Therapeutic margins in a novel preclinical model of retinitis pigmentosa

Richard J. Davis, Chun Wei Hsu, Yi Ting Tsai, Katherine J. Wert, Javier Sancho-Pelluz, Chyuan Sheng Lin, Stephen H. Tsang

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

The third-most common cause of autosomal recessive retinitis pigmentosa (RP) is due to defective cGMP phosphodiesterase-6 (PDE6). Previous work using viral gene therapy on PDE6-mutant mouse models demonstrated photoreceptors can be rescued if administered before degeneration. However, whether visual function can be rescued after degeneration onset has not been addressed. This is a clinically important question, as newly diagnosed patients exhibit considerable loss of rods and cones in their peripheral retinas. We have generated and characterized a tamoxifen inducible Cre-loxP rescue allele, Pde6bStop, which allows us to temporally correct PDE6-deficiency. Whereas untreated mutants exhibit degeneration, activation of Cre-loxP recombination in early embryogenesis produced stable long-term rescue. Reversal at later time-points showed partial long-term or short-lived rescue. Our results suggest stable restoration of retinal function by gene therapy can be achieved if a sufficient number of rods are treated. Because patients are generally diagnosed after extensive loss of rods, the success of clinical trials may depend on identifying patients as early as possible to maximize the number of treatable rods.

Original languageEnglish (US)
Pages (from-to)13475-13483
Number of pages9
JournalJournal of Neuroscience
Volume33
Issue number33
DOIs
StatePublished - Aug 20 2013
Externally publishedYes

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Type 6 Cyclic Nucleotide Phosphodiesterases
Retinitis Pigmentosa
Genetic Therapy
Vertebrate Photoreceptor Cells
Viral Genes
Tamoxifen
Genetic Recombination
Embryonic Development
Retina
Therapeutics
Alleles
Clinical Trials

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Davis, R. J., Hsu, C. W., Tsai, Y. T., Wert, K. J., Sancho-Pelluz, J., Lin, C. S., & Tsang, S. H. (2013). Therapeutic margins in a novel preclinical model of retinitis pigmentosa. Journal of Neuroscience, 33(33), 13475-13483. https://doi.org/10.1523/JNEUROSCI.0419-13.2013

Therapeutic margins in a novel preclinical model of retinitis pigmentosa. / Davis, Richard J.; Hsu, Chun Wei; Tsai, Yi Ting; Wert, Katherine J.; Sancho-Pelluz, Javier; Lin, Chyuan Sheng; Tsang, Stephen H.

In: Journal of Neuroscience, Vol. 33, No. 33, 20.08.2013, p. 13475-13483.

Research output: Contribution to journalArticle

Davis, RJ, Hsu, CW, Tsai, YT, Wert, KJ, Sancho-Pelluz, J, Lin, CS & Tsang, SH 2013, 'Therapeutic margins in a novel preclinical model of retinitis pigmentosa', Journal of Neuroscience, vol. 33, no. 33, pp. 13475-13483. https://doi.org/10.1523/JNEUROSCI.0419-13.2013
Davis, Richard J. ; Hsu, Chun Wei ; Tsai, Yi Ting ; Wert, Katherine J. ; Sancho-Pelluz, Javier ; Lin, Chyuan Sheng ; Tsang, Stephen H. / Therapeutic margins in a novel preclinical model of retinitis pigmentosa. In: Journal of Neuroscience. 2013 ; Vol. 33, No. 33. pp. 13475-13483.
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