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CRISPR/sgRNA-directed synergistic activation mediator (SAM) as a therapeutic tool for Parkinson´s disease.

Authors :
Narváez-Pérez LF
Paz-Bermúdez F
Avalos-Fuentes JA
Campos-Romo A
Florán-Garduño B
Segovia J
Source :
Gene therapy [Gene Ther] 2024 Jan; Vol. 31 (1-2), pp. 31-44. Date of Electronic Publication: 2023 Aug 04.
Publication Year :
2024

Abstract

Parkinson`s disease (PD) is the second most prevalent neurodegenerative disease, and different gene therapy strategies have been used as experimental treatments. As a proof-of-concept for the treatment of PD, we used SAM, a CRISPR gene activation system, to activate the endogenous tyrosine hydroxylase gene (th) of astrocytes to produce dopamine (DA) in the striatum of 6-OHDA-lesioned rats. Potential sgRNAs within the rat th promoter region were tested, and the expression of the Th protein was determined in the C6 glial cell line. Employing pseudo-lentivirus, the SAM complex and the selected sgRNA were transferred into cultures of rat astrocytes, and gene expression and Th protein synthesis were ascertained; furthermore, DA release into the culture medium was determined by HPLC. The DA-producing astrocytes were implanted into the striatum of 6-OHDA hemiparkinsonian rats. We observed motor behavior improvement in the lesioned rats that received DA-astrocytes compared to lesioned rats receiving astrocytes that did not produce DA. Our data indicate that the SAM-induced expression of the astrocyte´s endogenous th gene can generate DA-producing astrocytes that effectively reduce the motor asymmetry induced by the lesion.<br /> (© 2023. The Author(s).)

Details

Language :
English
ISSN :
1476-5462
Volume :
31
Issue :
1-2
Database :
MEDLINE
Journal :
Gene therapy
Publication Type :
Academic Journal
Accession number :
37542151
Full Text :
https://doi.org/10.1038/s41434-023-00414-0