Enhanced AAV transduction across preclinical CNS models: A comparative study in human brain organoids with cross-species evaluations
Abstract
Viral vectors based on recombinant adeno-associated virus (rAAV) have become the most widely used system for therapeutic gene delivery in the central nervous system (CNS). Despite clinical safety and efficacy in neurological applications, a barrier to adoption of the current generation of vectors lies in their limited efficiency, resulting in limited transduction of CNS target cells. To address this limitation, researchers have bioengineered fit-for-purpose AAVs with improved CNS tropism and tissue penetration. While the preclinical assessment of these novel AAVs is primarily conducted in animal models, human induced pluripotent stem cell (hiPSC)-derived organoids offer a unique opportunity to functionally evaluate novel AAV variants in a human context. In this study, we performed a comprehensive and unbiased evaluation of a large number of wild-type and bioengineered AAV capsids for their transduction efficiency in hiPSC-derived brain organoids. We demonstrate that efficient AAV transduction observed in organoids was recapitulated in vivo in both mouse and non-human primate models after cerebrospinal fluid (CSF) delivery. In summary, our study showcases the use of brain organoid systems for the pre-screening of novel AAV vectors. Additionally, we report data for novel AAV variants that exhibit improved CNS transduction efficiency when delivered via the CSF in in vivo preclinical models.
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BibTeX
@article{drouyer2026enhanced,
title = {{Enhanced AAV transduction across preclinical CNS models: A comparative study in human brain organoids with cross-species evaluations}},
author = {Matthieu Drouyer and Jessica Merjane and Teodora Nedelkoska and Adrian Westhaus and Suzanne Scott and Scott Lee and Peter Burke and Simon Mcmullan and Jose Lanciego and Ana Vicente and Ricardo Bugallo and Carmen Unzu and Gloria González-Aseguinolaza and Anai Gonzalez-Cordero and Leszek Lisowski and Peter G.R. Burke},
journal = {Molecular Therapy - Nucleic Acids},
year = {2026},
month = sep,
doi = {10.1016/j.omtn.2024.102264},
url = {https://hal.science/hal-05772044v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Enhanced AAV transduction across preclinical CNS models: A comparative study in human brain organoids with cross-species evaluations
AU - Matthieu Drouyer
AU - Jessica Merjane
AU - Teodora Nedelkoska
AU - Adrian Westhaus
AU - Suzanne Scott
AU - Scott Lee
AU - Peter Burke
AU - Simon Mcmullan
AU - Jose Lanciego
AU - Ana Vicente
AU - Ricardo Bugallo
AU - Carmen Unzu
AU - Gloria González-Aseguinolaza
AU - Anai Gonzalez-Cordero
AU - Leszek Lisowski
AU - Peter G.R. Burke
PY - 2026
DA - 2026/09/30
JO - Molecular Therapy - Nucleic Acids
DO - 10.1016/j.omtn.2024.102264
UR - https://hal.science/hal-05772044v1
AB - Viral vectors based on recombinant adeno-associated virus (rAAV) have become the most widely used system for therapeutic gene delivery in the central nervous system (CNS). Despite clinical safety and efficacy in neurological applications, a barrier to adoption of the current generation of vectors lies in their limited efficiency, resulting in limited transduction of CNS target cells. To address this limitation, researchers have bioengineered fit-for-purpose AAVs with improved CNS tropism and tissue penetration. While the preclinical assessment of these novel AAVs is primarily conducted in animal models, human induced pluripotent stem cell (hiPSC)-derived organoids offer a unique opportunity to functionally evaluate novel AAV variants in a human context. In this study, we performed a comprehensive and unbiased evaluation of a large number of wild-type and bioengineered AAV capsids for their transduction efficiency in hiPSC-derived brain organoids. We demonstrate that efficient AAV transduction observed in organoids was recapitulated in vivo in both mouse and non-human primate models after cerebrospinal fluid (CSF) delivery. In summary, our study showcases the use of brain organoid systems for the pre-screening of novel AAV vectors. Additionally, we report data for novel AAV variants that exhibit improved CNS transduction efficiency when delivered via the CSF in in vivo preclinical models.
SN - 2162-2531
ER -