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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Agarwal, Neeraj
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Columbia University (N.Y.)
Schools of Medicine
New York
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Dooley, Scott J; McDougald, Devin S; Fisher, Krishna J et al. (2018) Spliceosome-Mediated Pre-mRNA trans-Splicing Can Repair CEP290 mRNA. Mol Ther Nucleic Acids 12:294-308
Liu, Katherine Y; Sengillo, Jesse D; Velez, Gabriel et al. (2018) Missense mutation in SLIT2 associated with congenital myopia, anisometropia, connective tissue abnormalities, and obesity. Orphanet J Rare Dis 13:138
Albert, Silvia; Garanto, Alejandro; Sangermano, Riccardo et al. (2018) Identification and Rescue of Splice Defects Caused by Two Neighboring Deep-Intronic ABCA4 Mutations Underlying Stargardt Disease. Am J Hum Genet 102:517-527
Cui, Xuan; Jauregui, Ruben; Park, Karen Sophia et al. (2018) Multimodal characterization of a novel mutation causing vitamin B6-responsive gyrate atrophy. Ophthalmic Genet 39:512-516
Bryant, Laura; Lozynska, Olga; Han, Grace et al. (2018) On variants and disease-causing mutations: Case studies of a SEMA4A variant identified in inherited blindness. Ophthalmic Genet 39:144-146
Tanaka, Koji; Lee, Winston; Zernant, Jana et al. (2018) The Rapid-Onset Chorioretinopathy Phenotype of ABCA4 Disease. Ophthalmology 125:89-99
Trapani, Ivana (2018) Dual AAV Vectors for Stargardt Disease. Methods Mol Biol 1715:153-175
Ciccone, Lyam; Lee, Winston; Zernant, Jana et al. (2018) HYPERREFLECTIVE DEPOSITION IN THE BACKGROUND OF ADVANCED STARGARDT DISEASE. Retina 38:2214-2219
Song, Ji Yun; Aravand, Puya; Nikonov, Sergei et al. (2018) Amelioration of Neurosensory Structure and Function in Animal and Cellular Models of a Congenital Blindness. Mol Ther 26:1581-1593
Racz, Boglarka; Varadi, Andras; Kong, Jian et al. (2018) A non-retinoid antagonist of retinol-binding protein 4 rescues phenotype in a model of Stargardt disease without inhibiting the visual cycle. J Biol Chem 293:11574-11588

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