Robert Aramant, Ph.D.
Professor
Ocular Transplantation LLC
240 Audubon Medical Plaza
Louisville, KY 40217

Diana Arrington
Director, Corporate Development
Division of Therapeutic Proteins
GenVec, Inc.
65 West Watkins Mill Road
Gaithersburg, MD 20878

Werner Baumgartner, Ph.D.
Research Director
Ianus Foundation
4849 Cooper Point Road NW
Olympia, WA 98502

Patricia Becerra
Senior Investigator
Division of Therapeutic Proteins
National Eye Institute
7 Memorial Drive
Bethesda, MD 20892-0706

David Birch, Ph.D.
Research Director
Retina Foundation of the Southwest
9900 North Central Expressway, #400
Dallas, TX 75225

Ava Bittner, O.D.
Clinical Research Post-Doctoral Fellow
Lions Low Vision Center
Johns Hopkins Wilmer Eye Institute
550 North Broadway, 6th Floor
Baltimore, MD 21205-2020

Craig Blackstone, M.D., Ph.D.
Chief, Cellular Neurology Unit
National Institute of Neurological Disorders and Stroke
Building 35, Room 2C-913
Bethesda, MD 20892-3704

William Boyd, M.D.
Clinical Team Leader
Division of Anti-inflammatory, Analgesic, and
Ophthalmologic Drug Products
Food and Drug Administration
5600 Fishers Lane, HFD-550
Rockville, MD 20857-0001

Gerald Cagle, Ph.D.
Senior Vice President, Research and Development
Alcon Research, Ltd./NNRI
6201 South Freeway
Fort Worth, TX 76134-2099

Monica Camparini, M.D.
Ophthalmology
University of Parma
Via Gramsci, 14
Parma I-43100
Italy

Connie Cepko, Ph.D.
Professor of Genetics/Investigator
Department of Genetics
Howard Hughes Medical Institute
Harvard Medical School
77 Avenue Louis Pasteur, Nrb 360
Boston, MA 02115

Gerald Chader, Ph.D.
Chief Scientific Officer
Doheny Retina Institute
1450 San Pablo Street
Los Angeles, CA 90033-3699

K. V. Chalam, M.D., Ph.D.
Chairman
Department of Ophthalmology
University of Florida
580 West 8th Street
Jacksonville, FL 32209

Ching-Kang Chen, Ph.D.
Assistant Professor
Ophthalmology and Visual Sciences
University of Utah
EIHG31l0A
15 North 2030 East
Salt Lake City, UT 84112-5330

Introduction

The National Neurovision Research Institute (NNRI) hosted the Symposium to discuss, evaluate, and promote translational research for the development of prevention, treatments, and cures for retinal degenerative diseases. NNRI 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 among scientific, clinical, governmental, pharmaceutical, and financial communities and to encourage clinical trials of new candidate drugs and drug delivery systems for orphan retinal diseases.

NNRI is a nonprofit support organization of The Foundation Fighting Blindness (FFB). Founded in 1971, FFB is a nonprofit organization that has raised more than $140 million for scientific research to identify prevention, treatments, and cures for diseases of the retina causing blindness.

The 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 nonprofit 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.

NNRI 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.

As a nonprofit health foundation, NNRI will create a model of collaboration among nonprofit 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.

The Symposium brought 170 specialists from 12 countries to Washington, DC, from various communities including basic science, clinical science, pharmaceutical companies, government, venture capitalist organizations, legal entities, and nonprofits. During the 3-day event, 61 international specialists made 6 expert presentation sessions and led 14 breakout sessions and 1 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 included:

National Eye Institute, NIH
Office of Rare Diseases, NIH
Office of Orphan Products Development, FDA
National Institute of Neurological Diseases and Stroke, NIH
National Institute on Aging, NIH
National Institute on Deafness and Other Communication Disorders, NIH
National Heart, Lung, and Blood Institute
Alcon Laboratories, Inc.
W. K. Kellogg Foundation

Advances in Clinical Sciences

Dr. 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 encompasses at least 155 chromosomal loci of which 109 genes have been cloned. The worldwide prevalence is about 1 in 3,500. 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, choroideremia, 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.

Dr. 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 quantitative outcomes.

To illustrate new therapies for hereditary retinal diseases, Dr. Paul Sieving used two examples, 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.

In Search of Pathogenetic Mechanisms and Processes

In 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, 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 that 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.

Dr. 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.

Dr. 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.

Dr. 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 pigmentosa.

Dr. 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.

Dr. Mark Tso reviewed the histopathological features of a series of human eyes with retinitis pigmentosa, which were mostly enucleated postmortem. The degenerative photoreceptor cells attracted activation and invasion of microglia into the outer layers of the retina, attacking both rod and cone cells. Furthermore, these patients showed remarkable microglia infiltration in the optic nerve, resulting in optic neuritis and atrophy.

Dr. 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.

Dr. 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.

The Therapeutic Discovery Process

Dr. 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 lentiviral vectors.

In 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) bioengineered models, including many transgenic forms, which are available in rodents and even in large animals such as pigs; and (3) light-damage models.

The 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 noninvasively and to provide a test model for various forms of administration of therapy, including intravitreal, subretinal, and episcleral administration.

The 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 nanosystems for both extra-ocular and intra-ocular administration of drugs.

Furthermore, Dr. Jill Heemskirk, of the National Institute of Neurological Diseases and Stroke, described a High-Throughput Drug Screening Program for neurodegenerations. To expedite clinical trials, she and her colleagues are trying to find new indications for existing drugs or natural products for treatment of neurodegenerations. These drugs were assayed in simple (in vitro) assays of neurodegenerations. 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 neurodegenerative diseases. Drugs that produced "high hits" will be tested in animal models. She has compiled a list of approximately 1,000 compounds with known safety profiles and known therapeutic activities. These are compounds that 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.

Dr. Min Li, the director of 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.

A specific example of the therapeutic discovery process was highlighted by Dr. Lisa Wei for 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.

Dr. 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 bioengineered 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.

Dr. Timothy J. Schoen of the 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 biotechnical companies to start collaborative relationships with the FFB 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 were presented.

Initiating Clinical Trials

Because 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.

Dr. 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.

The 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. 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 presymptomatic treatment. Dr. 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. Daiger reviewed a summary of retinal degeneration genes in detail, which can be accessed via RetNet^TM at www.sph.uth.tmc.edu/Retnet/.

Dr. 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.

Dr. 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 7-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 of funding since 1983 and has provided support to a total of 450 grant applications. Thirty-eight products have been granted market approval.

Two 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. 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. Seddon reviewed nutriceutical supplements for patients with age-related macular degeneration.

Clinical 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.

Commercialization Dynamics

To move scientific discoveries from the laboratory into therapeutic programs for orphan diseases, extensive fostering of partnerships among academic institutions, nonprofit 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, nonprofit 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.

The NNRI Symposium followed this premise and therefore brought together basic scientists, clinicians, pharmacologists, legal experts, representatives from the pharmaceutical industry, biostatisticians, government regulatory agencies, government research institutes, philanthropists, investors, and nonprofit organizations to discuss the formation of these extensive partnerships.

Terrence 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.

Dr. 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.

Dr. 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.

Dr. 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.

Mr. 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.

Several examples of business development that were ongoing or were at planning stages for orphan retinal diseases were discussed during the Symposium.

Dr. 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.

Summary

In this post-genomic era, with remarkable discoveries of numerous mutant genes, 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, antioxidants, calcium channel blockers, neurotrophic factors, and others may all be implicated for amelioration of disease processes.

In 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.

Careful 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.

At 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 with 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 NNRI will continue to be a catalyst for acceleration of clinical trials for hereditary orphan retinal diseases.