AAV-Mediated Gene Therapy for Choroideremia: Preclinical Studies in Personalized Models

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 th...

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Published inPloS one Vol. 8; no. 5; p. e61396
Main Authors Vasireddy, Vidyullatha, Mills, Jason A., Gaddameedi, Rajashekhar, Basner-Tschakarjan, Etiena, Kohnke, Monika, Black, Aaron D., Alexandrov, Krill, Zhou, Shangzhen, Maguire, Albert M., Chung, Daniel C., Mac, Helen, Sullivan, Lisa, Gadue, Paul, Bennicelli, Jeannette L., French, Deborah L., Bennett, Jean
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 07.05.2013
Public Library of Science (PLoS)
Subjects
Adaptor Proteins, Signal Transducing - genetics
Animal models
Animals
Augmentation
Biology
Blindness
Cell Line
Choroideremia - genetics
Choroideremia - therapy
Degeneration
Dependovirus - genetics
Enzymatic activity
Female
Gene therapy
Genes
Genetic Therapy - adverse effects
Genetic Therapy - methods
Humans
Lymphoblasts
Male
Medicine
Mice
Mutation
Nyctalopia
Patients
Peripheral vision
Physicians
Plasmids - genetics
Pluripotency
Precision Medicine
Protein transport
Protein Transport - genetics
rab GTP-Binding Proteins - metabolism
Recovery of function
Retina
Retinal degeneration
Safety
Stem cells
Toxicity
Viruses
United States > US
Pennsylvania
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Summary: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.
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Conceived and designed the experiments: VV JAM RG EBT MK JLB DLF JB. Performed the experiments: VV JAM RG EBT ADB AMM DCC HM LS PG JLB JB SZ. Analyzed the data: VV JAM RG EBT ADB HM LS PG JLB DLF JB. Contributed reagents/materials/analysis tools: MK KA AMM JLB DLF JB SZ SZ. Wrote the paper: VV JB.
Competing Interests: JB and AMM are co-inventors of a patent for a method to treat or slow the development of blindness, but both waived any financial interest in this technology in 2002. JB serves on a scientific advisory board for Avalanche Technologies and is a co-founder of GenSight. The authors have a patent pending relating to material pertinent to this article. This patent, provisional patent 61/486608, “Proviral plasmids for production of recombinant adeno-associated virus,” describes the proviral plasmid, pAAV2.CBAe.hCHM, used to generate the experimental vector (AAV2.hCHM) used in this study. The pAAV2.CBAe.hCHM construct will also be used to generate a clinical vector to be used in human clinical trials. There are no further patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors and in compliance with US FDA regulations.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0061396