Gene Therapy Used to Produce and Sustain Dopamine in Brains of Primate Model of Parkinson’s

Gene Therapy Used to Produce and Sustain Dopamine in Brains of Primate Model of Parkinson’s

Direct delivery of two dopamine-synthesizing enzymes to the midbrain, using a safe and inactive form of an adenovirus, was able to effectively ease signs of motor difficulties in a primate model of Parkinson’s disease, a study reports.

Continuous dopamine production via a gene therapy approach may be a promising one-time treatment strategy for Parkinson’s patients, providing long-lasting improvement and lowering the chances of motor fluctuations and other side effects associated with oral dopaminergic medication, its researchers suggest.

The study, “Vector-mediated L-3,4-dihydroxyphenylalanine delivery reverses motor impairments in a primate model of Parkinson’s disease,” was published in the journal Brain.

Treatment with levodopa — a precursor molecule of dopamine — remains the leading standard treatment of Parkinson’s, easing effects caused by damaged or dead dopamine-producing brain cells, the main cause of this disease.

Such treatment effectively helps to manage Parkinson’s motor symptoms, but dopamine agonists often becomes less effective over time. This is believed to be due, at least in part, to lesser production of the enzymes involved in dopamine production.

Recently researchers have focused on developing types of gene therapy that might overcome the long-term ineffectiveness of available treatments.

An international team of researchers designed a gene therapy approach to re-establish the amount of available enzymes known as TH and GCH1 — both necessary for dopamine production — in the midbrain.

Using an engineered adeno-associated viral (AAV) vector to simultaneously deliver the DNA coding sequences of the two enzymes, researchers injected different doses of the gene therapy directly into the putamen — one of the brain areas mostly affected by the disease — of 29 rhesus monkeys. Four animals were left untreated as a control group.

The putamen is also the brain region where most dopamine-producing cells are located.

One group of animals, initially given the lowest dose, was given a second and higher dose six months after a first injection to simulate “a clinical scenario where patients entering early in the safety trial could be offered a therapeutic dose at the end of the trial.” All animals were analyzed 10 months after the initial dosing.

“The re-dosed animals showed a significant recovery over the following 2 months, reaching the same level of recovery as the initial high-dose treatment group,” the study notes.

Importantly, the primates had been treated with increasing L-DOPA doses before the injection of the gene therapy, “given twice daily for 2 weeks to induce L-DOPA-induced dyskinesia,” the scientists wrote.

Findings showed that the therapy induced a significant and dose-dependent improvement in motor control up to a level similar to that obtained with the optimal dose of injectable levodopa.

Reported improvements in motor function also came without any signs of dyskinesia — the uncontrolled, involuntary movements that are often associated with long-term levodopa use.

Analysis of brain tissue samples collected from the monkeys showed that this AAV-mediated gene therapy could induce an increase of 760- to 5600-fold of TH and 1.2- to 1.5-fold of GCH1 enzymes compared to untreated animals.

“These results provide proof-of-principle for continuous vector-mediated L-DOPA [dopamine] synthesis as a novel therapeutic strategy for Parkinson’s disease,” the researchers wrote.

“This gene therapy approach may thus offer the possibility to prolong and sustain the ‘good years’ many patients with Parkinson’s disease experience during the initial stages of L-DOPA therapy,” they added.

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