THE FOUNDATION FIGHTING BLINDNESS
Foundation Researchers Use Gene Therapy to Restore Retinal Function in
an Animal Model of Retinal Degeneration
FROM: Tom Hoglund
The Foundation Fighting Blindness, http://www.blindness.org
In the July issue of Nature Genetics, Foundation-supported researchers
used gene replacement therapy to treat a rodent model of retinal
degeneration. This is the first published study to show that gene
replacement therapy can restore function to photoreceptor cells.
These findings also demonstrate that gene replacement therapy can
create missing cellular components when genetic mutations interfere
with the development of a photoreceptor cell.
Dr. Gerald Chader, Chief Scientific Officer of The Foundation
Fighting Blindness commented, "Previous studies have established
'proof of principle' that gene replacement therapy can dramatically
slow the loss of photoreceptor cells in animal models with retinal
degenerative diseases. However, this study offers the first evidence
that gene replacement therapy can also restore retinal function. This
study gives us real hope that researchers may be able to develop
treatments that restore vision."
In the study, a team of scientists from London (Dr. Robin Ali and Dr
Shomi Bhattacharya from the Foundation's Research Center at the
Institute of Ophthalmology along with Dr. Adrian Thrasher at the
Institute of Child Health) tested gene replacement therapy in the rds
mouse. This mouse has an autosomal recessive retinal degeneration
that results from mutations in the peripherin/rds gene. Using
electroretinograms (ERG), a diagnostic tool that measures
photoreceptor cell function, ten-week old treated rds mice had
significant ERG recordings, indicating a marked improvement in retinal
function. Untreated rds mice of the same age have no detectable ERG
response.
Peripherin/rds Gene Key to Photoreceptor Cell Structure The
peripherin/rds gene produces a specialized protein that helps to form
the outer segment discs of photoreceptor cells. Outer segments are
the finger-like structures containing hundreds of light-sensitive
discs that absorb light. These discs contain rhodopsin, the visual
pigment that begins phototransduction, the process of turning light
into an electrical signal. This signal is then relayed to the visual
cortex, the part of the brain that interprets visual information.
Mutations in the recessive form of the rds mouse prevent the
peripherin/rds gene from producing its protein product. As a result,
photoreceptor cell outer segments and their light-sensitive discs fail
to form. Phototransduction and vision are not possible without these
crucial cellular components.
To verify that delivery of the peripherin/rds gene resulted in the
development of outer segments, the research team used a sophisticated
imaging technology called electron microscopy to examine the structure
of treated photoreceptor cells. Photoreceptor cells of treated rds
mice were able to generate outer segments containing light-sensitive
discs. By contrast, untreated rds mice have no outer segments.
Although treated mice had fewer outer segments than normal mice,
improvements in gene delivery techniques should allow researchers to
treat a greater portion of the retina in the future.
Limits of Gene Replacement Therapy This study offers "proof of
principle" that gene replacement therapy can restore photoreceptor
cell function. It also indicates that gene therapy can restore
missing photoreceptor cell components that result from genetic
mutations. However, it is important to note that gene replacement
therapy is not applicable to all retinal degenerative diseases. It is
only likely to be applicable to autosomal recessive diseases and some
X-linked diseases.
Ribozyme Gene Therapy For autosomal dominant diseases, ribozyme gene
therapy may be applicable. In dominant forms of retinal degeneration,
patients have a healthy functioning gene and a gene with a
disease-causing mutation. The mutant gene produces a dysfunctional,
toxic protein that damages the photoreceptor cell. Ribozymes are
molecules containing genetically encoded information that disrupt the
mutant gene's ability to produce the harmful protein. With the
diseased gene inactivated, the healthy gene can supply the
photoreceptor cell with the needed protein. In previous studies,
Foundation researchers have dramatically slowed retinal degeneration
in a rodent model with ribozyme therapy.
It is also important to note that treatment with both gene replacement
and ribozyme therapy must be administered before photoreceptor cells
have died.
Future Work Before the Food and Drug Administration will grant
approval for gene therapy clinical trials, researchers must thoroughly
test its safety and efficacy in the laboratory. Researchers must
further validate these initial findings in larger animal models with
eyes that more closely resemble human eyes. Because rodents
experience a much more rapid progression of vision loss than do larger
mammals, these experiments may take somewhat longer to gauge the
treatments effectiveness. Optimal doses must also be established to
insure that the gene or genetic information penetrates as many
photoreceptor cells as possible.
The safety of the gene delivery system must be tested to make sure it
does not cause a harmful immune response. In science, gene delivery
systems are called vectors. Vectors act like a fleet of microscopic
delivery trucks transporting genes into retinal cells. Vectors are
composed of genetically modified viruses. Viruses are extremely
effective at infiltrating cells. Viral vectors are modified to remove
their harmful qualities while still retaining their gene delivery
capabilities. Although new-generation vectors are thought to be safe,
Foundation researchers must establish their safety in the eye.
This gene therapy breakthrough and the recent report of sight
restoration in a mouse model with a severe retinal degenerative
disease called Leber congenital amaurosis offer the first real promise
that researchers can develop sight-restoring treatments for retinal
degenerative diseases.
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Date last modified August 19, 2000