New model of rare childhood blindness holds promise for testing preventive therapies

December 14, 2004

The development of a laboratory model for a rare, inherited form of blindness holds promise that scientists might one day be able to test new treatments to prevent or cure this devastating disease of the retina. This finding, from investigators at St. Jude Children's Research Hospital and Columbia University, will be published in the Dec. 20 issue of Molecular Brain Research (MBR).

The model for this disease, called Leber congenital amaurosis (LCA), is especially important because no treatments are currently available to prevent it. There are not enough patients to enroll in large clinical trials to test new prevention treatments; therefore, any potential new therapy must have a high probability of working. This is especially the case with LCA. Diseases with such a limited patient population discourage the expensive commercial research and development needed to find an effective treatment for it, according to Michael A. Dyer, Ph.D., assistant member of St. Jude Developmental Neurobiology. Dyer is first author of the MBR report. The investigators are now using the model to develop a gene therapy to prevent this form of blindness.

"The development of this model reflects an important goal at St. Jude of finding cures for rare devastating childhood diseases beyond cancer," Dyer said.

The LCA mice lack both copies of a gene called AIPL1, which is essential for the final development of light-sensitive cells in the retina called rods and cones. Rods are responsible for vision in low light and cones are responsible for color vision. LCA, which occurs in about one in 100,000 births, causes rods and cones to degenerate.

The researchers previously reported a potential role of the AIPL1 gene in rod and cone formation. However, the St. Jude-Columbia team demonstrated the link between the absence of AIPL1 during fetus development and the loss of vision that occurs shortly after birth. Based on this work, the investigators believe that the AIPL1 gene plays at least two critical roles in the eye development.

"We believe that this gene might regulate the multiplication of the primitive cells that give rise to the special cells that make up the mature retina," Dyer said. "Or, the gene might determine which specialized cell develops from a specific primitive cell. In fact, the gene might control both activities."

The researchers also hypothesize that AIPL1 regulates the formation of rod cells during the late stages of development of the retina, around the time of birth.

"Our lab is now working with St. Jude to determine if we can prevent this disease in LCA models by supplying the retinas of affected newborn mice with the missing AIPL1 gene," said Melanie Sohocki, Ph.D., assistant professor of Ophthalmic Science at Columbia University (New York) and senior author of the paper. "This approach appears to be a reasonable strategy because of the major role this gene plays in retinal development."

"The mouse model is an efficient tool for gaining insights into both normal and abnormal development of the retina," said Stacy Donovan, Ph.D., co-author of the paper and a postdoctoral student in Dyer's laboratory.

To produce the mouse model of LCA, the researchers inserted a fragment of DNA into part of the AIPL1 in mouse embryos, disrupting the gene. The embryos were then inserted into female mice that gave birth to mice with this genetic defect.

Using a variety of laboratory methods to study retinal cells, the team showed that AIPL1-deficiency causes severe retinal degeneration beginning around the second week of life in affected mice. The degeneration leads to loss of almost all photoreceptors by seven weeks of age.

When the team used a technique called electroretinography to measure the electrical activation of the rods and cones to light, there was no response, further demonstrating the lack of functioning photoreceptor cells in mice lacking AIPL1.

The findings in the LCA mouse model suggest a link to a previously developed mouse model called rd (retinal degeneration). In the rd model, mutations in an enzyme called PDE6 also lead to degeneration of rods and cones. As in the LCA mouse model, the rods of rd mice die within the first month of life. Also like the LCA model, the rod deaths are followed by cone deaths. This suggests that the lack of AIPL1 is needed for normal production and activity of PDE6; and that lack of AIPL1 leads to loss of this enzyme and subsequent degeneration of the retina.

The current work with the LCA model is a continuation of studies done in the laboratories of both Dyer and Sohocki to understand the genetic control of retinal development. Previously, Dyer's laboratory discovered that the gene Rb is essential for the formation of photoreceptors in the retina; and Sohocki's laboratory cloned the AIPL1 gene and was the first to report AIPL1 mutations in patients with LCA.
Other authors are Jiakun Zhang, Jonathan Gray (St. Jude); and Angelica Ortiz, Rebeca Tenney, Jian Kong and Rando Allikmets (Columbia.). The work was supported in part by Research to Prevent Blindness, the National Eye Institute, National Cancer Institute, Foundation Fighting Blindness, the Karl Kirchgessner Foundation and ALSAC. Dyer is a Pew Scholar in the Biomedical Sciences.

St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit

St. Jude Children's Research Hospital

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