Common AAV gene therapy vectors show nonselective transduction of ex vivo human brain tissue
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...
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Elsevier
2025-06-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050125000890 |
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| author | 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 |
| author_facet | 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 |
| author_sort | JP McGinnis |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-57945d8df17d44f888b4cdd14fa6d1b0 |
| institution | Kabale University |
| issn | 2329-0501 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj-art-57945d8df17d44f888b4cdd14fa6d1b02025-08-20T03:24:33ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012025-06-0133210149410.1016/j.omtm.2025.101494Common AAV gene therapy vectors show nonselective transduction of ex vivo human brain tissueJP McGinnis0Joshua Ortiz-Guzman1Maria Camila Guevara2Sai Mallannagari3Benjamin D.W. Belfort4Suyang Bao5Snigdha Srivastava6Maria Morkas7Emily Ji8Angela Addison9Evelyne K. Tantry10Sarah Chen11Ying Wang12Zihong Chen13Kalman A. Katlowitz14Jeffrey J. Lange15Melissa M. Blessing16Carrie A. Mohila17M. Cecilia Ljungberg18Guillermo Aldave19Ali Jalali20Akash Patel21Sameer A. Sheth22Howard L. Weiner23Shankar Gopinath24Ganesh Rao25Akdes Serin Harmanci26Daniel J. Curry27Benjamin R. Arenkiel28Department 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.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, USADepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USADepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USADepartment 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, USADepartment 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, USADepartment 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, USADepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USADepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USADepartment 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, USADepartment 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, USAJan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USAJan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USAJan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USADepartment of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USAStowers Institute for Medical Research, Kansas City, MO 64110, USADepartment of Pathology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USADepartment of Pathology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USAJan 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, USADepartment of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurosurgery, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USADepartment of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USADepartment of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USADepartment of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USADepartment of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurosurgery, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USADepartment of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USADepartment of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USADepartment of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USADepartment of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurosurgery, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USADepartment 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.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.http://www.sciencedirect.com/science/article/pii/S2329050125000890gene therapyhuman brainAAVAAV tropismhuman brain organotypic slice culture |
| spellingShingle | 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 Common AAV gene therapy vectors show nonselective transduction of ex vivo human brain tissue Molecular Therapy: Methods & Clinical Development gene therapy human brain AAV AAV tropism human brain organotypic slice culture |
| title | Common AAV gene therapy vectors show nonselective transduction of ex vivo human brain tissue |
| title_full | Common AAV gene therapy vectors show nonselective transduction of ex vivo human brain tissue |
| title_fullStr | Common AAV gene therapy vectors show nonselective transduction of ex vivo human brain tissue |
| title_full_unstemmed | Common AAV gene therapy vectors show nonselective transduction of ex vivo human brain tissue |
| title_short | Common AAV gene therapy vectors show nonselective transduction of ex vivo human brain tissue |
| title_sort | common aav gene therapy vectors show nonselective transduction of ex vivo human brain tissue |
| topic | gene therapy human brain AAV AAV tropism human brain organotypic slice culture |
| url | http://www.sciencedirect.com/science/article/pii/S2329050125000890 |
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