Congress Highlights:
Progress in
Retinal Degeneration
Research
From Scientific
Darkness to the Light
of Clinical Trials
ohenetihool
LGerald J. Chader, Ph.D., M.D.hc
Doheny Eye Institute
Los Angeles, CA USA
University atlo
os Angeles, CA
October 22, 2009
Q.: WHAT ARE WE DOING TO FIND NEW RD TREATMENTS?
Much Basic Science Progress
Researchers have now established a firm basis in the
genetics and cell biology of the RD diseases.
• We know many of the genetic and protein mutations
through genomics and proteomics.
• We also know the biochemical pathway (apoptosis)
that leads to photoreceptor cell death and we know
several neuron-survival agents that slow apoptosis.
• We have a much better idea of clinical and genetic
diagnosis of RP types and how this relates to the
use of therapeutics.
Now, building on this basic information what potential
treatments and cures for the RDs are here now or are
coming?
• But, before talking
about specific
treatments, we must
first understand the
2 different disease
situations that will
determine which
type of therapy
might or might not
be applied.
The first disease situation is…
When most or all of
the photoreceptors
are dead.
Here we use treatments
that replace the dead
cells or at least replace
their function in the
retina.
These could be:
1) Stem/Progenitor
cell transplantation
2) Electronic Prosthetic
Devices (Artificial
Vision)
3) Optogenetics Optical Photoswitchs
The second disease situation is…
When at least some
photoreceptor cells
yet are alive.
Here, we would use
treatments that prolong
photoreceptor life and
make them function
better such as:
4) Neuroprotection
5) Antioxidants Nutrition
6) Gene Therapy
1) Photoreceptor
Transplantation
• If photoreceptor cells are
dead, why not just
transplant normal
photoreceptor cells into
the RD retina from a
normal donor retina?
• Unfortunately, this has
shown only limited
success in many animal
studies and even in a
human clinical trial.
• So, direct photoreceptor
cell transplantation has
yet to be proven to be
effective for the human.
1) Alternative:
Stem Cell Use
• Stem cells are
primitive, multipotential cells that
have the ability to
develop into all
different adult cell
types – such as
photoreceptor cells.
• So, stem cells
transplanted into the
retina might replenish
the supply of
photoreceptor cells
that died due to
Q.: But - Can We Actually Transform Stem
Cells into Mature Photoreceptor Cells?
In an important preclinical
study, human embryonic
stem cells transplanted into
the retina of a mouse model
with a form of LCA
restore some visual
function.
A human clinical trial could
result.
Future
Treatment?
• Direct Photoreceptor cell
transplantation: Not yet!
• Embryonic Stem Cells →
Photoreceptor Cells: good
research is continuing. Many
photoreceptor characteristics
can be induced in the
embryonic cells.
• Research on other cell types is
being conducted to see if they
can be converted into mature
photoreceptor cells.
2) Artificial Vision
Uses an electronic prosthetic
device to replace the function
of dead photoreceptors.
The design is simple:
1) External camera captures
the light image
2) Computer processing
3) Electronic signal passes to
an array of electrodes
attached to remaining inner
retinal cells in the eye.
4) Finally, the signal is passed
down the optic nerve to the
brain to produce a visual
image.
Clinical
Trials?
• Second Sight Medical
Products implanted about 40
RP patients in Europe and the
Americas. Good results have
been reported in restoring at
least some functional vision.
Importantly, safety is very
good.
• Other groups such as in
Ireland, Australia, etc. are
doing great work.
• Professor Zrenner with Retina
Implants AG is doing excellent
clinical work on another type
of retinal device that should
lead to a commercial product
in the near future.
Future
Treatments?
• Several groups are doing
human testing including at
least three companies.
• SSMP has a prosthesis that
has received the EAU CMark and is available for
general implantation in RP
patients in Europe.
• Technologies are being
improved to allow for face
recognition and reading
ability in the future.
• Many animal and plant cells
3) Optogenetics have proteins that react to light
and produce an electrical signal.
• Molecular engineering can be
used to insert channelrhodopsin
or similar molecules into
surviving retinal bipolar or
Chlamydomonas is a
ganglion
cells
in
animals
to
tiny one-celled algae
make them light sensitive.
that contains a lightsensitive protein
• These signals can be passed on
called channel
to the brain for light perception.
rhodopsin
Future
Treatments?
• Basic work on Photoswitches is yet at an early
stage of development but is
progressing rapidly.
• Optogenetics could thus
give functional vision using
non-photoreceptor,
secondary neurons of the
retina.
Remember that the second disease
situation is……
when some living photoreceptors yet remain.
Possible therapies
would be:
4) Neuroprotection
5) Antioxidants Nutrition
6) Gene Therapy
4) Neuroprotection Neuroprotection is the use of
special small molecules or
electrical stimulation to protect
photoreceptor cells and make
them live longer.
• Many natural factors (growth
factors) in brain, retina and
other tissues have been found
that slow photoreceptor cell
death. One is named CNTF.
Another is the Rod-Derived
Cone Viability Factor.
• In other cases, small
molecular weight drugs can
make photoreceptor cells
work better.
Neuroprotection:
Clinical Trials?
• Neurotech is in clinical trials
with CNTF on RP and dry AMD
subjects. The CNTF is placed
inside the eye and enters the
retina where it helps to protect
the sick photoreceptor cells.
• A drug clinical trial using small
molecules called retinoids
looks successful in 2 specific
types of LCA.
• There are many types of
Neuroprotection that can be
used – some are general, some
only for specific types of RP.
Future
Treatments?
• The current Neurotech
clinical trial has shown
good results to date.
• It thus should produce
the first effective and
generally available
treatment for most forms
of RP and dry AMD.
• Other drugs as well as
electrical stimulation
can improve vision and
be used in the future.
5) Antioxidants
It is clear that antioxidants can slow disease
progression in some patients with mid-stage dry
AMD. This was proven in the AREDS clinical trials.
In Retinitis Pigmentosa, two research groups – Drs.
Van Veen and Campochiaro have
demonstrated that antioxidants
slow the course of retinal
degeneration in RP animal
models.
This is specifically by
inhibiting photoreceptor
cell death through
apoptosis.
.
Antioxidant Trial Dr. van Veen fed animals with
retinal degeneration a
special combination of
antioxidants and slowed
the degeneration process.
Together, these
antioxidants are called
RetinaComplex.
Ingredients:
Lutein, zeaxanthin, alpha-lipoic
acid, L-glutathione, extract of
lycium barbarum (wolfberry)
Based on this preclinical
work, a small clinical
trial in Spain has
finished on RP and dry
AMD patients. The
results look good. More
extensive trials are
planned.
Future
Treatments?
• First, the clinical trials such as
on RetinaComplex must be
completed.
• In the future, there are many
types of antioxidants that can
be tested in RP animal models
and then in the human.
• Until then, take your mother’s
advice – Eat your Vegetables!
They contain many good
antioxidants.
6) Gene
Therapy
• Gene Therapy is the
replacement of defective
mutated genes in living cells
with new, normal copies of the
gene.
• The new gene will synthesize a
normal protein that replaces
the mutated or missing protein
and restores photoreceptor cell
function.
• Long-term, positive effects of
Gene Therapy in RP animal
models have been shown even
if treatment is done fairly late
in the disease after significant
photoreceptor loss.
Gene Therapy Clinical Trials
The new and exciting news is that Gene Therapy will
not just slow down the RD disease process but it can
restore some visual function in the human.
• About 4 years ago, Dr. Robin Ali et al. started the first
gene therapy clinical trial supplying a normal copy of
the RPE65 gene to specific patients with LCA. Other
groups soon started similar trials and the patients
seem to be doing well with some restored vision.
• The focus now is on early treatment, i.e., children as
in the exciting work of Dr. Jean Bennett.
• This success can now be used as a model for
treatment of many other ocular diseases.
Future
Treatments?
Now, trials are in progress or
planned for:
• Stargardt’s Disease
• Several forms of LCA
• Retinoschisis
• Forms of Usher Syndrome
• Choroideremia
Also, for types of:
dominant,
recessive and
X-linked RP.
In Conclusion….
In the Past - No gene mutations for RP were known. We
had little idea as to the mechanism of photoreceptor
cell death and there were no agents know that could
slow photoreceptor degeneration and death.
Now – About one-half of the RP mutations are know.
Much is known about the basic mechanism of
photoreceptor cell death and how to inhibit it.
Electronic implants are available to patients.
Basic work in the fields of stem cell biology and in
Optogenetics show promise for future treatment.
Also, several Clinical Trials are in progress in
Neuroprotection, Gene Therapy, Antioxidant Therapy
that can actually improve vision.
What’s in the
future?
I hope you agree that
we are finally passing
out of the time of
scientific darkness
and into the
enlightened era of
clinical trials.
These should soon lead
to many new therapies
that will save and
restore vision in RD
patients.