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Report on Research on Rare Diseases in Children: FY 2000 to FY 2005

National Eye Institute (NEI)

Overview of NEI Rare Diseases in Children Research Activities, FY 2000–FY 2005

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 eye and vision. Children are our nation's greatest resource, and protecting their visual health and preventing eye diseases that afflict them with permanent visual impairment will help maintain our nation's prosperity and security in the future. Over the years, vision researchers supported by NEI have conducted many pioneering studies that have greatly advanced our understanding of eye diseases, including those classified as rare, and have provided eye-care professionals with new tools and methods to prevent or cure many sight-threatening conditions.

Recent Scientific Advances in Rare Diseases in Children Research

Leber's Congenital Amaurosis (LCA)

In 1869, Theodor Leber described an early-onset recessive retinal degeneration that caused incurable blindness in children. This disease became known as Leber's congenital amaurosis (LCA). For many childhood genetic diseases like LCA, no treatment is currently available; 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. Recently, NEI scientists have 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 analysis of 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 were dramatic.

Administration of compounds like 9-cis-retinal for LCA is an example of a pharmacological intervention that could restore vision and relieve the suffering and burden caused by some blinding diseases. Animal studies with 9-cis-retinal have opened the door to studies in humans that may contribute to the development of improved treatments for retinal degenerative diseases such as 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. The researchers inserted a wild-type RPE-65 gene into the retina of a dog using recombinant adenoassociated 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.

NEI has funded research on LCA from the Institute's inception and will continue to fund research on this disorder through FY 2005.

Retinopathy of Prematurity (ROP)

Many premature infants need supplemental oxygen soon after birth because their lungs are not sufficiently mature to efficiently bring oxygen into their bodies. Researchers have long known that supplemental oxygen, while helping infants survive, might increase cases of retinopathy of prematurity (ROP). ROP develops in very premature infants when abnormal blood vessels grow and spread throughout the retina. The scarring and bleeding caused by the excess growth of these blood vessels can lead to retinal detachment, resulting in vision loss. ROP develops in 14,000-16,000 infants each year who weigh less than 2 3/4 pounds (1,250 grams) at birth. In most cases (80%), the disease improves and leaves no permanent damage. However, 1,100-1,500 infants annually develop ROP that is severe enough to require surgical treatment, which usually will stop the growth of abnormal blood vessels and prevents retinal detachment. Even with these therapies, about 400-600 infants with ROP become legally blind each year.

Recent research had suggested that controlled amounts of supplemental oxygen keeps ROP from progressing from moderate to severe. If controlled amounts of supplemental oxygen could help prevent the progression of ROP, then infants could avoid this threat to their sight and consequently the invasive surgery for severe ROP, with its possible long-term side effects. In order to test the safety and efficacy of providing infants supplemental oxygen, NEI supported the Supplemental Therapeutic Oxygen for Pre-threshold ROP (STOP-ROP) study. Researchers found that while modest supplemental oxygen given to premature infants with moderate cases of ROP may not improve ROP outcomes, it definitely does not worsen outcomes. Although the relative risk/benefit of supplemental oxygen for each infant must be individually considered, clinicians need no longer be concerned that supplemental oxygen, as used in this study, will worsen pre-threshold ROP.

NEI has funded research on ROP from the Institute's inception and will continue to fund research on this disorder through FY 2005.


Early eye development of the vertebrate lens is controlled by specific genes that operate in a hierarchy of expression. The first of these genes to be identified was Pax-6. Mutations in Pax-6 are responsible for causing aniridia, a congenital malformation of the eye in which the iris is not completely formed, resulting in cataract formation and congenital glaucoma. Subsequent to this discovery, Pax-6 expression was found in other embryonic tissue, including the tissues destined to form the nose, suggesting its more general involvement in craniofacial development. The significance of Pax-6 as a key developmental regulator has been substantiated in a number of experimental systems, most notably mouse and Drosophila, and its protein product is now characterized at the structural and functional levels. Researchers now view Pax-6 as a "master gene" controlling the expression of downstream genes during development. Recent studies have described a number of genes downstream of Pax-6 that may play a significant role in eye formation. As these genes and their products are characterized, the developmental hierarchy controlling ocular and more generally craniofacial development will be pieced together to form a picture of the developmental process and enhance our understanding of the molecular basis of early eye developmental defects such as aniridia.

NEI has funded research on aniridia from the Institute's inception and will continue to fund research on this disorder through FY 2005.

X-linked Juvenile Retinoschisis

Juvenile retinoschisis is a degenerative X-linked recessive retinal disorder that gradually robs the patient of useful vision. The disease is characterized by the formation of a cystlike structures on the retina. Though not usually diagnosed until children start school, visual acuity is often reduced to 20/200 by the time the child reaches puberty. The disease symptoms are similar to those of macular degeneration, and in fact, most cases of juvenile macular degeneration are caused by retinoschisis. Peripheral vision is also affected by retinoschisis. Other complications associated with juvenile retinoschisis are strabismus, nystagmus, retinal detachment, and massive vitreous hemorrhages.

Researchers funded by NEI have localized the molecular defect of retinoschisis to the XLRS1 gene. These scientists have reported finding 23 different XLRS1 gene mutations in 28 patients affected by this disorder. Additionally, these researchers have demonstrated that molecular screening for retinoschisis is an effective diagnostic tool in at-risk males.

NEI has funded research on X-linked juvenile retinoschisis from the Institute's inception and will continue to fund research on this disorder through FY 2005.

Retinoblastoma (RB)

RB is mainly a disease of childhood and is now one of the best understood of all solid tumors. Ninety percent of individuals who inherit specific mutations in the RB gene will develop the tumor. Each year, 300 to 400 new cases of RB are diagnosed in the United States. Unfortunately, the most prevalent treatment for RB at this time is surgical removal of the affected eye. Scientists supported by NEI have recently published results of experiments that were undertaken to determine the toxicity and dose-response of vitamin D3 for the treatment of retinoblastoma. An analogue of vitamin D3 has been shown to inhibit growth of RB tumors in transgenic mice. The results of this research showed that in transgenic mice, it was possible to achieve an effective dose of the vitamin D3 analog that had no systemic toxicity.

NEI has funded research on RB from the Institute's inception and will continue to fund research on this disease through FY 2005.

Ongoing, New, and Planned Research Initiatives in Rare Diseases in Children

NEI will continue to fund high-quality investigator-initiated research on the prevention, etiology, pathology, and clinical intervention of rare childhood diseases that cause visual impairment and disability.

Rare Diseases-Related Program Activities, FY 2003–FY 2005

For more than 20 years, NEI and the National Advisory Eye Council (NAEC), through the Vision Research Program Planning Subcommittee, have attempted to meet their stewardship responsibilities through a comprehensive planning process. The process has resulted in the development and publication of a series of strategic plans addressing the most pressing visual health needs of the nation. To this end, the vision research community, the medical scientific research community at large, and NEI will pursue the highest-quality research to attempt to achieve the established goals of this plan, including better prevention, early diagnosis, and safe, effective treatments of rare diseases and disorders in children. NEI will continue, with the advice and guidance of the NAEC, to invest in the very best investigator-initiated research through FY 2005 and well beyond to protect our nation's children from the consequences of blinding rare diseases.

The NAEC and NEI have established the following goals for rare disease research in Vision Research: A National Plan 1999 - 2003:

  • Identify novel causes of inherited retinal degenerations; further examine the cellular and molecular mechanisms whereby identified gene defects cause retinal degenerations.

  • Further develop and critically evaluate therapies involving gene delivery, growth factors, and transplantation for the treatment of retinal disease.

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Last Reviewed: February 1, 2005
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