Gene Therapy Sustains Vision in Wet Macular Degeneration

Caroline Helwick

November 20, 2013

NEW ORLEANS — Gene therapy with a vascular endothelial growth-factor (VEGF)-binding protein for wet age-related macular degeneration has shown biologic activity and safety in early-phase trials.

"The number of patients is small, but it's an exciting approach. Subretinal injections have demonstrated safety, efficacy, and biological activity — anatomically and in terms of visual acuity — with a low retreatment rate," said Jeffrey Heier, MD, director of vitreoretinal service at Ophthalmic Consultants of Boston.

Dr. Heier presented preliminary research on subretinal injections with AAV2-sFlt01 here at the American Academy of Ophthalmology 2013 Annual Meeting.

The secreted extracellular domain of sFlt-1 — a soluble isoform of the VEGF receptor 1 — is a naturally occurring protein antagonist of VEGF. Genzyme developed a VEGF-binding protein that consists of domain 2 of Flt-1 linked to a human immunoglobulin G₁ heavy chain Fc fragment (sFlt01). This was combined with an adeno-associated virus (AAV) to produce AAV2-sFlt01.

Intravitreal AAV2-sFlt01 is under development by Genzyme, and subretinal AAV2-sFlt01 is under development by Avalanche Biotechnologies.

Gene therapy is simply a delivery system for drugs.

Also presenting research here was Albert Maguire, MD, from the University of Pennsylvania in Philadelphia, who has conducted seminal research in gene therapy for other retinal diseases. He noted that gene therapy is advancing for other retinal diseases, not just wet age-related macular degeneration.

"The field of in vivo gene therapy has largely emerged in the last 15 years, and has involved a variety of diseases in diverse organ systems. There have been an increasing number of clinical gene therapy trials for various retinal diseases," Dr. Maguire reported.

He said a major misconception about gene therapy is that its application is limited to genetic disease. "Gene therapy is simply a delivery system for drugs. Any disease that would benefit from the local production of a genetically engineered protein, peptide, RNA, or RNA fragment would be a potential candidate for gene therapy," he explained.

Gene therapy is a treatment in which genetic material is introduced in cells, either to compensate for an abnormal gene or to make a beneficial protein, which is the case with AAV2-sFlt01, Dr. Heier said.

"The human retina is ideally suited for developing gene-based therapies," he noted. Cell types are readily accessible through intravitreal and subretinal injection, retinal function and structure can be assessed noninvasively, and there are many natural animal models of retinal disease, he explained.

Retina Ideal Target

Dr. Maguire said he agrees. "The retina has several unique characteristics that make it a favorable target for gene therapy," he said. These pertain to size and volume, surface-volume ratio, immune privilege and deviation, and immunosuppressive factors.

For example, Dr. Maguire noted, "the amount of tissue requiring transduction for successful therapy is drastically less than for visceral organs. The amount of vector is hundreds of times less than that used in systemic therapy, translating into a commensurately smaller antigenic load."

The epithelial architecture of the retina allows the vector to come into contact with entire populations of cells. Also, contact with the systemic immune system promotes tolerance of foreign antigens.

The main difficulty with current anti-VEFG treatments for wet age-related macular degeneration is treatment burden, Dr. Heier said. "The long-term delivery of anti-VEGF therapy has been more difficult to achieve than we initially anticipated. Also, the current delivery of anti-VEGF therapy is based on burst pharmacokinetics, with peaks and troughs that have implications for safety and efficacy," he explained.

This is why the "promising results" of anti-VEGF therapy delivered using a gene therapy approach are so exciting, he said. "Gene therapy would involve a ramp-up phase and then produce sustained levels of the therapeutic. This approach may have an impact on efficacy, safety, and compliance."

In one animal model, primates were injected in 1 eye with AAV2-sFlt01. Five months later, both eyes were lasered to induce choroidal neovascularization, but it developed only in the untreated eye, not the treated eye.

The therapeutic protein was both "effective and enduring, lasting more than 1.5 years, in nonhuman primates following a single injection," Dr. Heier reported. "There was complete resolution of choroidal neovascularization leakage 17 months after a single injection.

Human Trials

On the basis of these encouraging data, a phase 1/2 clinical trial was initiated in 6 adults with wet age-related macular degeneration to evaluate the protein in low-dose and high-dose concentrations. Patients received ranibizumab (Lucentis) on day 0 and day 30; on day 7 they received subretinal delivery of AAV2-sFlt01. Patients were followed monthly for 1 year, with very strict retreatment criteria.

The primary phase 1 end point of safety was met. No patients had ocular inflammation or retinal tears or detachments, and there were no arterial thromboembolic events or clinically significant changes in laboratory parameters. "In the control arm, patients lost visual acuity; in the treated arm, patients gained vision," Dr. Heier reported.

By day 380, the high-dose group gained 12.5 letters and the low-dose group gained 8.7 letters; in the untreated control group, patients lost 3.5 letters. Central retinal thickness was also reduced with treatment, and this reduction was sustained out to 380 days.

Retreatment with ranibizumab to maintain vision was required less often during monthly follow-up visits in the gene therapy group than in the control group (0.33 vs 3.00 injections).

"For 6 patients, out of a possible 72 injections for the whole study, only 2 visits required retreatment," he said.

"One patient who had required 24 injections previously — every 4 to 8 weeks — had an excellent response over time," he said. "The patient's visual acuity improved by 15 letters, and there were no rescue injections in 12 months."

Other Gene Retinal Diseases

There are a number of ongoing clinical trials for the treatment of various retinal diseases, including wet age-related macular degeneration, Leber's congenital amaurosis type 2, Stargardt disease, choroideremia, Usher syndrome, and retinitis pigmentosa.

Currently, 237 people are enrolled in clinical trials that are evaluating AAV and lentiviral viral vectors. The choice of vector is based on the size of the therapeutic gene being administered.

Phase 1/2 trials evaluating vector-mediated retinal gene transfer have demonstrated favorable safety profiles. Preliminary data using wild-type RPE65 gene delivery in patients with Leber's congenital amaurosis have shown "compelling evidence for short-term safety and efficacy," said Dr. Maguire, who led such a study.

The 12 patients received, in their worst eye, a subretinal injection of AAV containing a gene encoding a protein needed for isomerohydrolase activity of the retinal pigment epithelium. All patients showed sustained improvement in subjective and objective measurements of vision. Patients had an increase of at least 2 log units in pupillary light responses. The greatest improvement was noted in children, all of whom gained ambulatory vision, he said.

"While there are challenges, gene therapy for age-related macular degeneration is very exciting and is something we should pursue," said Pravin Dugel, MD, from Retinal Consultants of Arizona in Phoenix. "I believe there is something real there."

Dr. Heier reports financial relationships with Genzyme, which is developing AAV-FLT01, Alcon Laboratories, Alimera, Allergan, Bausch + Lomb, Bayer Healthcare, Dutch Ophthalmic, Endo Optiks, Forsight Labs, Fovea Pharmaceuticals, Genentech, GlaxoSmithKline, Heidelberg Engineering, Kala Pharmaceuticals, Kanghong Pharma, Kato Pharmaceuticals, NeoVista, Nicox, Notal Vision, Novartis Pharmaceuticals, Orh Pharmaceutical, Ophthotech, QLT Ophthalmics, Reeneron, Roche, Santen, Sequenom, Thrombogenics, and Xcovery. Dr. Dugel reports financial relationships with Abbott Medical Optics, Acucela, Alcon Laboratories, Alimera Sciences, Allergan, ArticDx, Digisight, Genentech, LUX, Macusight, Neovista, Ophthotech, Ora, Regeneron, and ThromGenics.

American Academy of Ophthalmology (AAO) 2013 Annual Meeting. Presented November 15 (Dr. Maguire) and November 16 (Dr. Heier), 2013.


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