One-Time Gene Therapy Delivered Neurosurgically Delivered to Striatum Provided Sustained Motor Function Improvements in Parkinson Disease 

  • Gene therapy
  • Movement disorders
  • Parkinson disease

In an open-label phase 1b trial (NCT01973543), participants were treated with an adeno-associated viral vector containing DNA encoding for aromatic L-amino acid decarboxylase (VY-AADC now named NBIb-1817). The gene therapy was neurosurgically delivered directly to the striatum of 15 participants with advanced Parkinson disease (PD). As assessed by the modified Hoehn & Yahr scale, 14 of 15 participants treated with VY-AADC continued to show an improvement in disease staging after 3 years.

In the 3 years since receiving the 1-time treatment, participants had reduced mean on-time (as per self-reported diary) by a mean -0.15 to -1.91 hours from a baseline of 4.28 to 4.93 hours. On time without troublesome dyskinesia increased by a mean 0.26 to 2.23 hours from a baseline of 10.32 to 10.46 hours. Participants in this study also had motor function improvements of 0.2 to 19.0 points improvement on the clinician-administered Unified Parkinson Disease Rating Scale (UPDRS). Participants in the 2nd and 3rd cohorts reduced their required daily levodopa-equivalent dose by a mean -322.0 and -441.2 mg/day, respectively, from a baseline of 1507.0 and 1477.0 mg/day, respectively.

In a second open-label safety study (NCT03065192), 2 years after treatment, 7 participants had an average mean decrease in off time of 3.2 hours and an increase in time without troublesome dyskinesia of 2.1 hours from baselines of 9.3 and 6.6, respectively. These individuals also showed motor function improvements at this timepoint, with improved UPDRS Part III off medication scores representing a mean -12.0 points improvement from the baseline mean of 34.4 points. These individuals also had reduced daily levodopa-equivalent dose (mean -439.5 mg/day; baseline 1500.9 mg/day). 

“It is promising to see that after 3 years, a single administration of one-time investigational gene therapy treatment NBIb-1817 showed sustained reduction in “Off” time, as well as improvement in “on” time without troublesome dyskinesia and other measures of motor function in patients with Parkinson’s disease,” said Chad Christine, M.D., primary author, a lead investigator of the study and Professor of Neurology at the University of California, San Francisco (UCSF) Weill Institute for Neurosciences. “Parkinson’s disease patients’ motor function would be expected to worsen over three years, making these results very encouraging. The standard of care for advanced Parkinson’s disease has not significantly changed in decades and it is our hope that NBIb-1817 has the potential to become the first gene therapy for Parkinson’s disease.”

Preliminary safety data from both studies suggest that the gene therapy was well-tolerated, with no study drug-related serious adverse events (SAEs) reported. The most common adverse events reported were headache, hypoesthesia, and musculoskeletal pain (NCT01973543), and upper respiratory tract infection, headache, nausea, and depression (NCT03065192).
A phase 2 placebo-surgery controlled study (NCT03562494) of the gene therapy, which had been suspended because of the COVID-19 pandemic, is expected to resume and is actively enrolling participants patients who have been diagnosed with PD for at least 4 years and have at least  hours of off time during the day as measured by a validated self-reported patient diary.

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