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

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

Journal

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
ISSN: 1878-7479
Titre abrégé: Neurotherapeutics
Pays: United States
ID NLM: 101290381

Informations de publication

Date de publication:
24 Apr 2024
Historique:
received: 04 12 2023
revised: 29 03 2024
accepted: 11 04 2024
medline: 26 4 2024
pubmed: 26 4 2024
entrez: 25 4 2024
Statut: aheadofprint

Résumé

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.

Identifiants

DOI: 10.1016/j.neurot.2024.e00362 PMID: 38664194
pubmed: 38664194
pii: S1878-7479(24)00048-5
doi: 10.1016/j.neurot.2024.e00362
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

e00362

Informations de copyright

Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest L.C. is listed as a co-inventor in the patent application related to this work. L.C. is a founder of NeuroNovus Therapeutics Inc. and a member of the scientific advisory board. S.G. was the CEO of NeuroNovus Therapeutics Inc. The remaining authors declare no competing interests.

Auteurs

Zachary Finkel (Z)

Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA.

Fatima Esteban (F)

Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA.

Brianna Rodriguez (B)

Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA.

Tanner Clifford (T)

Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA.

Adelina Joseph (A)

Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA.

Hani Alostaz (H)

Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA.

Mridul Dalmia (M)

Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA.

Juan Gutierrez (J)

Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA; University of California, Santa Barbara, CA 93106, USA.

Matthew J Tamasi (MJ)

Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA.

Samuel Ming Zhang (SM)

Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA.

Jonah Simone (J)

Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA.

Hafize Petekci (H)

Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA.

Susmita Nath (S)

Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA.

Miriam Escott (M)

Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA.

Shivam Kumar Garg (SK)

Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA.

Adam J Gormley (AJ)

Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA.

Suneel Kumar (S)

Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA.

Sonia Gulati (S)

NeuroNovus Therapeutics Inc., 135 E 57th St., New York, NY 10022, USA.

Li Cai (L)

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.

Classifications MeSH