Preventing Photoreceptor Degeneration: The Role of ALG-2

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DESCRIPTION: (Applicant's Abstract) Eye diseases leading to retinal degeneration are the most common cause of hereditary blindness in humans. Prominent among these is retinitis pigmentosa (RP) affecting about 1 in 3000 people. RP consists of a clinically and genetically heterogeneous group of diseases. In more than 50% of the patients the molecular defect has not been determined, and there is no effective treatment available. Most forms of retinal degeneration involve the apoptosis of photoreceptor cells. Animal models of retinal degeneration are being used to test different strategies to either repair the genetic defect or to prevent photoreceptor cell apoptosis. Although gene repair is at least partially effective, this strategy is limited by the heterogeneity of the genetic defects underlying RP. Therefore, the rescue of photoreceptor cells through the prevention of apoptosis holds the promise of effecting multiple forms of the disease. Ample evidence indicates that Ca++ plays a pivotal role in the apoptosis of photoreceptor cells, but the mechanisms are unclear. Studies of ALG-2 presented in this proposal provide an opportunity to better understand how photoreceptor cells die and the role of Ca in this process. In addition, a gene therapy approach targeting ALG-2 may allow disparate genetic diseases to be treated in a single fashion. Specific Aims Include: 1. Deliver ALG-2 ribozymes or antisense ALG-2 constructs via an adeno-associated virus vector to photoreceptor cells of the rd/rd/tg+ mouse in order to interfere with the synthesis of ALG-2 and block apoptosis. 2. Demonstrate that a peptide derived from the ALG-2 sequence can block the formation of an ALG-2 dimer required for function. Vector delivery of a construct encoding the peptide, disrupting function, will augment studies of impaired ALG-2 synthesis and offer an alternative therapeutic approach.