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...""""""""

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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Resource-Related Research Projects (R24)
Project #
1R24EY019861-01A1
Application #
8018761
Study Section
Special Emphasis Panel (ZEY1-VSN (10))
Program Officer
Shen, Grace L
Project Start
2011-08-01
Project End
2016-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
1
Fiscal Year
2011
Total Cost
$1,502,680
Indirect Cost
Name
Columbia University (N.Y.)
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Lee, Winston; Schuerch, Kaspar; Zernant, Jana et al. (2017) Genotypic spectrum and phenotype correlations of ABCA4-associated disease in patients of south Asian descent. Eur J Hum Genet 25:735-743
Xu, Mingchu; Xie, Yajing Angela; Abouzeid, Hana et al. (2017) Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies. Am J Hum Genet 100:592-604
Bennett, Jean (2017) Taking Stock of Retinal Gene Therapy: Looking Back and Moving Forward. Mol Ther 25:1076-1094
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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
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
MacLaren, Robert E; Bennett, Jean; Schwartz, Steven D (2016) Gene Therapy and Stem Cell Transplantation in Retinal Disease: The New Frontier. Ophthalmology 123:S98-S106
Nõupuu, Kalev; Lee, Winston; Zernant, Jana et al. (2016) Recessive Stargardt disease phenocopying hydroxychloroquine retinopathy. Graefes Arch Clin Exp Ophthalmol 254:865-72

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