Genetic therapies may provide new treatment mode for CNV

Baltimore-A new class of compounds has been making headlines lately as a potential treatment of choroidal neovascularization (CNV) secondary to age-related macular degeneration. Genetic therapies can block messenger RNA (mRNA) coding for vascular endothelial growth factor (VEGF) and prevent VEGF synthesis.

John T. Thompson, MD, assistant professor, Wilmer Eye Institute, Johns Hopkins University, Baltimore, explained how this therapy works.

The most current therapies-such as ranibizumab (Lucentis, Genentech), bevacizumab (Avastin, Genentech), and pegaptanib (Macugen, OSI/Eyetech Pharmaceuticals)-that are still being evaluated block VEGF already released in the choroid or the subretinal space.

"RNA interference (RNAi) is a recently discovered natural cellular process during which RNA is used by cells to regulate the production of proteins. A small interfering RNA (siRNA) molecule can be used to silence a gene that would normally produce VEGF," Dr. Thompson said.

The normal sequence of events is that DNA for VEGF is translated to mRNA and then to a protein (VEGF) that is believed to cause disease.

The siRNA, he explained, degrades mRNA for VEGF, which prevents production of VEGF and hence prevents disease.

Double-stranded siRNA forms an RNA-induced silencing complex (RISC) that cleaves the double-stranded siRNA into a single-strand molecule that can degrade mRNA for a target protein such as VEGF.

"The RISC finds the appropriate sequence of 21 to 24 base pairs and cleaves the mRNA for VEGF," he explained. Thousands of such cleavages can be obtained from one RISC.

Dr. Thompson focused on the therapies using intravitreal siRNA being developed by Acuity Pharmaceuticals, although others, such as Alnylam Pharmaceuticals and Sirna Therapeutics, are doing similar work.

He described Cand5 (Acuity Pharmaceuticals), a synthetic double-stranded RNA that penetrates into the cytoplasm of retinal pigment epithelium and silences VEGF production in embryonic kidney and ovarian carcinoma cell lines. It has also inhibited neovascularization in a murine model of CNV.

Phase I protocol for Cand5

In a phase I study of Cand5, patients were included who had visual acuity between 20/50 and 20/320, lesions 12 disc areas or less, and composed of 50% or less of blood. All patients were 55 years or older.

An intravitreal injection of Cand5 was administered at day 0 and at 6 weeks. Pharmacokinetic studies were done at days 0 and 1. A total of 15 patients with any type of CNV were treated and five different doses (0.1, 0.33, 1.0, 1.5, and 3.0 mg) were administered.

"Pharmacokinetic studies showed that there were no plasma samples with detectable levels of Cand5, indicating that the agent was not absorbed into the systemic circulation," Dr. Thompson explained.

The pooled visual acuity data seem to show some initial stabilization of the CNV; however, by week 12 vision loss was occurring in some patients. Dr. Thompson emphasized that it is unclear if this is the natural history of the disease or a therapeutic effect of the drug.

"All five doses were well tolerated. There was no systemic absorption of Cand5. The most commonly reported adverse events were typical of intravitreal injections. There was no anterior segment inflammation reported," he pointed out.

The phase II clinical trial is now ongoing at more than 30 sites. The study is a randomized, double masked trial of three dose levels (0.2, 1.5, and 3 mg). Enrollment was greater than 50% at the time of the presentation.

Other intravitreal RNAi drugs

Alnylam Pharmaceuticals is developing an RNAi product that is a chemical modification of a siRNA against VEGF. A phase I trial is ongoing.