Adeno‐associated virus 8‐mediated gene therapy for choroideremia: preclinical studies in in vitro and in vivo models. (May 2014)

• Record Type: Journal Article
• Authors: Black, Aaron; Vasireddy, Vidyullatha; Chung, Daniel C.; Maguire, Albert M.; Gaddameedi, Rajashekhar; Tolmachova, Tania; Seabra, Miguel; Bennett, Jean
• Is Part Of: Journal of gene medicine. Volume 16:Number 5/6(2014)
• Page Start: 122
• Page End: 130
• Publication Date: 2014-05
• Subjects: Genetic transformation -- Periodicals; Gene Transfer -- Periodicals; Gene Therapy -- Periodicals; 616.042
• DOI: 10.1002/jgm.2768
• Languages: English
• ISSNs: 1099-498X

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <sec id="jgm2768-sec-0001" sec-type="section"> <title>Background</title> <p>Choroideremia (CHM) is a slowly progressive X‐linked retinal degeneration that results in a loss of photoreceptors, retinal pigment epithelium and choroid. <italic>CHM</italic>, the gene implicated in choroideremia, encodes Rab escort protein‐1 (REP‐1), which is involved in the post‐translational activation via prenylation of Rab proteins.</p> </sec> <sec id="jgm2768-sec-0002" sec-type="section"> <title>Methods</title> <p>We evaluated AAV8.CBA.hCHM, a recombinant adeno‐associated virus serotype 8 (rAAV8) vector, which targets retinal cells efficiently, for both therapeutic effect and safety <italic>in vitro</italic> and <italic>in vivo</italic> in a murine model. <italic>In vitro</italic> studies included western blot analyses and prenylation assays. <italic>In vivo</italic> studies included ophthalmoscopy, pupillometry, histology and immunofluorescence analysis.</p> </sec> <sec id="jgm2768-sec-0003" sec-type="section"> <title>Results</title> <p>Infection with AAV8.CBA.hCHM induced the expression of REP‐1 protein in a dose‐responsive fashion. Transduction with AAV8.CBA.hCHM reverses the biochemical and pathogenetic defects in CHM both <italic>in vitro</italic> and <italic>in vivo</italic> and showed no safety concerns in the <italic>in vivo</italic> investigations performed in the present study.</p> </sec> <sec id="jgm2768-sec-0004" sec-type="section"> <title>Conclusions</title> <p>AAV8 is a promising vector for human clin<italic>i</italic>cal gene therapy trials for choroideremia. Copyright © 2014 John Wiley & Sons, Ltd.</p> </sec> </abstract>