Striatal delivery of neurturin by CERE-120, an AAV2 vector for the treatment of dopaminergic neuron degeneration in Parkinson's disease.

Glial cell line-derived neurotrophic factor (GDNF) or its naturally occurring analog, neurturin (NTN), can potentially improve the function and delay the rate of degeneration of dopaminergic neurons in Parkinson's disease (PD). However, their delivery to the central nervous system has proven to be a significant challenge. Viral vector-mediated gene transfer offers a practical means to continuously supply neurotrophic factors in targeted areas of the brain. CERE-120 is an adeno-associated viral vector encoding NTN, developed for the treatment of PD. We found that the kinetics and pattern of NTN expression in the rat striatum following injection of CERE-120 is rapid, increases significantly up to 4 weeks, and exhibits a stable volume of distribution thereafter for at least 1 year, the longest time-point evaluated. Quantitative enzyme-linked immunosorbent assay confirmed that steady-state levels are maintained from 4 weeks onward. We demonstrated that NTN volume of distribution can be controlled by varying the dose of vector injected and that NTN delivered via CERE-120 was bioactive, as evidenced by the neuroprotection of DA neurons in the rat 6-hydroxydopamine lesion model. These data provided the foundation for further non-clinical development of CERE-120, leading to an ongoing clinical trial in PD patients.