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ATLANTA -- Early results of an open-label gene therapy trial in advancing Parkinson's disease (PD) patients showed the treatment was well tolerated and produced improvements in motor scores and "on" and "off" time, researchers reported at the annual .

, a gene therapy encoding aromatic L-amino acid decarboxylase (AADC) delivered surgically through an adeno-associated viral vector (AAV) into the putamen using real-time MRI, appeared safe and led to increases from baseline in AADC activity at 6 months on (18)^F-DOPA positron emission tomography (PET), said Chadwick Christine, MD, PhD, of the University of California, San Francisco, in a presentation here.

This increase in AADC activity "was strongly correlated with coverage of the putamen by VY-AADC01 during administration and was reflected by a decrease in the need for antiparkinsonian medications," Christine told 名媛直播. "A number of outcomes using clinical rating scales suggest that VY-AADC may offer clinical benefit to patients with advancing PD."

AADC is the primary enzyme that converts levodopa to dopamine. The goal of the therapy was to increase "on" time and decrease "off" time in levodopa-treated PD patients with motor fluctuations, noted Andrew Feigin, MD, of NYU Langone Health in New York City, who was involved in the F-DOPA PET data analysis of this study. "The data from this early phase trial suggest further study of this therapy in a randomized double-blind clinical trial is warranted," he told 名媛直播.

This phase Ib trial studied 15 patients with medically refractory Parkinson's disease, divided into three cohorts of five patients each:

• Cohort 1 received up to 450 μl/putamen of VY-AADC01 at a concentration of 8.3×10¹¹ viral genomes per millimeter (vg/mL) and was followed for 36 months
• Cohort 2 received up to 900 μl/putamen at 8.3×10¹¹ vg/ml and was followed for 18 months
• Cohort 3 received up to 900 μl/putamen at 2.6×10¹² vg/ml and was followed for 12 months

These volumes were considerably higher than ones used in the past. "Prior trials showed that AAV2-AADC was safe, but there was limited clinical efficacy," Christine said. "This may have been due to the limited volume of putamen treated with the gene therapy."

In cohort 3, VY-AADC01 infusions led to an AADC activity increase up to a mean of 79%, which was highly correlated with VY-AADC coverage of the putamen and improvements in daily dopaminergic treatment as measured by levodopa equivalent doses.

Cohort 1 patients showed a mean 2.3 hour improvement in diary "on" time without troublesome dyskinesia at 24 months, which was maintained through 36 months. Cohort 2 patients showed a 3.5 hour improvement at 18 months. Cohort 3 showed less improvement but had more severe baseline dyskinesia, Christine noted.

Mean change in Unified Parkinson's Disease Rating Scale III (UPDRS-III) "on" scores were -9.6 points in cohort 2 and -6.8 points in cohort 3 at 12 months. UPDRS-III "off" scores had an average change of -3.4 and -4.4 points for cohort 2 and cohort 3, respectively.

One patient experienced two serious adverse events related to surgery, pulmonary embolism, and related heart arrhythmia, but both resolved completely.

"These results are promising, but of course a number of issues remain that need to be addressed in a larger, controlled trial," Alexander Pantelyat, MD, of Johns Hopkins University School of Medicine in Baltimore, who was not involved in the research, told 名媛直播.

"Despite an attempt at uniform targeting of the putamen, multiple passes were used and the posterior putamen was 'usually targeted' according to the researchers, raising questions about uniform administration across participants," Pantelyat said.

Given the trajectories of cannulae used to deliver the gene therapy, it will be important to determine whether there is cognitive impairment associated with this therapy, he noted.

"This approach in general is unlikely to improve non-motor manifestations of advancing Parkinson's disease such as cognitive impairment and autonomic dysfunction because they involve anatomical structures outside of the striatum," Pantelyat added. "These non-motor manifestations are much more impactful on quality of life for many patients with advancing PD, thus limiting generalizability."