Gene Therapy Shows Early Signs of Parkinson's Improvement

Nancy A. Melville

October 23, 2018

ATLANTA — An investigative adenovirus-delivered gene therapy yielded encouraging improvement in symptoms of Parkinson's disease for patients whose condition was refractory to standard treatment. The therapy was well tolerated, and the effects were maintained through 36 months, preliminary results indicate.

"So far, we are seeing safety with this treatment and signals of a possible clinical benefit," said first author Chadwick W. Christine, MD, PhD, University of California, San Francisco, in presenting the findings here at ANA 2018: 143rd Annual Meeting of the American Neurological Association.

The therapy, called VY-AADC01 (Voyager Therapeutics), is injected directly into the putamen. It transfers DNA that encodes the enzyme aromatic L-amino acid decarboxylase (AADC), which is considered to be key in the conversion of levodopa into dopamine. Levels of this enzyme diminish over time in patients with Parkinson's disease.

"We believe that one reason levodopa treatment becomes less effective is that as Parkinson's disease progresses, there is a loss of AADC, the enzyme required to convert levodopa to dopamine," Christine told Medscape Medical News.

"VY-AADC01 encodes the gene for AADC," he said.

The most recent phase 1b study of the therapy involved 15 patients with Parkinson's disease who continued to experience motor fluctuations despite optimal treatment. The participants were divided into three groups, with five patients in each group.

  • Group 1 received up to 450 μl/putamen of VY-AADC01 at a concentration of 8.3×1011 viral genomes per millimeter (vg/mL). The follow-up period was 36 months.

  • Group 2 received up to 900 μl/putamen at 8.3×1011 vg/ml, with an 18-month follow-up.

  • Group 3 received up to 900 μl/putamen at 2.6×1012 vg/ml, with a 12-month follow-up.

To ensure coverage of the putamen, the bilateral infusions were mixed with the MRI contrast agent gadoteridol (Prohance, Bracco Diagnostics).

The results showed an increase in AADC activity of a mean of 79% (in group 3). This increase was strongly correlated with coverage of VY-AADC of the putamen.

Clinical improvements, assessed on the basis of changes in daily dopaminergic treatment of levodopa equivalent doses (LED), showed mean reductions in LED at 12 months of 10.2% in group 1; 32.8% in group 2; and 39.3% in group 3. The reductions were sustained at 18 months in groups 1 and 2.

"Many patients were able to reduce the amount of levodopa they were taking in either the dose or frequency of dose," Christine said.

Symptom assessments also showed a mean improvement of 2.3 hours in patient-completed Parkinson's diary "on" time, representing time with good mobility without dyskinesia, at 24 months in group 1. The improvement was maintained through 36 months. In group 2, clinically meaningful 3.5-hour improvement in Parkinson's diary "on" time was maintained at 18 months.

The corresponding improvement in group 3 was not as significant (1.5 hours at 12 months); however, the authors noted that those patients also had more severe dyskinesia at baseline.

Further improvements were seen in the mean change in scores on the Unified Parkinson's Disease Rating Scale III (UPDRS-III) ON, which reflects motor skills as assessed by physician examination. Scores exceeded the definitions for "clinically important differences" in group 2 (-9.6 points) and group 3 (-6.8 points) at 12 months, with changes in UPDRS-II OFF (measuring activities of daily living) of -3.4 in group 2 and -4.4 in group 3.

The infusions were well tolerated, with no reported vector-related serious adverse events.

Four patients experienced increased dyskinesia, although the effect was transient and was expected.

One patient experienced two serious adverse events that were related to surgery (pulmonary embolism and related heart arrhythmia). Both events resolved fully.

Christine noted that the pulmonary embolism may have been related to the long surgical infusion time.

In earlier studies with smaller infusions of VY-AADC and in clinical trials with other viral vectors, VY-AADC showed little benefit. The new findings underscore the fact that successful treatment appears to be volume-dependent, Christine said.

"Prior studies using AADC in Parkinson's disease suggested the coverage in the putamen was inadequate, so the volumes we used were increased dramatically compared to the previous studies around 2005 and 2010," he said.

Intraoperative MRI guidance and coinfusion with gadolinium to observe precise delivery of the gene therapy are also considered key to the process. In previous attempts with gene therapies, poor gene delivery was a limiting factor.

With the MRI-guided infusion with gadolinium, 18F-FDOPA positron-emission tomography can detect AADC activity and provide evidence of whether or not the gene transfer was successful.

"Dose-dependent increase in gadoteridol uptake is a functional measure of AADC activity, so it's a great measure of successful gene expression," Christine said.

Adenovirus vectors, which act as delivery vehicles for gene therapy without posing the risk from the virus, show greater stability and predictability than other viral vectors that have been studied, such as retroviruses.

Conrad C. Weihl, MD, PhD, a professor of neurology at Washington University in St. Louis, Missouri, said the research offers insights into a potentially important new direction for gene therapy and Parkinson's treatment.

"Gene therapy approaches are very novel and innovative in general, and targeting delivery to specific regions of the brain, such as the putamen, definitely adds another layer of innovation," he told Medscape Medical News.

Many questions remain, he noted.

"As far as the durability — I think that is something that is still unknown," Weihl said.

"The hope is that they these will be durable and last for a long period of time — perhaps indefinitely. When we use a specific type of virus, the premise is that it does get incorporated in the cell and it does persist in the cell, so the only thing that's stopping the cell from expressing it is if the cell were to die," he explained.

Weihl noted that safety issues will continue to be important as the research advances.

"Concerns about using a foreign virus include prompting some kind of an immune reaction, and I think those are things that need to be done cautiously. So going slow is appropriate because we don't want to do any harm," he said.

The study was funded by Voyager Therapeutics. Dr Christine and Dr Weihl have disclosed no relevant financial relationships.

ANA 2018: 143rd Annual Meeting of the American Neurological Association. Abstract 80, presented October 20, 2018.

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