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Key factors determining the efficacy of gene therapy for continuous DOPA delivery in the Parkinsonian brain

Cederfjäll, Erik LU ; Sahin, Gurdal LU and Kirik, Deniz LU (2012) In Neurobiology of Disease 48(2). p.222-227
Abstract
L-DOPA is currently the standard treatment for alleviating the motor symptoms in Parkinson's disease. The therapeutic efficacy, however, diminishes as the disease progresses. It has been suggested that the beneficial effect of L-DOPA could be reestablished by changing the mode of administration. Indeed, continuous delivery of L-DOPA has been shown to be an effective way to circumvent many of the side effects seen with traditional oral administration, which results in an intermittent supply of the dopamine precursor to the brain. However, all currently tested continuous dopaminergic stimulation approaches rely on peripheral administration. This is not ideal since it gives rise to off target effects and is difficult to maintain long-term.... (More)
L-DOPA is currently the standard treatment for alleviating the motor symptoms in Parkinson's disease. The therapeutic efficacy, however, diminishes as the disease progresses. It has been suggested that the beneficial effect of L-DOPA could be reestablished by changing the mode of administration. Indeed, continuous delivery of L-DOPA has been shown to be an effective way to circumvent many of the side effects seen with traditional oral administration, which results in an intermittent supply of the dopamine precursor to the brain. However, all currently tested continuous dopaminergic stimulation approaches rely on peripheral administration. This is not ideal since it gives rise to off target effects and is difficult to maintain long-term. Thus, there is an unmet need for an effective continuous administration method with an acceptable side effect profile. Viral-mediated gene therapy is a promising alternative paradigm that can meet this demand. Encouraging preclinical studies in animal models of Parkinson's disease showed therapeutic efficacy after expression of the genes encoding the enzymes required for biosynthesis of dopamine. Although the first phase I clinical trials using these approaches have been conducted, clear positive data in placebo controlled efficacy studies is still lacking. We are now at a critical junction and need to carefully review the preclinical data from the clinical translation perspective and identify the key factors that will determine the potential for success in gene therapy for Parkinson's disease. (C) 2011 Published by Elsevier Inc. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Adeno-associated viral vector, Aromatic L-amino acid decarboxylase, L-DOPA, Parkinson's disease, Tyrosine hydroxylase
in
Neurobiology of Disease
volume
48
issue
2
pages
222 - 227
publisher
Elsevier
external identifiers
  • wos:000307911400007
  • scopus:84865551695
ISSN
0969-9961
DOI
10.1016/j.nbd.2011.10.017
language
English
LU publication?
yes
id
a100ade7-6412-412d-9984-4a4cf114592f (old id 3146761)
date added to LUP
2012-11-01 10:25:47
date last changed
2017-11-19 03:00:25
@article{a100ade7-6412-412d-9984-4a4cf114592f,
  abstract     = {L-DOPA is currently the standard treatment for alleviating the motor symptoms in Parkinson's disease. The therapeutic efficacy, however, diminishes as the disease progresses. It has been suggested that the beneficial effect of L-DOPA could be reestablished by changing the mode of administration. Indeed, continuous delivery of L-DOPA has been shown to be an effective way to circumvent many of the side effects seen with traditional oral administration, which results in an intermittent supply of the dopamine precursor to the brain. However, all currently tested continuous dopaminergic stimulation approaches rely on peripheral administration. This is not ideal since it gives rise to off target effects and is difficult to maintain long-term. Thus, there is an unmet need for an effective continuous administration method with an acceptable side effect profile. Viral-mediated gene therapy is a promising alternative paradigm that can meet this demand. Encouraging preclinical studies in animal models of Parkinson's disease showed therapeutic efficacy after expression of the genes encoding the enzymes required for biosynthesis of dopamine. Although the first phase I clinical trials using these approaches have been conducted, clear positive data in placebo controlled efficacy studies is still lacking. We are now at a critical junction and need to carefully review the preclinical data from the clinical translation perspective and identify the key factors that will determine the potential for success in gene therapy for Parkinson's disease. (C) 2011 Published by Elsevier Inc.},
  author       = {Cederfjäll, Erik and Sahin, Gurdal and Kirik, Deniz},
  issn         = {0969-9961},
  keyword      = {Adeno-associated viral vector,Aromatic L-amino acid decarboxylase,L-DOPA,Parkinson's disease,Tyrosine hydroxylase},
  language     = {eng},
  number       = {2},
  pages        = {222--227},
  publisher    = {Elsevier},
  series       = {Neurobiology of Disease},
  title        = {Key factors determining the efficacy of gene therapy for continuous DOPA delivery in the Parkinsonian brain},
  url          = {http://dx.doi.org/10.1016/j.nbd.2011.10.017},
  volume       = {48},
  year         = {2012},
}