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Controlled striatal DOPA production from a gene delivery system in a rodent model of Parkinson's disease.

Cederfjäll, Erik LU ; Broom, Lauren LU and Kirik, Deniz LU (2015) In Molecular Therapy 23(5). p.896-906
Abstract
Conventional symptomatic treatment for Parkinson's disease (PD) with long term L-DOPA is complicated with development of drug-induced side effects. In vivo viral vector-mediated gene expression encoding tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) provides a drug delivery strategy of DOPA with distinct advantages over pharmacotherapy. Since the brain alterations made with current gene transfer techniques are irreversible, the therapeutic approaches taken to the clinic should preferably be controllable to match the needs of each individual during the course of their disease. We used a recently described tunable gene expression system based on the use of destabilized dihydrofolate reductase (DD) and generated a N-terminally... (More)
Conventional symptomatic treatment for Parkinson's disease (PD) with long term L-DOPA is complicated with development of drug-induced side effects. In vivo viral vector-mediated gene expression encoding tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) provides a drug delivery strategy of DOPA with distinct advantages over pharmacotherapy. Since the brain alterations made with current gene transfer techniques are irreversible, the therapeutic approaches taken to the clinic should preferably be controllable to match the needs of each individual during the course of their disease. We used a recently described tunable gene expression system based on the use of destabilized dihydrofolate reductase (DD) and generated a N-terminally coupled GCH1 enzyme (DD-GCH1) while the TH enzyme was constitutively expressed, packaged in adeno-associated viral (AAV) vectors. Expression of DD-GCH1 was regulated by the activating ligand trimethoprim (TMP) that crosses the blood-brain barrier. We show that the resulting intervention provides a TMP-dose dependent regulation of DOPA synthesis that is closely linked to the magnitude of functional effects. Our data constitutes the first proof of principle for controlled reconstitution of dopamine capacity in the brain and suggests that such next generation gene therapy strategies are now mature for pre-clinical development towards use in patients with PD.Molecular Therapy (2015); doi:10.1038/mt.2015.8. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Therapy
volume
23
issue
5
pages
896 - 906
publisher
Nature Publishing Group
external identifiers
  • pmid:25592335
  • wos:000353933200013
  • scopus:84929049610
ISSN
1525-0024
DOI
10.1038/mt.2015.8
language
English
LU publication?
yes
id
7cebde5e-89e8-40ab-9e92-521cf612050f (old id 5040359)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25592335?dopt=Abstract
date added to LUP
2015-02-03 17:33:37
date last changed
2017-09-10 03:19:19
@article{7cebde5e-89e8-40ab-9e92-521cf612050f,
  abstract     = {Conventional symptomatic treatment for Parkinson's disease (PD) with long term L-DOPA is complicated with development of drug-induced side effects. In vivo viral vector-mediated gene expression encoding tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) provides a drug delivery strategy of DOPA with distinct advantages over pharmacotherapy. Since the brain alterations made with current gene transfer techniques are irreversible, the therapeutic approaches taken to the clinic should preferably be controllable to match the needs of each individual during the course of their disease. We used a recently described tunable gene expression system based on the use of destabilized dihydrofolate reductase (DD) and generated a N-terminally coupled GCH1 enzyme (DD-GCH1) while the TH enzyme was constitutively expressed, packaged in adeno-associated viral (AAV) vectors. Expression of DD-GCH1 was regulated by the activating ligand trimethoprim (TMP) that crosses the blood-brain barrier. We show that the resulting intervention provides a TMP-dose dependent regulation of DOPA synthesis that is closely linked to the magnitude of functional effects. Our data constitutes the first proof of principle for controlled reconstitution of dopamine capacity in the brain and suggests that such next generation gene therapy strategies are now mature for pre-clinical development towards use in patients with PD.Molecular Therapy (2015); doi:10.1038/mt.2015.8.},
  author       = {Cederfjäll, Erik and Broom, Lauren and Kirik, Deniz},
  issn         = {1525-0024},
  language     = {eng},
  number       = {5},
  pages        = {896--906},
  publisher    = {Nature Publishing Group},
  series       = {Molecular Therapy},
  title        = {Controlled striatal DOPA production from a gene delivery system in a rodent model of Parkinson's disease.},
  url          = {http://dx.doi.org/10.1038/mt.2015.8},
  volume       = {23},
  year         = {2015},
}