期刊
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
卷 25, 期 -, 页码 476-489出版社
CELL PRESS
DOI: 10.1016/j.omtm.2022.04.014
关键词
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资金
- National Science Foundation [ACI-1548562]
- NSF at the Pittsburgh Supercomputing Center (PSC) [ACI-1445606, ACI-1928147]
- University of Pittsburgh Center for Research Computing
- NIH CORE grant [P30 EY08098]
- Eye and Ear Foundation of Pittsburgh
- Research to Prevent Blindness, New York, NY, USA
- UPMC Immune Transplant and Therapy Center
- NIH [UG3MH120094]
- Foundation Fighting Blindness
- Research to Prevent Blindness
- China Scholarship Council
- Third Xiangya Hospital
- Xiangya School of Medicine
This study evaluated the efficiency and tropism of 18 AAV serotypes in human retinal explants using a recently developed RNA sequencing AAV engineering pipeline. The top-performing serotypes, K91, K912, and 7m8, were further validated in non-human primate and human retinal explants. The findings provide important information for the translation of retinal gene therapies to the clinic.
Gene therapy is a rapidly developing field, and adeno-associated viruses (AAVs) are a leading viral-vector candidate for therapeutic gene delivery. Newly engineered AAVs with improved abilities are now entering the clinic. It has proven challenging, however, to predict the translational potential of gene therapies developed in animal models due to cross-species differences. Human retinal explants are the only available model of fully developed human retinal tissue and are thus important for the validation of candidate AAV vectors. In this study, we evaluated 18 wild-type and engineered AAV capsids in human retinal explants using a recently developed single-cell RNA sequencing (RNA-seq) AAV engineering pipeline (scAAVengr). Human retinal explants retained the same major cell types as fresh retina, with similar expression of cell-specific markers except for a photoreceptor population with altered expression of photoreceptor-specific genes. The efficiency and tropism of AAVs in human explants were quantified with single-cell resolution. The top-performing serotypes, K91, K912, and 7m8, were further validated in non-human primate and human retinal explants. Together, this study provides detailed information about the transcriptome profiles of retinal explants and quantifies the infectivity of leading AAV serotypes in human retina, accelerating the translation of retinal gene therapies to the clinic.
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