Therapeutic approaches for ABCA4-associated disorders

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DESCRIPTION (provided by applicant): ABCA4 is the transporter of vitamin A derivatives in the outer segment disk membranes of photoreceptors. In the absence of a functional ABCA4 protein vitamin A aldehyde forms excess bisretinoid adducts that are deposited in retinal pigment epithelium (RPE) triggering RPE cell death and causing secondary photoreceptor degeneration. Mutations in the ABCA4 gene are responsible for a wide variety of disorders, such as Stargardt disease (STGD), cone-rod dystrophy (CRD), retinitis pigmentosa (RP). Since mutations in the ABCA4 gene constitute the most prevalent cause of Mendelian retinal disease (1/20 people carry an ABCA4 variant), ABCA4-associated pathology is an important target for therapeutic interventions, such as proposed here. We have designed a series of translational studies to test the central hypothesis that replacing or augmenting the activity of the dysfunctional ABCA4 protein will be effective in preventing or delaying the pathology associated with STGD, CRD, and RP. The research program, a collaborative effort among geneticists, ophthalmologists, molecular biologists and cell biologists, is organized into four interrelated Modules. In the first Module, we propose to improve and expand our existing clinical and genetic databases of patients and well-characterized families where the disease is caused by mutations in the ABCA4 gene. Analysis of data accumulated in Module I will ultimately determine specific patient groups and criteria for future clinical trials. In Module II, we will develop and/or characterize animal models and utilize them to establish and test therapeutic outcome measures. In Modules III and IV, we will use these resources to determine the best therapeutic application, based on gene therapy or small molecule drugs, or their combination(s) for treatment of ABCA4-associated diseases. The outcome of these studies will serve as a platform for clinical trials geared to delay the onset, or arrest the progression, of all ABCA4-associated disorders. The essence of the proposed studies meet the stated primary goals ofthe "NEI Translational Research Program on Therapy for Visual Disorders" which is "...to support collaborative, multidisciplinary research programs focused on new therapeutic approaches to restore or prevent the loss of function due to visual system diseases... via gene therapy, pharmacological approaches, or development of appropriate delivery systems..." RELEVANCE (See instructions): ABCA4-associated disorders are the most prevalent causes of early adult vision loss. Estimated numbers of affected individuals in the US are in the range of tens, possibly even hundreds of thousands. There are currently no effective treatments for patients with ABCA4-associated diseases. Determining the specific treatment methods and schedules would form the basis of therapeutic applications for patients with ABCA4- associated disorders and would result in a profound improvement in the prognosis of this condition.