Grant: Operating Grant - PA: INMHA (bridge funding)

Aniridia is an eye disorder occurring once in 40,000-100,000 births. In at least 90% of cases, it is caused by half the normal amount of the protein PAX6 (paired box gene 6). Individuals with Aniridia are typically born with low vision, and regardless of treatment, become legally blind in their twenties. Aniridic-vision loss has three main causes: 1) underdevelopment of the retinal, 2) progressive glaucoma, and 3) progressive corneal clouding. Of these, glaucoma is the best managed, leaving the retina and cornea urgently in need of a new vision-saving therapy. There are many reasons gene therapy is an appropriate treatment strategy for aniridia. 1) There is a time to save vision. 2) The genetic cause is known. 3) PAX6 is a small protein easily put into a virus for therapy. 4) Only a small increase in the protein level may be therapeutic. 5) The cornea is known to be resistant to accidental overexpression of PAX6 during therapy. 6) The presence of a wild-type PAX6 means patients will be immunologically tolerant to the therapeutic protein. 7) The eye is relatively resistant to immune rejection problems and is developmentally malleable. 8) The eye is an accessible tissue and clinical delivery of virus to the eye has already been established by others. 9) There is an appropriate mouse model for therapy development. 10) A vision-saving treatment is lacking and PAX6 gene therapy offers promise to deliver one. This research will provide proof-of-principal for gene therapy in the mouse model of aniridia. It will also provide a tested gene-therapy construct for future trials. Together, these will lay the foundation for intermediate animal studies, and eventual clinical trials. This research will also pave the way for the development of novel gene-therapies for the many human genetic diseases that are caused by transcription factors.