Therapeutic margins in a novel preclinical model of retinitis pigmentosa.
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, Pde6b(Stop), 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.
Brown Glaucoma Laboratory, Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Richard J
RJ
Davis
Chun-Wei
CW
Hsu
Yi-Ting
YT
Tsai
Katherine J
KJ
Wert
Javier
J
Sancho-Pelluz
Chyuan-Sheng
CS
Lin
Stephen H
SH
Tsang
D000818:Animals; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000235:genetics / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004596:Electroretinography; D015316:Genetic Therapy / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D012174:Retinitis Pigmentosa / Q000235:genetics*
D054707:Cyclic Nucleotide Phosphodiesterases, Type 6