Design of a Single AAV Vector for Coexpression of TH and GCH1 to Establish Continuous DOPA Synthesis in a Rat Model of Parkinson's Disease.
Cederfjäll, Erik LU ; Sahin, Gurdal LU
; Kirik, Deniz
LU
and Björklund, Tomas
LU
(2012)
In Molecular Therapy
20(7).
p.1315-1326
- Abstract
- Preclinical efficacy of continuous delivery of 3,4-dihydroxyphenylalanine (DOPA) with adeno-associated viral (AAV) vectors has recently been documented in animal models of Parkinson's disease (PD). So far, all studies have utilized a mix of two monocistronic vectors expressing either of the two genes, tyrosine hydroxylase (TH) and GTP cyclohydrolase-1 (GCH1), needed for DOPA production. Here, we present a novel vector design that enables efficient DOPA production from a single AAV vector in rats with complete unilateral dopamine (DA) lesions. Functional efficacy was assessed with drug-induced and spontaneous motor behavioral tests where vector-treated animals showed near complete and stable recovery within 1 month. Recovery of motor... (More)
- Preclinical efficacy of continuous delivery of 3,4-dihydroxyphenylalanine (DOPA) with adeno-associated viral (AAV) vectors has recently been documented in animal models of Parkinson's disease (PD). So far, all studies have utilized a mix of two monocistronic vectors expressing either of the two genes, tyrosine hydroxylase (TH) and GTP cyclohydrolase-1 (GCH1), needed for DOPA production. Here, we present a novel vector design that enables efficient DOPA production from a single AAV vector in rats with complete unilateral dopamine (DA) lesions. Functional efficacy was assessed with drug-induced and spontaneous motor behavioral tests where vector-treated animals showed near complete and stable recovery within 1 month. Recovery of motor function was associated with restoration of extracellular DA levels as assessed by online microdialysis. Histological analysis showed robust transgene expression not only in the striatum but also in overlying cortical areas. In globus pallidus, we noted loss of NeuN staining, which might be due to different sensitivity in neuronal populations to transgene expression. Taken together, we present a single AAV vector design that result in efficient DOPA production and wide-spread transduction. This is a favorable starting point for continued translation toward a therapeutic application, although future studies need to carefully review target region, vector spread and dilution with this approach. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/2367497
- author
- Cederfjäll, Erik
LU
; Sahin, Gurdal
LU
; Kirik, Deniz
LU
and Björklund, Tomas
LU
- organization
- publishing date
- 2012
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Molecular Therapy
- volume
- 20
- issue
- 7
- pages
- 1315 - 1326
- publisher
- Nature Publishing Group
- external identifiers
-
- wos:000306034300006
- pmid:22294150
- scopus:84863494448
- pmid:22294150
- ISSN
- 1525-0024
- DOI
- 10.1038/mt.2012.1
- language
- English
- LU publication?
- yes
- id
- 89f3ff0c-0ca3-44a3-808e-ef1c93c03ae1 (old id 2367497)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/22294150?dopt=Abstract
- date added to LUP
- 2016-04-01 10:18:58
- date last changed
- 2022-02-10 00:53:22
@article{89f3ff0c-0ca3-44a3-808e-ef1c93c03ae1,
abstract = {{Preclinical efficacy of continuous delivery of 3,4-dihydroxyphenylalanine (DOPA) with adeno-associated viral (AAV) vectors has recently been documented in animal models of Parkinson's disease (PD). So far, all studies have utilized a mix of two monocistronic vectors expressing either of the two genes, tyrosine hydroxylase (TH) and GTP cyclohydrolase-1 (GCH1), needed for DOPA production. Here, we present a novel vector design that enables efficient DOPA production from a single AAV vector in rats with complete unilateral dopamine (DA) lesions. Functional efficacy was assessed with drug-induced and spontaneous motor behavioral tests where vector-treated animals showed near complete and stable recovery within 1 month. Recovery of motor function was associated with restoration of extracellular DA levels as assessed by online microdialysis. Histological analysis showed robust transgene expression not only in the striatum but also in overlying cortical areas. In globus pallidus, we noted loss of NeuN staining, which might be due to different sensitivity in neuronal populations to transgene expression. Taken together, we present a single AAV vector design that result in efficient DOPA production and wide-spread transduction. This is a favorable starting point for continued translation toward a therapeutic application, although future studies need to carefully review target region, vector spread and dilution with this approach.}},
author = {{Cederfjäll, Erik and Sahin, Gurdal and Kirik, Deniz and Björklund, Tomas}},
issn = {{1525-0024}},
language = {{eng}},
number = {{7}},
pages = {{1315--1326}},
publisher = {{Nature Publishing Group}},
series = {{Molecular Therapy}},
title = {{Design of a Single AAV Vector for Coexpression of TH and GCH1 to Establish Continuous DOPA Synthesis in a Rat Model of Parkinson's Disease.}},
url = {{https://lup.lub.lu.se/search/files/1738468/2596290.pdf}},
doi = {{10.1038/mt.2012.1}},
volume = {{20}},
year = {{2012}},
}