Sunday, May 25, 2014

Menu 21: A List of Writeups on Gene Therapy Used in Ophthalmology

As with my menu on stem cells used in ophthalmology (Menu 20), here is one for the current articles on the use of gene therapy in ophthalmology, with links to the full writeups.

(Updated May 25, 2014)

Gene Thearpy

After several discussions with Sean Ainsworth, the founder of RetroSense, and much online research, I think I have learned a little about what gene therapy is about, and its application in ophthalmology, especially in the possible restoration of vision in those who suffer from retinitis pigmentosa (RP). Thanks to Sean for whetting my appetite -- here is what I have learned.

In an announcement today, Oxford BioMedica said that it had gained approval from the FDA to begin a Phase I/IIa Clinical Trial for a form of Usher’s Syndrome, Type 1B, which leads to progressive retinitis pigmentosa combined with a congenital hearing defect.

In a news release that I found on the net, I learned that the Foundation Fighting Blindness was going to put $8.25 million into six gene therapy projects, either already underway or about to start. The release contains good information about several projects that I knew about, and others that I did not.

In  another of the presentations made during the Retina SubSpecialty Day Meeting, Dr. Stephen Tsang presented on factors and the genetics of retinitis pigmentosa. His paper was based on the article previously published by he and his co-author, Kyle Wolpert, that appeared in the November 2010 issue of Retinal Physician.

Gene Therapy in Ophthalmology Update 4: Table of Companies and Institutions Participating Nov. 2011

Again, this table is currently out-of-date. See Update 16.

A writeup about a start-up company, Hemera Biosciences, with a gene therapy approach to treating dry AMD.

Thanks to my friends at the Foundation Fighting Blindness, I learned about this first human clinical trial using gene therapy for treating recessive retinitis pigmentosa.

In this opus, I discuss my reasons why I think 2012 is going to be the year for gene therapy and also presented my table of current clinical trials underway. (Again, note there is now an updated table available via Update 16.)

A report on the progress being made in treating Leber’s using gene therapy, as reported by the Foundation Fighting Blindness.

Gene Therapy in Ophthalmology Update 9: Oxford BioMedica/OHSU Preparing to Treat First Usher Syndrome Patient & Oxford BioMedica Ophthalmic Program Update Mar. 2012

A report on the start of the program to treat Usher Syndrome patients at OSHU, and an update on other ophthalmic programs underway by Oxford BioMedica.

Gene Therapy in Ophthalmology Update 10: Gene Therapy Research in Dogs Cures X-Linked Retinitis Pigmentosa – Paves the Way for Similar Treatment in Humans  Mar. 2012

Researchers at several universities and laboratories collaborated to treat dogs afflicted with the x-linked form of retinitis pigmentosa, to deliver the therapeutic RPGR gene specifically to the diseased rods and cones, which led to functional and structural recovery. This is the first proof that this condition is treatable in an animal model and the researchers feel the results are promising and relevant for translation to humans afflicted with this disease.

Gene Therapy in Ophthalmology Update 11: Clinical Trial Details May 2012

In attempting to determine how many patients had been treated with gene therapy for eye disorders, I quickly found that no one was keeping track – at least no one that I could find.

So, I decided to try and get this data. I have now found reliable data for more than two-thirds of the 16 clinical trials underway and present this information in my new table. My latest table (available via Update 16) contains all of the newest data.

Editors Note: See Update 16 for access to the latest versions of the three tables.

Gene Therapy in Ophthalmology Update 12: First Gene Therapy Approval on the Horizon Jul. 2012

As Andrew Pollack writes in today’s NYTimes, “After more than two decades of dashed expectations, the field of gene therapy appears close to reaching a milestone: a regulatory approval. The European Medicines Agency has recommended approval of a gene therapy to treat a rare genetic disease.”

The therapy recommended for approval in Europe, called Glybera, was developed by uniQure, a Dutch company. It treats lipoprotein lipase deficiency, a disease that affects only several hundred people in the European Union and a similar number in North America.

People with the disease have a genetic mutation that prevents them from producing an enzyme needed to break down certain fat-carrying particles that circulate in the bloodstream after meals. Without the enzyme, so much fat can accumulate that the blood looks white rather than red.

The reason I believe that this is important is because it brings “legitimacy” to the whole field of regenerative medicine. As readers of this online Journal are aware, my interest is in the field of ophthalmology. As you may be further aware, I am currently tracking eleven clinical trials involving the use of stem cells to treat ophthalmic disorders and sixteen gene therapy clinical trials. Several of these are showing promising results and the above approval, when it comes, will bring increased attention to the whole of this field, including the ophthalmic trials.

Gene Therapy in Ophthalmology Update 13: New Clinical Site for Usher Syndrome Clinical Trials  Jul. 2012

The Foundation Fighting Blindness and Oxford BioMedica announced funding for a second clinical site to conduct a gene therapy trial for Ushers Syndrome. The site will be the Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts in Paris, and will join the ongoing clinical trial being held at the Oregon Health & Science University's Casey Eye Institute.

Gene Therapy in Ophthalmology Update 14: Early Positive Results in Ongoing Gene Therapy Wet AMD and Stargardt’s Disease Studies Aug. 2012

Last week, Oxford BioMedica and its partner Sanofi announced positive results in their ongoing gene therapy clinical trials for wet AMD and Stargardt’s disease. In an interim review of their Phase I (RetinoStat) and Phase I/IIa (StarGen) trials, the Data Safetly Monitoring Board (DSMB), an independent panel of specialists in the fields of ophthalmology, virology and vectorology, gave the go ahead to proceed to a final patient cohort in the Phase I study in the case of the RetinoStat trial, and to a third patient cohort in the Phase I/IIa study of the StarGen trial.

Gene Therapy in Ophthalmology Update 15: First Gene Therapy Treatment Approved! Nov. 2012

As I first wrote back in July (Update 12: First Gene Therapy Approval on the Horizon), the first approval of a gene therapy application in medicine was expected soon. It has now been accomplished. On November 2nd, the European Medicines Agency gave final approval to a gene therapy approach to treat a rare genetic disease.

The therapy, given approval in Europe, called Glybera, was developed by uniQure, a Dutch company. It treats lipoprotein lipase deficiency (LPLD), a disease that affects only several hundred people in the European Union and a similar number in North America.

The reason I am noting this accomplishment in this space, where I normally write about treatments for ocular diseases is, because it brings “legitimacy” to the whole field of regenerative medicine. As readers of this online Journal are aware, my interest is in the field of ophthalmology. As you may be further aware, I am currently tracking twenty one clinical trials involving the use of stem cells (or cell threapy) to treat ophthalmic disorders and sixteen gene therapy clinical trials. Several of these are showing promising results and the above approval will bring increased attention to the whole of this field, including the ophthalmic trials.

Gene Therapy in Ophthalmology Update 16: Current Tables Now Online Jan. 2013/May 2014

Access to the three updated tables of information about the companies and institutions active in gene therapy, the ophthalmic applications being pursued, and the clinical trials underway and completed.

Gene Therapy in Ophthalmology Update 17: Hemera Biosciences Obtains Initial Funding Mar. 2013

Hemera biosciences has obtained initial funding, along with the issuance of a US Patent covering their technology and can now begin manufacturing its drug, soluble CD59 (protectin), perform animal toxicology, and initiate a phase 1 clinical study.

To review, HMR59 is a gene therapy using an AAV2 vector to express a soluble form of a naturally occurring membrane bound protein called CD59 (sCD59), which blocks MAC. Membrane attack complex is the final common pathway of activation of the complement cascade, and is composed of complement factors C5b, C6, C7, C8 and C9 that assemble as a pore on cell membranes. The MAC pore induces ionic fluid shifts leading to cell destruction and ultimate death. 

HMR59 works by increasing the production of sCD59 by ocular cells. The sCD59 released from the cells will circulate throughout the eye and penetrate the retina to block MAC deposition and prevent cellular destruction. By blocking MAC, the remainder of the upstream complement cascade is left intact to perform its normal homeostatic roles.

Gene Therapy in Ophthalmology Update 18: A RetroSense Update  Mar. 2013

Since I first wrote about RetroSense in November 2010, I have learned that they are using a unique technology, called Optogenetic Therapy to treat retinitis pigmentosa and dry AMD. Optogenetics combines gene therapy and optical methods to provide vision where there is none.

The gene therapy allows the delivery of an “opsin” that converts second- or third-order non-light sensitive cells to become light sensitive to mimic the function of rods and cones.

Gene Therapy in Ophthalmology Update 19: A New Virus Vector for Safer Delivery of Gene Therapies Jun. 2013

Researchers at UCal Berkeley have found a gene therapy vector that can deliver genes deep into the retina via intravitreous delivery, instead of using a needle to deliver the virus sub-retinally.

This eliminates the need for a vitrectomy, anesthesia and a hospital stay to treat patients, allowing for a simple short office visit and injection into the vitreous, similar to the way anti-VEGF drugs for age-related macular degeneration are currently delivered.

Gene Therapy in Ophthalmology Update 20: Oxford BioMedica Gene Therapy Clinical Trials Resume Oct. 2013

As I have recently noted, both Oxford BioMedica and Genzyme had stopped recruiting for their respective gene therapy clinical trials this summer. Oxford announced the reason for its stoppage, but no word from Genzyme (and no response to my attempts to find out).

Well, Oxford announced today that it had resumed its clinical trial after receiving clearances from both the FDA and the French regulatory agency, ANSM.

Gene Therapy in Ophthalmology Update 21: New Gene Therapy Company, Spark Therapeutics, Launches Oct. 2013

Children’s Hospital of Philadelphia has spun out a new gene therapy company, Spark Therapeutics, that has taken over CHOP’s gene therapy programs. The new company takes over the advanced clinical trial for treating Leber’s Congenital Amaurosis, as well as an earlier stage trial for treating hemophilia B.

The Phase III clinical trial for Leber’s, is expected to be completed in mid-2015, and could become the first FDA-approved gene therapy treatment in the U.S.


Recently, I encountered a unique referral source, goldenretrevor/pra-research. This piqued my curiosity and I went to the site and took a look. It turns out that the site is run by the owner of a Golden Retriever, named Trevor, along with two Labrador Retriever siblings. It seems that Trevor had been diagnosed with photo receptor cone disease (prcd), associated with progressive retinal atrophy (PRA). This was discovered when the dog was a puppy and the owner decided to look into this disease to see if there was anything that could be done to prevent him from going blind.

In doing extensive research, the owner, Katie McCormick, discovered that there was little research being done in the field of PRA in animals, but that PRA is genetically similar to retinitis pigmentosa (RP) in humans, as one study noted, "Identical mutation in a novel retinal gene causes progressive rod-cone degeneration (prcd) in dogs, and retinitis pigmentosa in man." And, there was lots of research being done on RP.

In her blog entry on PRA Research, Katie describes how she set up a “Google Alert” using the terms “progressive retinal atrophy” and “retinitis pigmentosa” – which is how she found my Journal article on The Use of Gene Therapy in Treating RP and Dry AMD.

A Novel Gene Therapy Approach to Treating the Wet Form of AMD: The BioFactoryTM From Avalanche Biotech  Feb. 2012

I originally contacted this company in November 2010, when they were still in “stealth mode” and weren't able to share details about what they were doing. Recently, the company got back in touch to provide an update, having announced, in December 2011, a clinical trial of their gene therapy approach to treating the wet form of AMD.

Since their approach is unique, and possibly “game changing” for the treatment of the wet form of AMD, I asked if I could prepare a writeup about the company and its technology for publication in my online Journal, and the co-founder and CEO Tom Chalberg agreed to answer my questions, as best as he could. So, here in their own words is what Avalanche Biotech is all about.

An Update on Avalanche Biotechnologies: A Potential Longer-Lasting Wet AMD Treatment? May 2014

With the news of a collaboration between Avalanche and Regeneron, we decided to update our initial report on Avalanche to describe what the collaboration is all about, as well as a brief update of the clinical trial underway using Avalanche’s Ocular BioFactory. Could this approach to treating wet AMD lead to fewer injections – once every 18 months or several years – in controlling this sight-robbing disease?

Thursday, May 08, 2014

An Update on Avalanche Biotechnologies: A Potential Longer-Lasting Wet AMD Treatment?

There is breaking news this week about Avalanche Biotechnologies and I would like to share it, as well as a brief update on the clinical trial underway using their proprietary gene therapy approach to treating the wet form of AMD.

(Editors Note: For a comprehensive look at the company, its people, and technology, please take a look at my original writeup, placed online in late February 2012: A Novel Gene Therapy Approach to Treating the Wet Form of AMD: The BioFactoryTM From Avalanche Biotech.)

Now for the breaking news. On May 5th, in a joint announcement, Avalanche and Regeneron Pharmaceuticals said that they were undertaking a broad collaboration “to discover, develop and commercialize novel gene therapy products for the treatment of ophthalmic diseases. The collaboration covers novel gene therapy vectors and proprietary molecules, discovered jointly by Avalanche and Regeneron, and developed using the Avalanche Ocular BioFactoryTM, an adeno-associated virus (AAV)-based, proprietary, next-generation platform for the discovery and development and delivery of gene therapy vectors for ophthalmology.”

Under the terms of the agreement, Avalanche will receive an upfront cash payment, contingent payments of up to $640 million upon achievement of certain development and regulatory milestones, plus a royalty on worldwide net sales of collaboration products. The collaboration covers up to eight distinct therapeutic targets, and Regeneron will have exclusive worldwide rights for each product it moves forward in clinical development. In addition, Avalanche has the option to share in development costs and profits for products directed toward two collaboration therapeutic targets selected by Avalanche.

As part of the agreement, Regeneron has a time-limited right of first negotiation for certain rights to AVA-101, Avalanche's gene therapy product targeting vascular endothelial growth factor (VEGF) currently under development for the treatment of wet age-related macular degeneration (AMD), upon completion of the ongoing Phase 2a trial.

"We look forward to the opportunity to collaborate with Avalanche, a leader in the field of next-generation gene therapy technologies," said George D. Yancopoulos, M.D., Ph.D., Chief Scientific Officer of Regeneron and President of Regeneron Laboratories. "This collaboration highlights the commitment by Regeneron to invest in potentially breakthrough therapies that could benefit patients with sight-threatening diseases."

"We are excited to work with Regeneron to discover and develop novel gene therapy medicines for serious eye diseases," said Thomas W. Chalberg, Ph.D., co-founder and Chief Executive Officer of Avalanche Biotechnologies. "The collaboration will bring together Avalanche's novel platform technology with Regeneron's proprietary molecules and research capabilities, with the goal of creating a new class of next-generation biologics in ophthalmology. Regeneron is a terrific partner for their scientific leadership, as well as their product development capabilities and commercialization track-record."

For those of you not familiar with Regeneron Pharmaceuticals, they are a leading science-based biopharmaceutical company based in Tarrytown, New York that discovers, invents, develops, manufactures, and commercializes medicines for the treatment of serious medical conditions. Regeneron commercializes medicines for eye diseases, colorectal cancer, and a rare inflammatory condition, and has product candidates in development in other areas of high unmet medical need, including hypercholesterolemia, oncology, rheumatoid arthritis, asthma, and atopic dermatitis.

In the eye disease field, their major product is Eylea, an anti-vascular endothelial growth factor (VEGF) agent that is intravitrealy injected for the treatment of  wet AMD, in competition with Roche/Genentech's Avastin, and Lucentis.

The problem with the use of the current anti-VEGF drugs is the need for up to eight to twelve injections yearly, to maintain the gains in visual acuity and/or prevent the re-occurrence of the underlying neovascular degeneration. The reason for the collaboration with Avalanche is that its BioFactoryTM is expected to deliver a therapeutic protein to combat wet AMD for at least 18 months and, potentially for several years, from a single injection. (For more about this technology, again, please see my initial writeup.)

And that leads to the recent clinical trial update provided by founder and CEO, Thomas Chalberg at the the Angeogenisis, Exudation and Degeneration 2014 Conference, held in Miami, FL on February 8, 2014:

Retina Today, April 2014

Subretinal delivery of an ocular gene therapy drug was well tolerated, required fewer injections of anti-VEGF, and improved visual acuity in a phase 1 randomized clinical trial, reported Thomas W. Chalberg, PhD, at Angiogenesis, Exudation, and Degeneration 2014.(1)

One hundred microliters of AVA-101 (Ocular BioFactoryTM, Avalanche Biotechnologies) was injected subretinally in patients. Anti-VEGF protein levels ramp-up over 6 to 8 weeks, during which 2 injections of ranibizumab (Lucentis) were given. After 8 weeks, ranibizumab was only given to the treatment group on a prn basis as rescue therapy.

Patients were tracked for 12 months after injection and came in for monthly visits. The control group, which did not receive an injection of AVA-101, required a mean 3 injections of ranibizumab during the 12-month period. The treatment group required a mean 0.3 ranibizumab injections over the same period.

Patients received ranibizumab injections if fluid appeared on OCT or fluorescein angiography, or if there was vision loss attributable to increased area of choroidal neovascularization.

Patients in the study had experience with anti-VEGF treatment, averaging 18 intravitreal anti-VEGF treatments prior to study enrollment.

“Because these patients are coming heavily pre-treated, we didn’t necessarily expect them to gain additional vision,” Dr. Chalberg said. “But treated patients actually gained between 9 and 12 letters over 12 months.”

Dr. Chalberg reported no drug-related adverse events, retinal tears, or retinal detachments. Procedure-related adverse events were minor and self-resolving.

“Ocular gene therapy might be a long-term viable option for patients with wet AMD,” Dr. Chalberg said.

AVA-101 is a strand of therapeutic DNA packaged inside an adeno-associated virus (AAV), which, when injected subretinally, up-regulates the body’s production of anti-VEGF. Subretinal injection appeared to be safe and was well tolerated, Dr. Chalberg reported, and allowed AVA-101 injections to better stimulate anti-VEGF production than if delivered intravitrealy.

Dr. Chalberg reported that an on-going phase 2A study currently has 40 patients enrolled.


1. Chalberg TW. Anti-VEGF gene therapy: early clinical results using the Ocular BioFactoryTM in wet AMD. Paper presented at: Angiogenesis, Exudation, and Degeneration 2014; February 8, 2014; Miami, FL.