Annual Report on the Rare Diseases and Conditions Research Activities of the National Institutes of Health FY 2000
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National Eye Institute (NEI)
Overview of NEI Rare Diseases Research Activities NEI was created on August 16, 1968, by Public Law No. 90-489 for the purpose of supporting and conducting research for improving the prevention, diagnosis, and treatment of diseases that affect the eyes 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, NEI-supported vision researchers 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 June 1998, NEI published Vision Research: A National Plan: 1999 - 2003 . This plan is the sixth in a series that dates back to the publication of Vision Research Program Planning in 1975. The development and publication of the aforementioned plans address the Nation's visual health needs, including rare diseases of the eyes and visual pathways. Recent Scientific Advances in Rare Diseases Research Retinitis Pigmentosa (RP) and Related Disorders RP is a group of blinding hereditary retinal degenerative diseases 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 RP 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 age 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. Gene therapy is one of the more promising interventions to slow or stop the progression of this blinding eye disease and other inherited retinal degenerative diseases. Dominantly inherited diseases such as RP are an especially challenging problem for development of gene-based therapies. Ideally, the defective gene has to be replaced to eliminate the protein product responsible for causing the photoreceptor degeneration and loss. For this to happen, the gene must be inactivated, repaired, or replaced. Two different strategies have been developed by NEI-funded investigators to attack this problem. In the first case, triplex technology has been applied to the human rhodopsin gene that is involved in autosomal dominant RP (ADRP). The most common form of ADRP results from mutations in rhodopsin. Several so-called triplex-forming sites have been identified within the rhodopsin gene, and seven of these bind small DNA oligonucleotides. Such triplex-forming oligonucleotides (TFOs) bind to native DNA and offer a therapeutic potential by interrupting the expression of a disease-causing protein. In the second case, another group of investigators has developed a ribozyme-based approach to photoreceptor cell rescue. Ribozymes are small RNA molecules that cleave a complimentary mRNA sequence, blocking production of its protein. Results are encouraging: two different and biologically active ribozymes slow the rate of retinal degeneration in a transgenic rat model of the disease. Leber's Congenital Amaurosis (LCA) In 1869, Theodor Leber first described this recessively inherited retinal degeneration with RP-like pathology, which causes incurable childhood blindness. No treatment is currently available for many childhood genetic diseases like LCA, as the necessary gene is either missing or defective. With recent advances in our understanding of the basis for genetic diseases, scientists have been able to identify defective genes that are associated with specific diseases. Once the gene is identified, however, the patient is still faced with the prospect of no immediate cure. Such was the case for LCA, when in 1997 the disease-causing mutations in a gene known as RPE-65 were linked to an estimated 10% of LCA cases. NEI scientists recently produced mice lacking the RPE-65 gene. The absence of the RPE-65 gene produces a defect in the visual cycle, a series of biochemical events in the light-sensing retina that initiate vision. The defect eventually results in impairment of photoreceptor cell function and retinal degeneration. In order to better understand the function of RPE-65 , scientists studied the individual components of the visual cycle pathway and found that RPE-65 is involved in a biochemical reaction called an isomerization. Thus, the mice lacking RPE-65 allowed scientists to focus on the possible function of this molecule. Next, a way was found to bypass the defect in the visual cycle. For this, RPE-65- deficient mice were fed a form of vitamin A called 9-cis-retinal. This chemical is not normally found in photoreceptor cells, but it forms part of the functional visual pigment isorhodopsin. The resulting improved photoreceptor physiology and function was dramatic and showed that a potential pharmacologic intervention may help to restore vision to children with LCA. Dramatic progress toward finding a cure for LCA was recently reported by NEI-supported scientists. These scientists conducted experiments in which they successfully restored vision in a naturally occurring large animal model (dog) of LCA that suffers from visual impairment typical of that seen in children with LCA. These researchers inserted a wild-type RPE-65 gene into the retina of a dog using recombinant adeno-associated virus (AAV) as a vector. While this research shows great promise, there is still much work to be done before gene therapy can be used to treat human patients with LCA. Ocular Melanoma Although rare, choroidal melanoma is the most common primary eye cancer in adults. Many choroidal melanomas enlarge over time, lead to loss of vision, and spread to other parts of the body to eventually cause death. There had been uncertainty in the medical community about the value of giving radiation treatments prior to removal of the eye of patients with large ocular melanoma. In cancers occurring elsewhere in the body, prior radiation has reduced the rate of tumor recurrence after surgery. The Collaborative Ocular Melanoma Study (COMS) is the first controlled, randomized, multicenter clinical trial large enough to measure the survival rate of patients who received radiation treatment prior to eye removal. Patients with tumors large enough to require removal of the eye were randomized to either receive radiation treatment to the affected eye before it was removed or to have the eye removed without radiation treatment. After 5 years of follow-up, both groups had similar survival rates. About 60% of the patients are alive after 5 years of follow-up and these patients will be followed to determine the risks and long-term effects of both treatments. Radiation therapy is costly and has the potential for side effects. Unless a survival benefit is shown with further follow-up, it is unlikely doctors will advise radiation therapy use. Leber's Hereditary Optic Neuropathy (LHON) LHON is a maternally inherited genetic disease that results in substantial loss of central vision in affected patients. Most genetic diseases are caused by mutations in chromosomal DNA inside the cell nucleus. LHON, however, is the first disease to be associated with mutations of the small amounts of DNA that reside inside the mitochondria. This DNA encodes for subunits of complex 1 of the respiratory chain, the key biochemical cascade that manufactures the cell's supply of the high-energy molecule adenosine triphosphate. The three most common mutations causing LHON have now been identified, providing a useful diagnostic test for LHON and new insight into the pathogenesis of the disease. Hereditary Hyperferritinemia Cataract Syndrome (HHCS) HHCS is a genetic disorder in which L-ferritin is overexpressed, resulting in the formation of cataracts. HHCS was initially identified in a single family, but has since been found in other families. Through the use of expressed sequence tag (EST) analysis, gene arrays, and other state-of-the-art molecular biology techniques, NEI intramural scientists have sought to gain a greater understanding of this very rare disorder. Because L-ferritin was found to exist in such large amounts in affected HHCS lenses, these scientists have hypothesized that L-ferritin may destabilize other lens proteins, causing formation of cataracts; or that oxidative damage to the lens is the result of a disruption in the normal control of iron levels in the lens, causing the formation of cataract. NEI extramural researchers are studying potential preventive and therapeutic strategies by further studying the pathobiology of HHCS cataractogenesis. The efforts of these research activities may result not only in preventive strategies for individuals at risk for HHCS, but also in a greater understanding of the pathogenesis of cataracts in general. Ferritin is a major iron storage protein in cells, and it is a critical regulator of oxidative stress. Oxidative stress has been implicated as a major factor in the development of all cataracts. NEI-supported research on HHCS not only will benefit those individuals who are afflicted with this rare blinding disorder, but also may provide increased understanding and ultimately prevention of cataracts in general. Cataract remains the leading cause of blindness worldwide. Sjögren's Syndrome (Dry Eye) The hypothesis that lacrimal gland secretory cells actively provoke Sjögren's syndrome autoimmune responses has gained support on the basis of analyses of the intracellular traffic of histocompatibility molecules and autoantigens. The hypothesis is gaining further support due to new experiments based on autologous mixed cell reactions that may re-create autoimmune responses under defined cell culture conditions. A new autoantigen (the cytoskeletal component " -fodrin) implicated in Sjögren's syndrome autoimmunity has been identified. The autoantigen appears to have considerable specificity, since antibodies to it were found in the serum of 95% of patients with Sjögren's syndrome. No antibodies were found in normal individuals or in patients with other autoimmune disorders such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. Thus, " -fodrin may have considerable diagnostic potential. Moreover, neonatal vaccination with " -fodrin prevented development of the disease in mice, opening the possibility of new therapeutic approaches for Sjögren's syndrome. Corneal Dystrophies Corneal dystrophies are a heterogenous group of conditions that involve abnormal corneal development and result in defects in structure or clarity. Though relatively rare in the United States, the most common corneal dystrophy is keratoconus, which is characterized by a progressive thinning process of the cornea that may be accompanied by scarring. Keratoconus leads to progressive nearsightedness, astigmatism, and a cone-shaped cornea. Clinical care for keratoconus is time-consuming for patients and physicians because of its chronic progression and the difficulty of achieving a stable contact lens fit for visual rehabilitation. Linkage analysis has shown that four clinical types of corneal dystrophy result from mutations in a single gene. Granular, Reis Bucklers', lattice type 1, and Avellino corneal dystrophies all map to the $ ig-h3 gene, which encodes the keratoepithelin adhesion protein. It appears that in these four corneal dystrophies, the mutated keratoepithelin forms amyloidogenic intermediates that precipitate in the cornea, causing a progressive opacification. Three other corneal diseases also involve amyloid-like deposits: polymorphic amyloid degeneration, lattice corneal dystrophy type IIIA, and gelatinous drop-like dystrophy. Keratoepithelin is a good candidate gene for further investigation in these families. Because of the accessibility of the cornea, these disorders represent excellent model systems for study of the molecular details of amyloid depositions in devastating diseases such as Alzheimer's disease. 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. NEI-supported researchers have recently reported the development of a rat model to study blepharospasm. The researchers depleted a small amount of striatal dopamine and slightly weakened the eyelid-closure muscle (orbicularis oculi) in these animals. The results of this research showed that by themselves, neither of these procedures produced the characteristic uncontrollable blinking spasm of blepharospasm, but when the two procedures were combined they produced forceful blinking and spastic lid closure. NEI-supported scientists have reported that injecting the anticancer drug doxorubicin (DXN) 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%, offering alleviation from the spasms that are characteristic of this disease. To fully alleviate the spasms, however, patients must often undergo a series of painful DXN injections. NEI-supported researchers are trying to find a way of increasing the myotoxic effects of the DXN injection so that patients can have permanent relief of spasms with a minimum of treatments. Researchers injected bupivacaine and hyaluronidase 18 hours apart into the eyelids of rabbits. Two days later, the researchers injected the injured eyelids with DXN. The results of these experiments showed that the myotoxic effects of DXN were increased when the drug was injected 2 days after the animals' eyelids were injured with bupivacaine. The researchers also observed that the skin irritation that normally occurs as a result of DXN injection was no worse in the dual drug regimen than when DXN is administered alone. In May 2001, NEI-funded researchers reported the results of experiments in which Doxil, a liposome-encapsulated form of DXN, was injected into monkey eyes that had been preinjured with the bupivacaine/hyaluronidase protocol. The researchers showed that Doxil administered after preinjury of the eye with bupivacaine/hyaluronidase is an effective and safe treatment to remove orbicularis muscle fibers from monkey eyelid and thus offer permanent relief from blepharospasm. Additionally, these scientists also reported that this treatment regimen did not produce any bruising, ulceration, or other skin injuries at the injection site and may be a much less painful therapy for blepharospasm in human patients. Rare Diseases Research Initiatives NEI will continue to fund high-quality, investigator-initiated research on the prevention, etiology, pathology, and clinical intervention of rare diseases that cause visual impairment and disability. Rare Diseases Program Activities The National Advisory Eye Council and NEI have established the following goals for rare diseases research in Vision Research: A National Plan 1999-2003:
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