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 """""""" 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...""""""""

Public Health Relevance

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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Resource-Related Research Projects (R24)
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Special Emphasis Panel (ZEY1-VSN (10))
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Shen, Grace L
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Columbia University (N.Y.)
Schools of Medicine
New York
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Melillo, Paolo; Testa, Francesco; Rossi, Settimio et al. (2016) En Face Spectral-Domain Optical Coherence Tomography for the Monitoring of Lesion Area Progression in Stargardt Disease. Invest Ophthalmol Vis Sci 57:OCT247-52
Nõupuu, Kalev; Lee, Winston; Zernant, Jana et al. (2016) Recessive Stargardt disease phenocopying hydroxychloroquine retinopathy. Graefes Arch Clin Exp Ophthalmol 254:865-72
Lee, Winston; Schuerch, Kaspar; Xie, Yajing et al. (2016) Simultaneous Expression of ABCA4 and GPR143 Mutations: A Complex Phenotypic Manifestation. Invest Ophthalmol Vis Sci 57:3409-15
Lee, Winston; Xie, Yajing; Zernant, Jana et al. (2016) Complex inheritance of ABCA4 disease: four mutations in a family with multiple macular phenotypes. Hum Genet 135:9-19
Yuan, Bo; Neira, Juanita; Gu, Shen et al. (2016) Nonrecurrent PMP22-RAI1 contiguous gene deletions arise from replication-based mechanisms and result in Smith-Magenis syndrome with evident peripheral neuropathy. Hum Genet 135:1161-74
Bennett, Jean; Wellman, Jennifer; Marshall, Kathleen A et al. (2016) Safety and durability of effect of contralateral-eye administration of AAV2 gene therapy in patients with childhood-onset blindness caused by RPE65 mutations: a follow-on phase 1 trial. Lancet 388:661-72
Auricchio, Alberto; Trapani, Ivana; Allikmets, Rando (2015) Gene Therapy of ABCA4-Associated Diseases. Cold Spring Harb Perspect Med 5:a017301
Pang, Claudine E; Sarraf, David; Freund, K Bailey (2015) Reply: To PMID 25313711. Retina 35:e47-8
Duncker, Tobias; Tsang, Stephen H; Lee, Winston et al. (2015) Quantitative fundus autofluorescence distinguishes ABCA4-associated and non-ABCA4-associated bull's-eye maculopathy. Ophthalmology 122:345-55
Trapani, Ivana; Banfi, Sandro; Simonelli, Francesca et al. (2015) Gene therapy of inherited retinal degenerations: prospects and challenges. Hum Gene Ther 26:193-200

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