New approach to AMD turns off disease-causing genes

A new and promising therapeutic approach to treating diseases in which abnormal protein production is a problem, including AMD, is known as RNA interference (RNAi). RNAi is a biological method of turning off specific disease-causing genes and is being tested in at least two trials involving patients with AMD.

The objective with RNAi is to silence an overacting or overexpressing gene, which is a different approach from gene therapy because it does not involve insertion or deletion of any genetic material, said Roberto Guerciolini, MD, senior vice president of development and chief medical officer, Sirna Therapeutics, Boulder, CO. With RNAi, the genetic code remains unaltered.

A phase I, dose escalation trial of the company's lead development candidate, a chemically modified compound called Sirna-027, is nearing completion. Sirna-027 targets vascular endothelial growth factor receptor-1 (VEGFR-1), a key component of the VEGF pathway. VEGFR-1 is stimulated by both VEGF and placental growth factor (PlGF). By targeting VEGFR-1, Sirna-027 is designed to shut down activation of pathologic angiogenesis initiated by both VEGF and PlGF.

Visual acuity results were also positive. "At 8 weeks of treatment, we observed stabilization of visual acuity in all patients. There was not a single patient who had a decrease in visual acuity over that period, while you would have expected a reduction in a population with active disease," Dr. Guerciolini said.

In addition to this overall trend, 12 of 22 patients (52%) had an improvement of one to four lines of visual acuity (VA) on the ETDRS chart, and five of 22 (23%) had more than three lines improvement.

There was also some evidence of biological activity measured by optical coherence tomography; foveal thickness decreased at three of the four doses.

Following evaluation of data on the most recent patients enrolled in the phase I trial, a phase II, multidose study is expected to begin in March or April 2006.

Acuity Pharmaceuticals of Philadelphia also initiated a phase 1 clinical trial of an RNAi compound last fall and will report safety and efficacy results at the American Academy of Ophthalmology meeting in Chicago.

Acuity Pharmaceuticals is developing a VEGF inhibitor based on RNAi technology called Cand5 for treatment of wet AMD, said Samuel Reich, vice president of research and development and a co-founder of the company.

"We think that the mechanism of RNAi lends multiple advantages to inhibiting VEGF over other approaches," Reich said. He explained that other treatment modalities "mop up" VEGF, while Cand5 turns off or stops VEGF production at its source.

"A small amount of Cand5, when it gets into the back of the eye, tells the cells not to make VEGF and destroys VEGF messenger RNA before the VEGF protein is ever produced," he added.

Through clinical trials, Acuity Pharmaceuticals hopes to demonstrate safety, limited systemic exposure, and increased efficacy at inhibiting VEGF through smaller doses, Reich said.

"We're definitely very encouraged by the data so far," he said.