Subretinal therapy offers promise of lighter treatment burden for AMD


RGX-314 gene therapy offers patients the potential for a lower treatment burden with one subretinal injection of a gene therapy delivering an anti-vascular endothelial growth factor protein.

By Lynda Charters;

Reviewed by Jeffrey S. Heier, MD

Patients undergoing treatment for wet age-related macular degeneration (AMD) have a tremendous treatment burden depending on their response to medical therapy. However, a new therapy administered once subretinally might alleviate that burden.

Dr. Heier

RGX-314 gene therapy (REGENXBIO), an adeno-associated virus serotype 8 (AAV8) vector that delivers an anti-vascular endothelial growth factor (anti-VEGF) Fab protein, is under study to treat neovascular AMD by delivering the gene therapy construct. However, designing a surgical therapy is not for the faint of heart.

Jeffrey Heier, MD, co-president and medical director, Ophthalmic Consultants of Boston, discussed the challenges facing the investigators and the early surgical outcomes.

Gene therapy trials of intravitreal and subretinal delivery of therapeutic agents have been undertaken previously, and one of the most important reasons for the limited success of these enterprises is inadequate expression, Dr. Heier said.

The goal of the RGX-314 gene therapy platform is higher protein expression over a longer period with a lower risk of immune response.

“Most of the studies performed to date have used the adeno-associated virus 2 (AAV2) vector,” Dr. Heier said. “However, the AAV8 vector has demonstrated more efficient protein expression in the retinal pigment epithelial cells. RGX-314 has been reported to be on the order of 10-fold higher than results that were previously reported with the AAV2 vector.”



Intravitreal vs. subretinal gene therapy

When the investigators considered the various available delivery routes, intravitreal delivery was considered easy to use, safe, and performed during an office visit. However, intravitreal delivery is considered to be less efficient by 100 to 1,000 times compared with subretinal delivery.

Transduction via the intravitreal route is believed to be limited by the internal limiting membrane that acts as a barrier. In addition, and importantly, the pre-existing AAV neutralizing antibodies (NAbs) may neutralize gene therapy delivered intravitreally.

“There is a high prevalence of NAbs, up to 70% exposure to AAV2 and 30-50% to AAV,” Dr. Heier added. “When gene therapy is delivered intravitreally, there may be limited or no transgene expression in patients with these antibodies.”

In contrast, subretinal delivery is more invasive and requires a surgical procedure. However, this route is believed to deliver the best expression. The procedure has been reported to be safe in several trials.



It takes a village

Designing a surgical gene therapy trial requires great planning regarding the invasiveness of the procedure, the standardization of as many dimensions as possible tailored to the available equipment and techniques used by the surgeons.

Sessions were conducted in each participating study site’s operating room with attention to each individual vitrectomy machine to determine the ideal parameters for utilizing the MedOne syringe. After each procedure, the investigators get together to refine techniques and share their pearls.

During the phase I trial, all patients will be treated. Phase II offers additional challenges, such as controls and masking.

“The investigators spend a great deal of time standardizing and maximizing the procedures,” Dr. Heier said. “We developed a careful procedure manual and conducted extensive wet lab training to ensure that all surgeons approached the procedure in a similar fashion.”

The trial design requires administration of ranibizumab (Lucentis, Genentech) at baseline. One week later they are evaluated to determine a response to the treatment.

Eighteen patients are being randomized to 1 of 3 doses of 6 patients each, i.e., 3x109 genome copies (GC)/eye, 1x1010 GC/eye, and 6x1010 GC/eye. Safety reviews occurred 4 weeks after the last patients in each cohort were treated.



Delivery procedure

The procedure has been standardized with a standard small-gauge vitrectomy to perform a core vitrectomy performed under local anesthesia in the operating room. The delivery of the drug is done with a MedOne Microdose injector with a 38-gauge subretinal cannula attached to the vitrectomy machine.

The investigators are injecting 250 mcL subretinally into a healthy retinal tissue. They are targeting an area superior to the superotemporal arcade vessel or outside the arcades.

Dr. Heier explained that, if needed, a second bleb area could be selected. The bleb margin will be away from the fovea by at least 2 disc areas.

When the procedure is complete, an air-fluid exchange is performed and subconjunctival steroids are administered. The patients are not required to maintain a facedown position after surgery. They return for a follow-up evaluation the following day.

No major complications have reported in association with the treatment in the several patients who have undergone the procedure, Dr. Heier reported.

“Gene therapy for neovascular AMD offers the potential to alleviate the patients’ treatment burden,” Dr. Heier explained. “Other gene therapy studies for wet AMD conducted to date have indicated problems with protein expression. However, it is our hope that RGX-314 will have higher levels of protein.

“Designing a surgical trial for a medical disease is challenging,” he added. “The standardization and reproducibility of the procedure are the keys to success.”

Jeffrey S. Heier, MD


This article was adapted from a presentation that Dr. Heier delivered at the 2017 American Society of Retina Specialists. Dr. Heier is a scientific advisor to REGENXBIO.



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