Download Minutes of the 2007 Meeting of the Scientific and Medical Advisory

Minutes of the 2009 Meeting of the Scientific and
Medical Advisory Board of Retina International
Date: Monday, 4 May 2009
Venue: ARVO annual meeting, Ft. Lauderdale, FL USA
Attendees:
President: Ms. Christina Fasser
SMAB co-chairman: Drs. Eberhart Zrenner and Joe Hollyfield
SMAB Secretary: Dr. Jerry Chader
Invited Speakers:
Dr. Jean Bennett
Dr. Emily Chew
Dr. Mark Humayun
Dr. Daniel Martin
Dr. Javier Romero
Dr. Bernhard Weber
Dr. Eberhart Zrenner
Other Invited Participants:
Dr. Robin Ali
Dr. Sten Andriasson
Dr. A. Ciccodicola
Dr. Francoise Assimasopoulos
Dr. To Chi-ho
Dr. Patrick Corley
Dr. A. T. Moore
Dr. Ragnheiour Bragadottir
Dr. Nicolas Cuenca
Dr. John Flannery
Dr. Andreas Gal
Dr. Fredrik Ghosh
Dr. Christian Grimm
Dr. Elise Heon
Mr. Tom Hoglund
Dr. Peter Humphries
Dr. Artur Cideciyan
Dr. Frans Cremers
Dr. Nathan Mata
Dr. Weng Tao (Ms. K. Dickinson)
Dr. Theo van Veen
Dr. Scott Whitcup
Dr. Ruth Reese
Dr. Birgit Lorenz
Dr. Jean-Michel Rozer
Dr. Jose Sahel
Dr. Mike Michaelides
Dr. Diane Sharp
Dr. Andrea Vincent
Dr. Francis Munier
Dr. Isabelle Pinilla
Dr. Markus Preisig
Dr. F. Javier Romero
Dr. Sirkka-Liisa Rudanko
Dr. Eeva-Marja Sankila
Dr. Daniel Schorderet
Dr. Paul Sieving
Dr. Santa Tumminia
Dr. Marian Humphries
Dr. Reetta Jalkanen
Dr. Josselyn Kaplan
Dr. Caroline Klaver
Dr. Matthew LaVail
Dr. Elizabeth Mc Kennen
Dr. Robert Molday
Dr. Erica Strettoi
Dr. Bart Leroy
Dr. Miltiadis Tsilimbaris
Dr. Alan Laties
Dr. Eric Pierce
Dr. Anthony Moore
Agenda Items
A) Introduction
Ms. Fasser opened the meeting with a hearty greeting to all the participants and
thanks to all the speakers. After some other opening remarks, she turned over the
meeting to Drs. Zrenner and Hollyfield to begin the scientific presentations.
B) Scientific Program
Clinical Trials Note: Specifics about most clinical trials can be found at
“clinicaltrials.gov” on your computer search engine
Gene Replacement Clinical Trials
UPenn Trial on LCA- RPE65 Gene Therapy – Dr. A. Cideciyan, University
of Pennsylvania, Philadelphia, PA USA
Preclinical studies on gene replacement therapy in animal models of Leber Congenital
Amaurosis (LCA) were very successful. Specifically, the RPE65 gene was replaced in these
cases using an AAV viral vector with excellent safety and efficacy that has restored a
measure of sight in animals for a number of years. Based on this work, a Phase I clinical trial
began in 2007 in LCA subjects with the RPE65 mutation with the approval of the FDA and
support of the National Institutes of Health. The trial is led by Dr. Samuel Jacobson at the
University of Pennsylvania in Philadelphia where the patients are first entered into the trial
and examined before and after surgery. Surgery and gene-vector production occurs at the
University of Florida under the leadership of Drs. William Hauswirth and Barry Bryne.
Dr. Artur Cideciyan gave an update on this trial. The primary outcome of the trial is safety;
secondary outcomes include changes in vision. The trial was initially planned for 3 cohorts
(groups) of patients, each with three individual subjects, The first cohort consisted of 3 young
adults between 21 and 24 years of age. These patients received subretinal injections of the
AAV2 vector with the normal RPE65 gene. The results available through the first 90 days
post-treatment have been published and were encouraging. In terms of safety, there were no
vector-related Serious Adverse Events (SAEs) and no systemic toxicities. All patients selfreported and increase in visual sensitivity in their treated study eye compared with their
control eye. This was especially noticeable under reduced ambient light conditions. Using a
full-field stimulus test under dark-adapted conditions, the study eye showed significant
sensitivity increases.
Specialized methods of vision testing corroborated that there were significant improvements
in sensitivity localized to the area of treatment in the injected eye. The gene therapy
procedure improved both day vision originating in cone photoreceptors as well as night vision
originating in rod photoreceptors of the LCA patients. Day vision could be improved up to 50fold and night vision up to 63,000-fold compared to pretreatment levels.
Dr. Cideciyan stated that the first cohort of patients has passed the 1-year time point and
continue to do well. Specifically, there are no vector-related serious adverse events and the
intervention appears to be safe. Based on the positive results in the first cohort, the Data
Safety and Monitoring Committee has allowed the study to continue to the second cohort
which includes adults injected with a higher dose of vector and to the third cohort which
includes children.
CHOP Trial on LCA- RPE65 Gene Therapy – Dr. J. Bennett, University of
Pennsylvania, Philadelphia, PA USA
Dr. Bennet reported that at the Children’s Hospital of Philadelphia (CHOP) as well as in
Naples, Italy and Ghent, Belgium, work continues on investigating the effects of RPE65 gene
replacement in LCA subjects.
The first subject received a single unilateral subretinal injection of AAV2.hRPE65v2 in
October of 2007 and, since that time, 10 additional individuals have been enrolled and
received injections. Baseline testing, surgery and follow-up testing are carried out at CHOP.
CLIA testing for the RPE65 mutation was done by Dr. E. Stone at the Univ. of Iowa.
The first 3 subjects enrolled (Naples, Italy) are young adults (19-26 yrs at the time of
injection) and are now 15 months post-injection. They continue to do well as to both safety
and efficacy. Duplicate baseline testing is now done at CHOP and in Naples serving to
generate a robust data set.
Individuals enrolled over the last year include 4 children. All have recovered visual function
with improvement in their nystagmus. They are reading without aids.
The upper age limit (72 yr) was eliminated in the protocol since a therapeutic effect was
observed in the 26 yr old individuals in the first cohort. The oldest individual enrolled to date
is 44 yr old.
All the juvenile and adult subjects are doing well. Two of these patients are from Ghent,
Belgium so a third follow-up site is planned for this location.
In conclusion, Dr. Bennett said that the program in on target and the patients are happy with
the results – all asking to have their second eye injected.
Question: Are there plans for gene therapy in other RD diseases
Answer (Dr. Bennett): Yes, we have a list of others such as Stargardt and Usher but
funding is needed..
Question: was improvement in nystagmus observed in the other 2 clinical trials?
Answer (Drs. Cideciyan and Dr. Ali): No improvement was noted.
Retina Prosthesis Clinical Trials
Subretinal Implant - Retina Implant AG – Dr. Eberhart Zrenner, University
of Tuebingen, Tuebingen, Germany
Dr. Zrenner reported on progress in the clinical study of the SUBRET consortium. In the
current studies, subretinal implants were placed near the macula using a transchoroidal
approach in 11 patients. The electronic array is 3 x 3 mm in size and carries 1500
photodiodes, amplifiers and electrodes. It is powered by a subdermal cable.
Dr. Zrenner stated that, using this device, “Proof of Principle” has been established in that
blind RP patients could recognize unknown objects. From data obtained from the most
recently implanted 3 patients, it can be concluded that the active subretinal multielectrode
implants with currents close to recognition threshold (10 and 27 nC/electrode) produce
retinotopically correct patters.Stripe patterns of moderate luminance can be resolved by the
implanted patients up to 0.35 cycles/deg. Visual acuity measured by use of Landolt rings
reached levels of 1/50. VA = 20/2000. Standard tests include object recognition (e.g., apple
vs. banana) and letter recognition (4 cm height at 40 cm distance) presented on a table in
front of the subject.
Dr. Zrenner concluded that, again, he considers this as Proof of Principle that light-sensitive
subretinal multi-electrode devices are suited for restoration of useful visual percepts in blind
patients. He noted that this is the first time worldwidr that such high resolution has been
achieved by an implant in blind persons. This experience and calculations by various groups
indicate that at least 1000 electrodes are needed to achieve spatial resolution of this kind. He
added though that any prosthesis-mediated vision is yet very limited and further technical
developments and clinical studies will be necessary to arrive at a device that will allow for
such recognition abilities in daily living for blind RP patients.
Epiretinal Implant - Second Sight Medical Products (SSMP): Dr. Mark
Humayun, USC School of Medicine, Los Angeles, CA USA
Dr. Humayun and his collaborators including SSMP have taken an epiretinal approach to
implantation of their prosthetic array, i.e., on the vitreal side of the retina juxtaposed to retinal
ganglion cells.
Phase 1 of an FDA-approved clinical trial with 6 patients has been completed (2002-2004)
although patient testing continues. This device, the Argus I, had 16 electrodes in the retinal
array. More recently, an Investigational Device Exemption (IDE) has been obtained from the
US FDA to continue the implant studies using a 60 electrode array (Argus II). To date, over
20subjects have been implanted at 8 centers around the world. All subjects had bare light
perception or worse due to advanced Retinitis Pigmentosa. The average age of the subjects
is 60 + 9 years. Currently, the age limitation for enrollment has been dropped to age 25.
Surgically, the Argus II electronics were sutured episcleraly and a vitrectomy was performed.
Then, the electrode array was inserted through the pars plana and tacked to the retina in the
macular region.
To date in this ongoing trial, the safety of the device has been acceptable. Most of the
adverse events occurred around the time of surgery, i.e., within one month of the procedure.
All resolved and/or were successfully treated by the end of 6 months. There were no device
failures and no explants.
Concerning efficacy, all of the subjects can now perceive phosphenes. Significant
improvement has also been seen in spatial localization, motion detection, orientation and
mobility as well as in other specialized tasks. A logMAR value of 2.2 has been determined in
one of the subjects. All subjects have been able to take the Argus II system (including
glasses and battery-operated video processing unit) home for use outside the clinic.
Question: What are the target groups of patients?
Answer (Dr. Zrenner): Currently, all groups apply such devices in patients with hereditary
retinal degenerations. Others disease conditions could be considered but only after safety
and efficacy are established for the electronic retinal prostheses.
Antioxidant Clinical Trials
Age-Related Eye Disease Study 2 (AREDS2) – Dr. Emily Chew, National
Eye Institute, NIH, Bethesda, MD USA
With the successful conclusion of AREDS1, the AREDS 2 study is now designed to see if
a modified combination of vitamins, minerals and fish oil can further slow the course of AMD.
AREDS2 is designed to evaluate the usefulness of omega-3 long chain polyunsaturated fatty
acids (PUFAs) and lutein in the treatment of AMD and cataract. The study will also examine
the effects of the elimination of beta-carotene from the AREDS1 supplement and decreasing
the dose of zinc on the treatment of AMD.
Lutein and zeaxanthin are yellow pigments derived from plant sources that accumulate near
the macula of the retina and are thought to provide antioxidant protection to the central retina.
Fatty acids such as DHA and EPA are derived from fish oils and are also thought to have
antioxidant properties.
As of September of 2008, the study had enrolled 4,203 participants of ages 50 to 85 in 82
clinical centers both at academic institutions and at community practices. The dietary
supplements are taken by mouth. They include a tablet containing 10 mg lutein and 2 mg
zeaxanthin as well as 2 soft-gel capsules containing the DHA and EPA. In addition, all
participants are offered the possibility of being randomized into treatment with the original
AREDS formulation (“standard of care”) and 3 variations of this formula. These are 1) no
beta-carotene 2) lower zinc content and 2) no beta-carotene and lower zinc.
The primary goal (outcome) of the study will be to determine if the formulation changes the
progression to advanced AMD in patients at moderate to high risk for progression. Secondary
outcomes include progression to moderate vision loss, the occurrence of adverse events,
progression of lens opacities and the effect of the supplements on cognitive function and
cardiovascular health..
Dr Chew said that she and her coworkers plan to have 5 years of follow-up in the trial on the
ocular effects of the supplements. In collaboration with other NIH institutes, effects on both
cognitive function and cardiovascular function will also be carefully examined.
Question: Do you still recommend beta-carotene?
Answer (Dr. Chew): There is a very good risk:benefit ratio with beta-carotene in persons
who are not currently smoking. We found no increased mortality in participants randomly
assigned to antioxidant vitamins, including beta-carotene.
Moreover, there is actually reduced mortality seen with zinc supplementation although this
is yet a question with lutein.
RetinaComplex Clinical Study in Retinitis Pigmentosa Patients – Drs.
Javier Romero and Theo van Veen, University CEU Cardenal Herrera and
Mediterranean Ophthalmology Foundation, Valencia, Spain and University
of Tuebingen, Tuebingen, Germany
Previous work by Prof. van Veen established the efficacy of using a combination of potent
antioxidants called RetinaComplex in slowing the progression of retinal degeneration in
animal models of RP. Please see the minutes from last year’s SMAB meeting for a position
paper by Retina International on safety and efficacy issues in such use.
In the absence of Dr. Romero, Professor van Veen described the current clinical study. This
is a hospital-based prospective, randomized double-blind clinical study with an appropriate
control group being performed in Valencia, Spain. The first 12 months of the study have now
been concluded with a total of 44 subjects with Retinitis Pigmentosa. 23 subjects received
RetinaComplex and 21 subjects received placebo for 12 months. Written consent was
obtained from the participants after they were given a reasonable explanation of the study
details. A complete history of each participant with respect to age, gender, clinical symptoms,
etc. was collected using a questionnaire.
Blood samples are collected to check for 1) glycosylated hemoglobin (a marker for metabolic
control and possible diabetes) 2) zinc and vitamin E (to check for possible patient selfsupplementation) and 3) malondialdehyde (a lipid peroxidation product that is a marker for
oxidative stress).The fundus of each participant was exampled with an ophthalmoscope and
macular OCT performed. Miltifocal ERG as well as other functional studies such as
automated perimetry was performed and a general health evaluation questionnaire was
obtained. All these baseline parameters are being compared with the same parameters
obtained after 12 month RetinaComplex intake using appropriate statistical analysis.
From the intermediate data collected so far, no difference could be established between
paired data, except for the amplitude of the multifocal erg. The placebo group showed a
statistical difference between the data collected at the beginning of the study and the end of
the first 12 month period. Of importance though, the patients receiving RetinaComplex
showed no statistically significant difference between the two sets of data. This confirmsthat
there is a slower progression of disease in the treated subjects compared with those getting
only placebo. Although this study was initially planned for only 1 year, the promising results
obtained makes it worthwhile to continue the study for a longer period if proper funding can
be obtained. The results of the first two years of the study will be available in autumn of this
year.
Neuroprotection Clinical Trials
Brimonidine Study – Dr. S. Whitcup, Allergan Inc. Irvine, CA USA
Brimonidine is an alpha-2 agonist that is approved for use in lowering Intraocular Pressure
(IOP) in patients with glaucoma and ocular hypertension. It has also been shown to be
neuroprotective in animal models of glaucoma and retinal disease.
Dr. Whitcup reported that, this year at the ARVO meeting, investigators have shown that
brimonidine, delivered in a bioerodable intravitreal sustained-release implant enhances
visual-evoked responses in preclinical studies. In these studies, normal rabbits were used to
study the effect of the drug on sweep Visually Evoked Potential (sVEP). Animal were given
doses of 66 ug, 200 ug or 600 ug in the left eye with the right eye receiving placebo. With
different concentrations of brimonidine, statistical differences were observed in acuities
compared with baseline with high statistical significance. No abnormalities were observed in
retinal histology in the treated eye as well no abnormalities detected with color fundus
photography.
Currently, intravitreal sustained-release brimonidine implants are being studied in clinical
trials on patients with retinal disease including atrophic AMD and Retinitis Pigmentosa. The
trial is sponsored by Allergan, Inc. Two different concentrations of the drug are being studied.
For the AMD trial, the primary outcome is a change from baseline in size of geographic
atrophy on stereoscopic color fundus photography and with fluoroscein angiograqphy.
CNTF-ECT Clinical Trials – Ms. Kathleen Dickinson – Neurotech, Lincoln,
RI USA
CNTF is a natural compound found in the body that helps to protect neuronal cells from
damage, hence is a “neuron-survival” and “neurotrophic” agent. It has been shown to slow
the course of retinal degeneration in a number of RD animal models. A problem with
neurotrophic agents though is in the method of delivery to the retina. However, Neurotech
has devised an ingenious capsule that is implanted within the vitreous cavity of the eye that
delivers a sustained and safe dose of CNTF to the retina. This is called “Encapsulated Cell
Technology” or NT-501-ECT. Preclinical experiments were successful using this device,
showing relative safety as well as efficacy. Phase I of an FDA-approved trial also has
successfully been completed.
Dr. Dickinson first apologized that Dr. Weng Tao, who was initially scheduled to give the
Neurotech update was, at the last minute, unable to attend. She then proceeded to inform the
group as to the current advanced-phase trials on subjects with RP and on those with
Geographic Atrophy (GA). The trials are as follows: CNTF2 for dry AMD/GA; CNTF3 for late
stage RP; CNTF4 for early stage RP. For example, 51 patients with dry AMD are being
studied in the GA trial. To date in this ongoing work, the safety results are good in that
Neurotech has encountered no significant treatment-related Serious Adverse Events (SAEs).
No serum antibodies have developed against CNTF or the encapsulated cells that produce it.
Dr. Dickinson reported that the biological effect of NT-501 has been identified. OCT images
have demonstrated that there is improved definition of the Outer Nuclear Layer (ONL) of the
retina in treated subjects at 12 months, compared to baseline images. A significant increase
in retinal thickness, measured as total macular volume was determined by OCT. This was a
dose dependent effect and observed in all three CNTF protocols. These results are
consistent with published reports from preclinical observations. Retinal thickness was
determined by the Duke Reading Center to not to be due to cystoid macular edema,
epiretinal membrane formation, vitreoretinal traction or choroidal neovascularization.
Thus, the results appear to be encouraging such that CNTF-ECT might be the first treatment
generally available to both RP and dry AMD patients.
Fenretinide Trial – Dr. Nathan Mata – Sirion Therapeutics,, Tampa Fl, USA
In the retina, vitamin A is certainly needed for vision through the visual cycle. However, in
some retinal degenerative diseases, toxic byproducts of vitamin A can form, causing damage
and cell death. Thus, theoretically, somewhat lowering the vitamin A level in the retina could
slow the accumulation of the toxic byproducts and thus slow the degeneration.
Fenretinide is a low molecular weight drug that is a member of the retinoid (vitamin A) family
of compounds. As with vitamin A (retinol), fenretinide can bind to Retinol-Binding Protein
(RBP), a protein that transports retinol in the blood (serum) and delivers it to its target tissues
and cells such as Retinal Pigment Epithelium (RPE) cells. Fenretinide thus competes with
vitamin A for such binding on the RPB molecule and ultimately reduces the amount of serum
vitamin A available for entry into the RPE. In this way, the accumulation of toxic byproducts
should be reduced and the process of retinal degeneration also slowed.
Dr. Mata reported that, in January of 2008, Sirion Therapeutics began a two-year, doseranging phase II trial to investigate the efficacy of fenretinide in preventing or slowing the
growth of retinal lesions in patients with geographic atrophy secondary to AMD. The drug is
given orally at concentrations of 100 or 300 mg/day.
A 1-year interim analysis was performed in March of 2009 and the results were positive.
Among the subpopulation of patients who reached the 18 month visit, 78% of the subjects in
the 300 mg group had lesions less than the median of those receiving only placebo. A similar
treatment effect was observed in the subjects receiving the 100 mg dose, specifically in
subjects who had smaller lesions at baseline. This suggests that early intervention may result
in improved outcomes.
Concerning safety, most side effects were similar in occurrence in placebo and treated
groups. Importantly, despite a significant reduction in circulating retinol, the incidence of
delayed dark-adaption was comparable among placebo and treatment arms of the trial.
Concerning efficacy, the results look good to date in that over twice as many patients in the
group receiving only placebo developed neovascularization as in the fenretinide-treated
group.
Question: Genetically, a defect in the serum RBP gene can lead to retinal degeneration.
Could fenretinide thus cause a retinal degeneration?
Answer (Dr. Mata): The RBP level in patients is carefully monitored. The decrease in serum
RBL level is approximately 60%.
Question: Could fenretinide be used in Stargardt disease?
Answer (Dr. Mata): Currently, this use is not planned since fenretinide, as with other
retinoids, is a teratogenic agent and is therefore not appropriate for use in the young.
Question: Is there a change in the hyperfluorescence in the retinas of the treated subjects?
Answer (Dr. Mata): Data are being collected on this question.
Antineovascular Clinical Trial
Leucentis vs. AvastinTrial – Dr. Daniel Martin – Cleveland Clinic
Foundation, Cleveland, OH USA
In wet AMD, VEGF is a primary factor in neovascular development. Thus, inhibitors of the
action of VEGF can slow or stop the formation of the abnormal new vessels. One of these,
Lucentis, has been shown by Genentech to be particularly effective in treating wet AMD.
Lucentis (ranibizumab) is a human antibody fragment that functions as an anti-VEGF agent.
Similarly, Avastin (bevacizumab) is an antibody that acts against VEGF-like compounds and
has been extensively used in cancer therapy. With similar mechanisms of action but with
Avastin much less expensive than Lucentis, several studies around the world have started to
test the two agents “head to head” in the same study to determine if there are differences in
safety or efficacy between them.
Dr. Martin summarized these studies giving as an example the trial sponsored by the
National Eye Institute - “Comparison of AMD Treatments Trials: Lucentis vs. Avastin Trial”.
Current enrollment is 800-1200. Although the trial is proceeding well, he cited several
problems in trials such as this. For example, there is a large difference in US government
copayment in the drug use and thus difficulty in masking the bill so the type of drug remains
hidden. He felt that there is a need for government intervention (Congressional amendment)
for NIH-sponsored clinical trials such that appropriate masking can be done.
He said that investigators were now looking at the genetic background of the trial subjects to
see if there is any correlation between genotype and trial outcomes. Final results should be
available in 2010/2011.
Question: In patients with compromised blood-retinal barriers, what is the effect of antibodies
in the periphery?
Answer (Dr. Martin): A study has been started to measure systemic antibody levels.
Preclinical Science
RD Genotyping – Dr. Bernard Weber – University of Regensburg,
Regensburg, Germany
RD genotyping is important in giving the patient information about their disease and its
probable prognosis (progression). It is also important in some clinical trials and absolutely
necessary before gene replacement therapy can be done. Several laboratories,
commercial and academic, now perform RD genotyping, at least on selected genes
known to cause RD.
Dr. Weber spoke about the 300 kb Affymetrix re-sequencing array that is now available in
his laboratory at the University of Regensburg. This array allows for the testing of 72
genes associated with retinal dystrophies including the 3 genetic types of Retinitis
Pigmentosa – autosomal dominant, autosomal recessive and X-linked. It also can be used
for testing of macular dystrophy, Stargardt disease (dominant and recessive). Usher
syndrome and Bardet Biedl syndrome. The “Retchip” will be available for routine testing
after May, 2009.
Question: What are the costs of this array if only 1 patient is tested?
Answer (Dr. Weber): The total costs would amount to EUR 1.5.000-04.000 per patient
but, if mutation analysis is combined from different patients with different phenotypes,
costs can be lower.
AMD Genetics – Dr. Bernhard Weber – University of Regensburg,
Regensburg, Germany
In 2000, no genes were known whose mutations increased the risk for AMD. Today,
several gene mutations have been uncovered that together, account for a large
percentage of the risk in developing AMD. Interestingly, several of these mutations are in
genes involved in immune regulation.
Dr. Weber stated that there are two major genetic risk factors associated with AMD.
These are polymorphic variants in the CFH and ARMS2/HTRA1 genes. Case/control
association studies have also suggested several other risk factors with minor contributions
to disease such as Complement Component 2, Factor B, Complement Component 3 and
APOE. Yet others have been reported in single studies but have not been independently
replicated so far.
Continuation of this line of work will greatly aid our understanding of the molecular
pathogenesis of AMD and will allow the design of targeted therapies. Dr. Weber said that
an international consortium of investigators is needed to further this work since new genes
represent only a smaller percentage of unknown mutations in AMD patients and that 45,000 (and possibly up to 10,000) patients will probably be needed in the studies.
LCA Preclinical Therapy Studies – Dr. Frans Cremers – Radboud
University Nijmegen Medical Centre, Nijmegen, The Netherlands
Dr. Cremers updated the group on preclinical studies that should lead to a clinical trial on
gene replacement therapy of the LCA5 gene (lebercilin). After the identification of the
LCA5 gene in 2007, research groups from Bar Harbor (Dr. P. Nishina), Montreal (Dr. R.
Koenekoop), Nijmegen (Drs. F. Cremers, A. den Hollander, R. Roepman) and
Philadelphia (Dr. J. Bennett) as well as other members of these groups started a
collaboration to develop a gene therapy protocol for LCA patients with mutations in the
LCA5 gene. The core of this work is funded by the Foundation for Retinal Research as
well as additional funding by the Foundation Fighting Blindness, USA, FFB Canada and
the FRSQ and CIHR.
There are 4 important goals of the consortium:
To develop a mouse model that mimics human LCA5-associated vision loss.
Using sophisticated molecular techniques, homologous recombination was performed
generating homozygous Lca5 (-/-) mutant mice. The mutants show early-onset retinal
degeneration. In the next 2 years, these mice will be used to test gene-replacement
therapy using the lebercilin gene.
To perform gene replacement therapy in the LCA5 KO mice.
This work is now ongoing. The human LCA5 cDNA, driven by a constitutive promoter,
was cloned into adeno-associated virus construct and expression of the lebercilin
protein was confirmed in vitro by Western blot analysis.
To identify a sizable group of patients with LCA5 mutations.
Since the LCA5 mutation is so rare, the group has to date sequenced 400 patients with
LCA and 100 with arRP without detecting additional mutations in LCA. Worldwide,
about 1400 probands have been analyzed which identify 28 individuals with LCA5
mutations in 13 families.
To understand the role of the lebercilin protein in retinal function.
Dr. Cremers explained that the group aims to understand the function of lebercilin
through deciphering its protein network. Using protein-protein interaction experiments,
interacting proteins have been identified including microtubule-associated proteins,
ciliary transport proteins and other proteins of unknown function. Importantly,
lebercillin was found to interact with a ninein-like protein that also interacts with the
USH2A protein. All three proteins localize to the basal bodies of photoreceptor
connecting cilia. Thus, lebercilin probably forms a link between Usher syndrome and
LCA caused by mutations in ciliary proteins.
In summary, Dr. Cremers said that the work is on target to begin a clinical trial on gene
replacement therapy by 2011. To accomplish this though, extra efforts are needed to identify
enough patients with LCA5 mutations.
New Business, Announcements and Conclusion
Stem Cell Treatments – Dr. Robin Ali
Ms. Fasser asked Dr. Ali to say a few words about the potential of stem cell therapy in sight
restoration and current “treatments” in a number of countries. As discussed last year at the
SMAB meeting, advertisements in places such as the internet for several indications such as
blindness are now common. However, there are serious questions as to both safety and
efficacy of such applications.
Dr. Ali cited several examples of purported treatments in different countries that are delivered
for different forms of blindness. He feels that it is the “unmet” needs” of the patient that
stimulates these types of treatment and that there is an inability of the lay public to distinguish
between a true, scientific “trial” and an unsubstantiated “treatment”. He mentioned that grave
consequences can occur from such uncontrolled treatment including the potential for tumor
development.
Ms. Fasser asked Dr. Ali if he would write a draft of a position paper for consideration by
Retina International as to the current and future use of stem cells in treating retinal
degeneration. Dr. Ali agreed to do this.
European Vision Institute – EuroVisionNet.eu – Dr. Eberhart Zrenner –
University of Tuebingen, Tuebingen, Germany
Dr. Zrenner wished to bring to the attention of the SMAB meeting participants that the “Vision
Research Gateway” is a new web-based portal service for vision researchers in Europe as
well as others who are interested in basic and clinical progress in vision.
The website is meant to bring researchers together and stimulate communication as well as
to give vision research a higher profile and visibility in the general community.
The website can be accessed at www.vision-research.eu.
Rod-derived Cone Viability Factor (RdVF) – Dr. J.A. Sahel - Institut de la
Vision, Inserm, Paris, France
Ms. Fasser asked Dr. Sahel to summarize the work of his group on RdCVF.
RdCVF and RdVCVF2 are novel neurotrophic factors that promote the survival of cone
photoreceptor cells. They belong to the family of thioredoxin proteins that play an important
role in redox signaling in photoreceptor cells and are involved in protection from oxidative
stress.
Dr. Sahel said that the RdCVF signaling links oxidative stress in photoreceptors to
neuroprotective responses. This is especially true in rodents with light-induced damage.
Essentially, the relevant genes, Nxn11 and Nxn12, are part of a signaling pathway that
couples oxidative stress and cone photoreceptor cell survival. There are now good animal
model data demonstrating better ERG function after RdCVF treatment. In the future, this
could allow for treatment of RD patients, protecting cone photoreceptors and preventing
central vision loss.
Future Meetings
XVI World Congress of Retina International – Dr. A. Ciccodicola –
University of Naples, Naples, Italy
Dr. Ciccodicola reminded RI members to hold the dates of 26-27June 2010 for the next RI
World Congress. It will be held in Stresa, Italy at Lago Maggiore, a beautiful lake-side venue
in northern Italy. The theme of the meeting will be “Change our Vision – Bridging the Gap
from the Lab to the Patients”.
XIV International Symposium on Retinal Degeneration – Dr. Matthew
LaVail – University of California, San Francisco, CA, USA
Dr. LaVail announced that the next RD Symposium, RD 2010, would be held on July 13-17,
2010 in Mt.-Tremblant, Canada.
Conclusion
Ms. Fasser closed the meeting by thanking all the speakers for their presentations. She felt
that this was an excellent update of advances in moving towards treatments and cures for the
retinal degenerative diseases.
She wished all would have a productive ARVO meeting and looked forward to seeing
everyone again at next year’s SMAB meeting in Ft. Lauderdale and then at the RI Congress
in Italy.
For the minutes:
Dr. Gerald J. Chader
Doheny Retina Institute
Los Angeles, CA USA