Planning for clinical trials is somewhat like building a suspension bridge. On one side of the shore are the laboratory researchers; on the other shore, the clinicians. The Foundation Fighting Blindness is now at a point where strong, durable bridges between the laboratory and the clinic must be put into place to provide a conduit whereby promising treatments can reach patients. To arrive at our destination, several critical research needs must be met.

Genotyping
Imagine the horror of developing a successful treatment but not being able to identify the patients who would benefit from the treatment. Many gene and pharmaceutical therapies are gene specific and require that we know each patient’s genetic diagnosis, or genotype. Because so many mutant genes can cause disease, we need to genotype patients so that we can identify candidates for clinical trials and ultimately for treatment.

The good news is that we have the scientific ability to genotype patients. However, we sorely lack funding. Federal support for genetic research generally ends once a mutant gene is discovered. And, due to the genetic diversity underlying retinal degenerative diseases, private laboratories cannot offer affordable genetic testing services. To avert a future where clinical trials and treatments go begging for patients, we need your support to genotype every person with retinal disease.

Research Consortiums
Behind each treatment breakthrough is a team of talented scientists and ophthalmologists, whose collective achievement is greater than the sum of their individual contributions. This successful pattern of collaboration among scientists can be duplicated through funding support of small consortiums composed of clinical and laboratory researchers who focus on treating one specific disease. In most cases, these research groups require small grants to get started with greater funding as their collaborations take shape. However, the sooner we can fund this work, the faster we can recruit researchers for these working groups.

Animal Models
Food and Drug Administration approval to test a new therapy in clinical trials hinges on safety and efficacy data in an animal model of disease. The treatment breakthroughs reported by The Foundation result from animal model testing. However, animal models do not exist for every retinal degenerative disease. The more animal models discovered or created, the more diseases can become eligible for clinical trials. We need more funding to discover naturally occurring animal models and to genetically engineer rodent models of disease.

PRECLINICAL ASSESSMENT CENTERS (PCACS)

BACKGROUND INFORMATION

Over 9 million individuals in the United States are affected by retinal degenerations (RDs). Approximately 95% of these individuals are affected by age-related macular degeneration (AMD), and 5% lose vision to other forms of RD. The latter include retinitis pigmentosa (RP), usher syndrome (deaf-blindness), cone-rod dystrophies, and Stargardt disease, a juvenile form of macular degeneration. Whether by the staggering numbers of individuals over age 65 who lose vision to AMD, or by the equally staggering number of years individuals with RP spend without sight, these diseases take an enormous toll on society as well as on the individual. Although rapid advances have been made in identifying the molecular origins and disease mechanisms in recent years, there has not been a concomitant increase in new therapies available to the RD patient.

For inherited degenerative retinal disease, scientists have identified a number of potential treatment options, yet very few have been commercially developed. This is because pharmaceutical and biotech companies must be assured of recouping research and development expenses and achieving a substantial profit margin, something that drugs for small populations often cannot support. This proposal outlines a plan to off-set initial research and development costs faced by biotechnology and pharmaceutical companies to encourage their participation in bringing treatments and cures to individuals with inherited retinal degenerative diseases.

Currently, the vast majority of pharmaceutical and biotechnology companies that are developing drugs for diseases affecting large populations are not exploring alternative applications of those same compounds because of the large cost involved in setting up new screening facilities. We believe that it is possible to persuade these companies to enter the RD market if we provide the infrastructure and expertise to help test drugs/compounds that have potential for treating RD. For example, this approach has proven successful in the case of the drug, thalidomide, which was initially marketed as a sedative for pregnant women. The drug was later withdrawn when physicians reported that it caused severe birth defects. Nearly thirty years later, new uses have been discovered for thalidomide such as its treatment of cancer and the “wet form” of AMD. Thalidomide is safe for use in adult males and in females except during pregnancy.

Degenerative retinal disease has many similarities to other chronic diseases. Therefore, drugs being developed for the treatment of neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease may also be useful for treating retinitis pigmentosa. Likewise, angiostatic compounds that stop new blood vessels from nourishing growing cancers may also be of value in the treating the “wet form” of AMD. Other agents such as antioxidants and drugs that regulate lipid transport or utilization may also be of value in stopping or delaying the onset of the “dry form” of AMD.

We believe that the fastest way to develop a therapeutic treatment for Degenerative Retinal Disease will be to enlist the participation of pharmaceutical and biotechnology companies.

In order to further accelerate the identification and development of new treatments for degenerative retinal disease, the NNRI has established three Pre-Clinical Assessment Centers. The major objective of these Centers is to help stimulate and encourage biotech and pharmaceutical companies to identify and develop new treatments for degenerative retinal disease by providing them with low cost pre-clinical screening of compounds that appear promising for the treatment of RD diseases. After the initial primary screening, substances identified as potentially useful for treating RD will be further evaluated for safety and efficacy and moved toward Clinical Trials as rapidly as possible.

PRECLINICAL ASSESSMENT CENTERS

Center I “Rodent Models for the Assessment of Angiostatic Agents for potential use in the Treatment of AMD”

Director: Peter Campochiaro, M.D., Ph.D. Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD

Dr. Campochiaro’s laboratory is focused on understanding the pathophysiology of choroidal neovascularization (CNV) in age-related macular degeneration (AMD). Several different mouse models including the VEGF-Opsin Transgenic, doxycycline-induceable transgenic and laser injury model are utilized to evaluate the protection afforded by various angiostatic agents on the development, progression and treatment of CNV. Each model is distinct and provides unique information that is helpful in evaluating the efficacy of a particular angiostatic compound. Quantification of CNV and leakage is accomplished using “in vivo” fluoroscein imaging, flat mount histology and labled dextran studies.

Center II: Evaluation of Candidate Drugs in Rodent Models of Retinal Degeneration Director: Rong Wen, M.D., Ph.D., Scheie Eye Institute, University of Pennsylvania

Dr. Wen’s laboratory is interested in understanding the molecular mechanism of photoreceptor death in retinal degeneration as well as new approaches to therapies for retinal degenerative disorders. Although photoreceptor degenerations are caused by different genetic mutations, the phenotypes are quite similar. This similarity raises the possibility that a common underlying mechanism is responsible for most, if not all, photoreceptor degenerations including age-related macular degeneration. The idea of a common mechanism for photoreceptor degeneration may have profound significance in our understanding of the pathology of retinal degeneration as well as in the search for suitable treatments for retinal degenerations of different causes.

Center III: “Efficacy, Development and Apoptosis Studies in a Mammalian Organ Culture System”
Director: Theo van Veen, Ph.D., Retina Center, Univ. of Lund, Sweden

A process that is common to all degenerative retinal disease including AMD and RP is the abnormal induction of retinal cell death, known as apoptosis. Dr. Van Veen’s laboratory at the Wallenberg Retina Center is focused on understanding the basic mechanisms of apoptosis with the hope of identifying compound(s) that will retard or prevent the cell death that occurs in RD. Dr. Van Veen has developed a retinal organ culture system that allows for a rapid and sensitive screening of compounds that may have potential in treating degenerative retinal disease such as RP and AMD. The organ culture system is ideal for examining drugs that require a sustained concentration or are metabolized by ocular or extra-ocular tissues.

Through its Preclinical Assessment Centers, The Foundation has established a new business and scientific model for testing retinal degenerative disease therapies. With discovery of more and more promising treatments, these Centers are being stretched to meet demands. The Foundation needs to expand and enlarge this very important resource.

In the last few years, Foundation researchers have made amazing discoveries that have brought us close to realizing treatments and cures. The most difficult work of understanding these diseases and discovering experimental treatments is largely behind us. The future holds great promise, but our scientists need your support to help make treatments and cures a reality.