TITLE:
Tyrosine hydroxylase gene transfections to different sites of striatum in the rat model of Parkinson’s disease
AUTHORS:
Atso Raasmaja, Sarka Lehtonen, Tiina Kääriäinen, Pasi Lampela, Marko Huotari, Anne Lecklin
KEYWORDS:
Tyrosine Hydroxylase; Tetrahydrobiopterin; Adenovirus Vector; 6-Hydroxydopamine; Parkinson’s Disease; Gene Therapy
JOURNAL NAME:
Open Journal of Genetics,
Vol.3 No.2A,
June
26,
2013
ABSTRACT: The use of gene therapy
has been intensively studied as a potential method to treat Parkinson’s disease
(PD) and other degenerative brain diseases. However, the effects of
experimental measures and approaches on the outcome of gene delivery or on the
physiological state of target tissues have not been analyzed as much and
systematically. Therefore, we have infused adenovirus vectors expressing either
a therapeutic tyrosine hydroxylase (TH) gene or a lacZ reporter gene into
striatum in a rat model of PD. The experimental procedures were tested using
the Ad lacZ vector in order to optimize concentrations, volumes, infusion
speeds and transfection times. The expression of Ad lacZ vector was lower and declined
earlier in the lesioned than unlesioned striatum suggesting that the lesion affects
on the transfection efficiency and outcome of gene transfection. The effect of
three different approaches of Ad TH vector
transfection was compared: 1) the delivery of Ad TH gene vector alone
into one single site of striatum, 2) the delivery of Ad TH gene vector alone
into multiple sites of striatum, and 3) the delivery of Ad TH gene vector into
one site of striatum followed by a continuous infusion of tetrahydrobiopterin
(BH4) cofactor with a mini pump. There was a small and transient unsignificant
decrease in the turning behavior when the Ad TH vector was delivered into one
site of the striatum. Simultaneous infusion into several sites or together with
BH4 cofactor did not improve more the effect of gene delivery. Thus, although
the effects were unsignificant, the Ad TH transfection seemed to decrease the
turning behavior in the rat model of PD and the optimal effect was seen at some
specific doses and time points. Furthermore, the outcome of gene therapy could
depend in addition to the amount and efficacy of gene vectors also on the
physiological state and experimental strategies.