• Precision Subretinal Delivery for Gene Therapy


    “Gene therapy is happening today, and cell therapy may soon follow,” began Allen C. Ho, MD, at Friday’s Retina Subspecialty Day. “We’ve been working on improving the consistency and the precision of delivering these therapies to target tissues.”

    Although gene therapy is already a reality for the type of Leber congenital amaurosis associated with RPE65, clinical trials are moving toward promising therapies for more common conditions, such as advanced AMD. The first generation of these trials did not show efficacy, however. Optimizing treatment delivery to target tissues may help, Dr. Ho explained.

    The standard and familiar: PPV subretinal delivery. Transvitreal subretinal delivery after pars plana vitrectomy (PPV) has been shown to be safe, and it may be a familiar procedure for many surgeons.

    This delivery method is being used in the Regenxbio gene therapy trial for neovascular AMD. In this trial, patients who were previously treated with—and responsive to—intravitreal anti-VEGF therapy receive a single administration of different dose levels of the RGX-314 gene therapy. One of the procedures involves a standard microincision vitrectomy and delivery of 250 μL of the treatment into the subretinal space. “Many of you have done this kind of procedure,” noted Dr. Ho. Trials already suggest the safety of this procedure, he said.

    The commercially available MicroDose injection kit (MedOne Surgical) may be one way to further improve precision delivery. The microcalibrated 1-cc syringe connects to the viscous fluid injection system on a vitrectomy console, providing surgeons foot-pedal control and allowing precise microliter dosing, Dr. Ho said. For the trial, surgeons were trained in standardized procedures that are automated when possible, and surgical videos were reviewed to control for variability.

    Surgeons and clinical trials are also assessing cell therapies for atrophic AMD, such as the BioTime study. The problem with these cell therapies, he noted, is that patients often develop preretinal membranes, possibly due an egress of cells through the retinotomy.

    The new: a suprachoroidal-to-subretinal approach. These challenges have spurred the development of new approaches for delivering treatment to the subretinal space, such as the use of a suprachoroidal microcatheter. It is placed posteriorly along the inner sclera curvature and enters the subretinal space with a microneedle. This microcatheter and microneedle system was developed in collaboration with Kaleidoscope Innovation Design. The Gyroscope suprachoroidal system was FDA approved this year and cleared for use in the BioTime cell program.

    “The advantage of this is that no vitrectomy is needed, there is no retinotomy, and therefore you might get more precise and consistent dosing for these patients,” said Dr. Ho.

    Optimizing via imaging. Intraoperative 2-D and 3-D imaging, he added, will help optimize the procedure. Surgical 2-D bleb imaging can be recorded and may be useful for geographic atrophy studies. In the other hand, 3-D imaging will help target the subretinal space and improve dosing. —Kanaga Rajan, PhD

    Financial Disclosures: Dr. Ho: Aerpio: C,S; AGTC: C,S; Alcon Laboratories, Inc.: C,S; Allergan: C,S; Apellis: S; Asclepix: C; Beaver-Visitec International, Inc.: C; Chengdu Kanghong Biotechnology: C,S; Covalent Medical, LLC.: O; Genentech: C,S; Iconic: C,S; Iridex: C,S; Johnson & Johnson: C,S; Lineage / BioTime: C; National Eye Institute: S; ONL: C,O; Ophthotech: S; Optovue, Inc.: C,S; PanOptica: C,O; Regeneron Pharmaceuticals, Inc.: C,S; Regenexbio: C,S; Second Sight Medical Products, Inc.: C,S; Tyrogenix: C.

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