Hi,
Some of you may find this interesting:

----- Original Message -----
From: "Tom Hoglund" <[log in to unmask]>
To: <[log in to unmask]>
Sent: Wednesday, July 26, 2000 11:59 AM
Subject: [RPLIST] Gene Therapy Breakthrough


Dear All:

July has been nothing short of spectacular!  The study below is now the
second time this month that researchers have restored retinal function
in an animal model.

Regards,
Tom Hoglund
The Foundation Fighting Blindness


Foundation Researchers Use Gene Therapy to Restore Retinal Function in
an Animal Model of Retinal Degeneration

By Tom Hoglund

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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