title: Controlled Striatal DOPA Production From a Gene Delivery System in a Rodent Model of Parkinson's Disease.
abstract: Conventional symptomatic treatment for Parkinson's disease (PD) with long-term L-3,4-dihydroxyphenylalanine (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 preclinical development toward use in patients with PD.
authors.affiliation: Brain Repair and Imaging in Neural Systems (B.R.A.I.N.S) Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Cederfjäll
authors.affiliation: Brain Repair and Imaging in Neural Systems (B.R.A.I.N.S) Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: Lauren
authors.initials: L
authors.lastname: Broom
authors.affiliation: Brain Repair and Imaging in Neural Systems (B.R.A.I.N.S) Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden. Electronic address: deniz.kirik@med.lu.se.
authors.forename: Deniz
authors.initials: D
authors.lastname: Kirik
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D015415:Biomarkers; D002460:Cell Line; D003342:Corpus Striatum / Q000378:metabolism*; D000229:Dependovirus / Q000145:classification / Q000235:genetics; D004295:Dihydroxyphenylalanine / Q000096:biosynthesis*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005260:Female; D006136:GTP Cyclohydrolase / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D010641:Phenotype; D051381:Rats; D065288:Serogroup; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D014161:Transduction, Genetic; D019076:Transgenes; D014295:Trimethoprim / Q000008:administration & dosage / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D004295:Dihydroxyphenylalanine; D014295:Trimethoprim; D014446:Tyrosine 3-Monooxygenase; D013762:Tetrahydrofolate Dehydrogenase; D006136:GTP Cyclohydrolase; D004298:Dopamine