title: Adeno-associated virus 8-mediated gene therapy for choroideremia: preclinical studies in in vitro and in vivo models.
abstract: BACKGROUND
  Choroideremia (CHM) is a slowly progressive X-linked retinal degeneration that results in a loss of photoreceptors, retinal pigment epithelium and choroid. CHM, 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.
  
  
  METHODS
  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 in vitro and in vivo in a murine model. In vitro studies included western blot analyses and prenylation assays. In vivo studies included ophthalmoscopy, pupillometry, histology and immunofluorescence analysis.
  
  
  RESULTS
  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 in vitro and in vivo and showed no safety concerns in the in vivo investigations performed in the present study.
  
  
  CONCLUSIONS
  AAV8 is a promising vector for human clinical gene therapy trials for choroideremia.
authors: F.M. Kirby Center for Molecular Ophthalmology and Center for Advanced Retinal and Ophthalmic Therapeutics, Scheie Eye Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors: Aaron
authors: A
authors: Black
authors: Vidyullatha
authors: V
authors: Vasireddy
authors: Daniel C
authors: DC
authors: Chung
authors: Albert M
authors: AM
authors: Maguire
authors: Rajashekhar
authors: R
authors: Gaddameedi
authors: Tania
authors: T
authors: Tolmachova
authors: Miguel
authors: M
authors: Seabra
authors: Jean
authors: J
authors: Bennett
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D015794:Choroideremia / Q000235:genetics* / Q000628:therapy; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D023061:Gene Order; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D012160:Retina / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D014161:Transduction, Genetic; D019076:Transgenes
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C081787:CHM protein, human
keywords: adeno-associated virus; animal models; choroideremia; gene therapy; in vitro models; retina