Journal
HUMAN MOLECULAR GENETICS
Volume 23, Issue 2, Pages 514-523Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddt452
Keywords
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Funding
- National Institute of Health [5P30EY019007, R01EY018213, 5T32EY013933, 5T32DK007647-20]
- National Cancer Institute [5P30CA013696]
- Research to Prevent Blindness, New York, NY, USA
- Tistou and Charlotte Kerstan Foundation
- Research to Prevent Blindness Physician-Scientist Award
- Barbara and Donald Jonas Family Fund
- Schneeweiss Stem Cell Fund, New York State [N09G-302]
- Foundation Fighting Blindness New York Regional Research Center Grant [C-NY05-0705-0312]
- Joel Hoffman Fund
- Gale and Richard Siegel Stem Cell Fund
- Charles Culpeper Scholarship
- Irma T. Hirschl Charitable Trust
- Bernard and Anne Spitzer Stem Cell Fund
- Professor Gertrude Rothschild Stem Cell Foundation
- Gebroe Family Foundation
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Deficiencies in rod-specific cyclic guanosinemonophosphate (cGMP) phosphodiesterase-6 (PDE6) are the third most common cause of autosomal recessive retinitis pigmentosa (RP). Previously, viral gene therapy approaches on pre-clinical models with mutations in PDE6 have demonstrated that the photoreceptor cell survival and visual function can be rescued when the gene therapy virus is delivered into the subretinal space before the onset of disease. However, no studies have currently been published that analyze rescue effects after disease onset, a time when human RP patients are diagnosed by a clinician and would receive the treatment. We utilized the AAV2/8(Y733F)-Rho-Pde6 alpha gene therapy virus and injected it into a pre-clinical model of RP with a mutation within the alpha subunit of PDE6: Pde6 alpha(D670G). These mice were previously shown to have long-term photoreceptor cell rescue when this gene therapy virus was delivered before the onset of disease. Now, we have determined that subretinal transduction of this rod-specific transgene at post-natal day (P) 21, when approximately half of the photoreceptor cells have undergone degeneration, is more efficient in rescuing cone than rod photoreceptor function long term. Therefore, AAV2/8(Y733F)-Rho-Pde6a is an effective gene therapy treatment that can be utilized in the clinical setting, in human patients who have lost portions of their peripheral visual field and are in the mid-stage of disease when they first present to an eye-care professional.
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