title: Continuous DOPA synthesis from a single AAV: dosing and efficacy in models of Parkinson's disease.
abstract: We used a single adeno-associated viral (AAV) vector co-expressing tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) to investigate the relationship between vector dose, and the magnitude and rate of recovery in hemi-parkinsonian rats. Intrastriatal injections of >1E10 genomic copies (gc) of TH-GCH1 vector resulted in complete recovery in drug-naïve behavior tests. Lower vector dose gave partial to no functional improvement. Stereological quantification revealed no striatal NeuN+ cell loss in any of the groups, whereas a TH-GCH1 dose of >1E11 gc resulted in cell loss in globus pallidus. Thus, a TH-GCH1 dose of 1E10 gc gave complete recovery without causing neuronal loss. Safety and efficacy was also studied in non-human primates where the control vector resulted in co-expression of the transgenes in caudate-putamen. In the TH-GCH1 group, GCH1 expression was robust but TH was not detectable. Moreover, TH-GCH1 treatment did not result in functional improvement in non-human primates.
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. erik.ahlm_cederfjall@med.lu.se
authors.forename: Erik
authors.initials: E
authors.lastname: Cederfjäll
authors.forename: Nathalie
authors.initials: N
authors.lastname: Nilsson
authors.forename: Gurdal
authors.initials: G
authors.lastname: Sahin
authors.forename: Yaping
authors.initials: Y
authors.lastname: Chu
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Nikitidou
authors.forename: Tomas
authors.initials: T
authors.lastname: Björklund
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Kordower
authors.forename: Deniz
authors.initials: D
authors.lastname: Kirik
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D005822:Genetic Vectors; D007980:Levodopa / Q000096:biosynthesis* / Q000627:therapeutic use; D010300:Parkinson Disease / Q000188:drug therapy*; D051381:Rats; D014161:Transduction, Genetic; D019076:Transgenes
chemical_list: D007980:Levodopa