Gene Therapy for Parkinson’s Disease - Viral Vector Approaches in Neurobiology and Brain Diseases - page 173

Chapter 10

Gene Therapy for Parkinson's Disease

Erika Elgstrand Wettergren , Luis Quintino , Giuseppe Manfré ,
and Cecilia Lundberg

Abstract

Gene therapy is a promising future tool for treatment of Parkinson's disease (PD) and several different
strategies are currently being evaluated. Although many of these strategies have shown promising results
in animal models of PD and parkinsonian patients, some have been less effective and caused adverse side
effects. A vector system with high specifi city and appropriate expression level of the transgene is needed to
make gene therapy for PD as safe and benefi cial as possible. The vector should also be relevant for the
disease. Here, we present a method to design promoters relevant for PD, using microarray data from
patients, and validation of these in vivo. The method also includes fi ne-tuning of promoter candidates by
adding miRNA target sites to increase cell specifi city.

Key words Parkinson's disease, Gene therapy, Promoter, miRNA target, Cell specifi c

1 Introduction

Over the past decade, gene therapy has emerged as a promising
tool for future treatment of Parkinson's disease (PD). Current
treatment paradigms that are being evaluated include gene therapy
aimed at increasing striatal dopamine or DOPA levels, normalizing
the abnormal signaling in the basal ganglia or supporting remain-
ing dopaminergic neurons using neurotrophic factors. These dif-
ferent paradigms are described below.
Pharmacotherapy using orally administered levodopa ( L -DOPA)
is currently the most common treatment for PD. Although the
effi ciency of this treatment method is initially high, it decreases over
time as the disease progresses and side effects of the treatment
appear. This has led to the development of gene therapy paradigms
aimed to increase striatal dopamine or L -DOPA. There are currently
three different approaches being evaluated: (1) The continued
L -DOPA delivery approach aims to increase striatal L -DOPA levels
by introducing the genes of L -DOPA synthesizing enzymes
tyrosine hydroxylase (TH) and cofactor producing enzyme GTP