Download Retinal Degeneration: Proof of Principal, Medical Therapy and

Foresight: The
Promise of Clinical
Trials
Moving RD Treatments
From the Laboratory
Bench to the Patient
Bedside
LGerald J. Chader, Ph.D., M.D.hc
Department of Ophthalmology
Keck School of Medicine
University of Southern California
Los Angeles, CA USA University atlo
October 22, 2009
os Angeles, CA
Q.: WHAT ARE WE DOING TO FIND NEW RD TREATMENTS?
Great Basic Science Progress
• We know more than half of the genetic mutations that
lead to the different types of retinal degenerations.
• We also know the biochemical pathway called
“apoptosis” that leads to photoreceptor cell death
and we know several agents called neuron-survival
factors that slow apoptosis by protecting
photoreceptors.
• Animal models for many of the RD diseases are
known. These are invaluable since approval for
human clinical trials is much easier if efficacy and
safety can first be demonstrated in an animal model.
Now, building on this basic information, I want to
summarize 6 research areas that have or can lead to
clinical trials and finally to treatments for the RDs.
First though, let’s take a quick look
specifically at AMD
• Wet AMD is a special case in that the main
problem is growth and leakage of new, abnormal
blood vessels near the retina. This can be fairly
well controlled though through the use of drugs
such as anti-VEGF agents that are designed to
stop new vessel growth.
• For dry AMD, antioxidants can slow disease
progression as with the AREDS agents. Otherwise,
dry AMD is similar to RP and, in the main, the six
therapy areas I will cover pertain to dry AMD as
well as RP and the rare, allied diseases.
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.
• Dr. Norman Radtke in the
USA had government
approval to treat several
human RP patients by
transplantation of embryonic
photoreceptor cells in a
clinical trial. He reported
good safety but only very
limited efficacy.
• So, is there anything new?
YES! Recent Modifications of Old Transplant
Strategies Seem to Work • Dr. Robin Ali et al. used transplantation of young
photoreceptor cells to improve vision in a mouse
model of RD. These cells are past the embryo stage
used in most previous studies but are not yet well
developed photoreceptors. After transplantation,
visual signals are projected to the brain with resulting
light-driven changes in behavior of the animal.
• Dr. Tom Reh showed that small numbers of adult rod
photoreceptor cells can integrate into the mature RD
mouse retina and restore some functional vision.
Dr. Ali et al. now have shown
repair of
.
degenerate retinas by photoreceptor
transplantation in 6 different mouse RD
models. He reported “robust integration” of
the cells into the damaged retina even in late
stage disease.
• Bottom Line: In photoreceptor cell
transplantation, there are new ideas that could
lead to clinical trials and sight restoration.
• One of the most important is the use of
stem cell transplantation.
Stem Cell
Transplantation
• 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
sick retina might
replenish the supply
of photoreceptor cells
that died due to
degeneration.
Where are stem cells found?
Stem cells are, of course, present in embryonic (fetal)
tissue. However, small numbers have been found in
many adult tissues.
For example, Dr. Derek Van der Kooy first reported
stem cells close to the retina in the eye of the adult
mouse. These stem cells can be harvested and
appear to function as true retinal stem cells.
Also, some adult cells such as skin cells can be
reprogrammed to revert back into a primitive stem
cell and then induced to differentiate into another
mature cell type such as a photoreceptor cell.
There are examples of sight rescue in RP
animal models using stem cells:
Dr. Tom Reh developed a special type of retinal
cell from human embryonic stem cells.
• When these cells are injected into the eyes of
mice that have a form of LCA, they migrate
into the retina and settle in the photoreceptor
layer. There, they begin to express rod and
cone photoreceptor biochemical markers.
• Importantly, light responses are restored in
the treated animals.
• A clinical trial is being planned.
Ocata is conducting a clinical
Clinical Trials?
trial injecting undifferentiated
embryonic stem cells behind
1) Ocata
the retina to supply fresh cells
2) London Project to Cure
in Stargardt Disease and dry
Blindness
AMD.
3) California Project to
Cure Blindness
A group at RIKEN in Japan is
4) RIKEN (Japan)
conducting a clinical trial on
Also, Dr. Henry Klassen
wet AMD using stem cells.
in the US is starting a
Other groups are working on
clinical trial with 16 RP
cell replacement in AMD using
subjects. He hopes to not
only supply new
established cell lines of
photoreceptors but to
human ESCs. Preclinical
help save remaining
results have been good.
cone cells that are yet
Applications to RP are obvious.
alive.
Foresight: Future
Treatment?
• Direct Photoreceptor cell
transplantation?: Not yet!
• Stem Cell conversion to
photoreceptor cells?: research
is continuing and good
progress is being made.
• Photoreceptor repopulation
from other cell types?: good
progress is being made in
basic, preclinical research.
• And, there are many
opportunities for use of stem
cells that are not obtained from
new human embryos.
• Clinical trials are here!
2) Artificial Vision
Uses an electronic prosthetic
device to replace the function
of dead photoreceptors. This
includes a small “patch”
usually implanted on the
retinal surface. Depending on
design, the “patch” could
contain light-sensitive diodes
or tiny electrodes that react
to a visual stimulus. Either
way, it substitutes for the
dead photoreceptor cells,
replacing their function.
There Are Many Groups Around
the World Working on Artificial Vision
• Retina Implant AG in Germany is an outstanding
leader in this field. RI has a device, the Alpha AMS,
that is now available for implantation in Europe.
• Second Sight Medical Products has its Argus II
device implanted in over 200 recipients.
• Other academic groups and companies are doing
excellent work on other types of retinal devices that
should lead to commercial products in the next few
years. Groups in Japan, Korea, Australia, Ireland,
USA.
Implants are now available from
two companies:
1) The Alpha AMS from Retina Implant is
available at 6 sites in Germany with more
centers to be established in France,
England and Spain.
2) The Argus II is now available at several
hospitals in the USA and Europe. There
are 17 cities in North America where the
Argus II is available for implant. In Europe,
the Argus II is available in England,
France, Germany, The Netherlands and
soon at a site in Australia.
In Summary • Results from use of the Argus II and Alpha AMS
prosthetic devices have been very good.
• The medical and social needs are great.
- the financial reward is also great in savings in both
patient medical costs and government assistance.
• Safety issues seem to be satisfied – up to 10 yrs now.
• Improvements should greatly improve Quality of Life.
Restoration of reading ability and face recognition
will allow for performing almost normal household
tasks and ability in the workplace.
No other treatments are available or as widely applicable
to as many severely impaired RD patients.
Where Are We
Today?
• Clinical trials on RP have
been successfully concluded
but testing continues.
• The Alpha AMS system is
available in Europe.
• The ARGUS II system is
available for general
implantation in advanced RP
in Europe and the USA.
Studies on dry AMD have
begun.
• Technologies are being
improved to allow for face
recognition and reading
ability as well as color vision.
Brain
Prostheses
Groups have been working
on brain cortical prosthetic
devices that could bypass
the eye completely.
• In the past, the group of
Dr. William Dobelle
prematurely did human
implants with poor results.
• More recently, SSMP is
developing a cortical
prosthetic device called
Orion 1 that will bypass the
eye completely.
Cortical Implant
• Many animal and plant cells have
3) Optogenetics proteins that react to light and
(Photoswitches) produce an electrical signal.
• For example………..
• Molecular engineering can be
used to insert channelrhodopsin
molecules into remaining retinal
cells, e.g., ganglion cells, in RD
Chlamydomonas is a
animals to make them light
tiny one celled algae
sensitive.
that contains a lightsensitive protein
• The light signals can be passed
called channel
on to the brain which can then
rhodopsin
distinguish at least a “lights on”
or “lights off” situation.
Different types of photoswitches can be inserted into
different types of remaining cells in RD retinas.
• Dr. Roska has shown that photoswitches can
be inserted into retinal bipolar cells to restore
visual function in an RD mouse model.
• Dr. Tamai used a photoswitch called Channel
Rhodopsin2 targeted to ganglion cells in an
RD mouse retina to “restore effective vision”
• Dr. Roska showed that another photoswitch
called halorhodopsin can be used in surviving
cone cells to substitute for the native defective
phototransduction proteins and restore light
Optogenetics Companies
Several companies have formed or are forming
to bring Optogenetics to clinical trial. For
example, GenSight Biologics is a newly formed
gene therapy company in France.
• It is testing a therapy developed by Dr. Sahel
in Paris. He uses gene therapy to deliver a
gene expressing the light-sensitive protein
“halorhodopsin” to remaining retinal cells in
RP animal models. The halorhodopsin picks
up the light energy and gives a visual signal.
Foresight:
Future
Treatments?
Basic work on Photoswitches is yet
in development.
• Some photoswitches only work at
very high and dangerous light
intensities or at damaging light
wavelengths. Some react to light
too slowly to be useful in human
vision. Others, though, work well.
• Excellent work by several
investigators on insertion of
specific photoswitches into
remaining retinal cells in RP animal
models gives hope for restoration
of functional vision in the future
Is the use of neuron-survival
4) Neuroprotection agents to delay photoreceptor
death. This has been proven in
several RP animal models.
7 Days after PDT: PBS vs. CNTF
• In 1990, Dr. LaVail and his
group first showed that a
natural growth factor (bFGF)
could delay photoreceptor cell
degeneration when injected
PBS
into the eye of an animal model
of RP. Since then, many
natural factors in brain, retina
and other tissues like CNTF
have been found that inhibit
photoreceptor cell death.
CNTF
Collectively, these are now called
“Neurotrophic Factors” or
“Neuron-Survival Agents”
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 sick retina.
• In ECT, a small capsule is surgically
placed inside the eye of the patient.
Within the capsule are special living
cells that are bioengineered to
produce CNTF.
• The CNTF leaves the capsule and
enters the retina where it helps to
protect the sick photoreceptor cells.
Many Neuron-Survival Agents are
Available for Testing:
• For example, Dr. Sahel et al. have shown the
Rod-derived Cone Viability Factor (RdCVF) is
a potent agent that promotes cone cell
viability. Cone cells are the most important
type of photoreceptor cell since they are
used in central, sharp and color vision.
• Dr. LaVail and others have identified over 30
natural and man-made factors that can act as
neuron-survival agents, protecting retinal
photoreceptor cells and prolonging vision.
Electrical stimulation is another way to
prolong photoreceptor cell life and increase
visual function
• The idea of using electrical current therapeutically
is quite old but it has been updated. A clinical trial
has been conducted testing Transcorneal Electrical
Stimulation (TES) to test its effect on the RP retina.
The TES device is placed in front of the eye and
electrical stimulation is applied to the retina through
the cornea.
• Electrical stimulation of the retina might increase
secretion of neurotrophic agents, thus protecting
the retinal cells.
• Okuvision’s TES has CE Mark approval in Europe.
•
The
current
Neurotech
Foresight: Future
clinical trial should soon
Treatments?
be completed.
• It could produce the first
effective and generally
available treatment for
many forms of RP, allied
diseases and dry AMD.
• BUT - there are many
agents to test yet! Drugs,
Natural Factors. Alone or in
combination.
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.
The AREDS formulation is generally available for use.
In Retinitis Pigmentosa, two
research groups - Van Veen
and Campochiaro have
demonstrated that antioxidants slow the course of
retinal degeneration in RP
animal models. This is
specifically photoreceptor
cell death through
apoptosis.
Antioxidant Trial
Ingredients:
Lutein, zeaxanthin, alpha-lipoic
acid, L-glutathione, extract of
lycium barbarum (wolfberry)
Dr. van Veen fed animals with
retinal degeneration a
special combination of
antioxidants and slowed
the degeneration process.
Together, these agents are
called RetinaComplex.
Based on this preclinical
work, a small clinical trial in
Spain has finished on RP
and dry AMD patients.
Initial reports of the results
were good but we are
waiting for a final report.
More extensive trials must
be planned.
• For dry AMD, antioxidants
Foresight: Future work at least at mid-stage
Treatments?
disease.
• For RP, clinical trials such as
on RetinaComplex must be
completed.
• In the future, there are many
types of antioxidants that can
be tested in RP and AMD
animal models and then in the
human.
• For now, take your mother’s
advice: Eat your Fruits and
Vegetables!
6) Gene
Therapy
• Gene Therapy replaces defective
mutated genes in living cells with new,
normal copies of the gene.
• The new gene acts as a blueprint,
synthesizing a normal protein that
restores function in the cell.
• Different types of Gene Therapy are
available. These are suited for all
genetic types of RP – recessive,
dominant and X-linked.
• 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
• In
Lancelot
2001, Dr. Gus Aguirre
and coworkers reported
remarkable restoration of
visual function in Briard
dogs, a model for Leber’s
disease. (RPE65 mutation)
• It is now about 15 years
later and the treated dogs
saw better for their lifetime.
• More recently, many other
dogs have been treated and
the results appear to be
excellent. Even in older
dogs with few photoreceptor
cells remaining.
Gene Therapy Clinical Trials
The newer and exciting news is that Gene Therapy will
restore some visual function in the human.
• About 5 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 (e.g., Drs. Bennett, Jacobson) soon started
similar trials and most treated 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 retinal degenerative
diseases.
Clinical trials are ongoing/planned
Future
for:
Treatments? • Forms of dominant, recessive and X•
•
•
•
•
linked RP: MERTK – Abboud –S.A.
Forms of LCA: LCA 1 (GUCY2D) – UF;
LCA 5 – Lebercillin consortium
Stargardt’s Disease - ProgStar
Retinoschisis –AGTC, NEI
Forms of Usher Syndrome – Ushstat
Choroideremia – MacLaren –UK
Gene Therapy also can be tested in
combination with other therapies
such as neurotrophic or antioxidant agents.
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.
Over 25 years of hard work
at the laboratory bench
has led to many clinical
trials that are testing
meaningful and sightsaving therapies. This will
lead to new treatments that
will save and restore vision
in all RD patients.
I leave you with one last piece of
good news -• At the recent meeting of the RI Scientific &
Medical Advisory Board in Seattle WA, we
reached a significant milestone.
• At past meeting, we usually had about 15
short reports on basic RD research and
progress towards clinical trials.
• This year, all talks reported on clinical trials
with no time for any news on basic studies.
• We believe that this is tremendous progress,
again pointing to oncoming treatments for
all retinal degenerative diseases.
THANK YOU FOR YOUR
ATTENTION!
Any Questions?