|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
For background information on LCA visit www.nei.nih.gov/lca.
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 www.nih.gov.