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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety of a new treatment for Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease. The treatment, CNS10-NPC-GDNF, involves transplanting special cells into the brain that produce GDNF, a protein that helps nerve cells survive. The trial aims to determine the safety of placing these cells into the brain's motor cortex, which controls movement. Individuals with ALS symptoms for three years or less and experiencing arm weakness might be suitable candidates for this trial. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive it.

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.

Is there any evidence suggesting that CNS10-NPC-GDNF is likely to be safe for humans?

Research has shown that CNS10-NPC-GDNF, a treatment using specially modified cells, was safe in earlier studies. Researchers tested these cells by placing them in the spinal cord of people with Amyotrophic Lateral Sclerosis (ALS). The studies found that the cells were well-tolerated and did not cause serious side effects.

Additionally, tests have shown that CNS10-NPC-GDNF cells protect important nerve cells in the spinal cord. This suggests the treatment could be beneficial without major safety concerns.

However, while the treatment has been safely used in the spinal cord, it is now being tested in the motor cortex (a part of the brain) in people for the first time. Researchers are currently focusing on understanding its safety in this new area. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for ALS?

Researchers are excited about CNS10-NPC-GDNF for ALS because it offers a novel approach by targeting the motor cortex with glial cell line-derived neurotrophic factor (GDNF). Unlike the standard ALS treatments, which primarily focus on managing symptoms, this treatment aims to protect and even repair motor neurons directly. This is achieved by implanting neural progenitor cells that produce GDNF, potentially slowing the disease progression. The different dosages and targeting strategies in the trial arms—whether focusing on the dominant or non-dominant hand—also offer insights into optimizing delivery for maximum benefit. This innovative approach could pave the way for a new era in ALS therapies, offering hope for more effective disease modification.

What evidence suggests that CNS10-NPC-GDNF might be an effective treatment for ALS?

Research has shown that CNS10-NPC-GDNF, a treatment using specially designed cells, has potential for helping people with ALS. In earlier studies, researchers placed these cells into the spinal cord of ALS patients, and the treatment was well-tolerated. The goal is to slow the disease and possibly extend patients' lives. The cells release GDNF, a substance that supports nerve cell health. In this trial, participants will receive CNS10-NPC-GDNF in varying dosages and locations within the motor cortex of the brain. Although the current study focuses on placing these cells in the motor cortex, earlier results suggest they might help manage ALS symptoms. ^{1 2 5 6 7}

Who Is on the Research Team?

Richard Lewis, MD

Principal Investigator

Cedars-Sinai Medical Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05306457

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

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9499868/

Transplantation of human neural progenitor cells secreting ... CNS10-NPC-GDNF were transplanted unilaterally into the lumbar spinal cord of 18 ALS participants in a phase 1/2a study (NCT02943850). The primary endpoint of ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT02943850

NCT02943850 | CNS10-NPC-GDNF for the Treatment of ALS This study will be the first to use a genetically modified progenitor cells to treat a neurodegenerative disease.

4. cgtlive.com cgtlive.com/view/astrocyte-cell-therapy-well-tolerated-amyotrophic-lateral-sclerosis

Astrocyte Cell Therapy Well-Tolerated in Amyotrophic ... Participants progressed at a mean rate of 1.2 points per month (95% CI, –1.5 to –0.9) on ALS Functional Rating Scale Revise scores, typical with ...

5. alsnewstoday.com alsnewstoday.com/cns10-npc-gdnf/

CNS10-NPC-GDNF for ALS CNS10-NPC-GDNF is an experimental stem cell-based therapy being developed to potentially slow disease progression and extend survival in people ...

6. neals.org neals.org/als-trials/nct02943850

Human Neural Progenitor Cells Secreting Glial Cell Line ... In this study, we want to learn if CNS10-NPC-GDNF cells are safe to transplant into the spinal cords of people. Study Status: Not recruiting. Disease:.

7. als.net als.net/als-trial-navigator/500027/

CNS10-NPC-GDNF Delivered to the Motor Cortex for ALS In this study, we want to learn if CNS10-NPC-GDNF cells are safe to transplant into the motor cortex (brain) of people. What participation looks like. This ...