Direct delivery of an investigational cell therapy in patients with Parkinson's disease: an interim analysis of feasibility and safety of an open-label study using DBS-Plus clinical trial design

Abstract

Objective: To evaluate the interim feasibility, safety and clinical measures data of direct delivery of regenerating peripheral nerve tissue (PNT) to the substantia nigra (SN) in participants with Parkinson's disease (PD).

Methods: Eighteen (13 men/5 women) participants were unilaterally implanted with PNT to the SN, contralateral to the most affected side during the same surgery they were receiving deep brain stimulation (DBS) surgery. Autologous PNT was collected from the sural nerve. Participants were followed for safety and clinical outcomes for 2 years (including off-state Unified Parkinson's Disease Rating Scale (UPDRS) Part III assessments) with study visits every 6 months.

Results: All 18 participants scheduled to receive PNT implantation received targeted delivery to the SN in addition to their DBS. All subjects were discharged the following day except for two: post-op day 2; post-op day 3. The most common study-related adverse events were hypoaesthesia and hyperaesthesias to the lateral aspect of the foot and ankle of the biopsied nerve (6 of 18 participants experienced). Clinical measures did not identify any hastening of PD measures providing evidence of safety and tolerability. Off-state UPDRS Part III mean difference scores were reduced at 12 months compared with baseline (difference=-8.1, 95% CI -2.4 to -13.9 points, p=0.005). No complications involving dyskinesias were observed.

Conclusions: Targeting the SN for direct delivery of PNT was feasible with no serious adverse events related to the study intervention. Interim clinical outcomes show promising results meriting continued examination of this investigational approach.

Trial registration number: NCT02369003.

Keywords: NEUROSURGERY; PARKINSON'S DISEASE; SCHWANN CELL.

Conflict of interest statement

Competing interests: CvH has served as consultant to Boston Scientific and Brainlab.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Enrolment and surgical flow. DBS, deep brain stimulation; PD, Parkinson’s disease.

Figure 2

Postoperative MPRAGE scans displaying deep brain stimulation (DBS) electrode and graft cannula (implant trajectory and zone) tracks. DBS electrode and graft cannula placement in the coronal (A), parasagittal (B) and orthogonal to the trajectory (C) planes. Outlines of the substantia nigra (SN), subthalamic nucleus (STN) and red nucleus (RN) superimposed on the images (D–F) show implant zone relative to the SN.

Figure 3

(A) Multiple depths through the axial plane show abnormal 123I-ioflupane binding in the outlined striatal regions in one study participant. Values indicate different depths oriented based on A (anterior), P (posterior), L (left) and R (right). (B) Baseline comparison of the mean specific binding ratio (SBR) (ipsilateral and contralateral to the intended peripheral nerve tissue implant location) to the DaTQUANT normal database.

Figure 4

(A) 3D object depiction of the target zone. Using MPRAGE images, space-filling objects of the subthalamic nucleus (STN) (purple), substantia nigra (SN) (blue), red nucleus (RN) (red) depicted in different planes are shown. (B) Peripheral nerve tissue (PNT) placement within the SN on the left (n=10) and right (n=8) are shown. Black dots represent the centre point of deployment as determined from analysis of post-op MRI sequences. Composites were organised from the analysis of individual PNT placements using Elements software. Outlines are of objects shown in (A). A, anterior; D, dorsal; L, lateral; M, medial; P, posterior; V, ventral.