TY  - JOUR
TI  - Targeted Extracellular Vesicle Gene Therapy for Modulating Alpha-Synuclein Expression in Gut and Spinal Cord
VL  - 15
AV  - public
Y1  - 2023/04/13/
IS  - 4
N1  - © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
N2  - The development of effective disease-modifying therapies to halt Parkinson?s disease (PD) progression is required. In a subtype of PD patients, alpha-synuclein pathology may start in the enteric nervous system (ENS) or autonomic peripheral nervous system. Consequently, strategies to decrease the expression of alpha-synuclein in the ENS will be an approach to prevent PD progression at pre-clinical stages in these patients. In the present study, we aimed to assess if anti-alpha-synuclein shRNA-minicircles (MC) delivered by RVG-extracellular vesicles (RVG-EV) could downregulate alpha-synuclein expression in the intestine and spinal cord. RVG-EV containing shRNA-MC were injected intravenously in a PD mouse model, and alpha-synuclein downregulation was evaluated by qPCR and Western blot in the cord and distal intestine. Our results confirmed the downregulation of alpha-synuclein in the intestine and spinal cord of mice treated with the therapy. We demonstrated that the treatment with anti-alpha-synuclein shRNA-MC RVG-EV after the development of pathology is effective to downregulate alpha-synuclein expression in the brain as well as in the intestine and spinal cord. Moreover, we confirmed that a multidose treatment is necessary to maintain downregulation for long-term treatments. Our results support the potential use of anti-alpha-synuclein shRNA-MC RVG-EV as a therapy to delay or halt PD pathology progression.
ID  - discovery10168878
UR  - http://doi.org/10.3390/pharmaceutics15041230
PB  - MDPI AG
SN  - 1999-4923
JF  - Pharmaceutics
A1  - Izco, Maria
A1  - Schleef, Martin
A1  - Schmeer, Marco
A1  - Carlos, Estefania
A1  - Verona, Guglielmo
A1  - Alvarez-Erviti, Lydia
KW  - Parkinson?s disease; alpha-synuclein; gene therapy; exosomes; spinal cord; intestine
ER  -