Category Archives: Genetic Therapy

In recent years, new gene editing tools have been used for everything from genetic modification of plants to increase crop yields to, far more controversially, genetic tampering with human embryos. Could a form of gene therapy also be useful in helping treat cocaine addiction, a form of addiction that proves highly resistant to alternative approaches, such as conventional medical treatment and psychotherapy? Thats what researchers from the world-famous Mayo Clinic are hoping to prove.

They are seeking approval for the first-in-human studies of an innovative new single-dose gene therapy. Their approach involves the delivery of a gene coding for an enzyme, called AAV8-hCocH, which metabolizes cocaine in the body into harmless byproducts. In order to progress to this next step in their work, they first have to gain permission from the U.S. Food and Drug Administration (FDA) in the form of an Investigational New Drug Application.

The researchers have already demonstrated the safety of their approach in mice. In a prior experiment, they showed a complete lack of adverse effects in mice which had both been previously exposed to cocaine and those which had not.

Mice given one injection of AAV8-hCocH and regular daily injections of cocaine had far less tissue pathology than cocaine-injected mice with no vector treatment, the researchers wrote in the abstract for their paper describing the work. Biodistribution analysis showed the vector located almost exclusively in the liver. These results indicate that a liver-directed AAV8-hCocH gene transfer at reasonable dosage is safe, well-tolerated, and effective. Thus, gene transfer therapy emerges as a radically new approach to treat compulsive cocaine abuse.

This is not the first time similar work has been carried out. In February 2017, scientists at the University of British Columbia genetically engineered a mouse so as to be incapable of becoming addicted to cocaine. However, one of the researchers on the project told Digital Trends that transferring this work across to humans for possible treatment for addiction was not straightforward. Instead, that work was more focused on exploring the link between drug use and genetics and biochemistry.

Theres still a whole lot more research that needs to be done in this area. Even if the FDA grants the Mayo Clinic researchers permission for their human trials, well most likely be waiting a few years at least before this treatment could be rolled out to the general public. Its an exciting leap forward, nonetheless.

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Scientists want human trials for gene therapy that could help battle addiction - Digital Trends

LONGMONT, Colo. A few months ago, 2-year-old Maisie Forest was finally able to sit up on her own for the first time. Her development has been delayed by a rare genetic disorder called Spinal Muscular Atrophy, but last August, she received a groundbreaking treatment for the condition.

"It's a miracle drug," said Maisie's mother, Ciji Green. "It's not the cure, but we're talking about a disease that had no treatments four years ago," she added.

The "miracle drug" Green is referring to Zolgensma, a gene therapy for Spinal Muscular Atrophy made by Novartis-owned AveXis. On Tuesday, AveXis cut the ribbon on a new facility in Longmont where it will soon produce Zolgensma.

"Zolgensma is this first product weve had approved by the FDA for the treatment of kids with Spinal Muscular Atrophy," said AveXis President David Lennon.

The FDA approval came last May, just in time for Maisie to receive the treatment. But her mother still had to fight for the insurance company to pay for it. At $2.1 million per dose, Zolgensma is the most expensive drug or treatment ever made. Lennon said Novartis has invested half a billion dollars in the production of Zolgensma.

For Green, the cost is well worth the changes she's already seen in her daughter. Speaking to employees at the AveXis ribbon cutting, she called them heroes.

"To all of you it may just be a treatment, but to my family and so many others, its so much more," said Green.

AveXis says the same platform they used to produce Zolgensma might be applied to other therapies for other diseases in the future. The company is looking at developing treatments for Rett Syndrome, Friedreichs Ataxia, and an inherited form of Amyotrophic Lateral Sclerosis, or ALS.

"There are actually thousands of these kinds of diseases. Usually they impact a few hundred kids or adults every year, but altogether there are potentially millions of patients who have genetic diseases around the world," said Lennon.

Lennon said AveXis chose Longmont for its production facility in part because of the infrastructure already in place. The building at 4000 Nelson Rd. was previously occupied by pharmaceutical companies AstraZeneca and Amgen. He said the available talent was also a factor.

AveXis retained most of the employees from the previous tenants. With new hires, the Longmont facility currently has a staff of around 300 employees and expects to grow to 400 by the end of 2020.

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Gene therapy company begins operations in Longmont - The Denver Channel

XconomyBoston

Solid Biosciences is slashing its workforce, including two top executives, in order to devote the companys remaining resources to its experimental gene therapy for Duchenne muscular dystrophy.

The corporate restructuring announced Thursday comes two months after the FDA placed a hold on the study after safety problems emerged that were linked to the gene therapy, SGT-001. Cambridge, MA-based Solid Bio (NASDAQ: SLDB) says going forward it will focus on how to address the clinical hold and resume testing. With the corporate changes, Solid Bio says it has enough cash to last into next year. At the end of the third quarter of 2019, the company reported cash and other holdings totaling $105.7 million.

Following the announcement, Solid Bios stock price slid more than 17 percent to $3.66 per share in pre-market trading.

Solid Bio has been developing SGT-001 as a way to potentially address the genetic defect underpinning Duchenne. Patients who have the inherited disease dont make enough of the muscle protein dystrophin. The Solid Bio gene therapy uses an engineered virus to deliver genetic material intended to restore dystrophin production. But the company had also previously disclosed theres a chance that the dosing requirements of the gene therapy could increase the risk of side effects related to the virus used in the treatment.

The complications reported in the November clinical hold included an immune system reaction, a decrease in red blood cells, kidney injury, and blood circulation difficulties. Those problems are similar to ones cited in the FDAs 2018 clinical hold on tests of SGT-001. Months later, the agency allowed the study to resume but with additional safety measures.

Solid Bios board approved the corporate restructuring on Tuesday, according to a securities filing. In the first quarter of this year, the company expects to record a $2.1 million charge related to the layoffs, which will cut about one third of its workforce. Last years annual report states that the company had 111 full-time employees as of Dec. 31, 2018. Those leaving Solid Bio include Alvaro Amorrortu, the companys chief operating officer, and Jorge Quiroz, its chief medical officer. But both will continue to advise Solid Bio under consulting agreements.

Photo by Flickr user reynermedia via a Creative Commons license

Frank Vinluan is an Xconomy editor based in Research Triangle Park. You can reach him at fvinluan [[at]] xconomy.com.

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Solid Bio Restructures to Get Halted Gene Therapy Study Back on Track - Xconomy

INDIANAPOLIS (WTHR) Four-month-old Anthony Schmitz has spent his entire life on a ventilator in intensive care at Riley Hospital for Children. But Wednesday he received a gene therapy infusion that might save and change his life.

Zolgensma is a prescription gene therapy that costs $2.1 million for the one-time dose.

The drug has proven effective in treating children with spinal muscular atrophy (SMA) under the age of two.

Indiana Medicaid first rejected the treatment for Schmitz because he was on a ventilator but gave approval on appeal.

"Early diagnosis is key and don't give up, said Louise Johnson, Schmitzs mother. It's not a death sentence, so just keep fighting. It's a baby. Keep fighting."

"I think this was really a group decision that said, 'Yeah, medically this made sense for this child. So, the cost kind of fell by the wayside, said Dr. Larry Walsh, Riley Children's Health Pediatric Neurologist.

Zolgensma replaces the function of the missing or nonworking SMN1 gene with a new, working copy of a human SMN gene.

Without treatment, Anthony's life expectancy was about two years.

"No mom wants to bury their child, said Johnson, who is from Evansville. So, I just want to see him grow up with his brothers."

Schmitz received the treatment Wednesday morning.

The infusion took just over an hour. But it will be weeks, if not months, before doctors know if the medicine is working for him.

"Even if we can make some smaller difference where we do help his respiratory function, where he doesn't need to be on a ventilator - things like that - that would be a tremendous win I think for he and his family, said Dr. Walsh.

"The future is unknown, so I'm still nervous, said Johnson. But I'm more excited. I can't wait."

Indiana adopted newborn screening for SMA in 2018.

Schmitz is now part of a handful of babies to receive gene therapy infusion at Riley for the rare, progressive genetic disease.

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Local infant receives $2.1 million gene therapy infusion after initial Medicaid rejection - WTHR

The clotting disorder hemophilia A may become the third gene therapy that the US Food and Drug Administration approves, joining treatments for a form of retinal blindness in 2017, and spinal muscular atrophy in 2019.

Biomarin Pharmaceutical Inc. has submitted a biologics license application to FDA and documentation of clinical trial results to the European Medicines Agency, with reviews slated to begin early this year at both organizations.

An article in the January 2 New England Journal of Medicine from a UK research team presents the findings of a phase 3 analysis of continuing success of a phase 1/2 trial (instead of a new phase 3 trial). The hemophilia gene therapy called valoctocogene roxaparvovec for now can mean a one-time infusion that replaces the more than 100-150 infusions of clotting factor a patient takes each year, and can also alleviate the painful joint bleeding that is the hallmark of the disease.

The different clotting disorders result from mutations in different genes in the pathway that knits a clot from protein fibrils. Hemophilia A is a deficiency of clotting factor VIII, and is also called classic hemophilia. It accounts for 80 percent of people with the disease. The clotting disorder that threaded through the royal families of Europe was hemophilia B, which is a deficiency of factor IX.

Both hemophilias are transmitted by genes on the X chromosome, and therefore affect only males. One in 10,000 males has hemophilia A, and it arises as a new mutation (rather than being inherited), in about a third of cases.

The world focused on hemophilia A with the sad case of Ryan White. Born in 1971, Ryan was diagnosed at 3 days of age when his circumcision wound wouldnt stop bleeding.

Like many people with hemophilia A at the time, Ryan received weekly factor VIII pooled from donors. That would prove tragic, as President Reagan was late to the game of testing the blood supply for viruses. He refused to even utter the word AIDS until actor Rock Hudson died of it in 1985.

That was too late for Ryan White.

HIV as the cause of the mysterious new epidemic was identified in 1983, although for a time it was known by different names.

In 1984, Ryan had a lung biopsy to diagnose severe pneumonia that revealed that he was HIV positive. Nearly 90% of people with hemophilia who received clotting factors from pooled donor blood between 1979 and 1984 contracted HIV and/or hepatitis C.

Ryan survived longer than predicted, until the end of 1990. In the intervening years he catalyzed AIDS activism when he was denied admittance to school, and he and his family fought the discrimination and ignorance.

Hemophilia A gene therapy has been twenty years in the making.

By the end of the decade that began with Ryan Whites death, the first gene therapy for hemophilia A was being tested in a clinical trial in Pittsburgh. I was fortunate to interviewthe first patient soon after he received the gene therapy.

Like Ryan White, Don Miller had nearly bled to death when he was circumcised. He recalled other frightening incidents.

I fell at my grandmothers house and had a one-inch-long cut on the back of my leg. It took five weeks to stop bleeding. It leaked slowly, so I didnt need whole blood replacement. But if I moved a little the wrong way, it would open and bleed again.

Millers treatments paralleled the history of countering hemophilia, from whole blood infusions, to plasma replacement, to cryoprecipitate (a frozen plasma product containing clotting factors). Then he injected pooled factor VIII three times a month. But somehow he never contracted HIV, and thats what got him into the gene therapy clinical trial.

I lucked out, Miller told me. Besides his good fortune at dodging the HIV bullet, he was in the right place at the right time. Hed been a librarian at the University of Pittsburgh, where the clinical trial was to take place.

On June 1, 1999, Don Miller received the first of three injections of retroviruses engineered to carry factor VIII. Chiron Corp., one of the original wave of big biotech companies that was absorbed into Novartis in 2006, designed and manufactured the vector.

The goal of this first round of hemophilia A gene therapy wasnt to cure the disease, but to boost factor VIII levels a scant 2 to 7 percent, which was expected to dampen bleeds.

Don Miller hadnt had any side effects when I spoke with him, but I dont know how he fared. At the time, he spoke freely to the media, but I contacted his physician and she couldnt provide an update due to HIPAA regulations.

But that first hemophilia A gene therapy was safe. Some patients had transient increases in factor VIII, and for 5 of the 13, bleeds became less frequent.

When the gene therapy field emerged from several setbacks that began with the death of Jesse Gelsinger in 1999, the hemophilia strategy changed to a safer and more efficient vector. The clinical trial leading to the current FDA submission began with 15 patients who received the factor VIII gene delivered in adeno-associated virus serotype 5, starting in June 2015. A year later, 13 of the men treated with a single infusion had normal or near-normal levels of factor VIII.

The AAV5 vector coaxes greater expression of the gene than does the retrovirus used in the earlier trial. Plus, an added bit of control DNA (a promoter) directs the vector to the types of cells that normally make the factor in the liver and to white blood cells.

AAV5s capacity is only about 4,700 DNA bases, so the big factor VIII gene is trimmed a bit (as it was for the earlier trial too). Still, it had to be delivered in two viral shipments, with some assembly required, like sending a cell phone and its charger in separate Amazon prime boxes.

Unlike other vectors (lentivirus and retroviruses), AAV remains separate from the cells chromosomes, forming a DNA circle called an episome.

Two of the 15 patients received doses too low (6 or 20 trillion viruses per kilogram of body weight) to have an effect. But six men receiving an intermediate dose of 40 trillion viruses had no bleeding events; the annual number of needed factor VIII infusions for the three-year study period fell from 155 to 0.5, and only one man had a bleed in a large joint.

The high-dose (60 trillion viruses) men did the best: none required factor VIII infusions, bleeding events, or large joint bleeds.

Analysis of factor VIII levels and various biomarkers of the gene indicated that of the 13 men who responded, one is considered to no longer have hemophilia, eleven have mild disease, and one has moderate disease.

It all adds up to what the researchers call a sustained, clinically relevant benefit. Said lead author John Pasi, from the Royal London Haemophilia Centre, Barts Health NHS Trust:

Our 2017 paper showed that gene therapy could significantly boost factor VIII levels in men with hemophilia A. Our new data are critical in helping the scientific and medical communities understand this pioneering technology. This latest study confirms both safety and long-term beneficial impact. A long-term treatment that effectively ends the life-long regular injections can transform care and massively improve the quality of life of hundreds of thousands of people born with this challenging genetic condition.

Once an advisory committee to FDA agrees, valoctocogene roxaparvovec will debut with a catchier brand name. It may cost in the $400,000 to $1 million range (or higher) of other gene therapies in the US and Europe, but considering that current therapies for hemophilia A are about $270,000 annually without complications and can exceed $1 million if there are, a one-and-done gene therapy for hemophilia A sounds like a good deal.

Ricki Lewis is the GLPs senior contributing writer focusing on gene therapy and gene editing. She has a PhD in genetics and is a genetic counselor, science writer and author of The Forever Fix: Gene Therapy and the Boy Who Saved It, the only popular book about gene therapy. BIO. Follow her at her website or Twitter @rickilewis

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Will 2020 see the debut of promising gene therapy for hemophilia A? It's up to the FDA. - Genetic Literacy Project

The U.S. Food and Drug Administration (FDA) has lifted the clinical hold on a Phase 1/2 trial designed to test the gene therapy candidate PR001 in patients with type 2 Gaucher disease.

The team atPrevail Therapeutics expects to initiate patient dosing in the first half of 2020.

Prevail was awaiting a decision by the FDA to test higher doses of PR001 than initially planned. This request was supported by preclinical evidence of greater efficacy with no safety issues at such dosages. The investigational new drug (IND) application of PR001, an essential step to opening a clinical study, had first been accepted in June 2019.

PR001 uses a modified, harmless version of an adeno-associated virus (AAV9) to deliver a fully working version of the GBA1 gene to nerve cells. Mutations in this gene cause Gaucher disease by producing a defective enzyme called beta-glucocerebrosidase, which leads to the accumulation of fatty molecules inside cells.

In type 2 Gaucher disease, called acute infantile neuronopathic Gaucher disease, these toxic fatty molecules build up in the patients brain from early infancy, resulting in neurological symptoms.

By restoring production of normal beta-glucocerebrosidase in affected brain cells, a single dose of PR001 is intended to ease Gaucher symptoms and modify disease course.

Work in mice and monkeys showed that PR001 now being developed in collaboration with Lonza Pharma & Biotech is well-tolerated, leads to the production of a functional enzyme in nerve cells, reduces the accumulation of fatty molecules, and improves motor function.

We are pleased to now have an active IND for PR001 for the nGD [neuronopathic Gaucher disease] indication and look forward to initiating a Phase 1/2 clinical trial in the first half of 2020, Asa Abeliovich, MD, PhD, Prevails founder and CEO, said in a press release.

Patients with nGD have the most severe form of Gaucher disease and a significant unmet need for therapies to treat their neurological manifestations. We believe PR001 has tremendous potential, he added.

In addition, the company plans to initiate another Phase 1/2 study in people with type 3 Gaucher later this year. Patients with this type also experience neurological symptoms, but they are milder and progress slower than those seen in patients with type 2 Gaucher.

Prevail is also developing PR001 for GBA1 mutation-related Parkinsons disease. Mutations in the GBA1 gene are one of the most common genetic risk factors for Parkinsons. A Phase 1/2 clinical trial (NCT04127578), called PROPEL, is currently recruiting participants with Parkinsons to test PR001 administered directly into the cerebrospinal fluid (the liquid surrounding the brain and spinal cord).

With over three years of experience in the medical communications business, Catarina holds a BSc. in Biomedical Sciences and a MSc. in Neurosciences. Apart from writing, she has been involved in patient-oriented translational and clinical research.

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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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Type 2 Gaucher Trial of PR001 Gene Therapy Has Hold Lifted by FDA - Gaucher Disease News