Recovery of sight realized after gene-based treatment
in most severe form of retinal degeneration
PA) -- Researchers from Scheie Eye Institute at the
University of Pennsylvania Medical Center have developed
a gene therapy protocol that successfully restored sight
in dogs afflicted with a variation of Leber congenital
amaurosis (LCA) -- a severe form of retinal degeneration
that, in humans, renders infants permanently blind.
The work was done in collaboration with researchers
from Cornell University (who discovered the mutated
gene in dogs) and the University of Florida (who helped
establish the adeno-associated vector delivery vehicle).
The study will appear in the May issue of Nature
Much progress has been made in identifying the genetic
basis of retinal degeneration, making it possible to
test new treatments that target the fundamental defects
that cause such conditions. This testing is aided by
the identification of strains of animals -- including
mice and dogs -- which have blindness caused by the
identical genetic defects that occur in humans with
Under optimum conditions, normal protein transports
a Vitamin A-like compound to the retina, which is necessary
for sight. In some cases of animal and human LCA, wild-type
RPE65 -- the protein that transports the necessary Vitamin
A- like compound is missing from the gene, which results
According to Jean Bennett, MD, PhD, researcher at the
F.M. Kirby Center for Molecular Ophthalmology at Penn's
Scheie Eye Institute and a senior co-author of the study,
previous studies to reverse blindness in rodents have
been successful, but this is the first successful outcome
using larger animals. "The results are spectacular
-- in fact, they are the sort of findings that a scientist
usually only hopes to, but rarely does, see, in the
course of a career," she explains. "This study
takes a great stride forward in demonstrating that gene
therapy does not just slow down a retinal degenerative
disease, but can actually provide recovery of vision
to an animal that was previously blind."
In the Penn study, researchers injected a recombinant
adeno-associated virus (AAV) carrying wild-type RPE65
intra-occularly into the area between the photoreceptors
and the retinal pigment epithelium of three dogs. The
consequences of this injection were assessed through
an electroretinogram, which showed, 90 days after injection,
the waveforms of the treated eye to be similar in scope
to that of a sighted dog's eyes. The assessment presently
continues at regular intervals.
Qualitative visual assessment of the three treated dogs
took place four months after the injection occurred.
Results of behavioral testing were consistent with the
electrophysiological results. The treated dogs all avoided
collision with objects in front and to the right (the
side injected); yet consistently collided with objects
to the left. In contrast, the untreated dog did not
display avoidance behavior in any direction.
The diagnosis of this devastating disease usually begins
with the patient's parents, who notice soon after birth
that their child has roving eye movements and apparently
doesn't see. Confirmation of the disease by an ophthalmologist
or retina specialist via an electroretinogram (ERG)
studies the electrical activity of the retina in response
to light. These studies reveal grossly abnormal or absent
responses where, normally, there is a waveform similar
to an EKG tracing. With the patient resigned to a life
of special schooling, canes, guide dogs, and Braille,
the disease results in significant hardship and morbidity
for the child, the family and for society.
"We have worked hard for many, many years to develop
a treatment for retinal degeneration, and this is the
biggest leap forward yet," states Bennett. "However,
we are nowhere near the introduction of the missing
protein in humans to restore sight,"
"While this may prove to be the treatment method
used for other forms of retinal disease, such as macular
degeneration, this particular therapy is useful only
for LCA," adds co-author, Albert Maguire, MD.
Researchers who collaborated with Bennett and Maguire
include Penn researcher Samuel Jacobson, MD, PhD; Cornell
University researchers Gregory Acland, VMD, and Gustavo
Aguirre, VMD, PhD; and University of Florida researcher
William Hauswirth, PhD.
# # #
Editor's note: Dr. Bennett will be out of town until
Wednesday, May 2, 2001; however, you can reach her by
calling the Department of Public Affairs, at 215-662-2560.
To determine if this discovery is of relevance to
you or your family, please contact:
The Center for Hereditary Retinal Degenerations Director,
Samuel G. Jacobson, MD, PhD
Scheie Eye Institute 215-662-9981
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