AAV6 mediated Gsx1 expression in neural stem progenitor cells promotes neurogenesis and restores locomotor function after contusion spinal cord injury

Zachary Finkel; Fatima Esteban; Brianna Rodriguez; Tanner Clifford; Adelina Joseph; Hani Alostaz; Mridul Dalmia; Juan Gutierrez; Matthew J. Tamasi; Samuel Ming Zhang; Jonah Simone; Hafize Petekci; Susmita Nath; Miriam Escott; Shivam Kumar Garg; Adam J. Gormley; Suneel Kumar; Sonia Gulati; Li Cai

Neurotherapeutics (Jul 2024)

AAV6 mediated Gsx1 expression in neural stem progenitor cells promotes neurogenesis and restores locomotor function after contusion spinal cord injury

Zachary Finkel,
Fatima Esteban,
Brianna Rodriguez,
Tanner Clifford,
Adelina Joseph,
Hani Alostaz,
Mridul Dalmia,
Juan Gutierrez,
Matthew J. Tamasi,
Samuel Ming Zhang,
Jonah Simone,
Hafize Petekci,
Susmita Nath,
Miriam Escott,
Shivam Kumar Garg,
Adam J. Gormley,
Suneel Kumar,
Sonia Gulati,
Li Cai

Affiliations

Zachary Finkel: Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
Fatima Esteban: Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
Brianna Rodriguez: Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
Tanner Clifford: Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
Adelina Joseph: Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
Hani Alostaz: Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
Mridul Dalmia: Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
Juan Gutierrez: Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA; University of California, Santa Barbara, CA 93106, USA
Matthew J. Tamasi: Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
Samuel Ming Zhang: Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
Jonah Simone: Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
Hafize Petekci: Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
Susmita Nath: Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
Miriam Escott: Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
Shivam Kumar Garg: Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
Adam J. Gormley: Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
Suneel Kumar: Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
Sonia Gulati: NeuroNovus Therapeutics Inc., 135 E 57th St., New York, NY 10022, USA
Li Cai: Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA; NeuroNovus Therapeutics Inc., 135 E 57th St., New York, NY 10022, USA; Corresponding author.

Journal volume & issue: Vol. 21, no. 4
p. e00362

Abstract

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Genomic screened homeobox 1 (Gsx1 or Gsh1) is a neurogenic transcription factor required for the generation of excitatory and inhibitory interneurons during spinal cord development. In the adult, lentivirus (LV) mediated Gsx1 expression promotes neural regeneration and functional locomotor recovery in a mouse model of lateral hemisection spinal cord injury (SCI). The LV delivery method is clinically unsafe due to insertional mutations to the host DNA. In addition, the most common clinical case of SCI is contusion/compression. In this study, we identify that adeno-associated virus serotype 6 (AAV6) preferentially infects neural stem/progenitor cells (NSPCs) in the injured spinal cord. Using a rat model of contusion SCI, we demonstrate that AAV6 mediated Gsx1 expression promotes neurogenesis, increases the number of neuroblasts/immature neurons, restores excitatory/inhibitory neuron balance and serotonergic neuronal activity through the lesion core, and promotes locomotor functional recovery. Our findings support that AAV6 preferentially targets NSPCs for gene delivery and confirmed Gsx1 efficacy in clinically relevant rat model of contusion SCI.

Published in Neurotherapeutics

ISSN: 1933-7213 (Print); 1878-7479 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry: Neurology. Diseases of the nervous system
Website: https://www.sciencedirect.com/journal/neurotherapeutics

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