Source: Haematologica  |  Posted 6 years ago

By Earl R. Nichols

CHICAGO, IL -- November 1, 2005 -- Using what is known as an RNA duplex called small interfering RNA (siRNA), investigators are moving one step closer toward using gene therapy to combat age-related macular degeneration.

In an oral presentation here on October 14[^]th[] at the American Academy of Ophthalmology (AAO) annual meeting, John Thompson, MD, Assistant Professor, Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, United States, outlined recent gene therapy advances made in treating this disease.

"siRNA directed against vascular endothelial growth factor (VEGF) shows therapeutic potential in inhibiting VEGF produced by retinal pigmented epithelium cells for the treatment of AMD," Dr Thompson said.

Cand5, developed by Acuity Pharmaceuticals (Philadelphia, PA) is one such anti-VEGF small interfering RNA. The product is injected into the vitreous part of the eye and penetrates into the cytoplasm of the retinal pigment epithelium cells, where it inhibits VEGF production.

In a prospective phase 1 clinical trial, the safety and tolerability of Cand5 were evaluated at doses of 0.1 mg, 0.33 mg, 1.0 mg, 1,5 mg and 3.0 mg in groups of three patients per dose. Injections were delivered at day 0 and at week 6 and patients were followed for a total of 104 weeks.

Subjects were all more than 70 years of age and the particular lesion types -- predominantly classic, minimally classic and occult -- were evenly distributed across the five treatment groups.

Each of the doses of Cand5 was found to be safe and well tolerated following repeated administration at escalating doses, Dr. Thompson said. Pharmacokinetic analysis suggested that there was no systemic exposure to Cand5 at any dose level, meaning the therapeutic effect was confined to the retina and did not migrate anywhere else in the body.

No particular safety concerns with Cand5 were identified, and the most commonly reported adverse events were related to the injection procedure. No increases in intraocular pressure were observed.

Based on these findings, Dr. Thompson said, a phase 2 trial has been approved by the FDA and is now enrolling patients.

Another study using a similar siRNA (Sirna-027, Sirna Therapeutics, San Francisco, CA) reported improvements in ETDRS scores of 5 letters for those who received 100 mcg doses, and 10 letters for patients who received the 200 mcg dose. Follow-up for those patients was 84 days and 56 days respectively, he said.

Dr. Thompson concluded that siRNA has the potential to treat a variety of medical conditions. In vitro studies using cultured cells of renal and ovarian cancer have shown that it can inhibit VEGF growth in those tumors as well, he said, and it shows promise as a means of treating choroidal neovascularization secondary to age-related macular degeneration.

[Presentation title: Genetic Therapy for AMD. Retina Sub-specialty Day]