Foundation Fighting Blindness Clinical Research Institute
Symposium Proceedings Published in
The Journal of of Retinal and Vitreous Diseases
The First International Symposium on Translational Clinical
for Inherited and Orphan Retinal Diseases
Sponsored by the FFB Clinical Research Institute
November 5-7, 2004
Wardman Park Marriott Hotel
Mark O.M. Tso, M.D., D. Sc. and Morton F. Goldberg, M.D.
Institute hosted the Symposium to discuss, evaluate, and promote translational
research for the development of preventions, treatments, and
cures for retinal degenerative diseases. The FFB Clinical Research Institute was established
in 2002 to expedite the translation of laboratory-based research
into clinical trials for treatment of hereditary orphan retinal
diseases. The Symposium was a key strategic step by the Institute
to develop bridges of communication between scientific, clinical,
governmental, pharmaceutical and financial communities, and
to encourage clinical trials of new candidate drugs and drug
delivery systems for orphan retinal diseases.
The FFB Clinical Research Institute
is a non-profit support organization of The Foundation Fighting
Blindness (FFB). Founded in 1971, FFB is a non-profit organization
that has raised more than $140 million dollars for scientific
research to identify preventions, treatments, and cures for
diseases of the retina causing blindness.
objectives and guiding principles of this Symposium were to
bring experts from scientific and medical communities to meet
with representatives of pharmaceutical companies, government
regulatory agencies, government research institutes, philanthropists,
investors, and non-profit foundations to discuss opportunities
in drug discovery and commercialization of drugs for orphan
retinal diseases, such as: retinitis pigmentosa, Stargardt
disease, Usher syndrome, macular degeneration, and related
diseases. This Symposium also provided learning opportunities
and interactive channels among experts in different fields.
also intends to recruit new investigators and participants
into orphan retinal disease research programs by stimulating
their interest in exploring the potential benefits of therapy
for these diseases.
a non-profit health foundation, the Institute will create a model of
collaboration between non-profit organizations, the pharmaceutical
industry, and governmental agencies in providing innovative
treatments to populations with chronic degenerative diseases
of the retina, and to overcome bottlenecks in drug discovery
and drug commercialization of these new therapies.
Symposium brought 170 specialists from 12 countries to Washington,
D.C., from various communities: including basic science, clinical
science, pharmaceutical companies, government, venture capitalist
organizations, legal entities, and nonprofits. During the
three-day event, 61 international specialists made six expert
presentation sessions, lead 14 break-out sessions, and one
poster session, providing an exciting interchange of information
among the individuals from various fields. The Symposium was
further supported and endorsed unprecedentedly by seven government
agencies and two private foundations. These organizations
Office of Orphan Diseases (NIH)
Office of Orphan Products Development (FDA)
National Institute of Neurological Diseases and Stroke
National Institute of Aging
National Institute of Communicative Diseases and Deafness
National Heart, Lung and Blood Institute
Alcon Laboratories, Inc.
W. K. Kellogg Foundation
in Clinical Sciences
Richard G. Weleber gave an overview of inherited and orphan
retinal diseases that collectively affect less than 200,000
individuals in the United States, but represent the major
cause of incurable blindness and loss of vision, especially
among young adults. This group of diseases is largely genetically
based, and encompass at least 155 chromosonal loci of which
109 genes have been cloned. The worldwide prevalence is about
1 in 3500. They exhibit different inherited forms. Some of
the diseases may be part of a systemic syndrome, or the disease
process may localize in the retina alone. Dr. Weleber further
discussed phenotypes, genotypes, and challenges in therapy
for this group of diseases. He reviewed retinitis pigmentosa
and allied disorders, of which 50% are simplex, and 50% are
multiplex, with 20% autosomal dominant and 20% autosomal recessive,
10% X-linked, and rarely digenic. He further discussed allied
diseases, such as cone-rod dystrophies, Usher syndrome, Bardet-Biedl
syndrome, choroidoremia, and X-linked retinoschisis. Other
hereditary orphan retinal degenerations, including Leber's
congenital amaurosis, Stargardt disease, and fundus flavimaculatus,
were reviewed, and possible therapies were suggested.
Gerald Fishman led a discussion on Outcome Measurements of
Successful Therapies for this group of diseases, and commented
on the importance of proper selection of patients. He emphasized
the qualitative and quantitative use of full field electroretinography,
static perimetry, and kinetic perimetry. Dr. Fishman further
commented on the various patterns of visual field loss at
different stages of the diseases. The natural history of the
various forms of retinal degenerations must be clearly defined
before initiating clinical trials. To illustrate this, Dr.
Fishman showed different patterns of visual loss in retinitis
pigmentosa with cases of diffuse retinal involvement, regional
pigmentary degeneration in the superior or inferior retina,
or others with sharp demarcation of segmental loss. Dr. Fishman
further pointed out that the pathologic process in hereditary
retinal degeneration may involve other complicating presentations,
such as cystoid macular edema, optic atrophy, and others.
The definition of the natural courses of various forms of
these diseases, along with their genetic determination, should
allow comparable therapeutic interventions with measurable
illustrate new therapies for hereditary retinal diseases,
Dr. Paul Sieving used two examples, namely RPE 65 for Leber's
congenital amaurosis and CNTF-encapsulated cell technology
for treatment of retinitis pigmentosa. He briefly reviewed
the National Eye Institute's activities in support of this
field of research, linking them to the Neuroscience Blueprint
of 14 of the NIH institutes.
Search of Pathogenetic Mechanisms and Processes
inherited retinal degenerations, the pathologic process focuses
on the photoreceptor and the retinal pigment epithelial complex.
Dr. Dean Bok noted that photoreceptor cells are highly susceptible
to mutations expressed endogenously, locally or systemically.
He used four examples to illustrate the disease processes:
1) mutation of an RPE specific gene, namely, RPE65, which
causes disruption of photoreceptor functions; 2) A gene mutation
(ABCA-4) expressed in rod and cone cells, which results in
damage to the pigment epithelium. The diseased RPE compromises
photoreceptor cells, as in Stargardt disease; 3) A null mutation
in the rds gene which causes cell death; and 4) A mutation
of an ambiguously expressed gene such as SLC4 A7, which may
exert a highly selective, lethal effect on sensory cells.
Gerald J. Chader described pigment epithelium-derived factor
(PEDF) as a "protein for all seasons" and a good
candidate as a therapeutic agent in retinal degenerations.
It serves as a neuronal survival agent, an inhibitor of neo-vascularization,
and an inhibitor of glial cell growth. It is synthesized by
many cell types, including Muller cells and RPE cells.
Matthew LaVail gave an overview of issues for neurotrophic
factors and survival factors, such as CNTF, FGF, BDNF, NT3,
and interleukin 1beta. Most remarkable is CNTF, which successfully
slowed retinal degeneration in 13 different inherited types
of retinal degenerations in four different species. This class
of agent may act indirectly on photoreceptor cells through
Muller cells or RPE cells. While this group of survival factors
shows general beneficial effect in the degenerative process,
they are not disease specific.
Jose A. Sahel described the identification and characterization
of a rod-derived cone viability factor. This factor, RdCVF,
is a truncated thioredoxin-like protein specifically expressed
by rod cells. Sahel suggested that this protein offers new
treatment possibilities for saving cone cells in retinitis
Valina Dawson reviewed the pathologic and pathogenetic mechanisms
of PARP, a signaling molecule and a death molecule. PARP inhibitors
protect neural tissues against ischemic reperfusion injury
and limit neuronal cell death.
Mark Tso reviewed the histopathological features of a series
of human eyes with retinitis pigmentosa, which were mostly
enucleated post-mortem. The degenerative photoreceptor cells
attracted activation and invasion of microglial into the outer
layers of the retina, attacking both rod and cone cells. Furthermore,
these patients showed remarkable microglial infiltration in
the optic nerve, resulting in optic neuritis and atrophy.
Thaddeus Dryja presented pathologic changes in three examples
of human patients with retinal degenerations and gene defects.
A patient with a dominant mutation of GCAP1, showing dominant
cone degeneration, had cones dying slowly over their lifetime,
although some still survived at age 75. Dr. Dryja concluded
that a potential benefit of gene therapy in this disease may
be realized at all ages. In a second patient with a mutation
of PDEGB, all rods were shown to be dead early in life, probably
before age 4 and perhaps already at birth. Gene therapy may
successfully be applied only to newborns or fetuses. The third
case (a PDE65 gene defect) showed rod and cone photoreceptor
cells severely dysfunctional at the early stages of life,
such that gene therapy should probably be given in the first
or second decade of life. With these human cases, Dr. Dryja
concluded that the histopathologic evaluation of patients
with these retinal degenerations provided useful information
on the timing of initiation of therapies.
Dean Bok, at the closing of the Symposium, expressed optimism
that rapid progress in studies of pathogenetic mechanisms
in recent decades may soon lead to definitive therapies.
Therapeutic Discovery Process
Gerald Chader reviewed five approaches to therapeutic discovery:
1) transplantation of stem cells, especially those stem cells
occurring in the pigmented ciliary margin in the eyes of adult
mice. Stem cells from brains and other embryonic tissues may
also be transplanted into the retina; 2) pharmaceutical therapies
of neuronal survival agents, growth factors, or inhibitors
of apoptosis, which may be delivered transclerally or intravitreously
with various slow release mechanisms, including encapsulated
cell technology; 3) nutritional supplements, such as DHA and
vitamin A; 4) visual prosthesis in the form of a retinal "chip";
and 5) gene therapy using ribozyme therapy or gene replacement
therapy with adenoviral or lenti-viral vectors.
hereditary orphan retinal diseases, animal models are keys
to understanding of mechanisms, and provide evidence to justify
initiation of clinical testing. Animal models consist of three
major groups: 1) natural models, which have been found in
drosophila, zebra fish, chicken, rodents, cats, and dogs.
These animal models involve recessive, x-linked, and dominant
forms of retinal degeneration; 2) bio-engineered models, including
many transgenic forms, which are available in rodents and
even in large animals such as pigs; and 3) light-damage models.
primary function of photoreceptor cells is light reception,
but intense light can lead to photoreceptor degeneration.
The light damage model has been most helpful in exploring
candidate drugs for treatments of retinal degenerations. Dr.
Gustavo Aguirre described animal models and also showed a
good correlation between electrophysiological testing and
structural loss of photoreceptor cells. Furthermore, these
animal models may be tested with optical coherence tomography
to gauge the degenerative process non-invasively, and to provide
a test model for various forms of administration of therapy,
including intravitreal, sub-retinal and epi-scleral administration.
search for new therapies also involves new drug delivery systems.
Dr. Vincent L. Lee reviewed a multidisciplinary approach to
drug administration for various drugs in different platforms,
different biomaterials, variations in the microenvironment
of the administration site, and the progression of the disease
states. Most excitingly, he described the potentially unifying
platform of nano-systems for both extra-ocular and intra-ocular
administration of drugs.
Dr. Jill Heemskirk, of the National Institute of Neurological
Diseases and Stroke, described a High-Throughput Drug Screening
Program for neuro-degenerations. To expedite clinical trials,
she and her colleagues are trying to find new indications
for existing drugs or natural products for treatment of neuro-degenerations.
These drugs were assayed in simple (in vitro) assays of neuro-degenerations.
A group of investigators have contributed their data to a
central database. Currently, 29 different assays have been
funded in this program, to represent a broad variety of neuro-degenerative
diseases. Drugs that produced "high hits" will be
tested in animal models. She has compiled a list of approximately
1000 compounds with known safety profiles and known therapeutic
activities. These are compounds which would otherwise be inaccessible
to researchers. She is currently working with the pharmaceutical
industry to bring these compounds into the public domain.
A similar approach could be utilized for retinal degenerations.
Min Li, Director, Chem Core, and the Associate Director of
the High-Throughput Biology Center at Johns Hopkins University,
has developed both hardware and software for massive high-throughput
screening of candidate drugs.
specific example of the therapeutic discovery process was
highlighted by Dr. Lisa Wei for pigment epithelium-derived
factor (PEDF) for treatment of "wet" age-related
macular degeneration. She and her colleagues have completed
interim safety results with AdPEDF in a Phase I clinical trial
without serious adverse events and are looking forward to
the next clinical stage of investigation.
Weng Tao reviewed the process of development for encapsulated
cell technology for treatment of retinal degenerations via
intravitreal delivery of CNTF by cells that are bio-engineered
to produce the growth factor, and that are encapsulated within
a porous delivery system. Phase I of a clinical trial is being
conducted by Dr. Paul Sieving at the National Eye Institute.
Timothy J. Schoen of the Foundation Fighting Blindness (FFB)
further described the medical therapy program of FFB to accelerate
the translation of laboratory-based research to medical treatments
for retinal degenerations by engaging pharmaceutical and bio-technical
companies to start collaborative relationships with The Foundation
and its affiliated research scientists. FFB is establishing
clinical research centers, patient registries, histopathologic
facilities, medical therapy assessment centers, and development
of animal models. Specific examples of these arrangements
patients suffering from hereditary orphan retinal diseases
are not common, it is important to form national and international
patient registries to gather patients for clinical trials.
The patients in the registry must be carefully examined for
phenotypes and genotypes. Dr. Richard G. Weleber described
the patient registries at FFB-sponsored centers, and emphasized
how physician/patient relationships should be protected. Other
important issues include: privacy, confidentiality, and data
security per state and federal regulations and HIPPA requirements.
Leslie Hyman discussed study design and biostatistical consideration
for clinical trials of orphan retinal diseases. A clear statement
of study aims, definitions of outcomes, a sample size calculation,
eligibility criteria, inclusion and exclusion criteria, and
randomization must all be considered. In addition, masking
of observers and patients, planning the final analysis, standardized
measures, complete follow-up of all participants, and stopping
guidelines must be defined in advance. Because these diseases
are relatively uncommon, challenges in study design must be
met. Dr. Hyman advocated careful planning and consideration
of different methodological approaches before beginning a
clinical trial in order to avoid pitfalls arising during the
course, and at the end, of the trial.
need for genotyping before inception of clinical trials was
discussed in a workshop by Dr. Thaddeus Dryja, Dr. Edwin Stone,
and Dr. Stephen P. Daiger. The workshop reviewed the necessity
of genotyping for: 1) gene specific therapy; 2) cell specific
therapy; and 3) pan neuron therapy. Dr. Edwin Stone emphasized
the importance of matching a treatment to a specific genetic
disease, because identifying the gene-specific natural history
of a specific genetic disease would reduce the effect of individual
variability and may allow pre-symptomatic treatment. Stone
also cautioned that in clinical trials on diseases that have
multi-gene etiology, such as Leber's congenital amaurosis
(which has at least eight different genes involved), the genotypes
should be identified. Heterozygous variants must be interpreted
with great caution, especially when numerous genes are screened
simultaneously. Dr. Stephen P. Daiger reviewed a summary of
retinal degeneration genes in detail which can be accessed
via RetNet(TM) at www.sph.uth.tmc.edu/Retnet/.
Gerald Cagle reviewed the contemporary drug discovery process,
ranging from the finding of disease targets, as malfunctioning
proteins, enzymes, receptors, and ion channels, through screening
in vivo and in vitro, and finding compounds with desired biological
effects on the target. Standard safety evaluation of the drugs
must be completed before putting the drugs into clinical trials.
He reviewed the Phase I, II, and III, characteristics of the
drug development process.
William Boyd and Dr. Debra Lewis, both of the FDA, described
regulatory issues for clinical trials of orphan retinal diseases.
Special incentives to enhance the commercial value of therapy
of orphan diseases have been set up by Congress, including
seven-year marketing exclusivity to the first sponsor obtaining
FDA approval of a designated drug, extra credit (equaling
50% of clinical investigator expenses), exemption of some
application fees, and assistance in the drug development process.
The orphan product development grants program in the Office
of the Commissioner of the FDA has had a cumulative $150 million
dollars of funding since 1983, and has provided support to
a total of 450 grant applications. Thirty-eight products have
been granted market approval.
completed nutriceutical trials for retinitis pigmentosa were
discussed. These trials included vitamin A and docosahexanoic
acid (DHA) therapy, and were discussed by Dr. Robert Massof,
Dr. David Birch, and Dr. Johanna Seddon. Dr. Massof challenged
the interpretation of results of vitamin A and vitamin E intake,
as correlated with the rate of progression of retinitis pigmentosa
measured by the ERG amplitude. Dr. David Birch provided DHA
to patients with X-linked retinitis pigmentosa and observed
that the daily nutritional supplement of DHA elevates RBC
lipid concentrations of DHA. He believes that the RBC DHA
levels in these patients are correlated with the rate of ERG
loss. Dr. Johanna Seddon reviewed nutriceutical supplements
for patients with age-related macular degeneration.
trials for Parkinson's disease, Alzheimer's disease, amyotrophic
lateral sclerosis (ALS), and glaucoma were described by Dr.
Ted Dawson, Dr. Philip Wong, Dr. Jeffrey Rothstein, and Dr.
Robert Weinreb. The lessons from the clinical trials of these
neuronal degenerative diseases were applied to the photoreceptor
degenerations in hereditary retinal diseases.
move scientific discoveries from the laboratory into therapeutic
programs for orphan diseases, extensive fostering of partnerships
among academic institutions, non-profit organizations, government
agencies, pharmaceutical companies, venture capitalists, and
legal advisors is required. A group of experts, including
Dr. Stephen Ryan, Dr. Stephen Groft, Dr. Paul Sieving, Dr.
Katrina Gwinn-Hardy, and Dr. Gerald Cagle, shared their experiences.
Studies of disease mechanisms and therapeutic agents frequently
start at a university setting, supported by university resources,
non-profit organizations' funds, and governmental grants.
In order to move these discoveries to clinical trials, the
intellectual property of the discovery must first be clearly
established in order to attract financial support from pharmaceutical
companies or venture capitalists. Clinicians must obtain regulatory
approval from the FDA in order to proceed with a clinical
trial. Pharmaceutical companies are involved in the manufacturing
and sale of the therapeutic agents. Commercial dynamics must
be carefully managed in order to bring the treatment to patients.
FFB Clinical Research Institute Symposium followed this premise, and therefore brought
together basic scientists, clinicians, pharmacologists, legal
experts, and representatives from the pharmaceutical industry,
pharmacologists, bio-statisticians, government regulatory
agencies, government research institutes, philanthropists,
investors, and non-profit organizations to discuss the formation
of these extensive partnerships.
Ross, Esq., emphasized that intellectual property is the foundation
for initiation of clinical trials and commercialization. He
briefly discussed how intellectual property rights are derived,
developed, protected and transferred. Invention must be based
on: 1) usefulness, 2) novelty, and 3) timely filing of a patent
application. He discussed the relationship of trade secrets
and patent rights. He further described the transfer of intellectual
property from investors to companies, or from companies to
universities and clinics.
David Noskowitz presented some of the unique features of bringing
orphan drugs to the market. He reminded the audience that
orphan drugs face special study design requirements, because
of the very small patient population, relatively small studies,
and frequent multi-system involvement of the disease processes
with confounding variables, such that end points may not be
traditional, but may require multiple secondary and tertiary
definitions. He illustrated his principles by discussing lysosomal
therapy for storage disorders.
Gary Novack, Dr. Vincent Anido, and Mr. Anton Hopen further
discussed licensing compounds and handling of intellectual
property before initiating clinical trials. They identified
common fallacies, such as: 1) orphan drug status may have
fewer requirements and regulations for obtaining an IND and
NDA; 2) clinical trials involving pediatric patients may require
less effort; or 3) clinical trials may be conducted faster
outside the United States.
Anido discussed the decision-making processes and commercial
dynamics of clinical trials. Decision factors include: product
characteristics, new class of drugs, FDA guidelines for studies,
new or established market, and size of the market. He shared
his experience in bringing Vitrase for vitreous hemorrhage
and xibrom for ocular inflammation to the market.
James Blair discussed how venture capitalists would support
therapies targeting retinal diseases. He emphasized well-understood
mechanisms, innovative ideas in therapy, and definition of
clinical staging, and indicated that venture capitalists would
be willing to support therapies for orphan retinal diseases.
examples of business development that were ongoing, or were
at planning stages, for orphan retinal diseases were discussed
during the Symposium.
William Hauswirth shared the current development of RPE65
gene therapy for Leber's congenital amaurosis. He shared his
experience in how the therapeutic agent was developed and
confirmed by animal studies, and the need for current recruitment
of patients and genotype determination. An IND is being filed
as an orphan drug application. The trials and tribulations
of this process were discussed at length.
this post-genomic era, with remarkable discoveries of numerous
mutant genes, and recognition of new therapy systems and availability
of new commercial dynamics, more innovative therapies are
being proposed for historically incurable hereditary retinal
diseases. Development of therapies for these orphan diseases
will ordinarily start with identification of dysfunctional
molecules, pathogenetic mechanisms and pathologic processes.
Furthermore, since most patients with these hereditary diseases
only gradually lose their vision as they grow older, the dysfunctional
molecules most likely have been interacting with environmental
factors and other disease pathways, resulting in eventual
photoreceptor cell death. Since multiple pathways are therefore
frequently involved, therapeutic approaches with gene therapy,
dietary and vitamin supplements, anti-oxidants, calcium channel
blockers, neurotrophic factors, and others may all be implicated
for amelioration of disease processes.
this era of therapeutic discovery, massive screening of new
drugs will be needed to determine the chemistry, toxicology,
and dose response curves. Side effects, which may prevent
successful clinical trials, must be determined early.
management of commercial dynamics will be required to bring
the therapeutic agents to the patients successfully. Intellectual
property will be determined by the patentability and licensing
of drugs, with a financial forecast to gain support for relevant
research programs. The discovery process must be "de-risked"
to attract venture capitalists for the commercialization process.
The pharmaceutical industry is needed to help with the manufacturing
of therapeutic agents under good practices, and to assist
with the development of clinical trials.
the concluding session, Dr. Morton F. Goldberg and Gordon
Gund thanked the speakers and participants for their generous
and collegial sharing of ideas. Mr. Gund concluded by a commitment,
"It is no longer a question that we hope for vision -
it is a question of a promise for vision. It is not a question
whether or not we are going to find treatments and cures -
it is now only a question of when." They stated that
the Institute will continue to be a catalyst for acceleration of
clinical trials for hereditary orphan retinal diseases.