CNS10-NPC-GDNF for ALS

Overseen By Pablo Avalos

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Cedars-Sinai Medical Center

Must not be taking: Investigational drugs

Disqualifiers: Invasive ventilatory, Immunodeficiency, Unstable conditions, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 7

Duration: 3 months

16 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing the safety of placing special cells into the brains of ALS patients. These cells release a protein that helps brain cells stay alive and healthy. The study aims to see if this new treatment is safe for people.

Will I have to stop taking my current medications?

The trial requires that you are either not taking riluzole and/or edaravone or have been on a stable dose for at least 30 days. Other medications are not specified, so it's best to discuss with the trial team.

What data supports the effectiveness of the treatment CNS10-NPC-GDNF for ALS?

Research shows that CNS10-NPC-GDNF, which involves cells that produce a protective protein called GDNF, was safe in a study with ALS patients and helped protect nerve cells in the spinal cord. Additionally, GDNF levels are naturally higher in ALS patients, suggesting it may play a role in the body's response to the disease. ^{1 2 3 4 5}

Is CNS10-NPC-GDNF safe for humans?

The safety of a similar treatment, recombinant human ciliary neurotrophic factor (rhCNTF), was tested in patients with ALS. It was generally safe at lower doses, but higher doses caused side effects like fever, fatigue, cough, and weight loss. No serious neurological issues were reported, but some side effects were dose-related. ^{6 7 8 9 10}

What makes the CNS10-NPC-GDNF treatment unique for ALS?

CNS10-NPC-GDNF is unique because it involves transplanting human neural progenitor cells engineered to release GDNF (a protein that supports nerve cells) directly into the spinal cord, providing long-term support and protection for motor neurons, which is different from traditional drug treatments. ^{1 2 3 11 12}

Research Team

Richard Lewis, MD

Principal Investigator

Cedars-Sinai Medical Center

Eligibility Criteria

This trial is for adults over 18 with ALS symptoms for less than 3 years, who can consent and have a caregiver. They must be able to breathe well on their own (FVC ≥50%), travel to the site, and not be on certain drugs or have used stem cells before. Women must test negative for pregnancy and use birth control.

Inclusion Criteria

Medically able to tolerate the immunosuppression regimen as determined by the site PI

I have a confirmed diagnosis of ALS.

My lung function is at least half of what is expected for someone healthy.

Exclusion Criteria

Diagnosis of another active or unstable medical illness that may interfere with study participation at discretion of PI

Current drug or alcohol abuse

Using invasive ventilatory assistance

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive CNS10-NPC-GDNF cells transplanted into the motor cortex

3 months

Multiple surgeries with a minimum of one week to one month interval between surgeries

Follow-up

Participants are monitored for safety and effectiveness after treatment

15 months

7 visits for various assessments including CMAP, 9-hole peg test, PUMNS, fMRI, ATLIS, and strength testing

Treatment Details

Interventions

• CNS10-NPC-GDNF

Trial Overview The safety of CNS10-NPC-GDNF cell transplants into the brain's motor cortex is being tested. These are engineered stem cells that become neural cells producing GDNF, a protein aiding neural cell survival, previously tested in spinal cords but now in human brains.

Participant Groups

Group I: CNS10-NPC-GDNF - Group C Experimental Treatment 1 Intervention

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

Group II: CNS10-NPC-GDNF - Group B Experimental Treatment 1 Intervention

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

Group III: CNS10-NPC-GDNF - Group A Experimental Treatment 1 Intervention

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

Who Is Running the Clinical Trial?

Cedars-Sinai Medical Center

Lead Sponsor

Trials

523

Recruited

165,000+

California Institute for Regenerative Medicine (CIRM)

Collaborator

Trials

70

Recruited

3,300+

Findings from Research

Neurotrophins like BDNF, CNTF, and GDNF show strong potential for promoting the survival of motor neurons, making them promising candidates for treating neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS).

The review synthesizes both preclinical and clinical trial data, providing insights into the effectiveness of these neurotrophic factors and suggesting how past findings can guide future research and development in ALS treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurotrophic factors in the physiology of motor neurons and their role in the pathobiology and therapeutic approach to amyotrophic lateral sclerosis. Stansberry, WM., Pierchala, BA.[2023]

In a phase 1/2a study involving 18 ALS patients, transplantation of human neural progenitor cells engineered to produce GDNF was found to be safe, with no adverse effects on motor function after one year.

The transplanted cells survived and continued to produce GDNF for up to 42 months, suggesting a potential long-term therapeutic benefit in supporting spinal motor neurons in ALS patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transplantation of human neural progenitor cells secreting GDNF into the spinal cord of patients with ALS: a phase 1/2a trial. Baloh, RH., Johnson, JP., Avalos, P., et al.[2022]

In a study analyzing cerebrospinal fluid from 15 ALS patients and 11 healthy controls, no significant difference in BDNF levels was found, suggesting that BDNF may not play a role in ALS pathology.

However, GDNF was detected in 12 out of 15 ALS patients but not in any controls, indicating that ALS patients may have an enhanced ability to produce GDNF, which could be a response to the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GDNF but not BDNF is increased in cerebrospinal fluid in amyotrophic lateral sclerosis. Grundström, E., Lindholm, D., Johansson, A., et al.[2019]

In a multicenter trial involving 1,135 ALS patients, BDNF treatment did not show a significant benefit for overall survival compared to placebo, although a trend towards increased survival was noted in the 100 microg/kg group.

Post hoc analyses revealed that patients with early respiratory impairment and those experiencing altered bowel function as an adverse effect had significantly better survival rates with 100 microg/kg BDNF, suggesting potential specific benefits in these subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A controlled trial of recombinant methionyl human BDNF in ALS: The BDNF Study Group (Phase III). [2019]

Injecting human spinal cord-derived neural progenitor cells (hscNPCs) into the lumbar spinal cord of ALS transgenic mice significantly delayed symptom progression and improved motor function during late-stage disease, although it only extended survival by an average of 5 days.

The treatment led to increased production of growth factors like GDNF and IGF-1 in the spinal cord, suggesting that hscNPCs may help create a protective environment for motor neurons rather than directly replacing them.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intraspinal administration of human spinal cord-derived neural progenitor cells in the G93A-SOD1 mouse model of ALS delays symptom progression, prolongs survival and increases expression of endogenous neurotrophic factors. Knippenberg, S., Rath, KJ., Böselt, S., et al.[2018]

In a study involving 72 ALS patients, recombinant human ciliary neurotrophic factor (rhCNTF) was found to be well-tolerated at doses of 5 micrograms/kg/day or lower, showing similar tolerability to placebo.

At higher doses, rhCNTF was associated with several adverse effects, including anorexia, weight loss, and reactivation of herpes simplex virus, indicating that while it may have therapeutic potential, careful dose management is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity and tolerability of recombinant human ciliary neurotrophic factor in patients with amyotrophic lateral sclerosis. Miller, RG., Bryan, WW., Dietz, MA., et al.[2019]

In a study involving 57 ALS patients, recombinant human ciliary neurotrophic factor (rHCNTF) was found to be safe and well-tolerated at doses up to 30 micrograms/kg, with no adverse neurological effects reported.

Some patients experienced dose-limiting toxicities, such as febrile reactions and fatigue, particularly at the highest dose, indicating the need for careful dose management in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of recombinant human ciliary neurotrophic factor (rHCNTF) in patients with amyotrophic lateral sclerosis. The ALS CNTF Treatment Study (ACTS) Phase I-II Study Group. [2019]

In a study involving 570 ALS patients, recombinant human ciliary neurotrophic factor (rhCNTF) showed no beneficial effects on limb strength or pulmonary function, regardless of the dosage administered over 6 months.

The highest dose of rhCNTF (5 micrograms/kg/day) was associated with increased adverse events and a higher number of deaths, raising safety concerns about its use in ALS treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A placebo-controlled trial of recombinant human ciliary neurotrophic (rhCNTF) factor in amyotrophic lateral sclerosis. rhCNTF ALS Study Group. Miller, RG., Petajan, JH., Bryan, WW., et al.[2004]

In a study using transgenic ALS mice, blocking the p75 neurotrophin receptor (p75(NTR)) with a cyclic decapeptide antagonist did not change the onset or progression of ALS symptoms, indicating that this approach may not be effective in altering disease outcomes.

The research suggests that other pathways or receptors, beyond the NGF-p75(NTR) interaction, may play a significant role in motor neuron degeneration in ALS, highlighting the complexity of the disease mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of p75 neurotrophin receptor antagonist on disease progression in transgenic amyotrophic lateral sclerosis mice. Turner, BJ., Murray, SS., Piccenna, LG., et al.[2011]

The ALS CNTF Treatment Study involving 730 patients found that subcutaneous administration of recombinant human CNTF (rHCNTF) did not significantly slow disease progression in ALS, as there was no meaningful difference in muscle strength decline compared to placebo.

While rHCNTF was generally safe, side effects like anorexia and weight loss limited dosing for many patients, indicating that while it may be tolerable, its efficacy in treating ALS remains unproven.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A double-blind placebo-controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis. ALS CNTF Treatment Study Group. [2019]

Transplanting human cortical-derived neural progenitor cells that secrete GDNF into the cortex of ALS model rats protected motor neurons, delayed disease progression, and increased survival rates.

These cells also showed successful survival and GDNF expression in cynomolgus macaques without causing any adverse effects, indicating a potential safe and effective treatment strategy for ALS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transplantation of Neural Progenitor Cells Expressing Glial Cell Line-Derived Neurotrophic Factor into the Motor Cortex as a Strategy to Treat Amyotrophic Lateral Sclerosis. Thomsen, GM., Avalos, P., Ma, AA., et al.[2019]

Glial cell line-derived neurotropic factor (GDNF) is crucial for the development and health of motor neurons, suggesting it could help in treating motor neuron diseases.

GDNF may not only support the development of spinal cord motor neurons but also has the potential to protect and rescue injured motor neurons, indicating its promising clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Roles of glial cell line-derived neurotropic factor in motoneuron development and motoneuron disease]. Cai, W., Zhao, H., Yuan, Z.[2005]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Neurotrophic factors in the physiology of motor neurons and their role in the pathobiology and therapeutic approach to amyotrophic lateral sclerosis. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Transplantation of human neural progenitor cells secreting GDNF into the spinal cord of patients with ALS: a phase 1/2a trial. [2022]

3. England pubmed.ncbi.nlm.nih.gov

GDNF but not BDNF is increased in cerebrospinal fluid in amyotrophic lateral sclerosis. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

A controlled trial of recombinant methionyl human BDNF in ALS: The BDNF Study Group (Phase III). [2019]

5. England pubmed.ncbi.nlm.nih.gov

Intraspinal administration of human spinal cord-derived neural progenitor cells in the G93A-SOD1 mouse model of ALS delays symptom progression, prolongs survival and increases expression of endogenous neurotrophic factors. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

Toxicity and tolerability of recombinant human ciliary neurotrophic factor in patients with amyotrophic lateral sclerosis. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

A phase I study of recombinant human ciliary neurotrophic factor (rHCNTF) in patients with amyotrophic lateral sclerosis. The ALS CNTF Treatment Study (ACTS) Phase I-II Study Group. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

A placebo-controlled trial of recombinant human ciliary neurotrophic (rhCNTF) factor in amyotrophic lateral sclerosis. rhCNTF ALS Study Group. [2004]

9. United States pubmed.ncbi.nlm.nih.gov

Effect of p75 neurotrophin receptor antagonist on disease progression in transgenic amyotrophic lateral sclerosis mice. [2011]

10. United States pubmed.ncbi.nlm.nih.gov

A double-blind placebo-controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis. ALS CNTF Treatment Study Group. [2019]

11. England pubmed.ncbi.nlm.nih.gov

Transplantation of Neural Progenitor Cells Expressing Glial Cell Line-Derived Neurotrophic Factor into the Motor Cortex as a Strategy to Treat Amyotrophic Lateral Sclerosis. [2019]

12. China pubmed.ncbi.nlm.nih.gov

[Roles of glial cell line-derived neurotropic factor in motoneuron development and motoneuron disease]. [2005]