Transcript Retinal Degeneration: Proof of Principal, Medical Therapy

Research
Perspectives and the
Promise of Clinical
Trials for Treatment
of RP and Allied
Diseases:
ohenetihool
LGerald J. Chader, Ph.D., M.D.hc
Doheny Eye Institute
Los Angeles, CA USA
os Angeles, CA
University atlo
October 22, 2009
• Specifically, I would
like to summarize work
in 6 different areas that
can lead to treatments
for the RD diseases.
• 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
photoreceptor cells do not
function or are dead.
Here we use treatments
that replace the dead
cells or at least replace
their function.
These could be:
1) Cell transplantation
– use of normal cells
or the use of stem
cells
2) Electronic Prosthetic
Devices (Artificial
Vision)
3) Optogenetics
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
6) Gene Therapy
• But -- let’s start off with
methods of cell
replacement –
Transplantation.
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 previous
animal studies and even in
one human clinical trial.
• So, is there anything new?
• Yes, there are many recent
breakthrough studies
using cell transplantation.
For example,
• Ali et al. used transplantation of very young rod
photoreceptor cells called “rod precursors” into the
diseased retinas to improve vision in a mouse model of
vision loss. After transplantation, visual signals travel to the
brain with resulting restoration of some vision.
• Ali et al. have shown repair of degenerate retinas by
photoreceptor transplantation in 6 different mouse RD
models. “Good integration” of the transplanted cells was
observed even in late stage disease.
• Finally, there is also the use of stem cells for
transplantation.
Stem Cell
Transplantation
• Stem cells are
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
degeneration.
There are several examples of rescue in RP
animal models:
Reh et al. developed retinal progenitor cells from
human embryonic stem cells (hESC).
• When injected into the eye of mice with a form of
LCA , the hESCs migrated into the retina, settled
in the photoreceptor layer and expressed rod and
cone photoreceptor cell biochemical markers.
• Importantly, light responses are restored in the
animals.
• Some investigators are planning a clinical trial for
this stem cell therapy.
2) Use of stem cells gives good results in the RCS
rat model, one of the oldest animal models for RP.
3) Advanced Cell Technology (ACT) is conducting
a clinical trial using embryonic stem cells to supply
fresh RPE cells in Stargardt Disease and dry AMD.
This will be a good model for future studies on RP.
Future
Treatment?
• Direct Photoreceptor cell
transplantation: Not yet but
coming!
• ESC→Photoreceptor Cells:
good research is
continuing.
• Many opportunities are
now available for sight
restoration through
transplantation.
2) Artificial Vision
Uses an electronic
prosthetic device to
replace the function of
dead photoreceptors.
This is one of the big success
stories in restoration of
vision with successful
clinical trials and
commercial products now
available
Second Sight Medical Products has
successfully completed its clinical trial.
• There has been restoration of at least
some functional vision in RP patients.
• Safety is very good. Results have
persisted long term – 10 years.
•
ARGUS II is commercially available in
Europe and in the USA.
Other academic groups and companies are
doing excellent clinical work on other types of
retinal devices that should lead to commercial
products in the next few years. Groups in
Germany, Japan, Korea, Australia, Ireland,
USA.
Dr. Eberhart Zrenner (Retina Implant AG) in
Tuebingen is an outstanding leader in this field
along with researchers at Intelligent Implants
GmbH. Retina Implant has the European CE
Mark for use of their device
Future
Treatments?
• Several groups are doing
human testing including at
least three companies.
• SSMP has a device that is
available for general
implantation in advanced
RP as does Retina Implant
AG.
• Technologies are being
improved to allow for face
recognition and reading
ability.
This is NOT Vision of Terminator or
Geordi from Star Trek…..Yet
• Many animal and plant cells
3) Optogenetics
have proteins that react to light
(Photoswitches)
and produce an electrical signal.
• Molecular engineering can be
used to insert channelrhodopsin
molecules into retinal cells, e.g.,
ganglion cells in animals to
Chlamydomonas is a
make
them
light
sensitive.
tiny one celled algae
that contains a light• These light signals can be
sensitive protein
passed on to the brain which
called channel
can distinguish a “lights on” or
rhodopsin
“lights off” situation.
For example,
• Roska and coworkers have shown that lightactivated channels targeted to a particular type of
inner retinal cell can restore visual function in the
rd1 mouse model of retinal degeneration.
• Roska also showed that another photoswitch called
“halorhodopsin” can be used in cone cells to
substitute for the defective native proteins used in
the visual process and restore light sensitivity to a
mouse RP model.
Future Treatments?
Basic work on Photoswitches is yet
in early development.
• However, excellent work such as
by Roska and co-workers and
several other groups on insertion
of photoswitches into remaining
retinal cells in RP animal models
gives hope for restoration of
functional vision in the future.
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
6) Gene Therapy
4) Neuroprotection
7 Days after PDT: PBS vs. CNTF
PBS
CNTF
Many neuron-survival agents are
know which can delay
photoreceptor death in several
RP animal models.
• Many (30?) natural factors in
brain, retina and other tissues
have been found that inhibit
photoreceptor cell death.
These are now called
“Neurotrophic Factors” or
“Neuron-Survival Agents” .
One of them is named CNTF –
Ciliary Neurotrophic Factor.
Clinical Trials?
• Neurotech is in clinical trials
with CNTF on RP and dry AMD
subjects.
• Using a technique called
Encapsulated Cell Technology, they
deliver the neuron-survival protein
CNTF, to the retina.
• The CNTF leaves the capsule and
enters the retina where it helps to
protect the sick photoreceptor cells.
• Along with CNTF, Sahel et al. have
shown the Rod-derived Cone
Viability Factor (RdCVF) to be a
potent agent that promotes cone
Future
Treatments?
• The current Neurotech
clinical trial should soon
be completed. It could
produce the first effective
and generally available
treatment for many forms
of RP and dry AMD.
• BUT - there are many
agents to test yet! Drugs,
Modifiers, Natural Factors
such as RdCVF.
• Alone or in combination.
5) Antioxidants
The use of antioxidants must now be taken seriously.
They have been proven to delay the progression of
dry AMD, another form of retinal degeneration
Specifically in Retinitis Pigmentosa, two research
groups - Van Veen and Campochiaro have
demonstrated that antioxidants slow the course of
retinal degeneration in RP animal models.
.
van Veen fed animals with
Antioxidant Trial Dr.retinal
degeneration a
special combination of
antioxidants and slowed
the degeneration process.
Together, they 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 were reported to be
good but we are waiting for
scientific publication of the
results.
• Another mixture of
antioxidants is being used in
South Africa for RP patients.
Future Treatments?
• First, the clinical trial 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!
6) Gene
Therapy
• Gene Therapy replaces defective
mutated genes in living cells with
new, normal copies of the gene.
• Different types of Gene Therapy are
available for recessive, X-linked
and dominant forms of RP.
• Importantly, long-term, positive
effects of Gene Therapy in RP
animal models have been shown
even if treatment is done fairly late
in the disease process after
significant photoreceptor loss.
Gene Therapy Clinical Trials
The exciting news is that Gene Therapy will restore
some visual function in the human.
• About 5 years ago, 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.
• This success can now be used as a model for
treatment of many other types of RP diseases.
Clinical trials are ongoing or
Future
planned for:
Treatments? • Forms of dominant, recessive and Xlinked RP: MERTK – Abboud –S.A.
• Forms of LCA: LCA 1 (GUCY2D) – UF;
LCA 5 – Lebercillin consortium
• Stargardt’s Disease - StarGen
• Retinoschisis –AGTC, NEI
• Forms of Usher Syndrome – Naash
• Choroideremia – MacLaren –UK
So, as long as there are some
photoreceptor cells remaining, gene
therapy has a chance of improving
vision in almost all patients with RP
and allied diseases.
So, looking into
the future….
I hope you agree that we are
finally passing out of the
time of scientific darkness
and into the era of
enlightened clinical trials.
For scientists and clinicians,
there are now many
opportunities to do
meaningful and sightsaving research.
For patients, this will lead to
new therapies that will
save and restore vision in
all types of RD.