Safety/feasibility of targeting the substantia nigra with AAV2-neurturin in Parkinson patients

Abstract

Objective: In an effort to account for deficiencies in axonal transport that limit the effectiveness of neurotrophic factors, this study tested the safety and feasibility, in moderately advanced Parkinson disease (PD), of bilaterally administering the gene therapy vector AAV2-neurturin (CERE-120) to the putamen plus substantia nigra (SN, a relatively small structure deep within the midbrain, in proximity to critical neuronal and vascular structures).

Methods: After planning and minimizing risks of stereotactically targeting the SN, an open-label, dose-escalation safety trial was initiated in 6 subjects with PD who received bilateral stereotactic injections of CERE-120 into the SN and putamen.

Results: Two-year safety data for all subjects suggest the procedures were well-tolerated, with no serious adverse events. All adverse events and complications were expected for patients with PD undergoing stereotactic brain surgery.

Conclusions: Bilateral stereotactic administration of CERE-120 to the SN plus putamen in PD is feasible and this evaluation provides initial empirical support that it is safe and well-tolerated.

Classification of evidence: This study provides Class IV evidence that bilateral neurturin gene delivery (CERE-120) to the SN plus putamen in patients with moderately advanced PD is feasible and safe.

Trial registration: ClinicalTrials.gov NCT00985517.

Figure. Artist's rendition of the dosing scheme employed to bilaterally target the substantia nigra and putamen with AAV2-NRTN (CERE-120)

(A) A single needle tract was used to deliver 2 infusions into each substantia nigra (SN). (B) Three additional needle tracts were used to deliver 3 equally spaced infusions into each putamen. Note that only a single burr hole was required to accommodate the 4 needle tracts per each hemisphere. The initial, low-dose cohort received the same dose of CERE-120 into the SN as the high-dose cohort, but only about one-fourth the putaminal dose. See text for additional details. This figure is a variation of one previously published in “Translating the therapeutic potential of neurotrophic factors to clinical ‘proof of concept’: a personal saga achieving a career-long quest” and in “Advancing neurotrophic factors as treatments for age-related neurodegenerative diseases: developing and demonstrating ‘clinical proof-of-concept’ for AAV-neurturin (CERE-120) in Parkinson's disease,” © Elsevier (2012) with permission.