Biennial and Annual Report on the Rare Diseases Research Activities at the National Institutes of Health FY 2004

National Eye Institute (NEI)

Overview of Rare Diseases Research Activities

The National Eye Institute (NEI) was created on August 16, 1968, by Public Law 90-489 for the purpose of supporting and conducting research for improving the prevention, diagnosis, and treatment of diseases that affect the eye and vision. Eye diseases and blindness cost the Nation an estimated $38.4 billion per year. More than 12 million people in the United States suffer some significant impairment of vision. Over the years, vision researchers supported by the NEI have conducted many pioneering studies that have greatly advanced our understanding of eye diseases, including those classified as rare, and provided eye care professionals with new tools and methods to prevent or cure many sight-threatening conditions. In October 2003, the NEI released its strategic plan for vision research, National Plan for Eye and Vision Research. This plan is the seventh in the series that dates back to the publication of Vision Research Program Planning in 1975. The development and publication of the aforementioned plans address the visual health needs, including rare diseases of the eye and visual pathways, of the Nation.

Recent Scientific Advances in Rare Disease Research

Retinitis Pigmentosa and Related Disorders

Retinitis pigmentosa (RP) is a group of blinding hereditary retinal degenerative diseases that are characterized by a progressive loss of vision due to the degeneration of photoreceptor cells. RP patients frequently report night blindness and loss of mid-peripheral vision during adolescence and are usually legally blind by the age of 40. Photoreceptor cells of the retina (the rods and cones) are responsible for the capture of light and the initiation of an electrical signal to the brain in the process of vision. The study of signaling in photoreceptor cells, termed the visual phototransduction cascade, has provided a detailed molecular description of this pathway.

Adult bone marrow stem cells in retinitis pigmentosa. A recent NEI-supported study found that injections of autologous adult bone marrow-derived stem cells prevented cone cell loss in two rodent models of RP. For reasons that are not entirely understood, the sick and dying rod cells also cause cone photoreceptor cells to die. Cone cells are concentrated in the macula, the center of the retina, and provide the sharp visual acuity that allows us to read, recognize faces, and perform detailed tasks that require hand-eye coordination. As the disease progresses patients lose their central vision, resulting in severe visual impairment or total blindness.

This study raises the possibility that patients could receive an injection of their own bone marrow stem cells to preserve central vision.

Autoimmune Diseases

Bacterial toxin can prevent autoimmune uveitis. Human autoimmune uveitis comprises a group of inflammatory eye diseases affecting the interior of the eye that can severely compromise vision. Autoimmune uveitis is thought to be caused by an immune response to proteins in the retina of the eye. Current therapies consist of immunosuppressive drugs such as steroids, cyclosporin, antimetabolites, and alkylating agents, all of which have severe side effects. NEI-intramural scientists are using an animal model, experimental autoimmune uveitis (EAU) in laboratory mice, to study the disease and to develop novel therapies based on reprogramming the immune system (immunomodulation) rather than on immunosuppression using pharmacologic agents. Bacterial components tend to have strong effects on the immune response. The class of compounds known as bacterial toxins can alter immune responses when included in small nontoxic doses in an immunization protocol. Cholera toxin has been studied as an additive to mucosal vaccines and found to promote a particular type of response having a unique immune mediator profile known as Th2. In contrast, EAU and similar autoimmune diseases develop in the context of an immune response having a mediator profile known as Th1. Th1 and Th2 responses are mutually inhibitory. Promoting a Th2 response may inhibit the Th1 response involved in uveitis. These researchers are exploring the ability of cholera toxin to counteract the Th1 response leading to development of EAU in mice. They have found that a single injection of as little as 2 micrograms of cholera toxin (a harmless dose) into mice immunized at the same time with a uveitogenic regimen of the retinal antigen IRBP completely protected the mice from developing this blinding disease. The protected mice were not immunosuppressed but rather displayed evidence of immune deviation toward a Th2-like immune response. Further studies of the mechanisms involved showed that cholera toxin caused production of an immune mediator known as IL-4, which is known to promote Th2 responses. This mediator was responsible for diverting the immune response toward the harmless Th2 type, thereby replacing the harmful Th1 response and preventing disease. These data suggest that, in general, immunomodulatory treatments that skew the immune response toward the Th2 pathway may be beneficial in treating ocular autoimmune disease. It is important to note that in this animal model disease is prevented but not reversed; this is a valuable treatment paradigm, because chronic autoimmune disease depends on continuous recruitment of new autoreactive lymphocytes. If these new recruits can be redirected toward the harmless Th2 pathway, progression of disease will be interrupted.

Rare Disease-related Program Activities

The National Advisory Eye Council and the NEI have established the following goals for rare disease research in the National Plan for Eye and Vision Research.

  • Understand the pathogenesis of inherited retinal diseases.
  • Continue to develop models and a coordinated system to share animal model data and resources in the vision community.
  • Characterize the genes and proteins expressed in tissues of the ocular surface; determine the functional consequences of changes in expression and molecular interactions; and determine the epigenetic, hormonal, neural, and environmental influences under both normal and pathological conditions.

Rare Disease-related Program Scientific Conferences, Workshops, Symposium, and Meetings

On November 5, 2004, the NEI co-sponsored a 2-day symposium in Washington, DC, entitled The First International Symposium on Translational Clinical Research for Inherited and Orphan Retinal Diseases. The other co-sponsors included: National Neurovision Research Institute, Inc; Foundation Fighting Blindness; Office of Rare Diseases, NIH; National Institute on Aging; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute on Deafness and Other Communication Disorders; Office of Orphan Products Development, Food and Drug Administration; Alcon; and W. K. Kellogg Foundation.

The objectives of the symposium were to:

  • Promote drug and genetic translational clinical research for orphan retinal disease therapy.
  • Review status, case studies, and challenges of inherited orphan disease research.
  • Facilitate interaction across vision, neurology, gerontology, and audiology.
  • Define the strategies and dynamics for commercializing orphan disease treatments.
  • Prioritize and develop strategies for intellectual property, operational, and financial avenues to bring new therapies to patients.


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Last Reviewed: July 22, 2005