Promising Results in Phase 1 Gene Therapy Trial for Blinding Disease


Three young adults with an inherited form of blindness showed evidence of improved day and night vision following a specialized gene transfer procedure in a phase 1 clinical trial funded by the National Eye Institute (NEI), part of the National Institutes of Health. In addition no adverse effects from the therapy were reported. These findings are reported online in the Sept. 22 issue of Proceedings of the National Academy of Sciences and in the Sept. 7 issue of Human Gene Therapy. These new reports extend the findings of two other papers published earlier this year in the New England Journal of Medicine.

Patients in the study had one genetic form of Leber congenital amaurosis (LCA) caused by mutations in the RPE65 gene. In this form of LCA, retinal neurons called photoreceptor cells do not respond to light because the defective RPE65 proteins cannot produce sufficient vitamin A molecules necessary for healthy vision. Vision loss is severe from retinal degeneration in all forms of LCA. However, unlike many other forms of LCA, the RPE65 disease retains some relatively intact retina. Knowledge of the exact retinal locations of these non-functioning photoreceptor cells provides the opportunity to target the therapy and overcome the RPE65 gene defects.

Patients in the study received a subretinal injection to replace the nonfunctioning gene in pre-selected regions of the retina with less degeneration of photoreceptor cells. Each patient had visual impairment that had been present since birth due to the defective RPE65 gene. Over the 90-day period of the study, gene therapy was associated with improvement of visual function. This research was conducted at the University of Pennsylvania, Philadelphia, and the University of Florida, Gainesville.

This study is the first to show that gene therapy can improve both day and night vision in patients with LCA. Day vision was improved by 50-fold and night vision by 63,000-fold compared to pre-treatment levels. Restored vision was localized to the area of treatment in the treated eye.

“This study has partially restored vision in three young adults,” said Paul A. Sieving, M.D., Ph.D., director of the NEI. “This gene therapy trial builds on 15 years of research sponsored by the National Eye Institute and proves that we’re on the right track. We can now invest in further work to refine, and ultimately to expand, genetic treatment approaches.”

Researchers in this study were first to examine the enzymatic cycle of vision targeted by the treatment by measuring the speed with which the patients’ vision adjusted from bright to dim environments. They learned that, while the speed of day vision was near normal, that of night vision took more than eight hours to adjust to darkness as compared to one hour in normal eyes. “We did not suspect this from pre-clinical studies. The first clues came while interviewing patients about their visual experiences after treatment, and we immediately altered our testing strategies appropriately” says Artur V. Cideciyan, Ph.D., research associate professor of ophthalmology at the University of Pennsylvania. “In future studies, we will seek ways to make the restored vision even more useful to the daily lives of patients.”

“The converging results from three independent and contemporaneous clinical trials are remarkably encouraging for patients and for scientists and clinicians who have worked tirelessly for decades in the field of retinal degenerative disease” said Dr. Samuel G. Jacobson of the University of Pennsylvania’s Scheie Eye Institute, principal investigator of the trial. “No time to bask in the glory of the achievement, though. There are many next steps needed to be taken and soon.”

Given the positive results, the study will now be expanded to include more patients, confirm the safety and effectiveness of the therapy and advance the gene transfer techniques.

Further information about this trial NCT 00481546 can be found at For background information on LCA visit


Cideciyan AV, Aleman TS, Boye SL, Schwartz SB, Kaushal S, Roman AJ, Pang J-j, Sumaroka A, Windsor EAM, Wilson JM, Flotte TR, Fishman GA, Heon E, Stone EM, Byrne BJ, Jacobson SG, Hauswirth WW. Human gene therapy for RPE65-isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proceedings of the National Academy of Sciences USA, 2008 September 30, 105 (39):15112-15117.

Hauswirth WW, Aleman TS, Kaushal S, Cideciyan AV, Schwartz SB, Wang L, Conlon TJ, Boye SL, Flotte TR, Byrne BJ, Jacobson SG. Treatment of Leber Congenital Amaurosis due to RPE65 Mutations by Ocular Subretinal Injection of Adeno-associated Virus Gene Vector: Short-Term Results of a Phase 1 Trial. Human Gene Therapy, September 8 2008, published online ahead of print.

# # #

The National Eye Institute (NEI) is part of the National Institutes of Health (NIH) and is the Federal government’s lead agency for vision research that leads to sight-saving treatments and plays a key role in reducing visual impairment and blindness. For more information, visit the NEI Website at

The National Institutes of Health (NIH) - The Nation’s Medical Research Agency - includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit