Pharmacologically controlled neurotrophic factor gene therapy for Parkinson's disease

by Shi Cheng
Doctoral thesis
Date of Examination:2019-06-25
Date of issue:2019-07-24
Advisor:Dr. Sebastian Kügler
Referee:Dr. Sebastian Kügler
Referee:Prof. Dr. Markus Zweckstetter
Persistent Address: http://dx.doi.org/10.53846/goediss-7576

 

 

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Abstract

English

During the PhD thesis, two projects were carried out. In the first project, an inducible AAV-5 vector for expression of GDNF, under control of the approved small molecule drug mifepristone, was evaluated in rats. GDNF expression could be induced over a wide range up to four hundred-fold over endogenous background, and completely returns to baseline within 3 – 4 weeks, without showing any non-induced background expression. Treatment efficacy was evaluated in the 6-OHDA model of PD, where repeated short-term expression of GDNF restored motor capabilities. Pharmacokinetics of Mfp showed unexpected gender-related differences, which were overcome by CYP3A inhibition. In the second project, a “humanized” alpha-1 acid glycoprotein (hAAG) rat model was generated by AAV-1/2-LP1-hAAG intravenous injection. The gene therapy method was tested in the hAAG rat model, and a similar level of expression of GDNF was observed in the model rats and native rats.
Keywords: Parkinson's disease; gene therapy
 
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