo Life Systems. The business is using Precisions ARCUS platform and other new technologies for applications in crop improvement, animal genetics, industrial biotechnology and sustainable agriculture.

(C) N.C. Biotech Center

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FDA approves 2nd gene therapy cancer drug from Durham's Precision Bio for clinical trial - WRAL Tech Wire

Kari Branham, M.S., a genetic counselor at Kellogg, worked with Zions family to help them understand the genetic basis for Zions condition.

SEE ALSO: Retinitis Pigmentosa in Children: 5 Facts Families Should Know

We have seen such amazing progress with these conditions over the last 15-20 years,says Branham. We used to tell patients and their families that we would have to wait and see what happens, but now we can actually do something to help.

By going through the gene therapy process, Branham says the team is hopeful that this has changed Zions prognosis.

The treatment is designed to stop or slow the death of specialized cells in the retina, called photoreceptors, that send visual information to the brain.

Patients who have Leber congenital amaurosis have night blindness, says Besirli. One of the first treatment effects after receiving Luxturna is that (patients) are telling us that they function much better in dark.

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They can play outside much longer, they can navigate around the house and dont need nightlights anymore and can participate in indoor sports. Thats been a huge change in their lives.

Seven months after treatment, Zion, now age 7, and his family are back to their normal routine in Montrose, Mich., and monitor his progress during follow-up appointments at Kellogg.

Zion says hes looking forward to playing football and, with improved vision -- playing outside at night with his brothers.

We hope that with Zion we have changed the trajectory for him to the point that in his 20s he wont have significant vision loss we see with him now, says Branham.

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7-Year-Old Receives New FDA-Approved Retina Gene Therapy - University of Michigan Health System News

The first patient in a Phase 1/2 clinical trial of Fabry disease gene therapy candidate FLT190 has been dosed.

Enrollment is ongoing at the Royal Free Hospital, in London, U.K. More information and contacts are available here.

Fabry disease iscausedby a faulty GLAgene, which provides instructions to make an enzyme called alpha-galactosidase A (alpha-GAL A). When mutated, this gene leads to abnormal alpha-GAL A function, which results in the build-up of lipids (fatty molecules) known as globotriaosylceramide (Gb3) and globotriaosylsphingosine (LysoGb3) that can damage the heart, kidneys, or liver.

Freelines FLT190 is a gene therapy that uses an adeno-associated virus (AAV8) a harmless virus that does not cause disease or infection as a vehicle to deliver a healthy copy of the GLAgene in the hopes it will induce the production of normal alpha-GAL A. In contrast to the regular infusions of enzyme replacement therapy (ERT), this gene therapy is designed to be given in a single dose.

The international, multi-center MARVEL1 study (NCT04040049) will primarily study the safety of FLT190 in up to 12 adult male patients with classic (type 1) Fabry disease, as well as whether it results in continuous production of high levels of alpha-GAL A. Other goals include clearance of Gb3 and LysoGb3, alterations in kidney and skin biopsies, renal and cardiac function, assessing immune responses, and quality of life.

After taking FLT190 via slow intravenous infusion, participants will be monitored for nine months at outpatient visits, and then enter a long-term follow-up period. Both previously and untreated patients will be included, although in two separate parts dose escalation and dose expansion.

MARVEL1 is the first trial of an AAV-based gene therapy for Fabry disease, according to the company. The trial is estimated to end by March 2021.

The initiation of this clinical study is an important event for the patient community. I am hopeful that the promising preclinical data will translate into long term benefit for patients with Fabry [disease], Derralynn Hughes, MD, PhD, said in a press release. Hughes isa Fabry disease expert and senior lecturer at Royal Free Hospital.

Preclinical results in a mouse model of the disease revealed that a single injection of FLT190 into the blood led to a sustained increase of more than 1,000-fold in alpha-Gal A levels, compared to healthy mice. The levels of Gb3 were reduced markedly in the kidney, spleen and heart, as were those of LysoGb3, which have been suggested as anaccurate biomarker to diagnose and track Fabry disease. No adverse side effects were found.

Chris Hollowood, Freelines executive chairman, said that starting MARVEL1 and dosing the first patient is a significant milestone for the company.Continuous high expression of [alpha-GAL A] holds the potential for better treatment outcomes than is seen with ERT, the current standard of care. We believe we can access high expression at relatively low doses.

Besides Fabry disease, Freeline also is testing its AAV technology in hemophilia B, in which a Phase 2/3 trial (NCT03641703) is evaluating whether the potential gene therapy FLT180a is safe and provides long-term production of the clotting protein missing in these patients (factor IX).

These innovative gene therapies have the potential to change patients lives, Hollowood said.

Jos is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimers disease.

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First Patient Dosed in Trial of Fabry Gene Therapy Candidate FLT190 - Fabry Disease News

Last year, Bluebird Bio claimed anFDA breakthrough designation for its Lenti-D gene therapy for cerebral adrenoleukodystrophy (CALD) it has now revealed additional data to support a fast-track approval.

The updated results from the biotechs phase 2/3 Starbeam study were revealed at the European Paediatric Neurology Society (EPNS) congress in Athens, Greece.

CALD is caused by progressive destruction of the myelin sheath that surrounds nerves responsible for thinking and muscle control, resulting in a relentless deterioration that typically leads to a vegetative state or death within a few years of diagnosis. The condition mostly affects young males, with the majority of patients dying before the age of ten.

The only current treatment for the disease is stem cell transplant, but it carries a significant risk from the high-dose chemotherapy used to prepare patients for the procedure. Other potential complications include graft-versus-host (GvHD) disease, when the transplanted cells recognise the recipients cells as foreign and attack them.

Bluebird's treatment works by extracting patients' stem cells and modifying them with Lenti-D. They are then infused back into the patient, where they thenhave the potential to develop into multiple cell types that can produce a functional version of the ALD protein that is lacking in CALD.

Of the patient population involved in the study, as of 25 April 2019, 15 had completed the trial and are enrolled in a long-term follow-up study, 14 are currently still on-study, and three are no longer on-study.

The primary efficacy endpoint of the study is the number of patients who are alive and free of MFDs at month 24 MFDS are the six severe disabilities commonly attributed to CALD, which have the most severe effect on a patients ability to function independently.

The study demonstrated that of those patients who have or would reach 24 months of followup and complete the study, 88% continue to be MFD-free and alive. The 14 patients currently on study have less than 24 months of follow-up and have so far shown no evidence of MFDs.

Out of the 32 treated patients, three did not or will not meet the primary efficacy endpoint, two patients withdrew from the study and one experienced rapid disease progression early, which lead to MFDs and death.

The primary safety endpoint the number of patients experiencing GvHD by month 24 was also met. According to Bluebird, no events of acute or chronic GvHD were reported posttreatment and there were no reports of graft failure, cases of insertional oncogenesis or replication competent lentivirus. There were three adverse events potentially related to treatment of Lenti-D, but these resolved using standard measures.

Lenti-D is Bluebirds lead gene therapy programme,but the company has also made significant progress with its Celgene-partnered CAR-T cancer immunotherapy programme, reporting dramatic responses with its multiple myeloma candidatebb2121 last December.

It also received approval for its gene therapy Zynteglo earlier this year. The one-time gene therapy has been approved for patients 12 years and older with transfusion-dependent -thalassaemia (TDT), and has been shown in a series of small studies to free a majority of patients from the need to have regular blood transfusions.

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Bluebird bio reveals further encouraging data for CALD gene therapy - PMLiVE

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Newswise The Childrens Cancer Institute at the Joseph M. Sanzari Childrens Hospital at Hackensack Meridian Health Hackensack University Medical Center and the John Theurer Cancer Center have announced they are participating in a multicenter Phase I/II clinical trial of an investigational gene therapy from bluebird bio, Inc. This trial is specifically for adolescents and adults with severe sickle cell disease (SCD) who cannot be effectively treated using standard therapies such as antibiotics, vitamins, blood transfusions or any pain relieving medications. The study is evaluating the safety and effectiveness of LentiGlobin for sickle cell disease, a gene therapy produced using the patients own modified stem cells to treat their sickle cell disease.

By using the patients own cells to produce functional hemoglobin that can prevent sickling of their red blood cells, LentiGlobin for SCD offers patients the opportunity to treat their disease without the need to have a matched bone marrow donor. The John Theurer Cancer Center is one of a limited number of centers internationally, and the Joseph M. Sanzari Childrens Hospital is the only pediatric site in New Jersey, where the study, which is enrolling patients age 12-50, is taking place.

Sickle cell affects 100,000 Americans. It affects one in every 365 African American births and one in every 16,000 Hispanic American births, said Alfred P. Gillio, M.D., director, Childrens Cancer Institute and section chief, Pediatric Stem Cell Transplantation and Cellular Therapy Program, Joseph M. Sanzari Childrens Hospital at Hackensack University Medical Center. This trial is for patients who have severe sickle cell disease and seek advanced treatment options but do not have a well-matched stem cell donor. Only 15% of sickle cell patients have a matched sibling donor and only 25 percent of patients have a matched unrelated volunteer donor.

Sickle cell affects every organ in a patients body, said Stacey Rifkin-Zenenberg, D.O., FAAP, pediatric hematologist/oncologist, Childrens Cancer Institute, and section chief, Pain and Palliative Care, Joseph M. Sanzari Childrens Hospital at Hackensack University Medical Center. This disease really has a tremendous effect not only on the patient, but also the family.

Sickle cell disease is an inherited disease caused by a mutation in the beta-globin gene, resulting in abnormal hemoglobin and sickle-shaped red blood cells. Symptoms and complications of the disease include anemia, infections, stroke, poor quality of life and early death. To date, the only cure for sickle cell disease is receiving a stem cell transplant from a matched donor, but this is not a therapeutic option for many patients. Supportive care including hydroxyurea and blood transfusions can ameliorate symptoms of the disease. To date, without a marrow donor, there has been no alternate curative therapy. Life expectancy of a person with sickle cell disease is 20 to 40 years of age. In some cases, patients using disease modifying medications can live to 50 or 60.

This therapy may be a major advance for sickle cell patients and so far, the results look very promising, said Scott D. Rowley, M.D., FACP, hematologist, medical director, Stem Cell Transplantation and Cellular Therapy and medical director, BMT Cell Lab, John Theurer Cancer Center, Hackensack Meridian Health Hackensack University Medical Center, who is enrolling adult patients. This investigational treatment, which is a one-time therapy, may be an option for our patients who have no other treatment options.

The results from early clinical studies are encouraging, said Dr. Gillio. With this treatment, the patient is their own donor and we are modifying their own cells to add copies of a functional beta globin gene.

In the current study:

About Hackensack Meridian Health Hackensack University Medical Center

Hackensack Meridian Health Hackensack University Medical Center, a 781-bed nonprofit teaching and research hospital located in Bergen County, NJ, is the largest provider of inpatient and outpatient services in the state. Founded in 1888 as the countys first hospital, it is now part of the largest, most comprehensive and truly integrated health care network in New Jersey, offering a complete range of medical services, innovative research and life-enhancing care, which is comprised of 34,100 team members and more than 6,500 physicians. Hackensack University Medical Center is ranked #2 in New Jersey and #59 in the country in U.S. News & World Reports 2019-20 Best Hospital rankings and is ranked high-performing in the U.S. in colon cancer surgery,lung cancersurgery,COPD, heart failure, heart bypass surgery, aortic valve surgery,abdominal aortic aneurysm repair, knee replacement and hip replacement. Out of 4,500 hospitals evaluated, Hackensack is one of only 57 that received a top rating in all nine procedures and conditions. Hackensack University Medical Center is one of only five major academic medical centers in the nation to receive Healthgrades Americas 50 Best Hospitals Award for five or more years in a row. Beckers Hospital Review recognized Hackensack University Medical Center as one of the 100 Great Hospitals in America 2018. The medical center is one of the top 25 green hospitals in the country according to Practice Greenhealth, and received 26 Gold Seals of Approval by The Joint Commission more than any other hospital in the country. It was the first hospital in New Jersey and second in the nation to become a Magnet recognized hospital for nursing excellence; receiving its sixth consecutive designation in 2019. Hackensack University Medical Center has created an entire campus of award-winning care, including: John Theurer Cancer Center, a consortium member of the NCI-designated Georgetown Lombardi Comprehensive Cancer Center; the Heart & Vascular Hospital; and the Sarkis and Siran Gabrellian Womens and Childrens Pavilion, which houses the Joseph M. Sanzari Childrens Hospital and Donna A. Sanzari Womens Hospital, which was designed with The Deirdre Imus Environmental Health Center and listed on the Green Guides list of Top 10 Green Hospitals in the U.S. Hackensack University Medical Center is the Hometown Hospital of the New York Giants and the New York Red Bulls and is Official Medical Services Provider to THE NORTHERN TRUST PGA Golf Tournament. It remains committed to its community through fundraising and community events especially the Tackle Kids Cancer Campaign providing much needed research at the Childrens Cancer Institute housed at the Joseph M. Sanzari Childrens Hospital. To learn more, visit http://www.HackensackUMC.org.

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Joseph M. Sanzari Childrens Hospital and John Theurer Cancer Center Launch Clinical Trial Evaluating Gene Therapy for Severe Sickle Cell Disease in...

Tara Moore, a professor of personalised medicine at Ulster University, is working on a project that aims to develop a gene therapy treatment for corneal dystrophy.

The research, which Professor Moore discussed at a Four Liveries guest lecture for the Worshipful Company of Spectacle Makers at Painters Hall in London last week (12 September), is a collaboration between the Ulster University and Avellino Labs in the US.

Speaking to OT, Professor Moore explained: It is a new era of medicine where its much more personalised. Its not one-drug-fits-all or one therapy fits everyone. Its much more personalised to the person and to the exact reason that they have the disease they have.

The exact genetic mistake or mutation that causes [a persons] particular disease can be targeted now very specifically. We are now equipped with a way to target that DNA that we never thought would be possible, Professor Moore said.

Professor Moore and her team are applying CRISPR technologies to the eyes, specifically the front of the eye she explained. It is difficult to deliver to. But if we can overcome that battle, we can hopefully have a gene therapy that will be successful, she shared.

When discussing the future for the treatment, Professor Moore told OT: I would like to think we would end up at a stage in personalised medicine where everyone would be pre-screened for whatever mutations that they contain that predispose them to a particular disease and we could treat people.

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Personalised medicine: developing gene therapies - AOP

To a trained eye, the chromosome chart (karyotype) above has 4 irregularities, circled in red. Theyre chromosome pairs of uneven size.

The chromosomes represent genetic material missing or extra, but also a beautiful girl. Her father contacted me after he read my recent post about a friends child with a rare mutation in a single gene, a more typical driver of so-called diagnostic odysseys. Did I have any insight on treatments for his daughter? Hed send her lab reports.

The notations were in Hebrew, but the universal language of chromosome charts spoke clearly to me. The chromosome pairs are size-ordered, its members matching, but pairs 9, 14, 15, and 16 look like tall and short dance partners. This was something more profound than a single gene glitch, or even a missing or extra chromosome.

Shattered and Scattered

Aviya has an exceedingly rare condition called chromothripsis, which is Greek for shattered colored bodies. Breaks that sever both strands of the DNA double helix riddle one or more chromosomes. Lost pieces may have been ejected and glommed onto other chromosomes at or before fertilization, creating the karyotype that veers from the neat, normal, 23-pair organization.

Chromothripsis is best studied in cancer cells, where the genome is shot to smithereens, but only a few dozen people in the world are known to have it in all their cells. When the medical team at Schneider Childrens Medical Center in Israel discovered the childs condition, they told the parents that only 30 cases had been reported in the medical literature. Ever.

For some of the cases, researchers deduced how chromosomes broke long ago, in developing eggs. Since human eggs sit in an ovary for dozens of years before they mature at the moment of fertilization, enough time elapsed for natural DNA repair to fix some of the breaks and fill in small deletions.

In the few cases of fetuses surviving chromothripsis, enough of the genome must have been knit back together, even if in the wrong places, to sustain development and life. Sperm mature much too quickly, over a few months, to heal themselves in this way.

So a person with chromothripsis is about as rare as rare can be. Each case is unique, for the genomes of no two people that come apart in this highly unusual manner are stitched back together in exactly the same way.

The Diagnostic Odyssey

Aviya is now just past her second birthday and is beginning to walk, although she doesnt yet talk. Her symptoms unfolded early and rapidly, about 3 months after her birth in May 2017.

She started throwing up multiple times a day and regardless of how much or what she ate, breast milk or formula, she would not gain weight. She wasnt reaching developmental milestones. The physical therapist noted her hypotonia (low muscle tone, or floppiness), her dad recalled. Her weight steadily dropped, as the vomiting worsened.

Hospital stays followed. Tests and scans ruled out intestinal malrotation, while neurological tests and abdominal ultrasounds were normal too. Doctors inserted a nasogastric tube, for nutrition.

At 7 months old, Aviya started at the failure-to-thrive clinic at Schneiders, where she had tests and evaluations for physical therapy (PT) and occupational therapy (OT). She also met with an eating specialist.

Everyone poked and prodded and measured and checked. She had blood tests, gave stool samples, had CT scans, MRI images, and drank stuff for x-rays through the GI tract, Yosef said. The doctors initially suspected malrotation of the intestines behind the vomiting, but that didnt hold up. They didnt find any evidence or suspicion of anything amiss based on symptoms only, he added. Heart, brain, blood, all looked ok.

The next step: probing genetics. A chromosomal microarray test (CMA; for small deletions and insertions) and a karyotype revealed the four unusual chromosomes, deemed a complex chromosomal rearrangement. Tests for selected single-gene conditions, like Beckwith-Wiedemann syndrome, were negative.

Further analysis led to the chromothripsis explanation. Because the parents CMA tests and karyotypes were normal, their daughter hadnt inherited her unusual chromosomes they originated in her, likely an ultra rare event in a lone developing egg, followed by spectacular natural healing.

But deducing chromosomal origins and even contemplating whether a gene therapy might be possible for a situation so complex took a backseat to addressing Aviyas daily challenges. First, she had to be able to eat.

Focusing on Symptoms

Vomiting send Aviya to the hospital regularly. For 9 months she received supplemental feedings through a nasogastric tube, and the frequency of episodes slowed as she slowly gained weight. When the gaining once again slowed, and days-long bouts of vomiting led to more hospitalizations, doctors performed a procedure called PEG (for percutaneous endoscopic gastrostomy). A tube through the abdominal wall into her stomach now delivered nutrients. That was done on March 5th, 2019.

The vomiting finally ceased and Aviya has reached the 10th percentile in body weight, up from inexorably losing. Shes also catching up on gross motor skills and reaching developmental milestones. And shes intelligent. She understands basically everything you tell her, for the level of a 2-year-old, Yosef said. Thats pretty amazing considering the number of unusual chromosomes and how many genes affect brain function.

But boosting nutrition isnt the only intervention helping Aviya to overcome whatever limits her chromosomes have set. Yosef credits her overall improvement to the excellent care shes been receiving at a special education day care program near their home on the West Bank. Shes been attending since November, and she gets PT, OT, speech therapy, and does specialized exercises tailored to her abilities. Aviya also returns to the failure-to-thrive clinic every other month, down from once a week.

Instead of Fixing Genes, Address Symptoms

When parents become sucked down the rabbit hole of rare diseases, they quickly learn about biotech approaches: enzyme therapies, stem cells, antisense oligonucleotides, gene therapy, and even gene editing. Its overwhelming. Some of the parents DNA Science has featured rapidly became nearly as expert as some of the scientists developing new treatments (see Celebrating the Moms of Gene Therapy).

Would exome sequencing shed any more light on the situation, or it would just lead to more questions that no one has the answers to? Yosef asked me. Exome sequencing, which reveals the information in the part of the genome that encodes protein, might actually provide too much information, noting too many missing genes to consider treatments for all of them. But it might reveal which proteins Aviya cant make, and maybe that could lead to something.

The TMI issue also affects the utility of a gene therapy for chromothripsis: too many targets.

Specific mutations in single genes cause the conditions for which gene therapy has been FDA approved Luxturnato treat a form of inherited blindnessand Zolgensmato treat spinal muscular atrophy (SMA). The cost of gene therapy for now is prohibitive, although the manufacturers help with patient access. Zolgensma recently made headlines for its $2.1 million price tagand Luxturna for both eyes is about $850,000. The gene therapies, though, are intended to be one-and-done, or at least just in need of a booster. And the alternatives, in these two frontrunners, are blindness or death.

Given the cost of gene therapy and its restriction to genetic disruptions far simpler than the chaos of Aviyas chromosomes, its great that standard therapies are having an effect.

Shes been improving by leaps and bounds in everything, from how much she eats to what shes willing to try to her understanding of everything. Shes just so much better, since the PEG and beginning the special ed day care. She eats more, theres more variety to her food choices, and shes willing to try anything, Yosef said.

He knows that no research team or company is going to pursue a treatment for a sample size of one. What were doing is the best we can do. Its working, so if it aint broke dont fix it. If we find something else to do, then for sure well do it, but in the meantime, were doing the best that we figured out for now. Well see what the future holds.

So Ill end with a shout-out to the supportive therapies that help so many. Even after a sophisticated gene therapy that takes years, if not decades, to take to a clinical trial, supportive therapies are critical to maximizing any effect, on a daily basis. Perhaps no one knows that better than Lori Sames, whose daughter Hannah had gene therapy for giant axonal neuropathy in 2016. (See After Gene Therapy: Hannahs Journey Continues).

PT is incredibly important! When Hannah was a toddler and developed low muscle tone, our first sign something was wrong prior to her diagnosis, her first physical therapist emphasized how important it was to let her do everything. Do not pick her up and put her in her car seat. Open the door of the minivan and let her crawl in and hoist herself up into the car seat. Let her walk. If shes tired and asks to be carried for a bit, carry her for a bit. Keep her as active as you can for as long as you can.

Hannahs PT continues today. While standing, she does squats, leaning back as if shes sitting but powering back through to a stand before she touches the seat. Were trying to keep her hips and quads and hamstrings strong. We have her stand twice an hour and shes in the EasyStand device at least an hour a day. This is critically important for her internal organs and bone density, Lori recently told me.

Aviya is a wonderful, spirited child.

Shes a fun-loving, constantly happy kid, even though she has spent more time in the hospital then most people I know. Even while she was hospitalized she would always smile at the doctors and nurses and play with the other kids, with as much energy as she had. She loves taking things out of and putting them into bags or boxes. She loves hugging dolls and pretending to feed them. She loves playing outside with plants and watching ants going back and forth. She loves to be part of everything and to crawl around the house, and loves when people talk or sing to her and she talks and sings back, said her father.

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A Child's Shattered Chromosomes Illustrate the Value of Supportive Therapies | DNA Science Blog - PLoS Blogs

Good morning, everyone, and how are you today? We are doing just fine, thank you, courtesy of a warm and shiny sun and a delicious cool breeze wafting across the Pharmalot campus. Moreover, a soothing quietude has descended upon us now that our short person has left for the local schoolhouse and our official mascot has taken up his snoozing position in a faraway corner. As for us, yes, we are brewing our ritual cups of stimulation we favor hot-buttered rum today, for those keeping track. Meanwhile, here is the latest menu of interesting items for you. Hope you have a wonderful day and do keep in touch.

House Speaker Nancy Pelosi on Thursday formally unveiled her long-awaited plan to lower drug prices, giving Democrats an aggressive counter to the White Houses numerous and widely covered efforts to lower drug prices, STAT reports. The plan would enact an international price index, capping U.S. drug payments for Medicare at an average of foreign prices, and require the federal government to negotiate the cost of 250 prescription medicines, using the international price as a maximum price, and extend the negotiated price to insurers and the commercial market at large. The bill would also cap senior out-of-pocket drug expenses at $2,000 annually.

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Novartis says Pharmalittle: Pelosi unveils aggressive drug pricing plan - STAT

The collaboration agreed between the supply chain management services providers, McKesson and TrakCel, comes after the companies have jointly taken on the market entrance of a T-cell based allogeneic therapeutic product of an undisclosed late-stage biopharmaceutical developer.

The commercial launch of this product, which will be the first off-the-shelf product available, is expected in the fourth quarter of 2020, Akshay Peer, VP of sales and account management at TrakCel, told us.

Under the partnership and in order to serve this commercialization, as well as other future product launches, the two companies will develop a combined program, utilizing McKessons patient services alongside TrakCels data management software platform.

The special supply chain requirements of personalized treatments, such as cell and gene therapies, are due to the developers need to manage multiple players and organizations concurrently, according to Peer.

This includes different teams within site of care, shipping and logistics, manufacturing and storage, Peer added.

More specifically, according to TrakCels VP, the product journey consists of the below stations:

Layne Martin, VP of specialty distribution solutions at McKesson Life Sciences, commented that, as the wave of over 900 cell and gene products currently under review by the FDA come to market, supply chain service providers can begin to offer some standards to improve outcomes.

As the products evolve to the latest stages of development,a number of processes including patient scheduling and care have to be mapped, said Peer, adding that the case management teams that are in-charge of communicating with the patient and healthcare professionals need a dashboard view of the entire lifecycle development of the therapy.

According to the companies, the integrated platform is expected to enable the scale-up of products towards market delivery, for the increasing number of developers approaching the commercial launch of cell and gene therapies.

The platform will include automatic scheduling of product-specific workflows across multiple supply chain partners and care team members, and validated chain-of-identity tracking to guarantee correct drug product delivery.These capabilities ensure that the patient receives the correct, uncompromised treatment at the right time, McKesson stated.

Therefore, the integrated suite which will result from the collaboration is expected to provide a control tower view of the product distribution.

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TrakCel partners with McKesson - BioPharma-Reporter.com

The CharcotMarieTooth Association (CMTA) has granted $335,000 to two research projects focused on the development of new therapies for CharcotMarieTooth (CMT) disease type 1A, type 1B, and other demyelinating forms of CMT, including type 4.

CMTA has been funding projects for 30 years on research focused on discovering the mechanisms involved in CMT and on developing safe and effective therapies for the 2.8 million living with CMT worldwide.

The association launched its Strategy to Accelerate Research (STAR) initiative in 2008 to bring together scientists, pharmaceutical companies, and patients to create a multidisciplinary collaborative environment that would advance scientific and medical innovation in CMT.

CMTAsSTAR Advisory Board includes 30 leading scientists and clinicians who are responsible for analyzing the quality of ongoing projects and deciding which ones receive monetary support.

A grant totaling $154,000 was awarded to a collaboration project between three leading CMT experts Kleopas Kleopa, MD, PhD, from The Cyprus Institute of Neurology & Genetics; John Svaren, PhD, from the Waisman Center at the University of Wisconsin-Madison; and Steven Gray, PhD, from the University of Texas Southwestern Medical Center.

Their project will focus on the development of two different types of gene therapies. One therapy is designed to shut down the PMP22 gene, which is overactive in people with CMT1A. The second treatment candidate is designed to replace the defective genes responsible for the different forms of CMT4 and CMT1X.

The scientists will attempt to come up with safe viral vectors to deliver the modified versions of these genes to Schwann cells specialized cells that produce the fatty substance (myelin) protecting nerve cells which are defective in CMT.

The team is planning to test the efficacy of four different types of adeno-associated viruses (AAVs), developed by Gray, to determine the one that could better deliver the modified genes to Schwann cells in cases of CMT1A and CMT1X. The researchers will also test the efficacy of two AAVs in a mouse model of CMT1A.

The proposed experiments will seek to enable a translatable gene therapy approach for CMT1A, CMT1X, and various CMT4 forms. This will also be the first testing of AAV9 virus distribution to Schwann cells in a larger animal model (primate), the researchers said in their project proposal.

The second grant, which totaled $180,000, was awarded to a collaboration project between Maurizio DAntonio, PhD, from the IRCCS Ospedale San Raffaele and Ghjuvan Shackleford, PhD, from the Hunter James Kelly Research Institute.

Their project will focus on investigating the mechanisms of disease in a mouse model of late-onset CMT1B (named P0T124M) and discovering new therapeutic strategies to prevent the degeneration of nerve cells and their extensions (required for the proper transmission of nervous signals).

This project will identify signals and molecules that underlie glial support of axons, and could reveal new unifying therapeutic targets that are common to a large spectrum of neurodegenerative diseases, the researchers stated.

Joana is currently completing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. She also holds a BSc in Biology and an MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells cells that make up the lining of blood vessels found in the umbilical cord of newborns.

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CMTA Grants $335,000 to Projects that Advance Therapy Development - Charcot-Marie-Tooth News

Freeline has announced the dosing of the first patient in its MARVEL1 study, a multi-centre Phase I/II clinical trial of its liver-directed AAV gene therapy for Fabry Disease.

The study, which is the first clinical-stage adeno-associated virus (AAV) gene therapy study globally for Fabry Disease, leverages Freelines proprietary gene therapy platform, including its novel capsid, which has already shown clinical benefit for Haemophilia B patients.

The study aimed to deliver a replacement copy of the missing gene to the liver, which will then produce continuous high levels of GLA, offering the potential for therapy with a single treatment.

The initiation of the MARVEL1 study and dosing of the first patient is a significant milestone for Freeline, said Chris Hollowood, executive chairman of Freeline.

Continuous high expression of alpha GLA holds the potential for better treatment outcomes than is seen with ERT, the current standard of care. We believe we can access high expression at relatively low doses. With two programmes in the clinic on a common proprietary gene therapy platform, Freeline are building a leading systemic gene therapy company using next-generation AAV technology. These innovative gene therapies have the potential to change patients lives.

Fabry disease is a type of lysosomal storage disorder in which certain fatty molecules are not properly metabolised. Patients have a genetic mutation which leads to a deficiency of -galactosidase A enzyme (GLA) resulting in an accumulation of lipids, such as globotriaosylceramide (Gb3) and globotriaosylsphingosine (LysoGb3), throughout the body. This can cause highly debilitating progressive multi-organ disease.

It is estimated that Fabry Disease affects one in every 40,000 people. It is currently treated by enzyme replacement therapy (ERT), which requires regular and expensive infusions.

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First patient dosed in Fabry Disease gene therapy trial - PharmaTimes

HACKENSACK, N.J., Sept. 17, 2019 /PRNewswire/ --Parent Project Muscular Dystrophy (PPMD), a nonprofit organization leading the fight to end Duchenne muscular dystrophy (Duchenne), announced plans to award H. Lee Sweeney, PhD, and his team at the University of Florida (Gainesville) $1 million to continue their exploration of developing novel therapies that can address the causes of dilated heart failure in Duchenne and Becker muscular dystrophy. This $1 million investment is part of PPMD's Cardiac Initiative and a direct result of the Duchenne community's generosity during the organization's 2018 end of the year campaign, as well as the support of other Duchenne families and foundations, including the Killian Family, Team Joseph, Kindness Over Muscular Dystrophy, Another Day for Gray Foundation, and Small Heroes Foundation.

Duchenne isthe most common fatal genetic disorder diagnosed in childhood, affecting approximately one in 5,000 live male births. Duchenne is caused by a change in the dystrophin gene. For people with Duchenne, cardiac disease is an area of great concern. The absence of dystrophin in the heart contributes to a progressive deterioration of cardiac muscle and eventual dilated cardiomyopathy (DCM) or heart disease.

Gene therapy, utilizing AAV vector as the delivery vehicle, provides a potential strategy to deliver transgenes targeting the mechanisms underlying the development of dilated cardiomyopathy. This funding supports the development of a heart specific therapy using an AAV vector containing two transgenes to restore calcium handling and prevent mitochondrial dysfunction. This therapy will potentially be able to treat the hearts of people living with Duchenne and Becker, in a way that is independent of, or complementary to, micro-dystrophin based gene therapy.

PPMD's Founding President and CEO, Pat Furlong, lost both of her sons to heart failure resulting from Duchenne, so this project is particularly meaningful to her and her family: "Heart issues don't just affect some people with Duchenne; they affect ALL people with Duchenne. And while we have improved cardiac care in Duchenne, we still need treatments that repair our children's hearts. Since our organization began 25 years ago, we have been asking questions and trying to better understand the effect of this disease on the heart. Chris and Patrick died of heart failure, so the heart is at the center of Duchenne for me. That's why I am extremely proud to announce this $1 million investment into a gene therapy with the potential to heal the hearts of our loved ones. I am grateful to Dr. Sweeney and the amazing team at University of Florida, as well as the families in our community who believe in our mission and gave generously to help fund the fight to end Duchenne."

Dr. Sweeney, who has a long history in Duchenne research and has worked with PPMD for over two decades, says that PPMD's funding comes at a critical moment in the development of gene therapy: "These are exciting times for gene therapies especially for gene therapies for Duchenne and Becker muscular dystrophy. However, while the current therapies may potentially help the skeletal muscles of patients, there is more to learn and to develop before we can be confident that we are doing all we can for the hearts of patients. The funds provided by PPMD will allow us to move faster toward the goal of creating the best possible gene therapy for the hearts of people with Duchenne and Becker."

Dilated cardiomyopathy (DCM) is the most common type of human cardiomyopathy, occurring mostly in adults 20 to 60. It affects the heart's ventricles and atria, the lower and upper chambers of the heart, respectively. Most forms of DCM are acquired forms from a number of causes that include coronary heart disease, heart attack, high blood pressure, diabetes, thyroid disease, viral hepatitis, and viral infections that inflame the heart muscle. In the case of certain forms of Becker, as well as in most cases of Duchenne, cardiomyopathy can ultimately limit the patient's survival.

While cardiomyopathy associated with Duchenne is technically a dilated cardiomyopathy that progresses to heart failure, many clinicians don't consider it a typical DCM because the patients' hearts don't tend to dilate until rather late in the disease progression. However, this is likely due to the fact that the hearts are not significantly burdened because of the patients' skeletal muscle disease and lack of ability to exercise.

Although Duchenne hearts do not dilate until late in disease progression, they get progressively stiff at earlier time points. This is clearly due to progressive fibrosis, and is slowed by the use of anti-fibrotic drugs, such as ACE inhibitors or ARBs (Angiotensin II Receptor Blockers). Interestingly, because of the fibrosis and lack of burden on the heart, the left ventricular chamber is actually smaller in diameter than normal after age 8 and until late in disease progression, when it begins to dilate. Again, consistent with this being related to the fibrosis is the fact the individuals who were not given ACE inhibitors early in disease progression show the smallest ventricular diameters and progress the fastest once they begin to dilate.

In the case of Becker, there clearly is a subset of Becker patients that show a disproportionately rapid progression of their cardiac disease as compared to their skeletal muscle disease. This has called attention to the fact that there are some regions of the dystrophin molecule that are more important in the heart than they are in skeletal muscle, likely because of components that differ in importance or even in identity between the heart and skeletal muscle.further explore a novel gene therapy approach that will target the heart in people living with Duchenne and Becker muscular dystrophy.

To learn more about PPMD's Cardiac Initiative, click here.

About Parent Project Muscular Dystrophy

Duchenneis a fatal genetic disorder that slowly robs people of their muscle strength. Parent Project Muscular Dystrophy (PPMD) is the largest most comprehensive nonprofit organization in the United States focused on finding a cure for Duchenneour mission is to end Duchenne.

We demand optimal care standards and strive to ensure every family has access to expert healthcare providers, cutting edge treatments, and a community of support. We invest deeply in treatments for this generation of Duchenne patients and in research that will benefit future generations. Our advocacy efforts have secured hundreds of millions of dollars in funding and won two FDA approvals.

Everything we doand everything we have done since our founding in 1994helps those with Duchenne live longer, stronger lives. We will not rest until we end Duchenne for every single person affected by the disease. Join our fight against Duchenne at EndDuchenne.org and follow PPMD on Facebook, Twitter, andYouTube.

SOURCE Parent Project Muscular Dystrophy

Join the fight. End Duchenne.

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PPMD Awards University of Florida $1 Million for Novel Gene Therapy Approach Targeting the Heart - PRNewswire

An early-stage update on Adverum Biotechnologies intravitreal gene therapy has triggered investor concern, after patients with wet age-related macular degeneration (AMD) saw their vision deteriorate, despite signs that the treatment is improving retinal anatomy.

Adverum, on Wednesday, unveiled 24-week data from the OPTIC trial of its experimental therapy, ADVM-022, in six patients who have been administered with one dose of the therapy. On average, patients in the trial had severe disease with an average of 6.2 anti-VEGF injections in the eight months prior to screening and an average annualized injection frequency of 9.3 injections.

Over the six month period, patients did not require any anti-VEGF rescue injections and five of six patients saw a complete response with a total resolution of fluid following the Adverum injection. There were no serious adverse events, and the majority of side-effects were mild.

However, patients lost visual acuity by two letters on average, with a 90% confidence interval of -9.1 letters to +5.1 letters.

The range of individual patient data were not presented, though the wide confidence interval suggests that some patients may have experienced a loss of more than 10 letters during the course of the trial lack of rescue injections is difficult to square with declining vision. SVB Leerinks Mani Foroohar wrote in a note.

However, the study investigator insisted no loss in vision was due to wet AMD pathology and observed loss of visual acuity is due to normal variabilityin a small set of patients an assertion that, if proved out with additional follow-up, would very substantially improve the implied quality of this dataset.

Shares of the company which spectacularly failed years ago when it was christened Avalanche Biotechnologies $ADVM were down about 6.8% to $5.56 in Friday premarket trading. The stock sank on Thursday, evaporating millions from its market value.

This data suggest ADVM-022 is potentially active in delivering an expressible gene cassette in wet AMD, but mixed signals in this small dataset should lift some of the competitive overhang on RGNX shares, Foroohar added. RegenexBio experimental gene therapy for wet AMD, RGX-314, is currently in a Phase I/II trial.

Wet AMD, which is characterized by blurred vision or a blind spot in an individuals visual field, is typically caused by abnormal growth of blood vessels that leak fluid or blood into the macula. Macular degeneration is the leading cause of severe, irreversible vision loss in the elderly. Anti-VEGF injections such as Regenerons $REGN flagship Eylea, as well as Roches $RHBBY Lucentis and Avastin, are commonly used to treat wet AMD.

In April, the FDA imposed a clinical hold on an application to test ADVM-022 in humans, asking for additional data on Adverums chemistry, manufacturing and control process. In May, the hold was lifted. Late last year, the biotech abandoned its then lead experimental drug, ADVM-043, for the treatment of A1AT deficiency.

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Early snapshot of Adverum's eye gene therapy sparks concern about vision loss - Endpoints News

Prevail Therapeuticsis asking the U.S. Food and Drug Administration (FDA) to approved a request to open clinical trials, at higher doses than initially planned, into its investigational gene therapy PR001 in people with pediatric neuropathic Gauchers disease (type 2).

In its updated Investigational New Drug (IND) application, Prevail modified the original design of its clinical trial to allow for a higher starting dose of the therapy. This decision was based on conversations with the FDA and preclinical data supporting PR001 as a more effective and still safe treatment at higher doses, it announced in a press release.

The company is waiting on an FDA decision, and expects to start recruiting patients for a Phase 1/2 trial testing PR001 in children with neuropathic Gaucher in the first half of 2020. The IND, an essential step to opening a clinical study, was first filed in June.

We are dedicated to developing PR001 for pediatric nGD[neuropathic Gaucher disease], the most progressive form of Gaucher disease, which involves neurological manifestations that cause severe morbidity and mortality. We believe PR001 has tremendous potential to slow or stop disease progression in patients who currently have no disease-modifying therapeutic options, Asa Abeliovich, MD, PhD, founder, and CEO of Prevail, said in the release.

Gaucher disease is a hereditary condition caused by mutations in the GBA gene, which leads to the production of defective beta-glucocerebrosidase. This protein breaks down fatty molecules that are toxic if they accumulate inside the cells, leading to the array of symptomsassociated with Gauchers disease.

Toxic fatty molecules building in the brain lead to manifestations of neuropathic Gauchers, which can be observed from early infancy in type 2 disease.

PR001 uses a modified, harmless version of an adeno-associated virus (AAV9) to deliver a fullyworking copy of the GBA1 gene to nerve cells. This allows these cells to initiate processes that lead to the production of functional beta-glucocerebrosidase, which could ease the symptoms of neurotropic Gauchers disease. A single dose of PR001 has the potential to modify the disease with long-lasting effect.

Studies in mice and primatesfound that PR001 was well-tolerated and led to the expression of a functional protein in nerve cells, reducing the accumulation of fatty molecules and consequent symptoms.

AAV9 has been widely used to deliver gene therapies both in practice and in clinical trials. A transport vehicle for the corrected gene, it is engineered to be a harmless virus and can cross the blood-brain barrier, allowing it to reach nerve cells.

PR001 is also being developed and tested as a treatment of people with Parkinsons diseasewho have mutations in the GBA gene. Prevail has an open IND applicationfor trials here, and the therapy received fast-track designation by the FDA as a possible Parkinsons treatment.

Alejandra has a PhD in Genetics from So Paulo State University (UNESP) and is currently working as a scientific writer, editor, and translator. As a writer for BioNews, she is fulfilling her passion for making scientific data easily available and understandable to the general public. Aside from her work with BioNews, she also works as a language editor for non-English speaking authors and is an author of science books for kids.

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Ins Martins holds a BSc in Cell and Molecular Biology from Universidade Nova de Lisboa and is currently finishing her PhD in Biomedical Sciences at Universidade de Lisboa. Her work has been focused on blood vessels and their role in both hematopoiesis and cancer development.

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Type 2 Gaucher Trial of Gene Therapy PR001 May Open with Higher Dose - Gaucher Disease News

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A new gene therapy turns glial cellsabundant support cells in the braininto neurons, repairing damage that results from stroke and significantly improving motor function in mice.

Once researchers further develop the NeuroD1-based gene therapy, it could potentially help to treat stroke, which is a leading cause of disability in the US, with 800,000 new stroke patients every year.

The current treatment for stroke has a narrow time window, typically within a few hours after the occurrence of stroke, says lead author Yuchen Chen, a postdoctoral fellow at Penn State. Many patients cannot receive the treatment in time and as a result, often suffer from permanent disability caused by irreversible neuronal loss. There is an urgent need to develop a new therapy to regenerate new neurons and restore lost brain functions among stroke patients.

The human brain has approximately 86 billion neurons. While mini-strokes can be tolerated, moderate stroke involving the loss of billions of neurons leaves detrimental effects that do not spontaneously recover.

So, the critical question that is still unanswered in the neuroregeneration field is how can we regenerate billions of new neurons in a patients brain after stroke? says Gong Chen, professor of biology and chair in life sciences. The biggest obstacle for brain repair is that neurons cannot regenerate themselves. Many clinical trials for stroke have failed over the past several decades, largely because none of them can regenerate enough new neurons to replenish the lost neurons.

The reserchers pioneered a new approach to regenerate functional neurons using glial cells, a group of cells surrounding every single neuron in the brain that provide essential support to neurons. Unlike neurons, glial cells can divide and regenerate themselves, especially after brain injury.

I believe that turning glial cells that are already present in the brain into new neurons is the best way to replenish the lost neurons, says Gong Chen. These glial cells are the neighbors of the dead neurons in the brain and are likely to share the same ancestral cellular lineage.

The team previously reported that a single genetic neural factor, NeuroD1, could directly convert glial cells into functional neurons inside mouse brains with Alzheimers disease, but the total number of neurons generated was limited. The research team believed that this limited regeneration was due to the retroviral system used to deliver NeuroD1 to the brain.

In the current study, the research team used the AAV viral system, which is now the first choice for gene therapy in the nervous system, to deliver NeuroD1 into mouse motor cortex that a stroke had damaged.

Many neurons die after stroke but surviving glial cells can proliferate and form a glial scar in the stroke areas. The researchers designed their AAV system to express NeuroD1 preferentially in the glial cells that form these scars, turning them directly into neuronal cells. Such direct glia-to-neuron conversion technology not only increased neuronal density in the stroke areas, but also significantly reduced brain tissue loss the stroke caused.

Interestingly, the newly converted neurons showed similar neuronal properties to the neurons that were lost after stroke. This suggests a potential impact of the local glial lineage on the converted neuronal identity.

The most exciting finding of this study is to see the newly converted neurons being fully functional in firing repetitive action potentials and forming synaptic networks with other preexisting neurons, says Gong Chen. They also send out long-range axonal projections to the right targets and facilitate motor functional recovery.

A separate collaborative work led by Gregory Quirk, a professor at the University of Puerto Rico, further tested the NeuroD1-based gene therapy in a rat stroke model. Quirk and colleagues also found that this direct glia-to-neuron conversion technology can rescue cognitive functional deficits stroke induces.

Because glial cells are everywhere in the brain and can divide to regenerate themselves, our study provides the proof-of-concept that glial cells in the brain can be tapped as a fountain of youth to regenerate functional new neurons for brain repair not only for stroke but also for many other neurological disorders that result in neuronal loss, says Yuchen Chen. Our next step is to further test this technology and ultimately to translate it into clinically effective therapies to benefit millions of patients worldwide.

A paper describing the new therapy appears in the journal Molecular Therapy.

Additional researchers at Penn State and the University of Puerto Rico contributed to the work. The US National Institutes of Health and the Penn State Charles H. Skip Smith Endowment Fund supported the research.

Source: Penn State

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Therapy creates new neurons for faster stroke recovery - Futurity: Research News

Updated results from a Phase 2/3 clinical trial, Starbeam, evaluating bluebird bio's (BLUE -1.6%) gene therapy Lenti-D in patients with a rare severe inherited disorder called cerebral adrenoleukodystrophy (CALD) showed a sustained treatment effect. The data were presented at the European Pediatric Neurology Society Congress in Athens.

Treated patients remained free of major functional disabilities (MFDs) for as long as five years (and counting) with no reports of graft failure or treatment-related deaths. No new safety signals have been observed.

The study is assessing the safety and efficacy of autologous CD34+ hematopoietic stem cells transduced with Lenti-D lentiviral vector encoding human adrenoleukodystrophy protein. In other words, stem cells are extracted from the patient, modified with Lenti-D, then infused back into the patient after myeloablative conditioning (bone marrow activity is intentionally decreased to reduce the risk of complications).

88% (n=15/17) of treated patients who reached or would have reached 24 months' follow-up and completed the study are still alive and MFD-free.

Development is ongoing.

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Bluebird gene therapy shows sustained benefit in CALD study - Seeking Alpha

Gene therapy, also called gene transfer therapy, introduction of a normal gene into an individuals genome in order to repair a mutation that causes a genetic disease. When a normal gene is inserted into the nucleus of a mutant cell, the gene most likely will integrate into a chromosomal site different from the defective allele; although that may repair the mutation, a new mutation may result if the normal gene integrates into another functional gene. If the normal gene replaces the mutant allele, there is a chance that the transformed cells will proliferate and produce enough normal gene product for the entire body to be restored to the undiseased phenotype.

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cancer: Gene therapy

Knowledge about the genetic defects that lead to cancer suggests that cancer can be treated by fixing those altered genes. One strategy

Human gene therapy has been attempted on somatic (body) cells for diseases such as cystic fibrosis, adenosine deaminase deficiency, familial hypercholesterolemia, cancer, and severe combined immunodeficiency (SCID) syndrome. Somatic cells cured by gene therapy may reverse the symptoms of disease in the treated individual, but the modification is not passed on to the next generation. Germline gene therapy aims to place corrected cells inside the germ line (e.g., cells of the ovary or testis). If that is achieved, those cells will undergo meiosis and provide a normal gametic contribution to the next generation. Germline gene therapy has been achieved experimentally in animals but not in humans.

Scientists have also explored the possibility of combining gene therapy with stem cell therapy. In a preliminary test of that approach, scientists collected skin cells from a patient with alpha-1 antitrypsin deficiency (an inherited disorder associated with certain types of lung and liver disease), reprogrammed the cells into stem cells, corrected the causative gene mutation, and then stimulated the cells to mature into liver cells. The reprogrammed, genetically corrected cells functioned normally.

Prerequisites for gene therapy include finding the best delivery system (often a virus, typically referred to as a viral vector) for the gene, demonstrating that the transferred gene can express itself in the host cell, and establishing that the procedure is safe. Few clinical trials of gene therapy in humans have satisfied all those conditions, often because the delivery system fails to reach cells or the genes are not expressed by cells. Improved gene therapy systems are being developed by using nanotechnology. A promising application of that research involves packaging genes into nanoparticles that are targeted to cancer cells, thereby killing cancer cells specifically and leaving healthy cells unharmed.

Some aspects of gene therapy, including genetic manipulation and selection, research on embryonic tissue, and experimentation on human subjects, have aroused ethical controversy and safety concerns. Some objections to gene therapy are based on the view that humans should not play God and interfere in the natural order. On the other hand, others have argued that genetic engineering may be justified where it is consistent with the purposes of God as creator. Some critics are particularly concerned about the safety of germline gene therapy, because any harm caused by such treatment could be passed to successive generations. Benefits, however, would also be passed on indefinitely. There also has been concern that the use of somatic gene therapy may affect germ cells.

Although the successful use of somatic gene therapy has been reported, clinical trials have revealed risks. In 1999 American teenager Jesse Gelsinger died after having taken part in a gene therapy trial. In 2000 researchers in France announced that they had successfully used gene therapy to treat infants who suffered from X-linked SCID (XSCID; an inherited disorder that affects males). The researchers treated 11 patients, two of whom later developed a leukemia-like illness. Those outcomes highlight the difficulties foreseen in the use of viral vectors in somatic gene therapy. Although the viruses that are used as vectors are disabled so that they cannot replicate, patients may suffer an immune response.

Another concern associated with gene therapy is that it represents a form of eugenics, which aims to improve future generations through the selection of desired traits. Some have argued that gene therapy is eugenic but that it is a treatment that can be adopted to avoid disability. To others, such a view of gene therapy legitimates the so-called medical model of disability (in which disability is seen as an individual problem to be fixed with medicine) and raises peoples hopes for new treatments that may never materialize.

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Gene therapy | medicine | Britannica.com