Human NRTN blocking peptide

Neurotrophic factors play an important role in the regulation of functional properties of sensory neurons under normal and pathological conditions. The GDNF family member neurturin is one such factor that has been linked to modulating responsiveness to peripheral stimuli. Neurturin binds to the GFR alpha 2 receptor, a receptor found primarily in isolectin B-4-expressing polymodal cutaneous nociceptors. Previous work has shown that knockout of GFR alpha 2 alters heat, but not mechanical, responses in dissociated sensory neurons and reduces pain-related behaviors during the second phase of the formalin test. Research has also shown that overexpression of neurturin in basal keratinocytes increases behavioral responsiveness to mechanical stimulation and innocuous cooling of the skin without affecting noxious heat responses. Here we directly examined the impact of neurturin overexpression on cutaneous afferent function. We compared physiological responses of individual sensory neurons to mechanical and thermal stimulation of the skin, using an ex vivo skin-nerve-dorsal root ganglion-spinal cord preparation produced from neurturin-overexpressing (NRTN/OE) mice and wild-type littermate controls. We found that neurturin overexpression increases responsiveness to innocuous mechanical stimuli in A-fiber nociceptors, alters thermal responses in the polymodal sub population of C-fiber sensory neurons, and changes the relative numbers of mechanically sensitive but thermally insensitive C-fiber afferents. These results demonstrate the potential roles of different functional groups of sensory neurons in the behavioral changes observed in mice overexpressing cutaneous neurturin and highlight the importance of neurturin in regulating cutaneous afferent response properties. NEW & NOTEWORTHY GDNF family neurotrophic factors regulate the development and function of primary sensory neurons. Of these, neurturin has been shown to modulate mechanical and cooling sensitivity behaviorally. Here we show that overexpression of neurturin in basal keratinocytes regulates mechanical responsiveness in A-fiber primary sensory neurons while increasing the overall numbers of cold-sensing units. Results demonstrate a crucial role for cutaneous neurturin in modulating responsiveness to peripheral stimuli at the level of the primary afferent.

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.