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Common AAV gene therapy vectors show indiscriminate transduction of living human brain cell types
Abstract
The development of cell-type-specific gene therapy vectors for treating neurological diseases holds great promise, but has relied on animal models with limited translational utility. We have adapted an ex vivo organotypic model to evaluate adeno-associated virus (AAV) transduction properties in living slices of human brain tissue. Using fluorescent reporter expression and single-nucleus RNA sequencing, we found that common AAV vectors show broad transduction of normal cell types, with protein expression most apparent in astrocytes; this work introduces a pipeline for identifying and optimizing AAV gene therapy vectors in human brain samples.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Project design: JPM, JOG, DC, BA
IRB approval: JPM, DC
Human brain tissue consent and acquisition: JPM, JOG, CG, SM, BB, SS, EJ, MB, CM, GA, AP, AJ, SS, HW, SG, GR, DC
Virus production: YW, ZC, JOG
Tissue processing and virus application: JPM, JOG, CG, SM, SB, AA, ET, MCL, SC
Imaging analysis: JPM, JL, CG, SM, EJ, SC
Single-nucleus library prep: JPM, CG, SM, SB
Single-nucleus RNA sequencing analysis: JPM, SM, ASH, CG, SB
Funding: BA, DC, JOG
Initial manuscript draft: JPM Manuscript editing and review: all
Subject Area
- Biochemistry (17717)
- Bioengineering (13910)
- Bioinformatics (42018)
- Biophysics (21480)
- Cancer Biology (18629)
- Cell Biology (25537)
- Clinical Trials (138)
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- Evolutionary Biology (24356)
- Genetics (15617)
- Genomics (22531)
- Immunology (17755)
- Microbiology (40438)
- Molecular Biology (17200)
- Neuroscience (88706)
- Paleontology (667)
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- Pharmacology and Toxicology (4832)
- Physiology (7657)
- Plant Biology (15171)
- Synthetic Biology (4304)
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