Molecular Therapy: Methods & Clinical Development (Jun 2025)
Common AAV gene therapy vectors show nonselective transduction of ex vivo human brain tissue
- JP McGinnis,
- Joshua Ortiz-Guzman,
- Maria Camila Guevara,
- Sai Mallannagari,
- Benjamin D.W. Belfort,
- Suyang Bao,
- Snigdha Srivastava,
- Maria Morkas,
- Emily Ji,
- Angela Addison,
- Evelyne K. Tantry,
- Sarah Chen,
- Ying Wang,
- Zihong Chen,
- Kalman A. Katlowitz,
- Jeffrey J. Lange,
- Melissa M. Blessing,
- Carrie A. Mohila,
- M. Cecilia Ljungberg,
- Guillermo Aldave,
- Ali Jalali,
- Akash Patel,
- Sameer A. Sheth,
- Howard L. Weiner,
- Shankar Gopinath,
- Ganesh Rao,
- Akdes Serin Harmanci,
- Daniel J. Curry,
- Benjamin R. Arenkiel
Affiliations
- JP McGinnis
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA; Corresponding author: J.P. McGinnis, Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA.
- Joshua Ortiz-Guzman
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA
- Maria Camila Guevara
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Sai Mallannagari
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Benjamin D.W. Belfort
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA; Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA
- Suyang Bao
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Development, Disease Models & Therapeutics Graduate Program, Baylor College of Medicine, Houston, TX 77030, USA
- Snigdha Srivastava
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA; Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA
- Maria Morkas
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Emily Ji
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Angela Addison
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Development, Disease Models & Therapeutics Graduate Program, Baylor College of Medicine, Houston, TX 77030, USA
- Evelyne K. Tantry
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA
- Sarah Chen
- Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA
- Ying Wang
- Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA
- Zihong Chen
- Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA
- Kalman A. Katlowitz
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA
- Jeffrey J. Lange
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
- Melissa M. Blessing
- Department of Pathology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA
- Carrie A. Mohila
- Department of Pathology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA
- M. Cecilia Ljungberg
- Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA; Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA
- Guillermo Aldave
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurosurgery, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA
- Ali Jalali
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA
- Akash Patel
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA
- Sameer A. Sheth
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA
- Howard L. Weiner
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurosurgery, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA
- Shankar Gopinath
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA
- Ganesh Rao
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA
- Akdes Serin Harmanci
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA
- Daniel J. Curry
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurosurgery, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA
- Benjamin R. Arenkiel
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA; Corresponding author: Benjamin R. Arenkiel, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
- DOI
- https://doi.org/10.1016/j.omtm.2025.101494
- Journal volume & issue
-
Vol. 33,
no. 2
p. 101494
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.
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