National Eye Institute (NEI)

Overview of Rare Disease Research Activities

The National Eye Institute 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 from 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.

Recent Scientific Advances in Rare Disease Research

Retinitis Pigmentosa

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. The incidence of RP in the United States is about 1 in 3,500 births, and it affects more than 100,000 people. 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 the photoreceptor cells, termed the visual phototransduction cascade, has provided a detailed molecular description of this pathway. Current research has now turned to establishing the complete molecular basis of visual signal termination. The availability of animal models, transgenic mice and knockout mice, with mutations in the genes for key components of the visual phototransduction cascade, provides a special opportunity and a very powerful research tool. These animal models are being used to investigate the molecular mechanisms of signal termination. Four of the nine genes that have been identified as causing Retinitis Pigmentosa encode proteins of the phototransduction cascade. Thus, the investigation of these animal models has great potential to provide valuable information on the pathogenesis of Retinitis Pigmentosa.

Gyrate Atrophy

NEI intramural scientists are conducting research on gyrate atrophy, a genetic disorder in which patients are missing a specific gene, known as ornithine amino transferase (OAT). This rare but well characterized genetic error leads to a blinding retinal degeneration. Investigators have been able to develop an adenovirus construct of the missing gene. Researchers have successfully inserted the gene into animal models of gyrate atrophy and have determined that it successfully propagates in these animals. For human studies, scientists have devised a novel method of supplying the missing gene to the patient. They have taken a small skin biopsy from the patient, inserted the gene in the skin cells and then grow these cells to form a patch that can be allografted onto the patient. Hopefully, this graft will grow normally and also deliver the new gene systemically to the patient. Using these techniques, investigators plan to treat the first gyrate atrophy patient in the very near future. If this therapeutic approach is successful, work could be extended to other retinal degenerations, including some forms of retinitis pigmentosa.

Cystinosis

Nephropathic cystinosis is an autosomal, recessively inherited storage disease of childhood in which non-protein cysteine accumulates within the cellular lysosomes until crystals form and the cell dies. Young patients with nephropathic cystinosis experience extreme photophobia (visual intolerance of light), corneal erosions, and kidney dysfunction or failure. The disease becomes evident between the forth and sixth months of life. NEI-supported scientists continue to investigate the treatment of nephropathic cystinosis. Results from a double-masked NEI clinical trial designed to assess the effectiveness of topical ophthalmic cysteamine to treat nephropathic cystinosis have demonstrated the depletion of cystine deposits in the cornea. Patients with topical ophthalmic cysteamine have shown significant decrease in crystals in treated eyes, as well as relief from the pain of photophobia.

Retinoblastoma

Retinoblastoma (RB), a sight- and life-threatening intraocular malignant tumor of childhood that arises in the retina, has been found to be associated with loss or alteration of the RB gene. The estimated annual incidence of retinoblastoma is between 1 in 15,000 to 1 in 34,000 people. Scientists have demonstrated that the introduction of a cloned RB gene into cultured retinoblastoma cells significantly inhibited cell growth and suppressed tumorigenesis in mice. In studies of RB gene expression and replacement in other types of tumor cells, scientists have shown that RB gene replacement modifies the neoplastic properties of both osteosarcoma and prostate cancer cells. These studies point to the possible utility of gene therapy in treatment of some types of cancer. Although molecular genetics research has pinpointed the cause of retinoblastoma, a major obstacle has been the lack of an animal model for this disease. NEI-supported scientists have developed a mouse model of retinoblastoma using gene "knockout" or embryonic stem cell homologous recombination technology. This model provides scientists the opportunity to study the process of malignant transformation in RB. It also will assist with developing and testing drugs to treat retinoblastoma.

Motor Neural-Ophthalmic Disorders

Blepharospasm, a motor neuro-ophthalmic disorder, is characterized by a forcible involuntary closure of the eyelids that may last as long as several minutes and usually occurs in people at midlife. While the etiology of this condition is not well understood, researchers believe that in some people the condition may be a form of Parkinson's disease. In other people the condition may accompany other neurologic disorders such as Bell's palsy and hemiplegia. NEI-supported scientists have previously shown botulinum A toxin provides temporary relief from blepharospasm.

NEI-supported scientists have recently reported that injecting doxorubicin (DXN), an anti-cancer drug, directly into the eyelids may offer permanent relief from blepharospasm. DXN acts by reducing the number of muscle fibers in the orbicularis oculi muscle by as much as 70 percent offering alleviation from the spasms that are characteristic of this disease. In a phase one clinical trial, over half of the patients who were treated with DXN had significant relief from eyelid muscle spasms without further treatment. Unfortunately, DXN does have side effects: including inflammation and skin ulceration at the injection site. Researchers are working to develop other agents that could be administered prior to DXN injection that would maximize the myotoxic effects of DXN while minimizing its unwanted side effects.

Hypomelanotic Disorders

Hypomelanotic disorders are characterized by deficiencies of the hormone melanin and results in a loss of ocular and skin pigmentation. These disorders include, but are not limited to, the following rare diseases: Ocular albinism and X chromosome-linked deficiency of pigmentation, limited to the uvea and retinal pigment epithelium. These diseases cause decreased vision, photophobia, nystagmus, diaphanous irides, and light yellow fundi. Chediak-Higashi disease is a rare fatal disease of childhood, identified by generalized decreased pigmentation, with localized hyperpigmentation, peculiar cytoplasmic inclusions of the leukocytes, hepatosplenomegaly, and a predisposition to malignant lymphomas. The ocular manifestations are albinism of the eye, photophobia, increased lacrimation, and nystagmus. Tyrosinase-positive oculotaneous albinism and hemorrhagic diathesis, caused by defective platlets and accumulation of ceroid-like material in the reticuloendothelial system, oral muscosa, and urine characterize Hermansky-Pudlak syndrome. Also, nystagmus, photophobia, and decreased vision may occur.

Researchers are investigating mutations in specific genetic loci that are known to control pigmentation. These scientists are planning to study the eyes and skin of inbred mice with various mutations that affect pigmentation.

The goal of this research is to understand the pathogenesis of genetic mutations that may be responsible for a reduction of ocular pigmentation and the associated ocular morbidity with these diseases. NEI-intramural researchers are currently recruiting patients with hypomelanotic disorders such as ocular albinism, oculocutaneous albinism, Chediak-Higashi disease, Hermansky-Pudlak syndrome, and iris transillumination defects to determine visual function with these conditions and to evaluate the changes in visual function over time.

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