Journal article
Common AAV gene therapy vectors show nonselective transduction of ex vivo human brain tissue
Molecular therapy. Methods & clinical development, Vol.33(2), 101494
06/12/2025
DOI: 10.1016/j.omtm.2025.101494
PMCID: PMC12169722
PMID: 40525125
Abstract
The ability to deliver a therapeutic sequence to a specific cell type in the human brain would make possible innumerable therapeutic options for some of our most challenging diseases; however, studies on adeno-associated virus (AAV) vector tropism have generally relied on animal models with limited translational utility. For this reason, establishing the tropism of common adeno-associated virus (AAV) vectors in living human brain tissue serves as an important baseline for further optimization, as well as a determination of human brain cell types transduced by clinically approved gene therapy vectors AAV2 and AAV9. We have adapted an ex vivo organotypic model to evaluate 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.
Details
- Title: Subtitle
- Common AAV gene therapy vectors show nonselective transduction of ex vivo human brain tissue
- Creators
- Jp McGinnisJoshua Ortiz-GuzmanMaria Camila GuevaraSai MallannagariBenjamin D.W. BelfortSuyang BaoSnigdha SrivastavaMaria MorkasEmily JiAngela AddisonEvelyne K. TantrySarah ChenYing Wang - Texas Children's HospitalZihong ChenKalman A. KatlowitzJeffrey J. LangeMelissa M. BlessingCarrie A. MohilaM. Cecilia LjungbergGuillermo AldaveAli JalaliAkash PatelSameer A. ShethHoward L. WeinerShankar GopinathGanesh RaoAkdes Serin HarmanciDaniel CurryBenjamin R. Arenkiel
- Resource Type
- Journal article
- Publication Details
- Molecular therapy. Methods & clinical development, Vol.33(2), 101494
- DOI
- 10.1016/j.omtm.2025.101494
- PMID
- 40525125
- PMCID
- PMC12169722
- NLM abbreviation
- Mol Ther Methods Clin Dev
- ISSN
- 2329-0501
- eISSN
- 2329-0501
- Publisher
- CELL PRESS
- Grant note
- Cytometry and Cell Sorting Core at Baylor College of MedicineCPRIT Core Facility Support Award: CPRIT-RP180672 NIH: S10OD032189 CPRIT: RP200504
The majority of the funding for this project came from a generous gift from the Wilsey family. The project was also supported in part by the NRI Neuroconnectivity and Viral Core (supported via NIH P50HD103555) and the RNA In Situ Hybridization Core facility at Baylor College of Medicine (supported by a Shared Instrumentation grant from the NIH 1S10OD016167 and the NIH IDDRC grant P50 HD103555 from the Eunice Kennedy Shriver National Institute Of Child Health & Human Development) . Thisproject was further supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the CPRIT Core Facility Support Award (CPRIT-RP180672) , the NIH (CA125123 and RR024574) and the assistance of Joel M. Sederstrom, and by the Single Cell Genomics Core at Baylor College of Medicine with funding from the CPRIT RP200504 and the NIH S10OD032189.
- Language
- English
- Electronic publication date
- 05/21/2025
- Date published
- 06/12/2025
- Academic Unit
- Pathology
- Record Identifier
- 9984825636102771
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