Feasibility and Safety of autoloGous UncondItioneD pEripheral Nerve Tissue Delivery to the Substantia Nigra (GUIDE) (GUIDE)

Feasibility and Safety of autoloGous UncondItioneD pEripheral Nerve Tissue Delivery to the Substantia Nigra (GUIDE)

Feasibility and Safety of autoloGous UncondItioneD pEripheral Nerve Tissue Delivery to the Substantia Nigra

This is an open-label, non-randomized, single-arm trial design to actively follow participants for 12 months. Ten participants will be enrolled to receive bilateral delivery of Peripheral Nerve Tissue (PNT) to the Substantia Nigra at the time of Deep Brain Stimulation (DBS) surgery. After 12 months, participants will be followed long term through annual visits for the rest of their lives. Participants will serve as their own donor for the tissue.

We recently designed open-label safety studies to investigate the use of an autologous source of cellular tissue from the peripheral nervous system (van Horne et al., 2017, 2018; Quintero et al. 2022), reparative peripheral (sural) nerve tissue containing a variety of cells and neuroprotective factors (Chau et al. 2022). While our previous studies have used injury-activated peripheral nerve tissue (PNT), where the sural nerve is transected and allowed to regenerate in situ for up to about 2 weeks before implantation, here we propose to use naïve, previously uninjured, nerve tissue delivered bilaterally to the substantia nigra at the time participants are undergoing deep brain stimulation (DBS) surgery. Participants will be assessed preoperatively, then undergo DBS surgery and delivery of autologous PNT, and then assessed postoperatively at two weeks after surgery, 6 months, 12 months and annually thereafter for adverse events and clinical outcomes.

At the time participants are receiving the standard of care deep brain stimulation (DBS) surgery, a standard incision on the lateral aspect near the ankle is made, the sural nerve is identified, an about 3 cm biopsy of the sural nerve is obtained and the incision is closed. From the biopsied section, the epinerium is removed, fascicles are cut, and (~5 pieces per side; ~ 5mm length x 1.5 mm diameter: approximately 10 cubic millimeters) implanted bilaterally into the substantia nigra.

Number of adverse events and serious adverse events associated with bilateral PNT deployment to the substantia nigra.

Mean change in MDS-UPDRS (Movement Disorder Society-Unified Parkinson's Disease Rating Scale) Part III scores for participants at 12, and 6 months compared to baseline. Mean change of the MDS-UPDRS Part I scores for participants at 6,12 months compared to baseline. Mean change of the MDS-UPDRS Part II scores for participants at 6,12 months compared to baseline. (95% confidence interval) Scale runs from 0-132 with smaller scores indicating fewer symptoms.

Mean change of the PDQ-8, Modified scores for participants at 6, 12 months compared to baseline. (95% confidence interval). Scale runs from 0-32 with lower scores indicating fewer symptoms.

Mean change of the Modified Schwab and England Scale scores for participants at 6, 12 months compared to baseline. (95% confidence interval). Scale runs from 0%-100% with a higher score indicating the participant has more independence in their daily activities.

Mean change for neuropsychological assessment scores at 12 months compared to baseline. (95% confidence interval)

Mean change in specific binding ratio in the posterior putamen for participants at 12 months compared to baseline (95% confidence interval).

Inclusion Criteria: Undergoing DBS Diagnosis of clinically established or clinically probably PD (Parkinson's disease) as defined by MDS criteria Age 40-75, inclusive Able and willing to undergo ioflupane/SPECT Able to tolerate the surgical procedure Able to undergo all planned assessments Available access to the sural nerve Exclusion Criteria: Any condition that would not make the subject a candidate for DBS Previous PD surgery or intracranial surgery Typical, nonparkinsonian syndrome ioflupane/SPECT signal Female who is pregnant, lactating, or of child-bearing potential unwilling to use an adequate birth control method during the period of the study Unable to undergo an MRI An obstructed trajectory path to the substantia nigra

van Horne CG, Quintero JE, Slevin JT, Anderson-Mooney A, Gurwell JA, Welleford AS, Lamm JR, Wagner RP, Gerhardt GA. Peripheral nerve grafts implanted into the substantia nigra in patients with Parkinson's disease during deep brain stimulation surgery: 1-year follow-up study of safety, feasibility, and clinical outcome. J Neurosurg. 2018 Dec 1;129(6):1550-1561. doi: 10.3171/2017.8.JNS163222.

Quintero JE, Slevin JT, Gurwell JA, McLouth CJ, El Khouli R, Chau MJ, Guduru Z, Gerhardt GA, van Horne CG. 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. BMJ Neurol Open. 2022 Jul 14;4(2):e000301. doi: 10.1136/bmjno-2022-000301. eCollection 2022.