Dopamine Gene Therapy for Parkinson’s Disease in a Nonhuman Primate Without Associated Dyskinesia

A gene therapy approach for the treatment of Parkinson’s disease. Several high-profile patients—fighter Muhammad Ali, Attorney General Janet Reno, Pope John Paul II, and Michael J. Fox—have thrust Parkinson’s disease (PD) into the popular press in the last decade. But it was nearly 50 years ago that l-dopa was introduced as a therapy for patients with PD, and this drug, with its troublesome side effects, remains the frontline treatment for this debilitating disease that has no cure. Now, an international team of researchers describe a potential treatment for PD that uses a multigene therapy approach designed to restore continuous synthesis of the neurotransmitter dopamine in the PD brain. PD arises from the destruction of a region of the midbrain called the substantia nigra, which is part of the basal ganglia—structures in the brain that control movement and motivation. Neurons in the substantia nigra produce the neurotransmitter dopamine, a key regulator of voluntary movement, cognition, and behavior. Currently, the basis of PD therapy is to replenish the brain’s dopamine stores, which is achieved through periodic oral administration of the drug l-dopa, a blood-brain barrier–crossing dopamine precursor. Although l-dopa treatment has restored motor function in millions of PD patients, this drug does not block the progressive neurodegeneration associated with the disease and, over time, can spur troublesome side effects, such as freezing and involuntary movement. These movement-related repercussions are caused by intermittent oral delivery of l-dopa, which gives rise to peaks and valleys in brain dopamine concentrations. Thus, scientists have sought treatment approaches that deliver dopamine in a continuous manner. To this end, Jarraya et al. have designed a gene therapy protocol in which the genes that encode the key dopamine biosynthetic enzymes are introduced directly into the brain to produce a perpetual, artificial dopamine factory in neurons of the striatum, the basal ganglia nucleus that receives most of the substantia nigra–released dopamine. In normal brains, the tyrosine hydroxylase enzyme converts the amino acid tyrosine to l-dopa, which is then turned into dopamine by aromatic l-amino acid decarboxylase. Another enzyme, guanosine 5′-triphosphate cyclohydrolase 1, produces a molecule that is reduced in PD brains and is needed for efficient dopamine synthesis. Because of vector-related size constraints, genes encoding these enzymes have previously been introduced into animal models of PD in three separate viral vectors and have delivered some benefits. However, for use in the clinic, it would be preferable to use one vector that encodes all three genes. Jarraya et al. used a lentiviral vector system to create such a vector and tested it in rhesus macaque monkeys artificially induced to have PD. The results of the experiments performed by Jarraya et al. reveal that one can achieve sustained, functional concentrations of dopamine in the brains of the parkinsonian monkeys and effect an improvement in mobility and a reduction in disability within the first 6 weeks after injection of the gene-carrying vector. Most encouraging is the fact that these effects were maintained, without the troublesome involuntary movements observed in l-dopa–treated patients, for more than a year in treated animals. Although these results are promising, a number of caveats remain, including the fact that the dopamine factory introduced by gene transfer resides in striatal neurons that do not normally produce dopamine. The ongoing phase 1 and 2 clinical trial conducted by the same group represents the ultimate test of the proof-of-concept findings described in this translational study. In Parkinson’s disease, degeneration of specific neurons in the midbrain can cause severe motor deficits, including tremors and the inability to initiate movement. The standard treatment is administration of pharmacological agents that transiently increase concentrations of brain dopamine and thereby discontinuously modulate neuronal activity in the striatum, the primary target of dopaminergic neurons. The resulting intermittent dopamine alleviates parkinsonian symptoms but is also thought to cause abnormal involuntary movements, called dyskinesias. To investigate gene therapy for Parkinson’s disease, we simulated the disease in macaque monkeys by treating them with the complex I mitochondrial inhibitor 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which induces selective degeneration of dopamine-producing neurons. In this model, we demonstrated that injection of a tricistronic lentiviral vector encoding the critical genes for dopamine synthesis (tyrosine hydroxylase, aromatic l-amino acid decarboxylase, and guanosine 5′-triphosphate cyclohydrolase 1) into the striatum safely restored extracellular concentrations of dopamine and corrected the motor deficits for 12 months without associated dyskinesias. Gene therapy–mediated dopamine replacement may be able to correct Parkinsonism in patients without the complications of dyskinesias.