Retinitis pigmentosa (RP) is a genetically heterogeneous disorder characterized by death of the light-sensing photoreceptor cells of the outer neural retina. Although collectively quite common, individually each disease- causing gene is quite rare. Three genes, USH2A, ABCA4 and RHO, account for a large portion of disease and elicit a wide-range of RP clinical phenotypes caused by an array of different disease-causing mutations. In this proposal we will use CRISPR/Cas9-mediated genome editing to target and correct three different classes of disease-causing mutations: 1) an intronic cryptic splice site mutation in USH2A; 2) an exonic coding sequence mutation in ABCA4; and 3) a dominant gain-of-function mutation in RHO. Using a CRISPR-based strategy will allow for disease-causing genes to remain under control of their endogenous promoters, allow for correction of large genes not amenable to gene replacement therapy and provide an avenue to `turn off' harmful dominant gain of function mutations. These genome-editing approaches will be tested on patient-derived induced pluripotent stem cells with molecularly confirmed mutations. Correcting cells that harbor a disease-causing mutation will allow for generation of cells for future autologous transplantation studies in human patients. The studies outlined in this proposal will pave the way for a new gene augmentation and stem cell-based therapeutic avenues for treatment of retinitis pigmentosa.

Public Health Relevance

Retinitis pigmentosa (RP) is a genetically heterogeneous disorder characterized by death of the light-sensing photoreceptor cells of the outer neural retina. Three genes, USH2A, ABCA4 and RHO are some of the most common disease causing genes, each of which elicit a wide-range of RP clinical phenotypes caused by an array of different disease-causing mutations. We propose to use CRISPR-mediated genome editing approaches to correct patient-derived induced pluripotent stem cells in vitro and a large animal model of RP in vivo in order to develop new gene and stem cell-based modalities to treat patients with RP.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY026008-03
Application #
9452972
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Shen, Grace L
Project Start
2016-04-01
Project End
2019-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Iowa
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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Stone, Edwin M; Andorf, Jeaneen L; Whitmore, S Scott et al. (2017) Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease. Ophthalmology 124:1314-1331
Burnight, Erin R; Gupta, Manav; Wiley, Luke A et al. (2017) Using CRISPR-Cas9 to Generate Gene-Corrected Autologous iPSCs for the Treatment of Inherited Retinal Degeneration. Mol Ther 25:1999-2013