siRNA Turns Off Bad Genes

by Dan Roberts
(updated April 2009)
A new type of anti-VEGF drug called “small interference RNA (siRNA),” is showing promise in its ability to turn off genes that cause wet AMD.
A preliminary primate study in early 2004 showed that, at the highest dose used in the study siRNA (formerly called RNAi) “reduced the incidence of clinically significant vascular leakage to zero by week three and for the duration of the study, and at day 35 neovascularization was inhibited by greater than 65 percent in the high dose group. No adverse effects were observed.” (“Intravitreal injection of VEGF siRNA Inhibits growth and leakage in a non-human primate laser induced model of CNV,” by Tolentino, et al., Retina, the Journal of Retinal and Vitreous Diseases, Feb 2004.)
Acuity Pharmaceuticals (Philadelphia, PA) has developed and begun testing on anti-VEGF (vascular endothelial growth factor) small interfering RNA labeled Cand5. In a phase 1 clinical trial, the safety and tolerability of Cand5 were evaluated in subjects who were all more than 70 years of age with predominantly classic, minimally classic and occult wet AMD. In a presentation to the American Academy of Ophthalmology (AAO) annual meeting, John Thompson, MD (Assistant Professor, Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland) reported that Cand5 was found to be safe and well tolerated following repeated administration at escalating doses. As a result of these findings, a phase 2 trial was approved by the FDA.
New York Times writer Andrew Pollack provided a good explanation of how the process works (“Method to Turn Off Bad Genes Is Set for Tests on Human Eyes,” 9/14/04):
“RNA [ribonucleic acid] is a string of chemical units, called bases, that represent the letters of the genetic code. It serves as a messenger, carrying the recipe for a protein from the DNA in the genes to the cell’s protein-making machinery. Proteins form much of the structure of a cell and carry out much of its activities.
“While DNA has two strands (the double helix) RNA is usually single-stranded. If cells sense double-stranded RNA, they act to destroy it and any other RNA with the same sequence. Some researchers think that this RNA interference mechanism might have evolved as a defense against viruses, which sometimes create double-stranded RNA.
“Scientists can harness this mechanism to prevent any gene in the body from being used to make a protein, effectively shutting off the gene. They synthesize a short string of double-stranded RNA that corresponds to part of the messenger RNA carrying the protein recipe. Rather than creating the protein, the cell destroys the messenger.”
Other companies have demonstrated that wet AMD can be treated by blocking the action of VEGF, which causes the formation of leaking blood vessels. (See Antiangiogenic Drugs Are Stopping Neovascularization in Wet Macular Degeneration.) But instead of blocking the action of the protein, the siRNA approach turns off the gene, blocking the protein from being formed in the first place.
In a communication from Gislin Dagnelie, Ph.D. (Assistant Professor of Ophthalmology and Director of Low Vision Services, Lions Vision Research & Rehab Center, Johns Hopkins University School of Medicine), MD Support learned that siRNA therapy is especially important for dominant forms of retinitis pigmentosa (RP), “where the same mechanism could be applied in families with known [genetic] mutations.” Assuming that there are no significant side effects, he said, affected children could get such treatments, which would keep them from ever having any RP symptoms. The bad gene, however, could still be passed on to their children.
Dr. Dagnelie then offered a cautionary note: “Each genetic defect would require its own siRNA, and developing these treatments is not cheap, as separate safety and efficacy trials will be needed for each variant. But once a few of them have been shown [to be] safe and the mechanisms are all understood, the manufacturing and evaluation processes may be streamlined. This is very exciting, not just as a development in the fight against wet AMD, but as an example for other diseases where blocking the action of a bad gene could prevent most of the damage the disease causes.”
Initial clinical trials were conducted in Baltimore and Cleveland. Future studies will also be conducted in additional cities in the U.S. For information regarding the trials, contact Theresa Nicholson.
UPDATE 1: On November 13, 2006, John Thompson, M.D., reported to the 2006 AAO annual meeting that studies have found no significant difference in three dose levels of bevasiranib, Acuity’s siRNA drug under study. Results indicate that treatment with direct VEGF inhibitors may be necessary initially before treatment with bevasirinab. Hopefully, said Dr. Thompson, a Phase III study will show effectiveness of the drug as long term treatment.
UPDATE 2: In 2008, the journal Nature carried reports by Dr. Jayakrishna Ambati and colleagues, who found that siRNA is toxic to blood endothelial cells, which line blood vessels. Then, in April 2009, new findings were published in the online issue of Proceedings of the National Academy of Sciences. In concert with Sandro De Falco and Arturo Brunetti (Naples), Ambati et al found that siRNAs, by activating an immune receptor called toll-like receptor 3 (TLR3), also generically block blood and lymphatic vessel growth in muscle tissue as well. This indicates that siRNA may be utilized in the treatment of diseases of the lymphatic system, as well.