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Administration of a barcoded AAV capsid library to the putamen of non-human primates identifies variants with efficient retrograde transport

Dzhashiashvili, Yulia ; McBride, Jodi L. ; Fabyanic, Emily ; Huang, Xin ; Kelly, Brian M. ; Walton-Gibbs, Greglynn D. ; Vemireddi, Vimala ; Wicks, Joan ; Nayal, Mohamad and Hippen, Ariel A. , et al. (2025) In Molecular Therapy
Abstract

Adeno-associated viral vectors have become a leading choice for gene therapy in the central nervous system due to their safety profile, efficient neuronal transduction, and capacity for sustained transgene expression. We previously reported that AAV2-derived capsids developed using the BRAVE (Barcoded Rational AAV Vector Evolution) approach have enhanced retrograde transport properties in the rodent brain, compared with parental AAV2. Retrograde transport enables broader coverage of connected brain regions after a single focal intraparenchymal brain injection and is therefore a powerful tool for delivery of vectors to distant sites with potentially higher specificity, transduction efficacy, and safety. Because transport properties can... (More)

Adeno-associated viral vectors have become a leading choice for gene therapy in the central nervous system due to their safety profile, efficient neuronal transduction, and capacity for sustained transgene expression. We previously reported that AAV2-derived capsids developed using the BRAVE (Barcoded Rational AAV Vector Evolution) approach have enhanced retrograde transport properties in the rodent brain, compared with parental AAV2. Retrograde transport enables broader coverage of connected brain regions after a single focal intraparenchymal brain injection and is therefore a powerful tool for delivery of vectors to distant sites with potentially higher specificity, transduction efficacy, and safety. Because transport properties can vary among species, we further characterized a barcoded library of 25 BRAVE-derived AAV2 capsid variants, along with the parental AAV2 serotype and benchmark AAV capsids, in brains of adult cynomolgus monkeys after intraputaminal dosing. Based on RNA and DNA amplicon sequencing, single-nucleus RNA sequencing, and histological assessment, we report here capsid variants with enhanced retrograde transport and expression compared with the parental AAV2 capsid. These properties make them potentially useful for disease indications in which broader brain coverage is desirable beyond the injection site.

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organization
publishing date
type
Contribution to journal
publication status
in press
subject
keywords
AAV, gene delivery, Huntington’s disease, intraparenchymal, NHP, Parkinson’s disease, retrograde
in
Molecular Therapy
publisher
Nature Publishing Group
external identifiers
  • scopus:105025434785
  • pmid:41376158
ISSN
1525-0016
DOI
10.1016/j.ymthe.2025.12.009
language
English
LU publication?
yes
id
d6fc9b7e-16ae-4bd7-856c-08924fd8f44d
date added to LUP
2026-02-27 11:01:59
date last changed
2026-03-27 17:57:45
@article{d6fc9b7e-16ae-4bd7-856c-08924fd8f44d,
  abstract     = {{<p>Adeno-associated viral vectors have become a leading choice for gene therapy in the central nervous system due to their safety profile, efficient neuronal transduction, and capacity for sustained transgene expression. We previously reported that AAV2-derived capsids developed using the BRAVE (Barcoded Rational AAV Vector Evolution) approach have enhanced retrograde transport properties in the rodent brain, compared with parental AAV2. Retrograde transport enables broader coverage of connected brain regions after a single focal intraparenchymal brain injection and is therefore a powerful tool for delivery of vectors to distant sites with potentially higher specificity, transduction efficacy, and safety. Because transport properties can vary among species, we further characterized a barcoded library of 25 BRAVE-derived AAV2 capsid variants, along with the parental AAV2 serotype and benchmark AAV capsids, in brains of adult cynomolgus monkeys after intraputaminal dosing. Based on RNA and DNA amplicon sequencing, single-nucleus RNA sequencing, and histological assessment, we report here capsid variants with enhanced retrograde transport and expression compared with the parental AAV2 capsid. These properties make them potentially useful for disease indications in which broader brain coverage is desirable beyond the injection site.</p>}},
  author       = {{Dzhashiashvili, Yulia and McBride, Jodi L. and Fabyanic, Emily and Huang, Xin and Kelly, Brian M. and Walton-Gibbs, Greglynn D. and Vemireddi, Vimala and Wicks, Joan and Nayal, Mohamad and Hippen, Ariel A. and Yu, Zhenming and Raman, Pichai and Ramsburg, Elizabeth and Davidsson, Marcus and Engel, Esteban A. and Björklund, Tomas}},
  issn         = {{1525-0016}},
  keywords     = {{AAV; gene delivery; Huntington’s disease; intraparenchymal; NHP; Parkinson’s disease; retrograde}},
  language     = {{eng}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Molecular Therapy}},
  title        = {{Administration of a barcoded AAV capsid library to the putamen of non-human primates identifies variants with efficient retrograde transport}},
  url          = {{http://dx.doi.org/10.1016/j.ymthe.2025.12.009}},
  doi          = {{10.1016/j.ymthe.2025.12.009}},
  year         = {{2025}},
}