Advances in Gene Therapy for Movement Disorders

Abstract

Summary:After nearly 20 years of preclinical experimentation with various gene delivery approaches in animal models of Parkinson's disease (PD), clinical trials are finally underway. The risk/benefit ratio for these procedures is now generally considered acceptable under approved protocols. The current vehicle for gene delivery to the human brain is recombinant adeno-associated viral vector, which is nonpathogenic and non-self-amplifying. Candidate genes tested in PD patients encode 1) glutamic acid decarboxylase, which is injected into the subthalamic nucleus to catalyze biosynthesis of the inhibitory neurotransmitter ␥-aminobutyric acid and so essentially mimic deep brain stimulation of this nucleus; 2) aromatic Lamino acid decarboxylase, which converts L-dopa to dopamine; and 3) neurturin, a member of the glial cell line-derived neurotrophic factor family. Unraveling the genetic underpinnings of PD could allow gene therapy to go beyond modulating neurotransmission or providing trophic effects to dopaminergic neurons by delivering a specific missing or defective gene. For example, the parkin gene (PARK2) is linked to recessively inherited PD due to loss of function mutations; it prevents ␣-synuclein-induced degeneration of nigral dopaminergic neurons in rats and nonhuman primates. On the other hand, for dominantly inherited Huntington's disease (HD), in which an expanded polyglutamine tract imparts to the protein huntingtin a toxic gain of function, repressing expression of the mutant allele in the striatum using RNA interference technology mitigates pathology and delays the phenotype in a mouse model. Here we review the current state of preclinical and clinical gene therapy studies conducted in PD and HD.

Gene therapy using lactoferrin-modified nanoparticles in a rotenone-induced chronic Parkinson model

“…Till now, gene therapy of PD using therapeutic genes encoding glial cell line-derived neurotrophic factor (GDNF) family has been extensively studied in animals, even advanced to clinical testing [14,15]. GDNF is generally believed to possess most potent trophic effects on dopaminergic neurons [16].…”

Microspheres for Targeting Delivery of Anticancer Drugs

“…Therefore, gene therapy of PD using therapeutic genes encoding GDNF family has been extensively studied in animals, even advanced to clinical testing (Hong et al, 2008;Mochizuki et al, 2008). Zhang and Pardridge (2009) reported that rats with experimental PD are treated with intravenous GDNF plasmid DNA (designated pTHproGDNF) and nonviral gene therapy using Trojan horse liposomes targeted with a MAb to the rat TfR.…”

Gene Therapy in Parkinsonʼs Disease

“…(106, 108–113) One approach focuses on increasing dopamine production via direct delivery of genes involved in neurotransmitter synthesis while a second method is designed to change the neuronal phenotype bypassing the need for dopamine, both approaches should the ameliorate symptoms associated with PD. These therapies are also intended to delay development of end-stage disease, an important accomplishment in a progressive age-related disorder such as PD.…”