A group of gene therapy experts called for better research tools and more careful monitoring of side effects to treatment, but stopped short in a high-profile meeting Thursday of advocating for major changes to how studies in the fast-growing field are conducted.
The committee, which the Food and Drug Administration convened for advice on the risks to gene therapy, proposed a number of ways research could potentially be made safer, such as by improving how patients are screened for clinical trials. None of the panel members, though, suggested slowing research in any significant fashion, rejecting, for instance, the idea of imposing an upper limit on gene therapy doses to lower risks.
"While the meeting was an excellent update on pre-clinical and clinical adverse events in the field, it largely left untouched what measures might actually be taken to help future-proof this field," said Anthony Davies, founder and CEO of Dark Horse Consulting, which specializes in gene therapy.
Experts said that inconsistent standards in how gene therapies are produced, and how certain safety risks are assessed, made it difficult to come up with recommendations that could be broadly applied.
The meeting, which will continue Friday, comes after a series of safety incidents in gene therapy clinical trials resurfaced some longstanding concerns, as well as new worries about the use of high treatment doses. The deaths last year of three children in a study of a neuromuscular disease therapy, in particular, appear to have spurred the FDA to seek the experts' advice.
"Our enthusiasm for this field must be balanced by caution," said Wilson Bryan, director of the FDA's Office of Tissues and Advanced Therapies, in a presentation opening the meeting Thursday. "The greatest risks in drug development fall on the patients who receive an investigational product."
The FDA split the first day of the meeting into two sessions, focusing the first on the persistent worry that injecting genes into cells might eventually spur cancer, and the second on the liver injury that can be caused by treatment. The committee will discuss brain toxicity Friday.
In discussing the risk of cancer, experts spent considerable time weighing findings from testing in animals, some of which dates back more than 20 years. Results have shown that a commonly used delivery tool, the adeno-associated virus or AAV, can fuse itself into the genomes of certain animals and, at least in mice, that integration is associated with liver cancer.
Concerns around whether this risk can play out similarly in humans grew earlier this year when a patient given an experimental hemophilia gene therapy developed by the biotech company UniQure was diagnosed with liver cancer.
UniQure has since exonerated its gene therapy, and experts at the FDA panel noted the risk remains theoretical. Other research in larger animals and in humans haven't replicated the worrisome findings in mice. A study following dogs given a hemophilia gene therapy and presented at the meeting by University of Pennsylvania researcher Denise Sabatino, for example, showed AAV did get into the genome but didn't lead to cancer.
"[T]his is something that will need to be monitored very carefully, [but] so far, the signal in the clinic doesn't seem to be very strong," said Christopher Breuer, the director of the center for regenerative medicine at Nationwide Children's Hospital, a top gene therapy hub.
Pfizer, which has invested heavily in gene therapy, argued companies shouldn't have to run more studies looking for integration events in animals until there is "clear causality in humans," according to a public comment filed with the FDA. Pfizer claimed additional experiments using human cell lines to assess risk would be more relevant.
FDA panelists, meanwhile, said longer animal tests might more effectively capture any cancer risk of AAV, as will tracking the health of the more than 800 children who have so far received the Novartis spinal muscular atrophy treatment Zolgensma. Experts also suggested closer scrutiny of gene therapy components.
But several were hesitant to make broad recommendations to the FDA as there aren't set rules for every aspect of how gene therapies are made.
"We are starting to get a sense of the scientific issues that are out there, but we need to start to drive towards some type of standardization," said Taby Ahsan, the head of biologics analytical development at MD Anderson Cancer Center. "Understanding that will help us give solid recommendations for preclinical study design as we move forward."
While the cancer risk of AAV gene therapy in humans remains theoretical, liver toxicity is one of the most common side effects reported in clinical testing to date and, in a few cases, has led to serious health problems.
In a study of a gene therapy developed by Audentes Therapeutics, for instance, three young children given a very high dose developed liver damage and later died, although the exact link between their deaths and the treatment is still unclear. Two cases of acute liver failure have also been reported in patients treated with Zolgensma, and many hemophilia patients across several gene therapy studies have experienced significant increases in liver enzyme counts, a potentially worrisome sign.
"I think that a lot of the studies have missed opportunities to involve hepatologists early on," said Theo Heller, a liver specialist at the National Institute of Diabetes and Digestive and Kidney Diseases, at the meeting. "Hepatotoxicity is such a common side effect of this therapy."
Experts did call on researchers to more comprehensively assess and screen for preexisting liver conditions, which they said might affect how side effects develop.
"We do need careful screening," said Lisa Butterfield, the meeting's chair and vice president of the Parker Institute for Cancer Immunotherapy at the University of California, San Francisco. "We need to focus on more than just fluctuations in blood work."
The committee made few other concrete recommendations on how best to manage the risk of liver problems, though. In particular, they opposed placing an upper limit on the gene therapy doses that could be tested, although research suggests the worst health consequences to liver toxicity only emerge at higher doses.
A major sticking point, some members noted, was the difficulty in characterizing the make-up of gene therapy doses, which can contain extraneous material alongside the therapeutic DNA.
"It confounds this question of toxicity and toxic side effects of AAV perhaps because, again, going back, we don't have reference standards for the field," said Charles Venditti, a senior investigator with the National Human Genome Research Institute.
Read more:
At FDA meeting, gene therapy experts wrestle with field's blindspots - BioPharma Dive
- About the Gene Therapy Review - November 8th, 2009 [November 8th, 2009]
- Contribute an Article - November 8th, 2009 [November 8th, 2009]
- EBSCO Publishing Deal - November 8th, 2009 [November 8th, 2009]
- Advertising Opportunities - November 8th, 2009 [November 8th, 2009]
- Instructions for Authors - November 8th, 2009 [November 8th, 2009]
- Isis Collaboration With Ortho-McNeil Inc for Metabolic Diseases - November 8th, 2009 [November 8th, 2009]
- Dystrophin Gene Transfer safe in Duchenne muscular dystrophy - November 8th, 2009 [November 8th, 2009]
- Researchers Identify Gene for Rare Form of Spinal Muscular Atrophy - November 8th, 2009 [November 8th, 2009]
- Fatal brain cancer tamed by New gene therapy - November 8th, 2009 [November 8th, 2009]
- Gene therapy effective in fighting obesity in mice - November 8th, 2009 [November 8th, 2009]
- Genzyme gene therapy for people with peripheral artery disease failed in a clinical trial to help them regain some mobility - November 8th, 2009 [November 8th, 2009]
- Gene Therapy May Stall Inherited Emphysema - December 31st, 2009 [December 31st, 2009]
- Gene Therapy and Stem Cells Save Limb - December 31st, 2009 [December 31st, 2009]
- TNVitamins.com – $10 Off Of $50 order - May 7th, 2011 [May 7th, 2011]
- 15% Off Any PetAlive Order - May 7th, 2011 [May 7th, 2011]
- At PetAlive – $10 off order of $50 or more - May 7th, 2011 [May 7th, 2011]
- Native Remedies coupon – 5% Off Any Order - May 7th, 2011 [May 7th, 2011]
- Native Remedies – Save $5 coupon - May 7th, 2011 [May 7th, 2011]
- Welcome to the Gene Therapy Review - May 15th, 2011 [May 15th, 2011]
- Editorial Board - May 15th, 2011 [May 15th, 2011]
- Gene Therapy Job Board - May 15th, 2011 [May 15th, 2011]
- Corporate Membership - May 22nd, 2011 [May 22nd, 2011]
- Native Remedies coupon – 25% Off Any Order - May 29th, 2011 [May 29th, 2011]
- What is Gene Therapy? - June 19th, 2011 [June 19th, 2011]
- Research and Markets: Recent Advances in Cancer Research and Therapy - Increased Research on one of the Major Causes ... - April 25th, 2012 [April 25th, 2012]
- Gene Therapy part 2 - Video - April 30th, 2012 [April 30th, 2012]
- Gene therapy reverses Parkinson's symptoms: study - Video - April 30th, 2012 [April 30th, 2012]
- CBS This Morning - Gene therapy reverses Parkinson's symptoms: study - Video - April 30th, 2012 [April 30th, 2012]
- Engineering adenoviruses for gene therapy - Video - April 30th, 2012 [April 30th, 2012]
- What is Gene Therapy (The General Explains) - Video - April 30th, 2012 [April 30th, 2012]
- What is Gene Therapy - Animation - Video - April 30th, 2012 [April 30th, 2012]
- Microbiology Gene Therapy - Video - April 30th, 2012 [April 30th, 2012]
- Gene Therapy in Detail - Video - April 30th, 2012 [April 30th, 2012]
- Breakthrough in Haemophilia treatment - Video - April 30th, 2012 [April 30th, 2012]
- Virology Seminar - Gene Therapy - April 30th, 2012 [April 30th, 2012]
- Gene Therapy Video - Video - April 30th, 2012 [April 30th, 2012]
- Study: Gene Therapy for HIV Safe, But Effectiveness Still Unclear - May 4th, 2012 [May 4th, 2012]
- Gene Therapy Safe in Decade-Long HIV Study That May Widen Use - May 4th, 2012 [May 4th, 2012]
- Gene therapy for HIV safe, but effectiveness still unclear - May 4th, 2012 [May 4th, 2012]
- A Step Forward For Gene Therapy To Treat HIV - May 4th, 2012 [May 4th, 2012]
- A Media Event on Clinical Developments in Gene and Cell Therapy - May 4th, 2012 [May 4th, 2012]
- Families of SMA Awards New Funding to Advance a CNS Delivered Gene Therapy for Spinal Muscular Atrophy - May 4th, 2012 [May 4th, 2012]
- AIDS gene therapy safe -- is it a "cure"? - May 4th, 2012 [May 4th, 2012]
- Generational Achievements in Gene and Cell Therapy Honored at ASGCT 15th Annual Meeting - May 5th, 2012 [May 5th, 2012]
- Lewis speaks on gene therapy at Lexington Community Education event - May 7th, 2012 [May 7th, 2012]
- Penn researchers report a gene-therapy success - May 10th, 2012 [May 10th, 2012]
- Gene therapy for hearing loss: Potential and limitations - May 13th, 2012 [May 13th, 2012]
- Gene therapy extends mouse lifespan by 24 pc - May 16th, 2012 [May 16th, 2012]
- Gene therapy dramatically extends mouse lifespan - May 16th, 2012 [May 16th, 2012]
- Gene therapy may extend life: Study - May 16th, 2012 [May 16th, 2012]
- First gene therapy successful against aging-associated decline: Mouse lifespan extended up to 24% with a single ... - May 16th, 2012 [May 16th, 2012]
- Gene Therapy Extends Mouse Lifespan - May 16th, 2012 [May 16th, 2012]
- Gene Therapy for Brain Disease - May 17th, 2012 [May 17th, 2012]
- Children with rare, incurable brain disease improve after gene therapy - May 17th, 2012 [May 17th, 2012]
- FIRST Anti-Aging Gene Therapy (Brainstorm Ep72) - Video - May 23rd, 2012 [May 23rd, 2012]
- Gene therapy can correct forms of severe combined immunodeficiency - May 25th, 2012 [May 25th, 2012]
- RetroSense Therapeutics Completes pre-IND Meeting for RST-001 - May 25th, 2012 [May 25th, 2012]
- Gene therapy can correct forms of severe combined immunodeficiency, study suggests - May 26th, 2012 [May 26th, 2012]
- Alliance for Cancer Gene Therapy celebrates 10 years - May 29th, 2012 [May 29th, 2012]
- Research on gene therapy by Prasad Eye - June 1st, 2012 [June 1st, 2012]
- Baxter Announces Collaboration with Chatham Therapeutics for Factor IX Hemophilia B Gene Therapy Treatment - June 5th, 2012 [June 5th, 2012]
- Transgenomic Launches Breakthrough Blood-Based Cancer Gene Testing Technology at 2012 ASCO Annual Meeting - June 5th, 2012 [June 5th, 2012]
- Baxter Inks Deal with Chatham - June 6th, 2012 [June 6th, 2012]
- PIK3CA Gene Patent for Predicting Response to Targeted Therapy Issued – Exclusively Licensed to Transgenomic - June 11th, 2012 [June 11th, 2012]
- SalutarisMD Announces Positive Case Report of a New Investigational Wet AMD Therapy at ARVO - June 15th, 2012 [June 15th, 2012]
- Research and Markets: Gene Therapy - Global Strategic Business Report - 2012 - June 15th, 2012 [June 15th, 2012]
- New York Law Firm’s MesotheliomaHelp.net Site Publishes Interview with Gene Therapy Author - June 17th, 2012 [June 17th, 2012]
- uniQure Extends Collaboration with Protein Sciences Corporation on Use of its expresSF+® Cell Line for Gene Therapy - June 19th, 2012 [June 19th, 2012]
- Anti-cocaine vaccine described in Human Gene Therapy Journal - June 19th, 2012 [June 19th, 2012]
- bluebird bio Receives U.S. and European Orphan Drug Designation for Novel Gene Therapy to Treat Adrenoleukodystrophy - June 19th, 2012 [June 19th, 2012]
- Close to a cure: Greater Hartford takes on rare Jewish genetic disease - June 19th, 2012 [June 19th, 2012]
- Gene Therapy Helps Treat Children with Rare Brain Disorder - June 20th, 2012 [June 20th, 2012]
- Gold nanoparticles capable of 'unzipping' DNA - June 21st, 2012 [June 21st, 2012]
- ‘Gene-silencing’ drug can halt and reverse deadly brain disorder - June 21st, 2012 [June 21st, 2012]
- uniQure Collaborates with UCSF on GDNF Gene Therapy in Parkinson's Disease - June 22nd, 2012 [June 22nd, 2012]
- Gene-silencing method offers possible therapy for Huntington's disease - June 22nd, 2012 [June 22nd, 2012]
- Gene mutations cause massive brain asymmetry - June 24th, 2012 [June 24th, 2012]
- Research and Markets: Translational Regenerative Medicine - Oncology, CNS and Cardiovascular-Rich Pipeline Features ... - June 25th, 2012 [June 25th, 2012]
- Stress Blocks Gene That Guards Brain Against Depression - June 26th, 2012 [June 26th, 2012]
- Targeted gene therapy enhances treatment for Pompe disease - June 26th, 2012 [June 26th, 2012]