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

doi:10.1016/j.neurot.2024.e00362

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

Neurotherapeutics. 2024 Apr 24:e00362. doi: 10.1016/j.neurot.2024.e00362. Online ahead of print.

Authors

Zachary Finkel¹, Fatima Esteban¹, Brianna Rodriguez¹, Tanner Clifford¹, Adelina Joseph¹, Hani Alostaz¹, Mridul Dalmia¹, Juan Gutierrez², Matthew J Tamasi¹, Samuel Ming Zhang¹, Jonah Simone¹, Hafize Petekci¹, Susmita Nath¹, Miriam Escott¹, Shivam Kumar Garg¹, Adam J Gormley¹, Suneel Kumar¹, Sonia Gulati³, Li Cai⁴

Affiliations

¹ Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA.
² Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA; University of California, Santa Barbara, CA 93106, USA.
³ NeuroNovus Therapeutics Inc., 135 E 57th St., New York, NY 10022, USA.
⁴ 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. Electronic address: lcai@rutgers.edu.

PMID: 38664194
DOI: 10.1016/j.neurot.2024.e00362

Abstract

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.

Keywords: Gene therapy; Genomic screened homeobox 1 (Gsh1 or Gsx1); Neural regeneration; Neural stem/progenitor cell; Neurogenesis; Traumatic spinal cord injury.

Abstract

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