I
n a Phase 3 gene therapy trial intended to improve vision among patients with Leber hereditary optic neuropathy, recipients gained somewhat better sight in both eyes even though only one was treated. The results and an investigation into possible explanations for the findings were published December 9 in Science Translational Medicine.
The paper has very strong clinical implications that a single injection maybe is enough for bilateral effects, says Thomas Corydon, who studies ocular gene therapy at Aarhaus University in Denmark and was not involved in the work.
The onset of Leber hereditary optic neuropathy (LHON) is sudden. Patientsusually young menstart losing vision at the center of one eye. Within months, the other eye follows, leaving them legally blind. The disease is caused by a point mutation in the mitochondrial genome that leads to dysfunction and death of retinal ganglion cells, the axons of which make up the optic nerve. About 70 percent of patients have the same mutation, known as MT-ND4.
If you're going to start somewhere, it makes sense to tackle this variant, says Patrick Yu-Wai-Man, an ophthalmologist at the University of Cambridge in the United Kingdom. He and his collaborators, including teams from GenSight Biologics and a group led by University of Pittsburg Medical Center ophthalmologist Jos-Alain Sahel, as well as other groups, previously showed that the point mutation could be corrected in animal models and in cell culture using gene therapy.
Its difficult to get genetic material into the mitochondrial genome because mitochondria have two membranes, an outer and inner membrane, Yu-Wai-Man explains. In the clinical trial, he, Sahel, and colleagues overcame this hurdle by injecting an AAV vector containing a wildtype copy of the ND4gene with an added mitochondrial-targeting sequencea strategy that had already been shown to correctly direct the protein product of ND4 and other mitochondrial genes to the organelle.
Each of 37 patients received the therapeutic virus via a single injection into the vitreous fluid within one eye six to 12 months after the onset of vision loss. They also got a sham treatment in the other eye: a surgeon pressed the eye with a blunt cannula to simulate an injection.
We thought that, if there was going to be an effect, it would be isolated to that eye and then the other one would be the perfect internal control, Yu-Wai-Man tells The Scientist. But as it turns out, that wasnt the case.
With a slight delay in the sham-treated eye, both eyes started to improve. By 96 weeks after treatment, 29 of the patients had gained visual acuity in both eyes and reported increases in their quality of life.
Patients do improve, but, even with the treatment, they still function at a very low level, says Byron Lam, an ophthalmologist at the University of Miami who was not involved in the study. Most of the subjects were still near legal blindness at the end of the study.
To determine how the bilateral effect might be happening, Yu-Wai-Man and colleagues injected the therapeutic virus into one eye of three monkeys. Three months later, they found viral DNA in the noninjected eye and optic nerve. This raises the possibility that the viral vector supplies the wildtype protein in the untreated eye, but its not firm proof.
Finding viral DNA in the untreated eye in primates is a little short of being definitive because DNA expression alone doesnt prove that youre getting a therapeutic effect. Detecting DNA doesnt mean there is mRNA expression or protein production, says Mark Pennesi, an ophthalmologist at Oregon Health & Science University who did not participate in the work.
Previous work has shown that there could be transneuronal spread of the vector, but we also need to keep a critical mind and think that there might be other explanations, agrees Yu-Wai-Man. It could be that injecting the vector in one eye leads to some form of localized inflammation that induces mitochondrial biogenesis, thus making the mitochondria work better, he adds. Another option is that improvement in one eye leads to reorganization in the part of the brain that interprets signals from the eye, which could enhance vision overall.
Clearly, further investigations are needed to understand the underlying mechanisms of how the interocular diffusion of viral DNA vector occurs and whether there are other mechanisms by which the optic nerves directly communicate, Bin Li, an ophthalmologist at Tongji Hospital in China who was not involved in the study, writes in an email to The Scientist.Li explains that his group has also reported that material injected in one eye can reach the other optic nerve.
These findings have implications for how this type of research should be performed in the future, he writes. Theyve shown that contralateral sham-treated eyes cannot serve as true internal control for clinical studies.
When you read this paper, you get a little excited, and then in some ways, you get a little disappointed, because it does look like theres some kind of positive effect with this treatmentthat it does do something more than what would happen with just the natural history of the disease. Unfortunately, the results are confounded by the fact that you treat one eye, but then there is improvement in the untreated control eye, Pennisi tells The Scientist. The question then really becomes . . . why did you get that result?
Along with academic collaborators, Yu-Wai-Man, who consults for GenSight Biologics, will continue to explore this question as they focus on ongoing clinical trials of this therapeutic.
P. Yu-Wai-Man et al., Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy,Science Translational Medicine,doi:10.1126/scitranslmed.aaz7423, 2020.
Correction (December 14): The story has been updated to remove mention of a company that was not involved in the work and to specify which fluid compartment in the eye was injected.The Scientist regrets the error.
Originally posted here:
Gene Therapy in One Eye Improves Vision in Both Eyes - The Scientist
- 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]