PT  - JOURNAL ARTICLE
AU  - Poppy Datta
AU  - Avri Ruffcorn
AU  - Seongjin Seo
TI  - Limited time window for retinal gene therapy in a preclinical model of ciliopathy
AID  - 10.1101/2020.05.05.072793
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.05.05.072793
4099  - http://biorxiv.org/content/early/2020/05/06/2020.05.05.072793.short
4100  - http://biorxiv.org/content/early/2020/05/06/2020.05.05.072793.full
AB  - Retinal degeneration is a common clinical feature of ciliopathies, a group of genetic diseases linked to ciliary dysfunction, and gene therapy is an attractive treatment option to prevent vision loss. Although the efficacy of retinal gene therapy is well established by multiple proof-of-concept preclinical studies, its long-term effect, particularly when treatments are given at advanced disease stages, is controversial. Incomplete treatment and intrinsic variability of gene delivery methods may contribute to the variable outcomes. Here, we used a genetic rescue approach to “optimally” treat retinal degeneration at various disease stages and examined the long-term efficacy of gene therapy in a mouse model of ciliopathy. We used a Bardet-Biedl syndrome type 17 (BBS17) mouse model, in which the gene-trap that suppresses Bbs17 (also known as Lztfl1) expression can be removed by tamoxifen administration, restoring normal gene expression systemically. Our data indicate that therapeutic effects of retinal gene therapy decrease gradually as treatments are given at later stages. These results suggest the presence of limited time window for successful gene therapy in certain retinal degenerations. Our study also implies that the long-term efficacy of retinal gene therapy may depend on not only the timing of treatment but also other factors such as the function of mutated genes and residual activities of mutant alleles.Competing Interest StatementThe authors have declared no competing interest.AAVadeno-associated virusBBSBardet-Biedl syndrome,CMVcytomegalovirusDAPI4′,6-Diamidine-2′-phenylindole dihydrochlorideERGelectroretinographyFLPflippaseFRTflippase recognition targetIFTintraflagellar transportIRDinherited retinal degenerationISinner segmentLCALeber congenital amaurosisONLouter nuclear layerOSouter segmentPpost-natal dayPTIpost-tamoxifen injectionqRT-PCRquantitative reverse transcription polymerase chain reactionRPretinitis pigmentosaSCRstandard combined responseTEMtransmission electron microscopyTMXtamoxifen