title: Long-Term Safety of Patients with Parkinson's Disease Receiving rAAV2-Neurturin (CERE-120) Gene Transfer.
abstract: The objective of this study was to assess the long-term safety of surgically administered recombinant adeno-associated virus serotype-2 (rAAV2)-neurturin (NRTN) to patients with advanced Parkinson's disease. Publications from prior trials reported no unexpected or troubling adverse events related to the vector or transgene comprising rAAV2-NRTN. Because rAAV2-NRTN produces long-term NRTN expression, subjects were enrolled in a long-term safety assessment protocol of rAAV2-NRTN. This article presents safety data for up to 5 years, well beyond that reported in the initial publications. Data from 53 patients are included; 47 received rAAV2-NRTN bilaterally to the putamen, whereas 6 subjects received rAAV2-NRTN bilaterally into putamen-plus-substantia nigra. Patients underwent in-person safety assessments on a quarterly to bi-annual basis, including adverse event monitoring, physical and neurological examinations, brain MRI, and laboratory testing. Parkinsonian status was assessed in an unblinded fashion. Fifty-three subjects completed the long-term safety protocol. Nine nonserious adverse events (non-SAEs) in 6 subjects were deemed "possibly related" to rAAV2-NRTN by the principal investigator, whereas none were deemed "related" to rAAV2-NRTN. Over the course of long-term observation, 33 SAEs were reported in 18 subjects, all of who received rAAV2-NRTN into putamen-only; 31 SAEs were deemed not related to rAAV2-NRTN, and 2 were deemed unlikely related. Safety assessments showed no clinically relevant changes in examination, imaging, or laboratory studies. Motor status, on average, was stable or apparently modestly improved (relative to baseline) over the course of the open-label, long-term follow-up. These findings provide evidence for the long-term safety of neurturin when delivered to the putamen or the putamen-plus-substantia nigra via stereotactic surgery and rAAV2 gene transfer. They therefore supplement the safety results reported in four prior publications from the same subjects, significantly extending the safety data for gene therapy and neurotrophic factor expression targeting the brain and adding to growing evidence that rAAV vector-mediated gene therapy to the CNS can be administered safely.
authors.affiliation: 1 University of California , San Francisco, San Francisco, California.
authors.forename: William J
authors.initials: WJ
authors.lastname: Marks
authors.affiliation: 2 Ionis Pharmaceuticals , Carlsbad, California.
authors.forename: Tiffany L
authors.initials: TL
authors.lastname: Baumann
authors.affiliation: 3 RTBioconsultants, Inc. , San Diego, California.
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Bartus
mesh_terms: D001921:Brain / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D008875:Middle Aged; D051101:Neurturin / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics / Q000628:therapy*; D011699:Putamen / Q000378:metabolism; D012449:Safety
chemical_list: C495053:NRTN protein, human; D051101:Neurturin