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Published on: August 7, 2015
AAV-mediated gene therapy for choroideremia: preclinical studies in personalized models
Vidyullatha Vasireddy1, Jason A Mills, Rajashekhar Gaddameedi
1F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.
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.
Insights
Gene therapy successfully restored Rab Escort Protein 1 (REP1) function in patient-derived cells for choroideremia (CHM). This approach shows promise for future clinical trials targeting this X-linked retinal degeneration.
Area of Science:
- Ophthalmology
- Genetics
- Molecular Biology
Background:
- Choroideremia (CHM) is an X-linked retinal degeneration causing progressive vision loss, typically leading to blindness by mid-life.
- The disease results from a loss-of-function mutation in the Rab Escort Protein 1 (REP1) gene, crucial for retinal cell health.
- Current treatment options are limited, making gene therapy a promising therapeutic strategy.
Purpose of the Study:
- To evaluate the potential of gene augmentation therapy for choroideremia by restoring REP1 function.
- To assess the safety and efficacy of delivering CHM cDNA using recombinant adeno-associated virus (rAAV) vectors.
- To establish personalized in vitro models for testing gene therapy in CHM patients.
Main Methods:
- Utilized lymphoblasts and induced pluripotent stem cells (iPSCs) from human CHM patients as personalized in vitro models.
- Delivered complementary DNA (cDNA) encoding REP1 via rAAV vectors to affected cells.
- Assessed REP1 enzymatic activity and protein trafficking restoration post-gene transfer.
- Evaluated preliminary safety by examining retinal histopathology in normal-sighted mice.
Main Results:
- Successful restoration of REP1 enzymatic activity and proper protein trafficking in patient-derived cells.
- Efficient gene transfer was achieved using rAAV vectors.
- Preliminary safety evaluation in mice showed no significant acute retinal histopathologic effects.
- In vitro models demonstrated the feasibility of restoring REP1 function.
Conclusions:
- Gene augmentation therapy using rAAV vectors is a viable strategy for treating choroideremia.
- Restoration of REP1 function in patient-derived cells is achievable, with encouraging preliminary safety data.
- These findings provide a strong foundation for advancing gene therapy for CHM towards human clinical trials.
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