Optimized adeno-associated viral vector-mediated striatal DOPA delivery restores sensorimotor function and prevents dyskinesias in a model of advanced Parkinson's disease.

Brain : a Journal of Neurology
Tomas BjörklundDeniz Kirik

Abstract

Viral vector-mediated gene transfer utilizing adeno-associated viral vectors has recently entered clinical testing as a novel tool for delivery of therapeutic agents to the brain. Clinical trials in Parkinson's disease using adeno-associated viral vector-based gene therapy have shown the safety of the approach. Further efforts in this area will show if gene-based approaches can rival the therapeutic efficacy achieved with the best pharmacological therapy or other, already established, surgical interventions. One of the strategies under development for clinical application is continuous 3,4-dihydroxyphenylalanine delivery. This approach has been shown to be efficient in restoring motor function and reducing established dyskinesias in rats with a partial lesion of the nigrostriatal dopamine projection. Here we utilized high purity recombinant adeno-associated viral vectors serotype 5 coding for tyrosine hydroxylase and its co-factor synthesizing enzyme guanosine-5'-triphosphate cyclohydrolase-1, delivered at an optimal ratio of 5 : 1, to show that the enhanced 3,4-dihydroxyphenylalanine production obtained with this optimized delivery system results in robust recovery of function in spontaneous motor tests after complete dopamine...Continue Reading

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Citations

Apr 12, 2011·Current Neurology and Neuroscience Reports·Jennifer Witt, William J Marks
Feb 2, 2012·Molecular Therapy : the Journal of the American Society of Gene Therapy·Erik CederfjällTomas Björklund
Oct 1, 2011·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Yoland SmithMahlon R DeLong
Dec 14, 2011·The Neurologist·Maria Cruz Rodriguez-OrozOriol de Fabregues
Apr 5, 2012·Cold Spring Harbor Perspectives in Medicine·Philippe G CounePatrick Aebischer
Jun 16, 2012·Parkinson's Disease·Nicola TambascoPaolo Calabresi
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Sep 1, 2011·Progress in Neurobiology·Philippe HuotJonathan M Brotchie
Jun 12, 2012·Parkinson's Disease·Iciar Aviles-OlmosThomas Foltynie
Jan 17, 2015·Molecular Therapy : the Journal of the American Society of Gene Therapy·Erik CederfjällDeniz Kirik
Feb 22, 2014·The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry·David S OjalaDavid V Schaffer
Dec 26, 2018·Journal of Parkinson's Disease·Tomas Björklund
Jun 7, 2013·Expert Review of Neurotherapeutics·Michael R Douglas
Mar 3, 2021·Nature Reviews. Drug Discovery·Georg C TerstappenWandong Zhang
Aug 15, 2021·Drug Metabolism and Personalized Therapy·Taiwo G Olubodun-ObadunOlufunmilayo O Adeyemi

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