Safety and tolerability of putaminal AADC gene therapy for Parkinson disease

Abstract

Background: In Parkinson disease (PD), the benefit of levodopa therapy becomes less marked over time, perhaps because degeneration of nigrostrial neurons causes progressive loss of aromatic l-amino acid decarboxylase (AADC), the enzyme that converts levodopa into dopamine. In a primate model of PD, intrastriatal infusion of an adeno-associated viral type 2 vector containing the human AADC gene (AAV-hAADC) results in robust response to low-dose levodopa without the side effects associated with higher doses. These data prompted a clinical trial.

Methods: Patients with moderately advanced PD received bilateral intraputaminal infusion of AAV-hAADC vector. Low-dose and high-dose cohorts (5 patients in each) were studied using standardized clinical rating scales at baseline and 6 months. PET scans using the AADC tracer [(18)F]fluoro-L-m-tyrosine (FMT) were performed as a measure of gene expression.

Results: The gene therapy was well tolerated, but 1 symptomatic and 2 asymptomatic intracranial hemorrhages followed the operative procedure. Total and motor rating scales improved in both cohorts. Motor diaries also showed increased on-time and reduced off-time without increased "on" time dyskinesia. At 6 months, FMT PET showed a 30% increase of putaminal uptake in the low-dose cohort and a 75% increase in the high-dose cohort.

Conclusion: This study provides class IV evidence that bilateral intrastriatal infusion of adeno-associated viral type 2 vector containing the human AADC gene improves mean scores on the Unified Parkinson's Disease Rating Scale by approximately 30% in the on and off states, but the surgical procedure may be associated with an increased risk of intracranial hemorrhage and self-limited headache.

Figure 1 Total and motor UPDRS scores for individual patients at baseline and 6 months after treatment in both the on- and off-states UPDRS = Unified Parkinson’s Disease Rating Scale.

Figure 2 Time spent in different motor states at baseline and at 3 and 6 months postoperatively BL = baseline.

Figure 3 Plot showing change in FMT uptake of both putamens (mean ± SEM) over time for each cohort These improvements were significant for both the low-dose (1 month, p = 0.02; 6 months, p = 0.009) and high-dose (1 month, p = 0.007; 6 months, p = 0.004) cohorts. FMT = [¹⁸F]fluoro-l-m-tyrosine.