CNS10-NPC-GDNF Delivered to the Motor Cortex for ALS

• ClinicalTrials.gov Identifier: NCT05306457
• Recruitment Status: Recruiting
• First Posted: April 1, 2022
• Last Update Posted: January 20, 2023
• Sponsor: Cedars-Sinai Medical Center
• Collaborator: California Institute for Regenerative Medicine (CIRM)
• Information provided by (Responsible Party): Clive Svendsen, Cedars-Sinai Medical Center

Study Description

Brief Summary:

The investigator is examining the safety of transplanting cells, that have been engineered to produce a growth factor, into the motor cortex (brain) of patients with Amyotrophic Lateral Sclerosis (ALS). The cells are called neural progenitor cells, which are a type of stem cell that can become several different types of cells in the nervous system. These cells have been derived to specifically become astrocytes, which is a type of neural cell. The growth factor is called glial cell line-derived neurotrophic factor, or GDNF. GDNF is a protein that promotes the survival of many types of neural cells. Therefore, the cells are called "CNS10-NPC-GDNF." The investigational treatment has been tested in people by delivering it to the spinal cord. However, it has only been delivered to the motor cortex of animals. In this study, we want to learn if CNS10-NPC-GDNF cells are safe to transplant into the motor cortex (brain) of people.

Condition or disease	Intervention/treatment	Phase
Amyotrophic Lateral Sclerosis	Biological: CNS10-NPC-GDNF	Phase 1

Detailed Description:

This study will be the first to use a genetically modified progenitor cell line delivered to the motor cortex to treat a neurodegenerative disease. This is a Phase 1/2a, single-center, safety study of two escalating doses of human neural progenitor cells expressing GDNF (CNS10-NPC-GDNF) delivered unilaterally to the "hand-knob" area of the motor cortex of patients with ALS.

Subjects meeting all Eligibility Criteria and providing Informed Consent will be enrolled in one of three sequential dosing groups. Subjects will be treated sequentially with a minimum of one month interval between surgeries for the first three subjects in each dosing cohort. The remaining subjects in the cohort will be treated with a minimum interval of at least one week between surgeries.

Primary Outcome:

Safety, as evaluated by:

• Adverse Events and Serious Adverse Events
• Post-op MRI and/or CT (with contrast) and as clinically indicated

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 16 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Human Neural Progenitor Cells Secreting Glial Cell Line-Derived Neurotrophic Factor (CNS10-NPC-GDNF) Delivered to the Motor Cortex for the Treatment of Amyotrophic Lateral Sclerosis
• Actual Study Start Date: May 8, 2022
• Estimated Primary Completion Date: September 2023
• Estimated Study Completion Date: September 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: CNS10-NPC-GDNF - Group A; Unilateral, Motor Cortex, 0.25x10^6 cells in 10 µL/site, 21 sites (5.25x10^6 total cells) - Motor cortex corresponding to the non-dominant hand	Biological: CNS10-NPC-GDNF; Unilateral injections of CNS10-NPC-GDNF into the motor cortex
Experimental: CNS10-NPC-GDNF - Group B; Unilateral, Motor Cortex, 0.5x10^6 cells in 10 µL/site, 21 sites (10.5x10^6 total cells) - Motor cortex corresponding to the non-dominant hand	Biological: CNS10-NPC-GDNF; Unilateral injections of CNS10-NPC-GDNF into the motor cortex
Experimental: CNS10-NPC-GDNF - Group C; Unilateral Motor Cortex, 0.5x10^6 cells in 10 µL/site, 21 sites (10.5x10^6 total cells) - Motor cortex corresponding to the dominant hand	Biological: CNS10-NPC-GDNF; Unilateral injections of CNS10-NPC-GDNF into the motor cortex

Outcome Measures

Primary Outcome Measures :

1. Safety, as evaluated by the incidence of Adverse Events and Serious Adverse Events and their relationship to the treatment [ Time Frame: 12 months post-operatively ]
2. Safety, as evaluated by changes from baseline in the brain MRI [ Time Frame: 12 months post-operatively ]

Secondary Outcome Measures :

1. Force Generation via Accurate Test of Limb Isometric Strength (ATLIS) testing [ Time Frame: ATLIS testing will be performed 7 times over 15 months ]
   Change from baseline for force generation by ATLIS
2. Pinch Strength [ Time Frame: Pinch Strength testing will be performed 7 times over 15 months ]
   Change from baseline for pinch strength
3. Hand/Wrist Strength [ Time Frame: Hand/Wrist strength testing will be performed 7 times over 15 months ]
   Change from baseline for Hand/Wrist strength using Hand-held dynamometer
4. Compound Motor Action Potential (CMAP) [ Time Frame: CMAP will be performed 7 times over 15 months ]
   Change from baseline for CMAP
5. Functional Hand assessments using 9-hole peg test [ Time Frame: 9-hole peg testing will be performed 7 times over 15 months ]
   Change from baseline for 9-hole peg test
6. Penn Upper Motor Neuron Score (PUMNS) [ Time Frame: PUMNS will be performed 7 times over 15 months ]
   Change from baseline for Penn Upper Motor Neuron Score. (Scale of 0-32, where 0 is normal)
7. Hand Knob - Functional MRI (fMRI) [ Time Frame: fMRI will be performed up to 4 times over 15 months ]
   Changes from baseline in brain activity in the hand knob area evaluated by fMRI

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion:

1. Confirmed diagnosis of ALS (Possible, Lab-supported Probable, Probable or Definite El Escorial Criteria)
2. Duration of ALS symptoms ≤ 36 months
3. Progressive weakness in upper extremities, with EMG supported evidence of denervation in both upper extremities
4. Forced Vital Capacity ≥50% of predicted normal in supine
5. Age: 18 years or older
6. Able to provide Informed Consent
7. Be geographically accessible to the study site and able to travel to study site for required visits
8. Have caregiver to assist in the transportation and care required by participation in the study
9. Not taking riluzole and/or edaravone or on a stable dose for ≥ 30 day
10. For women of child bearing capacity, negative pregnancy test prior to surgery and willingness to use birth control for the duration of the trial.
11. Medically able to undergo craniotomy as determined by the site PI and/or investigators
12. Medically able to tolerate the immunosuppression regimen as determined by the site PI

Exclusion:

1. Using invasive ventilatory assistance
2. Diagnosis of another active or unstable medical illness that may interfere with study participation at discretion of PI

3. Presence of any of the following conditions:

   1. Current drug or alcohol abuse
   2. Any known immunodeficiency syndrome
   3. Unstable medical condition
   4. Unstable psychiatric illness including psychosis and untreated major depression within 90 days of screening
4. Persons of child bearing capacity not willing to practice birth control
5. Receiving any investigational device/biologic/drug in the past 30 days or any previous exposure to stem cell therapy
6. Any condition in the upper extremities that precludes serial strength or coordination testing
7. Any condition that the investigators feel may pose complications for the surgery
8. Any condition or ALS disease phenotype that the site PI feels may interfere with participation in the study or in the interpretation of study endpoints
9. Allergy to Beta-Lactam antibiotics
10. Donor Specific Antibodies (DSA) ≥ 2500MFI or CPRA ≥ 20%
11. Contraindications to MRI

Contacts and Locations

Contacts

Contact: Pablo Avalos; 310-248-8584; Pablo.avalos@cshs.org

Locations

United States, California

Cedars-Sinai Medical Center; Recruiting

Los Angeles, California, United States, 90048

Contact: Pablo Avalos 310-248-8584

Principal Investigator: Richard Lewis, MD

Sponsors and Collaborators

Cedars-Sinai Medical Center

California Institute for Regenerative Medicine (CIRM)

Investigators

• Principal Investigator: Richard Lewis, MD; Cedars-Sinai Medical Center

More Information

• Responsible Party: Clive Svendsen, Executive Director, Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center
• ClinicalTrials.gov Identifier: NCT05306457
• Other Study ID Numbers: STUDY00000278
• First Posted: April 1, 2022
• Last Update Posted: January 20, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Clive Svendsen, Cedars-Sinai Medical Center:

ALS; Stem cells; Growth Factor; Regenerative; Neural Progenitor Cells; NPC; Transplantation

Additional relevant MeSH terms:

Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Sclerosis; Pathologic Processes; Neurodegenerative Diseases; Nervous System Diseases; Neuromuscular Diseases; Spinal Cord Diseases; Central Nervous System Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Metabolic Diseases