NurOwn Stem Cell Trial

Overview

NurOwn (NCT03280056) was a landmark Phase 3 clinical trial evaluating autologous mesenchymal stem cell (MSC) therapy for amyotrophic lateral sclerosis, conducted by BrainStorm Cell Therapeutics. This trial represented one of the most advanced stem cell approaches for neurodegenerative disease, utilizing the patient's own cells that were engineered to secrete neurotrophic factors before being reintroduced into the body[@nurown2021][@stem2020].

The trial completed in 2020 and generated important data on the safety and potential efficacy of stem cell therapy in ALS, while also providing insights into the challenges of cell-based approaches for neurodegenerative diseases. While primarily focused on ALS, the findings from NurOwn have implications for broader neurodegenerative disease research, including Parkinson's disease and other conditions where neurotrophic factor support may be beneficial.

Trial Details

| Attribute | Value |
|-----------|-------|
| NCT Number | NCT03280056 |
| Phase | Phase 3 |
| Status | Completed (results published) |
| Sponsor | BrainStorm Cell Therapeutics |
| Enrollment | 196 patients |
| Duration | 28 weeks treatment |
| Study Period | 2017-2020 |
| Locations | US (multiple centers) |
| Randomization | 2:1 (active:placebo) |
| Delivery Route | Intrathecal injection |

Mechanism of Action

NurOwn utilizes a sophisticated autologous stem cell approach that represents one of the most advanced cell therapy platforms in neurodegeneration[@mazzini2015]:

Overview

NurOwn (NCT03280056) was a landmark Phase 3 clinical trial evaluating autologous mesenchymal stem cell (MSC) therapy for amyotrophic lateral sclerosis, conducted by BrainStorm Cell Therapeutics. This trial represented one of the most advanced stem cell approaches for neurodegenerative disease, utilizing the patient's own cells that were engineered to secrete neurotrophic factors before being reintroduced into the body[@nurown2021][@stem2020].

The trial completed in 2020 and generated important data on the safety and potential efficacy of stem cell therapy in ALS, while also providing insights into the challenges of cell-based approaches for neurodegenerative diseases. While primarily focused on ALS, the findings from NurOwn have implications for broader neurodegenerative disease research, including Parkinson's disease and other conditions where neurotrophic factor support may be beneficial.

Trial Details

| Attribute | Value |
|-----------|-------|
| NCT Number | NCT03280056 |
| Phase | Phase 3 |
| Status | Completed (results published) |
| Sponsor | BrainStorm Cell Therapeutics |
| Enrollment | 196 patients |
| Duration | 28 weeks treatment |
| Study Period | 2017-2020 |
| Locations | US (multiple centers) |
| Randomization | 2:1 (active:placebo) |
| Delivery Route | Intrathecal injection |

Mechanism of Action

NurOwn utilizes a sophisticated autologous stem cell approach that represents one of the most advanced cell therapy platforms in neurodegeneration[@mazzini2015]:

Mesenchymal Stem Cell (MSC) Platform

• Patient's own bone marrow is aspirated
• MSCs are isolated and expanded in culture
• Autologous cells avoid immune rejection concerns

• Cells are cultured under proprietary conditions
• Induces secretion of multiple neurotrophic factors
• Cells become "MSC-NTF" cells (mesenchymal stem cells - neurotrophic factors)

• BDNF (Brain-Derived Neurotrophic Factor): Supports motor neuron survival and synaptic function
• GDNF (Glial Cell Line-Derived Neurotrophic Factor): Potent motor neuron protector
• HGF (Hepatocyte Growth Factor): Anti-inflammatory and neuroprotective properties
• VEGF (Vascular Endothelial Growth Factor): Supports neurovascular health and angiogenesis
• IGF-1 (Insulin-like Growth Factor): Promotes neuronal survival and metabolism

• Intrathecal injection (into spinal canal)
• Allows direct access to cerebrospinal fluid circulation
• Cells migrate to areas of injury in the spinal cord and brain

Therapeutic Mechanisms

The neurotrophic factors secreted by NurOwn cells work through multiple pathways[@berry2019]:

• Provides growth factors directly to dying motor neurons
• Supports axonal sprouting and synaptic function
• Promotes neuronal survival in hostile microenvironment

• Reduces pro-inflammatory immune responses
• Modulates microglial activation
• Creates favorable microenvironment for neuron survival
• May reduce autoimmune components of neurodegeneration

• Secreted factors block programmed cell death pathways
• Protects remaining motor neurons from excitotoxicity
• Promotes anti-apoptotic signaling cascades

• Some evidence of neural differentiation potential
• May replace lost support cells (oligodendrocytes)
• Could promote remyelination in affected pathways

Trial Design

Study Structure

• Design: Randomized, double-blind, placebo-controlled
• Randomization: 2:1 treatment:placebo
• Treatment Schedule: 3 injections (baseline, week 8, week 16)
• Follow-up: 28 weeks total treatment period

Patient Population

• Diagnosis: Definite or probable ALS (El Escorial revised criteria)
• Age: 18-60 years
• Disease Duration: ≤2 years from diagnosis
• Forced Vital Capacity: ≥60% predicted
• ALSFRS-R: ≥26 points at baseline

Inclusion/Exclusion Criteria

Key Inclusion:

• Diagnosis of sporadic or familial ALS
• Uprright walking capability (or assistive devices)
• Ability to undergo intrathecal injection
• Signed informed consent

• Significant cardiac, hepatic, or renal disease
• Active infection
• Immunosuppressive therapy
• Prior stem cell therapy

Endpoints

Primary:

• Rate of decline in ALSFRS-R (Revised ALS Functional Rating Scale)
• Change from baseline to week 28

• Slow vital capacity (SVC) change
• Muscle strength (hand-held dynamometry)
• Quality of life (ALSAQ-40)
• CSF neurotrophic factor levels
• Safety and tolerability

Results

Primary Endpoint Analysis

Secondary Endpoints

• Mixed results across different measures
• Some positive trends in slower disease progression
• Safety profile was consistent with prior phases

Biomarker Findings

• Elevated CSF neurotrophic factors in treatment arm
• Demonstrated successful cell engraftment and function
• Correlation between BDNF levels and clinical response observed

Clinical Implications

Lessons Learned

• Autologous cells show patient-to-patient variability
• Optimal dosing and timing remain unclear
• Delivery method affects distribution

• ALS involves multiple pathophysiological pathways
• Single-mechanism approaches may be insufficient
• Combination approaches may be needed

• Subgroup analyses can reveal hidden benefits
• Biomarker-driven enrichment strategies may improve signal detection
• Longer follow-up may be needed for cell therapies

Relevance to Other Neurodegenerative Diseases

While NurOwn targeted ALS, the platform has implications for:

| Disease | Rationale | Status |
|---------|-----------|--------|
| Parkinson's Disease | GDNF supports dopaminergic neurons | Preclinical |
| Multiple Sclerosis | Immunomodulation, remyelination | Preclinical |
| Alzheimer's Disease | BDNF supports memory circuits | Research |
| Spinal Cord Injury | Neurotrophic support, regeneration | Research |

Competitive Landscape

Stem cell approaches for neurodegeneration:

| Approach | Company | Indication | Stage |
|----------|---------|------------|-------|
| NurOwn | BrainStorm | ALS | Phase 3 |
| CNS10-NPC-GDNF | Neuralstem | ALS | Phase 1/2 |
| IT-Remedy | CytoMed | ALS | Phase 1 |
| MSC therapy | Various | PD | Preclinical |

Future Directions

• Allogeneic "off-the-shelf" cell products
• Gene-modified cells for enhanced factor secretion
• Combination cell-gene approaches

• Different neurotrophic factor profiles for different diseases
• Engineered cells with enhanced survival and function

• Intravenous vs intrathecal comparison
• Direct CNS injection approaches
• Biomaterial encapsulation for sustained release

Related Pages

• [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
• [Stem Cell Therapy](/therapeutics/stem-cell-therapy-neurodegeneration)
• [Neurotrophic Factors](/mechanisms/neurotrophic-factor-signaling)
• [ALS Treatment Pipeline](/therapeutics/als-treatment-pipeline)

References

Overview

NurOwn (NCT03280056) was a landmark Phase 3 clinical trial evaluating autologous mesenchymal stem cell (MSC) therapy for amyotrophic lateral sclerosis, conducted by BrainStorm Cell Therapeutics. This trial represented one of the most advanced stem cell approaches for neurodegenerative disease, utilizing the patient's own cells that were engineered to secrete neurotrophic factors before being reintroduced into the body[@nurown2021][@stem2020].

The trial completed in 2020 and generated important data on the safety and potential efficacy of stem cell therapy in ALS, while also providing insights into the challenges of cell-based approaches for neurodegenerative diseases.

Trial Details

| Attribute | Value |
|-----------|-------|
| NCT Number | NCT03280056 |
| Phase | Phase 3 |
| Status | Completed (results published) |
| Sponsor | BrainStorm Cell Therapeutics |
| Enrollment | 196 patients |
| Duration | 28 weeks treatment |
| Study Period | 2017-2020 |
| Locations | US (multiple centers) |

Mechanism of Action

NurOwn utilizes a sophisticated autologous stem cell approach:

Mesenchymal Stem Cell (MSC) Platform

• Patient's own bone marrow is aspirated
• MSCs are isolated and expanded in culture
• Autologous cells avoid immune rejection concerns

• Cells are cultured under proprietary conditions
• Induces secretion of multiple neurotrophic factors
• Cells become "MSC-NTF" cells

• BDNF (Brain-Derived Neurotrophic Factor): Supports motor neuron survival
• GDNF (Glial Cell Line-Derived Neurotrophic Factor): Potent motor neuron protector
• HGF (Hepatocyte Growth Factor): Anti-inflammatory and neuroprotective
• VEGF (Vascular Endothelial Growth Factor): Supports neurovascular health
• IGF-1 (Insulin-like Growth Factor): Promotes neuronal survival

• Intrathecal injection (into spinal canal)
• Allows direct access to cerebrospinal fluid
• Cells migrate to areas of injury

Therapeutic Mechanisms

• Provides growth factors directly to dying motor neurons
• Supports axonal sprouting and synaptic function

• Reduces pro-inflammatory immune responses
• Creates favorable microenvironment for neuron survival

• Secreted factors block programmed cell death pathways
• Protects remaining motor neurons

• Some evidence of neural differentiation potential
• May replace lost support cells

Trial Design

Study Structure

• Design: Randomized, double-blind, placebo-controlled
• Randomization: 2:1 treatment:placebo
• Treatment Schedule: 3 injections (baseline, 8 weeks, 16 weeks)

Patient Population

• Diagnosis: Definite or probable ALS (El Escorial revised criteria)
• Age: 18-60 years
• Disease Duration: ≤2 years from diagnosis
• ALSFRS-R: ≥20 at screening
• Forced Vital Capacity (FVC): ≥50% predicted

Inclusion Criteria

• On stable riluzole for ≥30 days
• Not on edaravone (until amendment)
• Adequate venous access for cell collection
• Able to undergo lumbar puncture

Exclusion Criteria

• Active infection
• Cancer within 5 years
• Autoimmune disease
• Previous stem cell therapy
• Significant cardiac, hepatic, or renal disease

Endpoints

Primary Endpoint

• ALSFRS-R Change: Rate of decline from baseline to Week 28

Secondary Endpoints

• Pulmonary Function: Slow vital capacity (SVC) change
• Muscle Strength: Hand-held dynamometry
• Biomarkers: Neurofilament light chain (NfL) in CSF
• Safety: Adverse events, serious adverse events
• Quality of Life: ALSAQ-40

Exploratory Endpoints

• Biomarker responses in CSF
• Survival analysis
• Subgroup efficacy analyses

Results

Primary Outcome

• Overall Population: Did not meet statistically significant benefit
• Treatment Difference: Modest slowing of decline in ALSFRS-R
• Statistical Significance: p = 0.308 (not significant in ITT population)

Pre-Specified Subgroup Analyses

Fast Progressors

• Patients with faster disease progression showed significant benefit
• ALSFRS-R decline reduced by approximately 40%
• Suggests greatest benefit in those with aggressive disease

Earlier Disease

• Trend toward benefit in patients with shorter disease duration
• Supports early intervention hypothesis

Biomarker Results

• Neurofilament Light Chain (NfL): Reduced in treatment group
• Suggests neuroprotective effect at cellular level
• Biomarker evidence complements clinical findings

Safety Profile

• Generally well-tolerated
• Common adverse events: Headache, back pain (procedure-related)
• No cell-related serious adverse events
• No tumor formation observed
• Low dropout rate due to treatment

Clinical Significance

The NurOwn trial represents an important step in cell therapy for neurodegenerative diseases:

Challenges and Considerations

• Intrathecal delivery is invasive
• Autologous cells require individual manufacturing
• Variable patient responses
• Need for better biomarkers of efficacy
• Optimal timing of intervention unclear
• [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
• [Stem Cell Therapy](/therapeutics/stem-cell-therapy)
• [Mesenchymal Stem Cells](/cell-types/mesenchymal-stem-cells)
• [Neurotrophic Factors](/mechanisms/neurotrophic-factors)
• [BDNF](/proteins/bdnf)
• [GDNF](/proteins/gdnf)
• [Motor Neurons](/cell-types/motor-neurons)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/genes/ar)

External Links

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
• [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

References