CNS10-NPC-GDNF for the Treatment of ALS

Human Neural Progenitor Cells Secreting Glial Cell Line-Derived Neurotrophic Factor (CNS10-NPC-GDNF) for the Treatment of Amyotrophic Lateral Sclerosis

The investigator is examining the safety of transplanting cells that have been engineered to produce a growth factor into the spinal cord 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 neuronal 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 neuronal cells. Therefore, the cells are called "CNS10-NPC-GDNF." The investigational treatment has been tested in animals, but it has not yet been tested in people. In this study, we want to learn if CNS10-NPC-GDNF cells are safe to transplant into the spinal cords of people.

Study Overview

• Status: Completed
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Biological: Stem cell (HPC) implantation; Device: Stereotactic surgical device

Detailed Description

This study will be the first to use a genetically modified progenitor cells to treat a neurodegenerative disease. This is a Phase 1/2a, single-center, blinded (as to side of injection), safety study of two escalating doses of human neural progenitor cells expressing GDNF (CNS10-NPC-GDNF) delivered unilaterally to the lumbar region in ALS subjects with moderate leg involvement.

Subjects meeting all Eligibility Criteria and providing Informed Consent will be enrolled in one of two 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 two weeks between surgeries.

Specific aims:

Safety, as evaluated by:

• Adverse Events and Serious Adverse Events
• Clinical laboratory assessments, as clinically indicated (hematology, chemistry, immunology)

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Confirmed diagnosis of ALS (Lab-supported Probable, Probable or Definite EI Escorial Criteria)
2. Duration of symptoms ≤ 36 months
3. Progressive weakness in lower extremities, with EMG supported evidence of denervation in both lower extremities.
4. Forced Vital Capacity >60% of predicted normal in supine.
5. Male/Female; Age: 18 and 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 or on a stable dose for ≥ 30 days
10. For women of child bearing capacity, negative pregnancy test prior to surgery
11. Medically able to undergo thoracolumbar laminectomy or laminoplasty as determined by the site PI and Neurosurgeon
12. Medically able to tolerate the immunosuppression regimen as determined by the site PI

Exclusion Criteria:

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 past 30 days or any previous exposure to stem cell therapy
6. Any condition in the lower extremities which precludes serial strength testing
7. Any condition that the Neurosurgeon feels 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Stem cell implantation; Subjects meeting all Eligibility Criteria and providing Informed Consent will be enrolled in one of two sequential dosing groups (Group A and B). 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. There will be 9 subjects in each group. No control group is included. All patients will received unilateral lumbar spinal cord injections of CNS10-NPC-GDNF cells.

Biological: Stem cell (HPC) implantation; All patients will received unilateral lumbar spinal cord injections of CNS10-NPC-GDNF cells.; Device: Stereotactic surgical device; A newly developed stereotactic frame is being evaluated as a part of this trial

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety evaluated by Adverse Events and Serious Adverse Events, post-operative MRI, and clinical laboratory assessments	Safety, as evaluated by: Adverse Events and Serious Adverse Events; Post-op MRI; Clinical laboratory assessments, as clinically indicated (hematology, chemistry, immunology)	Patients will be followed postoperatively for 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compound Motor Action Potential (CMAP)	Compound Motor Action Potential - CMAP (Tibialis anterior)	CMAP will be performed 7 times over 15 months
Force Generation via ATLIS testing	Lower extremity Force Generation via ATLIS testing	ATLIS testing will be performed 7 times over 15 months
Quantitative Muscle MRI	Quantitative Muscle MRI of bilateral lower extremities	Muscle MRI will be performed 6 times over 15 months
Electrical Impedance Myography (EIM)	Lower Extremity Electrical Impedance Myography (EIM)	EIM will be performed 7 times over 15 months
Assessment of glial cell line derived neurotrophic factor (GDNF) in the cerebral spianl fluid (CSF)	Assessment of GDNF in the CSF	CSF will be collected at 3 time points over 12 months

Collaborators and Investigators

• Sponsor: Cedars-Sinai Medical Center
• Collaborators: California Institute for Regenerative Medicine (CIRM)
• Investigators: Principal Investigator: Robert H. Baloh, MD, PhD, Cedars-Sinai Medical Center

Publications and helpful links

General Publications

• Baloh RH, Johnson JP, Avalos P, Allred P, Svendsen S, Gowing G, Roxas K, Wu A, Donahue B, Osborne S, Lawless G, Shelley B, Wheeler K, Prina C, Fine D, Kendra-Romito T, Stokes H, Manoukian V, Muthukumaran A, Garcia L, Banuelos MG, Godoy M, Bresee C, Yu H, Drazin D, Ross L, Naruse R, Babu H, Macklin EA, Vo A, Elsayegh A, Tourtellotte W, Maya M, Burford M, Diaz F, Patil CG, Lewis RA, Svendsen CN. Transplantation of human neural progenitor cells secreting GDNF into the spinal cord of patients with ALS: a phase 1/2a trial. Nat Med. 2022 Sep;28(9):1813-1822. doi: 10.1038/s41591-022-01956-3. Epub 2022 Sep 5.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2017
• Primary Completion (Actual): October 18, 2019
• Study Completion (Actual): October 18, 2019

Study Registration Dates

• First Submitted: October 20, 2016
• First Submitted That Met QC Criteria: October 21, 2016
• First Posted (Estimate): October 25, 2016

Study Record Updates

• Last Update Posted (Actual): July 15, 2020
• Last Update Submitted That Met QC Criteria: July 13, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: ALS; stem cells; growth factor
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis
• Other Study ID Numbers: Pro00042350

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes