eprintid: 10168878
rev_number: 6
eprint_status: archive
userid: 699
dir: disk0/10/16/88/78
datestamp: 2023-04-26 13:15:19
lastmod: 2023-04-26 13:15:19
status_changed: 2023-04-26 13:15:19
type: article
metadata_visibility: show
sword_depositor: 699
creators_name: Izco, Maria
creators_name: Schleef, Martin
creators_name: Schmeer, Marco
creators_name: Carlos, Estefania
creators_name: Verona, Guglielmo
creators_name: Alvarez-Erviti, Lydia
title: Targeted Extracellular Vesicle Gene Therapy for Modulating Alpha-Synuclein Expression in Gut and Spinal Cord
ispublished: pub
divisions: UCL
divisions: B02
divisions: C10
divisions: D17
divisions: G90
keywords: Parkinson’s disease; alpha-synuclein; gene therapy; exosomes; spinal cord; intestine
note: © 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/).
abstract: 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.
date: 2023-04-13
date_type: published
publisher: MDPI AG
official_url: http://doi.org/10.3390/pharmaceutics15041230
oa_status: green
full_text_type: pub
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 2017920
doi: 10.3390/pharmaceutics15041230
lyricists_name: Verona, Guglielmo
lyricists_id: GVERO54
actors_name: Flynn, Bernadette
actors_id: BFFLY94
actors_role: owner
full_text_status: public
publication: Pharmaceutics
volume: 15
number: 4
article_number: 1230
issn: 1999-4923
citation:        Izco, Maria;    Schleef, Martin;    Schmeer, Marco;    Carlos, Estefania;    Verona, Guglielmo;    Alvarez-Erviti, Lydia;      (2023)    Targeted Extracellular Vesicle Gene Therapy for Modulating Alpha-Synuclein Expression in Gut and Spinal Cord.                   Pharmaceutics , 15  (4)    , Article 1230.  10.3390/pharmaceutics15041230 <https://doi.org/10.3390/pharmaceutics15041230>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10168878/1/pharmaceutics-15-01230.pdf