Retinal Degeneration Proof of Pr by chenshu


									Present and Future Treatments
   for Retinal Degenerative
    Diseases: An Overview

         Gerald J. Chader
      Doheny Retina Institute
       USC Medical School
         Los Angeles, CA
           The Needs:
      Treatment Availability
• No generally effective treatment is yet
  available for Retinitis Pigmentosa or allied
  diseases such as Usher Syndrome (deaf-
  blindness). Vitamin A supplements might help
• Similarly, no effective treatment other than
  nutritional supplementation is available for
  the millions with dry AMD.
• Treatment is available for wet AMD but it is
  expensive and often must be repeated.
Current and Future Treatments
All treatments will not benefit all RP or AMD
• Thus, RP treatments must be divided into 2
   1) treatments used when some photoreceptors
  remain alive and functional. These treatments
  prolong the life of the photoreceptor cell.
    2) treatments used when photoreceptors are
  dead and need to be replaced.
Luckily, we have good clinical techniques like
  OCT to distinguish between these 2 conditions.
       Current and Upcoming
         RP Clinical Trials
There are three major possible
 treatments where the patient yet has
 viable photoreceptor cells in their
These are: 1) Gene Therapy
           2) Pharmaceutical Therapy
            3) Nutritional Therapy
Without photoreceptors, these will not
First, let’s look at some of the progress
               in RD Genetics
 For Retinitis Pigmentosa:
 In 1990, the first RP gene mutation was
   found. This was for the rhodopsin
   gene in work by Drs. Humphries,
   Dryja and their groups.
 Now: Over 100 gene mutations have
   been found for the forms of RP and
   other rare diseases. About 50 %
 These are compiled on the Internet at a
   site called “Retnet”.
  What about AMD Genes?
• In 2000, no genes were identified whose
  mutations were known to cause or
  predispose to AMD.
• This has been difficult since AMD is a
  “complex disease” where both genes and
  environment (e.g., smoking) lead to or speed
  up the disease process.
• Now, at about 10 genes are known whose
  mutations cause or are associated with
  about 70% of AMD cases. Several more are
  yet to be identified.
    Progress in Cell Biology
Q.: How do photoreceptor cells actually die?
A.: No matter what the initial mutational insult,
  the common final pathway to death is by
  Apoptosis (Programmed Cell Death). This
  process is now well studied.
So, with all this basic science information on
  RD genetics and cell biology, certain
  possible routes to therapy are clear:
  – replace defective genes
  – prolong the life of photoreceptor cells
  – replace dead photoreceptor cells
   1) Gene Replacement Therapy
• Gene Therapy is the replacement of a
  defective (mutated) gene such that an
  important protein (e.g., enzyme) is again
  synthesized and present in the cell. With this,
  the photoreceptors function better and live
• What is a gene anyway?
  A gene is a small segment of the long DNA
  strand in the nucleus of our cells that acts as
  a blueprint for synthesizing a specific protein
  within the cell.
  A mutated gene is a defective gene that
  produces a disabled protein or none at all. If
  that protein serves an important function in
  the cell, the cell will not function properly
  and possibly will die.
            Gene Therapy
• In Gene Therapy, a modified virus called a
  “vector” is used as a truck/vehicle to bring
  the normal, replacement gene into the cell to
  produce a normal protein product.
• The virus is modified such that it cannot
  reproduce but it can yet penetrate a target
  cell efficiently with its cargo – the normal
Since it is estimated that about half of the RP
  gene mutations are known for humans, we
  have the theoretical possibility of replacing
  many of these genes in the future and
  treating many RP patients.
      Gene Replacement Therapy
Starting in the ’90, several groups showed that
  they could replace defective genes in animal
  models affected by RP and partially restore
  visual function. For example:
• In 2001, a group of scientists reported good
  restoration of visual function in a dog model
  for Leber’s disease.
• Even now, almost 8 years later, the dogs first
  treated are still seeing very well. Other dogs
  have more recently been treated and the
  results are excellent.
• Older dogs with relatively advanced disease
  have been treated with good results. This
  demonstrates that there is hope even for
  some patients with advanced RP.
Gene therapy restores vision in a canine
model of childhood blindness. Nature
Genetics 2001 May;28(1):92-5.
Gene Therapy Clinical Trials
• Based on the excellent preclinical animal
  studies, Clinical Trials for Gene Replacement
  Therapy in patients with Leber Congenital
  Amaurosis (LCA) have begun. One in London
  and two in Philadelphia. Other trials are
  planned around the world.
• These trials replace the mutated RPE65 gene
  in RPE cells of LCA patients. The RPE65
  protein is critical in the visual cycle. Retinal
  dysfunction and ultimately degeneration is
  the result if the protein does not function
• No final results on safety or efficacy have yet
  been reported but the initial results are good.
     2) Pharmaceutical Therapy
Pharmaceutical Therapy is the use of an agent
  that will prolong the life and function of a
  photoreceptor cell.
• Some agents available are natural proteins
  found in the body that are called “neuron-
  survival agents”. Some other agents are man-
  made drugs that function similarly.
• In 1990, it was shown that the natural growth
  factor, bFGF, could delay photoreceptor cell
  degeneration in an animal RP model.
• Since then, many factors found in small
  amounts in brain, retina and other tissues
  have been shown to slow photoreceptor cell
  death when delivered to the retinas of RD
  animal models.
       Pharmaceutical Therapy:
            Clinical Trials
• There are currently two Pharmaceutical
  Clinical Trials underway. One in RP patients
  and one in dry AMD patients. These Trials are
  testing a neuron-survival agent called CNTF.
• The company Neurotech has a special tiny
  capsule that can be implanted within the eye
  that produces the CNTF. The CNTF then
  diffuses to the retina where it helps
  remaining photoreceptor cells to survive and
  even function better.
• If the trials are successful, this will probably
  be the first treatment generally available to
  RP and dry AMD patients. (Maybe next year?)
      Neurotech Clinical Trial
• The Neurotech device with CNTF was well
  tested in an animal model of RP and found to
  be very effective in slowing the degeneration.
• The safety results of Phase 1 of Neurotech’s
  Clinical Trial are excellent. In 3 of 10 RP
  patients tested, even some improvement in
  vision was noted.
• Based on these results, there are high
  expectations for positive efficacy results
  from the Phase 2 and 3 parts of the Trials.
• Keep in touch with FFB for updates!
        3) Nutrition: For RP
The use of nutrition as a therapy in RP is
  controversial but now must be taken
  seriously in prevention or at least slowing
  down the degenerative process.
• In 1993, Dr. Eliot Berson found that
  vitamin A supplementation slows RP to a
  small extent in some patients. On the
  other hand, Vitamin E was found to be
• Thus, the use of vitamin A has been the
  only treatment available to RP patients.
• BUT – due to the small effect in only some
  patients and the fact that vitamin A can
  be toxic to some patients, many
  Ophthalmologists do not recommend the
  Antioxidants slow photoreceptor
          cell death in RP
• Recently, two noted investigators (Profs.
  Theo van Veen and Peter Campochiaro)
  reported that the use of antioxidants was
  very effective in slowing the disease course
  in rodent models of RP.
• Using sophisticated techniques, they showed
  that severe oxidative damage occurred in the
  retinal photoreceptor cells preceding cell
  death in the models of RP.
• BUT, supplementation with a specific
  cocktail of antioxidants greatly reduced the
  oxidative damage and slowed photoreceptor
  cell death.
• Importantly, the supplements were given by
  mouth to the animals. No injection is needed.
        The RetinaComplex
In his studies, Prof. van Veen fed the RD
    animals a combination of 4 antioxidants
    that are individually well known to have
    high antioxidant properties.
• Lutein and Zeaxanthin– natural plant
    pigments known to be concentrated in the
    human retina and probably function there
    as antioxidants
• L-Glutathione – a natural antioxidant found
    in the body and concentrated in the eye.
•   Alpha-Lipoic Acid – a general, potent
 Q. What about Safety and Efficacy
       of the Antioxidants?
• High doses of the antioxidants were used but
  no toxicity to the animals was observed. No
  toxicity for these antioxidants has been
  reported in the scientific literature for
• The supplements are taken by mouth and so
  need no invasive procedures as in gene
  therapy or ECT.
• The supplements were effective in RP animal
  models with very rapid photoreceptor
  degeneration and so are probably effective
  on even aggressive forms of RD in the human
  much less those with a slower time course.
     RetinaComplex Clinical Trial
A clinical trial has now begun to test the
  effectiveness of the antioxidant agents in
• This trial is in Spain sponsored by Dr. F.J.
  Romero and will probably take 2 years or
  more to complete. Good results at 1 year.
The supplement is already available for
  purchase over the internet – it is called
• It is probably safe since the supplement
  ingredients are classified by the US FDA as
  safe “nutrients” rather than untested “drugs”.
     A Clinical Trial for AMD
• A Trial with lutein is underway in AMD patients at
  the NEI. Lutein/Zeaxanthin are carotenoids in fruits
  and vegetables that are concentrated in the retina
  (particularly macula) and may act as antioxidants.
• So far, lutein has not shown any protective effect in
  RP patients (Jacobson et al., 2002).
• However, a small experiment is now being
  conducted on human RP patients that could lead to
  a larger Trial to determine if there is any efficacy in
  dietary supplements of lutein alone for RP.
       Current and Upcoming
           Clinical Trials
Now, let’s consider 2 treatments where
  very few or no photoreceptor cells
  remain alive.
Possible treatments here would include:
• Donor Photoreceptor Cell and Stem
  Cell Transplantation
• The use of Electronic Prosthetic
      4) Photoreceptor Cell
   Transplantation Clinical Trial
• The idea of replacing dead photoreceptor
  cells with new, donor photoreceptors by
  transplantation has long been worked on.
• There is a small human Clinical Trial on
  transplantation of photoreceptor cells being
  conducted by Dr. Norman Radtke in the USA.
• It has proven the relatively safety of the
  technique. BUT, unfortunately, there has not
  been much good news from the study as to
  improvement in vision in the patients.
Thus, with only very modest positive results
  from both animal and human studies, it is
  difficult to see how this will be a viable
  treatment in the future.
       Transplantation: Stem Cells
But, an exciting new area of research is in the
  study of Stem Cell transplantation.
• Stem cells are cells that have the potential of
  multiplying and developing into almost any
  type of cell in the body.
• Thus, theoretically, stem cells could be
  transplanted into the retinal space where
  photoreceptor cells have died and could
  develop and replace them.
• However, proper and complex biological
  signals have to be given to the stem cells
  such that they develop into mature,
  functional photoreceptor cells – instead of
  other cell types.
        Stem Cell Definition

• Stem cells are primitive, multipotential cells
  that are most often associated with early
  embryonic tissues that have not yet matured
  into a specific cell and tissue type.
• Stem cell have two major characteristics:
  - they can multiple greatly in number and…,
  - with a proper set of signals, they can stop
     multiplying and develop into one of many
     different adult cell types – such as
     photoreceptor cells.
   Stem Cells - Quo Vadis?
• Stem cell research is at a very early
  stage of study. Few photoreceptor
  characteristics yet can be induced to
  develop in the cells.
• Safety issues are also very important
  but poorly studied to date.
• Thus, although the potential is great,
  much work yet needs to be done on
  stem cells before they can be used to
  replace dead photoreceptor cells in
  the retina.
 Stem Cell Treatment in Humans
• To date, no positive stem cell Clinical Trials have been
  conducted on any form of retinal degeneration.
• In spite of this, stem cell treatments are being given in
  many countries to patients with many conditions
  including blindness. These cannot be considered to be
  safe and the effectiveness is highly questionable.
• Encouragement though comes from a press release a
  few days ago from the company StemCells Inc.
  They have used human stem cells in a rodent model of
  RP and found “preservation of the photoreceptors and
  stabilization of visual function” in the transplanted
• Bottom Line: Great potential but more work needs to be
  5) Electronic Prosthetic Devices
        for Sight Restoration
These fall into 2 categories:
1) Brain (cortical) electronic implants
2) Retinal implants – within the eye but
   either in front or behind the retina
For the retinal implants, there are many
   different designs and surgical
   approaches from groups around the
   Brain Prosthetic Devices
Three main groups of investigators have worked
  or are working on brain prosthetic devices that
  will have the potential to bypass the eye
• One group has prematurely done human
  implants with poor results.
• A second group continues to do mainly basic
  lab work.
• The third group is doing excellent work in
  monkey and is planning a human clinical trial.
Cortical Implant
  How Does the Retinal Prosthesis
• The device uses electrical signals to
  bypass defective or dead photoreceptors
  and stimulate remaining viable, non-
  photoreceptor cells of the retina.
• Images come from an external video
  camera worn behind the patient’s glasses.
• The images are transmitted through a
  computer to electrodes (called an array)
  attached to the retina to reproduce the
  visual image in the brain.
    Visual Prosthetic Devices

The Retinal Chip     The Retinal Chip Electrode
       Retinal Prosthesis Trials
Groups in many countries are developing
  retinal prostheses.
There are 4 groups around the world that have
  implanted human subjects with retinal
  prosthetic devices of different design.
• Optobionics Co. (Chicago, IL) – poor design
  such that it does not function well or at all.
• 2 excellent German companies – early stages
  of human testing – e.g., Retina Implant AG.
• Second Sight (Sylmar, CA) – with Dr. Mark
  Humayun, has already implanted 6 subjects
  in a Phase 1 study and now over 15 subjects
  in a Phase 2 Clinical Trial that recently
        Phase 1 Patient Update
Chronic studies on human implants have
  been done on an early electrode device
  with 16 electrodes -- from February 2002.
 Six patients were implanted. There were
  NO device failures.
 All subjects saw discrete visual images
  (called phosphenes) and could again
  perform visual spatial and motion tasks.
 Mobility (walking and navigation) has been

   The remaining 5 patients use the device at
Retinal Prostheses – The Future
• Clinical trials continue. If successful,
  commercial models should soon become
  available for implant.
• Designs are improving to increase the
  number of electrodes touching the retina.
• Theoretically, a design with about 1,000
  electrodes is needed to give reading ability
  and face recognition.
• The prosthetic device may be the best hope
  for restoring sight to severely affected RP
  and dry AMD patients.
This is NOT Vision of Terminator or
       Geordi from Star Trek !
    In Conclusion for RP….
Several Clinical Trials are in progress. Proof of
  Principle for several other types of therapies
  has been established.
• For example, Gene Therapy work on a dog
  model of RP-LCA shows not only sight
  restoration but a long term, positive effect.
• Other basic work in the fields of gene
  therapy, stem cell research, pharmaceutical
  therapy, nutrition and electronic implants
  shows promise in current and for starting
  future Clinical Trials.
  What Clinical Trials Can We
  Expect for RD in the Future?
Groups of investigators are now working
   on several of the Rare Diseases to
   move to Trials.
1) Leber Disease: Three groups have
   started Clinical Trials on Gene
   Replacement Therapy for a form of
   LCA. At least one other group also is
   planning an LCA Trial but with
   replacement of another gene whose
   mutation leads to a form of LCA.
       Future Clinical Trials
2) Stargardt Disease: Dr. Rando
  Allikmets and coworkers are working
  on Gene Replacement Therapy of the
  mutated gene in a rodent model of
  Stargardt Disease. So far, the results
  are preliminary but good and, if finally
  positive for safety and efficacy, a
  Clinical Trial is planned.
  Other research groups are working on
  other types of therapy for Stargardt
      Future Clinical Trials

3) Usher Disease: Research groups are
  working on both Usher 1 and Usher 3
  to replace the mutated genes in the
  two conditions through Gene Therapy.
• Producing good animal models in both
  conditions has been a problem that is
  currently being worked on.
• Even Gene Therapy on the cochlea of
  the ear is being assessed as to
  possible restoration of hearing.
       Future Clinical Trials

4) Choroideremia: Scientists are close to
  producing a good rodent model for
  Choroideremia. They will then use
  Gene Therapy to replace the mutated
  gene in the model. If successful, a
  human Clinical Trial can be planned.
5) Similar Gene Replacement is planned
  for some of the other Rare Diseases
  such as Retinoschisis.
     What about AMD?
Dry AMD – nutrition therapy. The
 antioxidants studied in the AREDS
 clinical trial of the NEI are available.
Wet AMD – several drugs now have been
 approved by government agencies in
 many countries to slow the growth of
 new, abnormal blood vessels. The best
 known is Lucentis.
             Nutrition and AMD

AREDS Antioxidant Treatment
A Clinical Trial for antioxidants in treating AMD
   has been completed by the National Eye
   Institute. It was called the Age-Related Eye
   Disease Study (AREDS).
It found that some nutritional supplements
   helped in AMD. The antioxidant nutrients
   studied were B-carotene and vitamins C and
   E along with the mineral zinc.
The antioxidants only slow the course of the
   disease at a specific (mid) stage of AMD.
The antioxidants are available for sale although
   a physician should be consulted before using
      Clinical Treatments –
            Wet AMD
• Lucentis – Genentech has an agent,
  “Lucentis” for wet AMD. Lucentis is an
  antibody that works against VEGF, a small
  protein that calls in the new, abnormal blood
  vessels. Lucentis actually improves vision.
• One of the problems with Lucentis though is
  that it must be injected into the eye.
• Also, there usually have to be repeat
• Another problem is the high cost but a similar
  agent, Avastin, is available at much lower
     Wet AMD Clinical Trials –
       Gene Therapy Trial
• GenVec is conducting a Gene Therapy
  Clinical Trial for wet AMD. It delivers the
  PEDF gene into the eye. Phase 1 of the Trial
  is completed and the safety results are very
• PEDF is a natural protein that has both
  antineovascular and neuron-survival
  properties. Thus, it could be used for both
  AMD and RP.
• If the results on wet AMD are positive,
  GenVec could then move on to the use of
  PEDF in RP and in dry AMD along with wet
 AMD Clinical Trials - Nutrition
• As I mentioned before, a Nutrition Trial called
  AREDS2 with lutein is underway in AMD
  patients at the NEI in the USA.
• Lutein/Zeaxanthin are carotenoids, the
  colored pigments in fruits and vegetables,
  that are concentrated in the human retina –
  especially the macula. It is thought that they
  act as antioxidants and thus protect
  photoreceptor cells from oxidative damage.
• This Trial will take several years though to
  complete. Until then, take your mother’s
  advice and “Eat your fruits and vegetables!”
             In Conclusion….
Several Clinical Trials are planned or are
  already in progress for different types of RD
For example, Gene Therapy work in RP animal
  models shows not only sight restoration but
  a long term, positive effect. Is this a “cure”?
• Other basic work in the fields of gene
  therapy, stem cell research, pharmaceutical
  therapy, nutrition and electronic implants
  shows promise with several Clinical Trials in
• The retinal prosthetic device could be the
  best hope for sight restoration for patients
  with advanced retinal degeneration.
         A Final Thought…..

• We can treat and, in some cases,
  maybe even cure diseases in many
  animal models of retinal degeneration.
• Many human Clinical Trials are
  starting such that treatments are
  coming soon.
• These are expensive and time
  consuming….. but who can put a price
  on restoring sight?

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