TY - JOUR
T1 - Mid-stage intervention achieves similar efficacy as conventional early-stage treatment using gene therapy in a pre-clinical model of retinitis pigmentosa
AU - Wert, Katherine J.
AU - Sancho-Pelluz, Javier
AU - Tsang, Stephen H.
N1 - Funding Information:
This work was supported by the National Institute of Health Core (5P30EY019007), National Cancer Institute Core (5P30CA013696) and unrestricted funds from Research to Prevent Blindness, New York, NY, USA. S.H.T. is a member of the RD-CURE Consortium and is supported by Tistou and Charlotte Kerstan Foundation, the National Institute of Health (R01EY018213), the Research to Prevent Blindness Physician-Scientist Award, the Barbara and Donald Jonas Family Fund, the Schneeweiss Stem Cell Fund, New York State (N09G-302) and the Foundation Fighting Blindness New York Regional Research Center Grant (C-NY05-0705-0312), the 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 and Gebroe Family Foundation. K.J.W. is supported by the National Institute of Health (5T32EY013933, 5T32DK007647-20).
PY - 2014/1
Y1 - 2014/1
N2 - 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 survivalandvisual functioncanberescuedwhenthegenetherapy virus is delivered into the subretinalspace 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-Pde6α gene therapy virus and injected it into a pre-clinical model of RP with a mutation within the alpha subunit of PDE6: Pde6αD670G. 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-Pde6α 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.
AB - 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 survivalandvisual functioncanberescuedwhenthegenetherapy virus is delivered into the subretinalspace 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-Pde6α gene therapy virus and injected it into a pre-clinical model of RP with a mutation within the alpha subunit of PDE6: Pde6αD670G. 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-Pde6α 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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U2 - 10.1093/hmg/ddt452
DO - 10.1093/hmg/ddt452
M3 - Article
C2 - 24101599
AN - SCOPUS:84898826569
SN - 0964-6906
VL - 23
SP - 514
EP - 523
JO - Human molecular genetics
JF - Human molecular genetics
IS - 2
ER -