Autologous suraL nervE Grafting to the Substantia nigrA in Patients With Synuclienopathies (LEAP)

A Phase I Study of the Feasibility and Safety of SuraL nervE Tissue Grafting to the Substantia nigrA in Patients With Synucleinopathies (LEAP)

This phase I double-blind study focuses on the safety and feasibility of implanting autologous peripheral nerve tissue (PNT) into the substantia nigra area of the brain in persons who have been diagnosed with either Parkinson's disease (PD) or Multiple System Atrophy (MSA). 7 participants will be enrolled, with 4 participants receiving the graft and 3 receiving a sham surgery. Eligible participants will be early in their diagnosis with a lower burden of symptoms. Participants will be followed initially for one year after surgery.

Study Overview

• Status: Recruiting
• Conditions: Multiple System Atrophy; Parkinsons Disease
• Intervention / Treatment: Procedure: Sural Nerve Graft to the Substantia Nigra; Procedure: Sham surgery

Detailed Description

This phase I double blind clinical trial will be used to plan future, larger clinical trials that would test how autologous cells from the peripheral nerve may help in the repair of damaged brain cells in Parkinson's Disease (PD) or Multiple System Atrophy (MSA) and slow the progression of the diseases. We will be judging the feasibility of implanting a participant's own cells from a nerve in the leg into the substantia nigra area of the brain. Patients eligible for participation will be at an earlier in stage of the disease with symptoms being less severe and therefore would not yet qualify for DBS. The LEAP trial is a study where the first participant will receive an implantation of the cells from their own sural nerve (a nerve near the ankle), into the substantia nigra on both sides of their brain. The 6 participants who follow, will be randomized to one of two arms. The 3 participants assigned to the experimental arm will receive the graft. The 3 participants assigned to the control arm will receive a sham surgical procedure, where the sural nerve will be biopsied, and bilateral scalp incisions will be made. Those who do not receive the cells initially may be eligible to undergo another surgery at the end of the study, after un-blinding has occurred, to receive the cell implants.

• Study Type: Interventional
• Enrollment (Estimated): 7
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Jaimie Hixson; Phone Number: 859-323-1908; Email: jaimie.henderson@uky.edu
• Study Contact Backup: Name: Group Monitored Email; Email: nervegraft@uky.edu

Study Locations

• United States
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • Recruiting
      • University Of Kentucky
      • Contact: Jaimie Hixson; Phone Number: 859-323-1908; Email: jaimie.henderson@uky.edu
      • Principal Investigator: Craig van Horne, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of clinically established or clinically probable PD or MSA as defined by MDS criteria
• Disease duration greater than 2 years
• Age 40-75, inclusive
• MDS-Unified Parkinson's Disease Rating Scale (UPDRS) Part III greater than or equal to 20 points but less than or equal to 35 points, off anti-parkinsonian medication for PD or MDS-Unified Multiple System Atrophy Rating Scale (UMSARS) less than or equal to 30 points off anti-parkinsonian medication
• No MDS-UPDRS Part III score >3 on items 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.14 while off medication
• 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:

• Previous PD surgery or intracranial surgery
• Ongoing major medical or psychiatric disorder incl. depression and psychosis
• Other concomitant treatment with neuroleptics
• Typical, nonparkinsonian syndrome ioflupane/SPECT signal
• Unable to undergo an MRI
• An obstructed trajectory path to the substantia nigra
• Significant microvascular disease
• Use of anticoagulants other than aspirin
• Female who is pregnant, lactating, or of child-bearing potential unwilling to use an adequate birth control method during the period of the study
• Consent capacity will be assessed and determined during and throughout a participant's neuropsychological exam. A participant who experiences a decline in consent capacity prior to surgery, will be removed from the study by the PI. A decline in consent capacity after surgery will not result in the removal of the participant in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo Group	Procedure: Sham surgery; Participants assigned to this arm will have the sural nerve from one of their ankles biopsied in the same fashion as the experimental arm. Bilateral incisions will be made on the participants scalp but no burr holes into the skull and no cannula passes into the brain will occur.
Experimental: Nerve Graft Recipients	Procedure: Sural Nerve Graft to the Substantia Nigra; Participants assigned to this arm will have the sural nerve biopsied from one of their ankles. This cellular tissue will be deposited bilaterally into the substantia nigra area of their brain by a specialized cannula via bilateral scalp incisions and skull burr holes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Meet recruitment goal	Ability to recruit, enroll, and assign participants to the trial within 12 months of the trial opening.	Trial opening through 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Study-related serious adverse events as assessed by MedDRA v.27	Total number of serious adverse events associated with bilateral PNT collection and deployment to the substantia nigra. Serious adverse events will be defined as an abscess, tumor, infection of the bed of the graft, altered mental state, seizure, ankle or foot infection, wound dehiscence at the ankle incision, spread of neuropathy of the ankle or foot on the ipsilateral side of the nerve biopsy, or other event determined by the PI/investigators to be important.	Enrollment through 12 months
Study-related adverse events as assessed by MedDRA v27	Total number of adverse events experienced by participants categorized by System Organ Class and/or High Level Group Term using MedDRA v27 for designation.	Enrollment through 6 month study visit
Number of deployment attempts required to deliver bilateral PNT	Per protocol, the surgeon has two chances to successfully deploy 60% of the PNT tissue loaded in the guide-tube into the brain per hemisphere. The number of attempted deployments will be documented and if <60% of the tissue is deployed after two attempts, a failed delivery will be documented and no other attempts will be made.	During the procedure
Duration of procedure	Number of minutes it takes for the procedure to be completed. This will be defined by the anesthesia start time and anesthesia end time.	During the procedure
Length of hospital admission	The number of days each participant is admitted to the inpatient hospital for the procedure and acute post-operative care.	Admission for the procedure through hospital discharge
Percent of study visit completed by participants	The number of designated study visits completed compared to the total number of study visits that are scheduled to occur.	Enrollement through 12 month study visit
Change in Neuropsychological diagnosis	Changes in participant neuropsychological diagnoses during scheduled evaluations will be reported. e.g. No cognitive diagnosis progressing to mild neurocognitive disorder.	Baseline and 12 months
Mean change in Neuropsychological assessment scores	Participants complete a neuropsychological assessment battery that meets the MDS guidelines for determining mild cognitive impairment/mild neurocognitive disorder. Domains include attention and working memory, executive functioning, memory (verbal and visual), language, and visuospatial skills. Participants' raw scores will be converted to standardized scores based on appropriate norms (e.g., age-based norms). Participants' 12 month re-evaluation will be compared to their baseline pre-surgical assessment to determine change from baseline on each measure. A change that exceeds 1.5 standard deviation from their baseline performance will be considered notable.	Baseline to 12 months
Mean change in Montreal Cognitive Assessment (MoCA) scores	Mean change in MoCA scores for participants at study visits compared to baseline by group allocation. Assessment is scored from 0-30 with a score of 26 or better indicating normal cognition. A score less than 26 indicates a cognitive deficit.	Baseline, 4 weeks, 6 months, and 12 months
Mean change of the Movement Disorder Society - Unified Parkinsons Disease Rating Scale (MDS-UPDRS) Part I scores	MDS-UPDRS Part I scores non-motor symptoms effecting activities of daily living in those with Parkinson's Disease. Scores range from 0-52 with higher scores indicating greater symptom severity.	4 weeks, 6 and 12 months as compared to baseline
Mean change of the MDS-UPDRS Part II scores	MDS-UPDRS Part II scores motor symptoms effecting activities of daily living in those with Parkinson's Disease. Scores range from 0-52 with higher scores indicating greater symptom severity.	4 weeks, 6 months, and 12 months compared to baseline
Mean change in MDS-UPDRS Part III scores	MDS-UPDRS Part III scores motor symptoms associated with Parkinson's Disease. Part III scores range from 0-132 with higher scores indicating higher symptom severity.	4 weeks, 6 and 12 months compared to baseline
Mean change in MDS-UPDRS Part IV scores	MDS-UPDRS Part IV scores motor complications such as fluctuations and dyskinesia's associated with anti-Parkinson's medications. Scores range from 0-24 with higher scores indicating greater severity in motor complications.	4 weeks, 6 and 12 months compared to baseline
Mean change of the Movement Disorder Society - Unified Multiple System Atrophy Rating Scale (MDS-UMSARS) Part I scores	MDS-UMSARS Part I rates patient reported functional disabilities. Scores for this section range from 0-48 with higher scores indicating greater disability	4 weeks, 6 and 12 months as compared to baseline
Mean change of the MDS-UMSARS Part II scores	MDS-UMSARS Part II scores motor symptoms associated with multiple system atrophy. Scores range from 0-56 with higher scores indicating greater symptom severity.	4 weeks, 6 months, and 12 months compared to baseline
Mean change in MDS-UMSARS Part III scores	MDS-UMSARS Part III assesses orthostatic hypertension symptoms. This part examines blood pressure changes when a participant stands up after laying down for two minutes. It is scored as either a "Yes" the participant experiences orthostatic hypertension, or a "No" the participant does not don't experience orthostatic hypertension.	4 weeks, 6 and 12 months compared to baseline
Mean change in MDS-UMSARS Part IV scores	MDS-UMSARS Part IV assess the participants global disability. Scores range from 1-5 with 1 being completely independent and 5 being totally dependent/bedridden.	4 weeks, 6 and 12 months compared to baseline
Mean change in Parkinson's Disease Questionnaire-8 (PDQ-8) quality of life scores	Assess changes in participant's quality of life. Questionnaire is scored from 0-32 with higher scores indicating poorer quality of life.	Monthly through 12 month study visit compared to baseline
Mean change in Modified Schwab and England Scale of Activities of Daily Living scores	Mean change participant independence levels as measured in Schwab and England Scale of Activities of Daily Living scores. 100% = completed independent and 0% being completely dependent.	At 6 and 12 months compared to baseline
Mean change in Non-motor symptom scale scores	Assessment used to identify Parkinson's disease related non-motor symptoms experienced by participants. The scale measures the frequency and severity of symptoms and is scored from 0-360 with higher scores indicating more frequent and severe symptoms.	Baseline and 12 months
Participants electing to receive Deep Brain Stimulator (DBS)	Number of study participants who elect to have DBS implanted prior to completing the 12 month study visit.	Enrollment through 12 month study visit

Collaborators and Investigators

• Sponsor: Craig van Horne, MD, PhD
• Collaborators: National Center for Advancing Translational Sciences (NCATS); University of Kentucky CCTS
• Investigators: Principal Investigator: Craig van Horne, MD, PhD, University Of Kentucky

Publications and helpful links

General Publications

• 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.
• van Horne CG, Quintero JE, Gurwell JA, Wagner RP, Slevin JT, Gerhardt GA. Implantation of autologous peripheral nerve grafts into the substantia nigra of subjects with idiopathic Parkinson's disease treated with bilateral STN DBS: a report of safety and feasibility. J Neurosurg. 2017 Apr;126(4):1140-1147. doi: 10.3171/2016.2.JNS151988. Epub 2016 May 6.
• 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. Epub 2018 Feb 18.

Study record dates

Study Major Dates

• Study Start (Actual): February 25, 2025
• Primary Completion (Estimated): December 2, 2028
• Study Completion (Estimated): December 2, 2030

Study Registration Dates

• First Submitted: November 7, 2024
• First Submitted That Met QC Criteria: November 8, 2024
• First Posted (Actual): November 12, 2024

Study Record Updates

• Last Update Posted (Actual): April 1, 2026
• Last Update Submitted That Met QC Criteria: March 26, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Multiple System Atrophy; Synucleinopathies; Parkinsons Disease; Cell and Tissue Based Therapy
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolic Diseases; Neurodegenerative Diseases; Movement Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Proteostasis Deficiencies; Primary Dysautonomias; Autonomic Nervous System Diseases; Nutritional and Metabolic Diseases; Synucleinopathies; Parkinson Disease; Multiple System Atrophy
• Other Study ID Numbers: 95534; UL1TR001998 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Images and results may be made available to other researchers by asking participants, at the time of consent, their willingness to permit sharing of data and bio-specimens.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No