Clinical trial NCT02943850: CNS10-NPC-GDNF for the Treatment of ALS
Official title: Human Neural Progenitor Cells Secreting Glial Cell Line-Derived Neurotrophic Factor (CNS10-NPC-GDNF) for the Treatment of Amyotrophic Lateral Sclerosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Amyotrophic Lateral Sclerosis
Keywords: stem cells
growth factor
ALS
Lead sponsor: Cedars-Sinai Medical Center
Sponsor class: OTHER
Collaborators: name: California Institute for Regenerative Medicine (CIRM)
First posted: 2016-10-25
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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)

Eligibility criteria: 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

Primary outcomes:
measure: Safety evaluated by Adverse Events and Serious Adverse Events, post-operative MRI, and clinical laboratory assessments
timeFrame: Patients will be followed postoperatively for 12 months
Secondary outcomes:
measure: Compound Motor Action Potential (CMAP)
timeFrame: CMAP will be performed 7 times over 15 months
measure: Force Generation via ATLIS testing
timeFrame: ATLIS testing will be performed 7 times over 15 months
measure: Quantitative Muscle MRI
timeFrame: Muscle MRI will be performed 6 times over 15 months
measure: Electrical Impedance Myography (EIM)
timeFrame: EIM will be performed 7 times over 15 months
measure: Assessment of glial cell line derived neurotrophic factor (GDNF) in the cerebral spianl fluid (CSF)
timeFrame: CSF will be collected at 3 time points over 12 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
Study officials:
affiliation: Cedars-Sinai Medical Center
name: Robert H. Baloh, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.