title: AAV-mediated gene therapy for choroideremia: preclinical studies in personalized models.
abstract: Choroideremia (CHM) is an X- linked retinal degeneration that is symptomatic in the 1(st) or 2(nd) decade of life causing nyctalopia and loss of peripheral vision. The disease progresses through mid-life, when most patients become blind. CHM is a favorable target for gene augmentation therapy, as the disease is due to loss of function of a protein necessary for retinal cell health, Rab Escort Protein 1 (REP1).The CHM cDNA can be packaged in recombinant adeno-associated virus (rAAV), which has an established track record in human gene therapy studies, and, in addition, there are sensitive and quantitative assays to document REP1 activity. An animal model that accurately reflects the human condition is not available. In this study, we tested the ability to restore REP1 function in personalized in vitro models of CHM: lymphoblasts and induced pluripotent stems cells (iPSCs) from human patients. The initial step of evaluating safety of the treatment was carried out by evaluating for acute retinal histopathologic effects in normal-sighted mice and no obvious toxicity was identified. Delivery of the CHM cDNA to affected cells restores REP1 enzymatic activity and also restores proper protein trafficking. The gene transfer is efficient and the preliminary safety data are encouraging. These studies pave the way for a human clinical trial of gene therapy for CHM.
authors.affiliation: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Vidyullatha
authors.initials: V
authors.lastname: Vasireddy
authors.forename: Jason A
authors.initials: JA
authors.lastname: Mills
authors.forename: Rajashekhar
authors.initials: R
authors.lastname: Gaddameedi
authors.forename: Etiena
authors.initials: E
authors.lastname: Basner-Tschakarjan
authors.forename: Monika
authors.initials: M
authors.lastname: Kohnke
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Black
authors.forename: Krill
authors.initials: K
authors.lastname: Alexandrov
authors.forename: Shangzhen
authors.initials: S
authors.lastname: Zhou
authors.forename: Albert M
authors.initials: AM
authors.lastname: Maguire
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Chung
authors.forename: Helen
authors.initials: H
authors.lastname: Mac
authors.forename: Lisa
authors.initials: L
authors.lastname: Sullivan
authors.forename: Paul
authors.initials: P
authors.lastname: Gadue
authors.forename: Jeannette L
authors.initials: JL
authors.lastname: Bennicelli
authors.forename: Deborah L
authors.initials: DL
authors.lastname: French
authors.forename: Jean
authors.initials: J
authors.lastname: Bennett
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D002460:Cell Line; D015794:Choroideremia / Q000235:genetics* / Q000628:therapy*; D000229:Dependovirus / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D008297:Male; D051379:Mice; D010957:Plasmids / Q000235:genetics; D057285:Precision Medicine; D021381:Protein Transport / Q000235:genetics; D012449:Safety; D020691:rab GTP-Binding Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C081787:CHM protein, human; D020691:rab GTP-Binding Proteins