Gene Therapy for Parkinson Disease(<SPECIAL ISSUE>Parkinson Disease)

Adeno-associated viruses (AAV) are small, non-enveloped, single-stranded DNA viruses of the Parvoviridae family. More than one hundred genotypes of AAVs have been isolated from primates, in which they seem to be non-pathogenic. AAV-2 has been the most extensively studied, particularly as a vector for gene therapy. Pure and high titer recombinant AAV (rAAV) vectors can be generated using a helper plasmid containing the minimum adenovirus genome sequences necessary for helper functions. These rAAV vectors offer safe, efficient, and long-term expression of transgenes in mammalian brain neurons without triggering a substantial immune response. rAAV vectors have led to significant functional recovery in animal models, making their use in gene therapy for Parkinson disease (PD) promising. Three different rAAV vector-based protocols for treating for PD are currently in phase 1 clinical trials. One is the gene transfer of aromatic L-amino acid decarboxylase (AADC) in combination with oral administration of L-dopa. Although patients would still need to take L-dopa to control their PD symptoms with this approach, the dose could be lowered and the duration of the ON period prolonged. If two other enzymes, tyrosine hydroxylase and guanosine triphosphate cyclohydrolase I, could also be provided, L-dopa could be produced in the striatum, making the patient drug-free. The gene expression has to be regulated since excess synthesis of dopamine may cause adverse effects. The second clinical trial is transduction of the subthalamic nucleus with rAAV vectors expressing glutamic acid decarboxylase (GAD) to produce γ-aminobutyric acid (GABA), an inhibitory transmitter. The aim of the strategy is to modulate the activity of subthalamic neurons, an effect similar to deep brain stimulation. The third clinical trial is delivery of an rAAV vector expressing neurturin, a neurotrophic factor for dopaminergic neurons, into the putamen to block or slow down the ongoing degeneration. Neuro-imaging techniques and genetic analyses of familial patients could help identify individuals at risk for PD before they develop symptoms. They would be able to receive early the gene therapy given to symptomatic PD patients. Gene therapy using rAAV vectors seems to be a promising way of treating PD.