Gene Therapy Studies Successful in Slowing Neovascularization

by Dan Roberts
January 2002
(Updated February 2006)
Researchers at Johns Hopkins’ Wilmer Eye Institute have been able to successfully slow blood vessel growth in laboratory mice in two different experiments involving injection of genes, and human trials have begun.
In one study (Mori, K., et al., “Inhibition of Choroidal Neovascularization by Intravenous Injection of Adenoviral Vectors Expressing Secretable Endostatin,” American Journal of Pathology, 159: 313-320.), a gene was injected which causes the body to produce endostatin, a substance which has been reported to inhibit abnormal blood vessel growth in tumors. The endostatin reduced retinal neovascularization in the mice by about 50%, and the more endostatin in the bloodstream, the lower the amount of neovascularization. More study is needed to determine if any organs are adversely affected by the procedure.
In the second study (Mori, K., et al., “Pigment Epithelium-Derived Factor Inhibits Retinal and Choroidal Neovascularization,” Journal of Cellular Physiology, 188: 253-263.), viral vectors were injected which contained the gene for pigment epithelium-derived factor (PEDF). This is a protein in the eye which promotes survival of retinal and other nerve cells.
In this study, the viral carrier was injected directly into the eye, which eliminated possible damage from the high levels of PEDF to the rest of the body. The mice with induced macular degeneration showed a reduction of blood vessel growth by as much as 65%. Mice with induced diabetic retinopathy showed a reduction of 90%.
These results are highly significant, and they raise hopes that gene therapy may someday be an effective treatment for stopping or preventing neovascularization in people with the wet form of macular degeneration and similar diseases.
The endostatin study was supported by the U.S. Public Health Service, the National Eye Institute, the Juvenile Diabetes Foundation, Research to Prevent Blindness and CIBA Vision Inc., a division of Novartis Ltd. Pharmaceuticals. The PEDF study was sponsored in part by the Juvenile Diabetes Foundation and the National Eye Institute.
Results of a phase I trial to evaluate the safety and feasibility of intravitreous AdPEDF in humans was published as a poster presentation at the 2004 ARVO meeting. The title was *AdPEDF Therapy for Subfoveal Choroidal Neovascularization (CNV): Preliminary Phase I Results*. (Authors: P.Campochiaro, M.Klein, E.Holz, A.Gupta, D.Saperstein, S.Bressler1, L.L. Wei, A.Ray, R.N. Frank, T.Stout.)
After a single intravitreous injection of AdPEDF in a small sample population and one-year follow-up, researchers have concluded that the viral vector is proving to be well-tolerated and safe for human application. The trial is ongoing, with additional subjects being enrolled.
February 7, 2006: GenVec announced that “a prolonged therapeutic effect may be achieved after a single injection of AdPEDF.” This came as a result of finding that “subjects in the phase I trials who received higher doses of AdPEDF showed no increase in the size of retinal lesions at six and twelve months post-injection, compared to patients in the lower dose group whose lesions increased over time. Visual acuity in patients in the higher dose group was stable for the entire twelve months of the study, while those treated in the lower dose group appeared to show deterioration at six and twelve months.”