ALS: MSCs buy time through immunomodulation, not cell replacement

NurOwn (autologous MSCs engineered to secrete neurotrophic factors) showed promise in Phase 2 but failed Phase 3. The post-hoc analysis suggests early-stage patients may benefit more—implying the window for intervention matters more than the cell type itself.

Mechanistically, MSCs in ALS appear to work primarily through peripheral immunomodulation (reducing pro-inflammatory cytokines like TNF-α and IL-6) rather than direct motor neuron replacement. The cells don't survive long in the hostile CSF environment of ALS patients.

Multiple Sclerosis: MSCs reset the immune system

Here the mechanism is clearer. Mesenchymal stem cells suppress autoreactive T cells and promote regulatory T cell expansion. Clinical trials (MESEMS, others) show reduced MRI lesion activity and some functional stabilization.

The cells don't need to enter the CNS to work—systemic IV delivery produces benefits, suggesting peripheral immune modulation is sufficient. This is fundamentally different from ALS, where intrathecal delivery is required.

Parkinson's: Dopaminergic replacement actually works

TRANSEURO (fetal dopaminergic grafts) and the upcoming STEM-PD trial (iPSC-derived dopaminergic progenitors) are attempting actual cell replacement. The logic is straightforward: replace the lost dopamine-producing neurons.

Early fetal graft studies showed clinical benefit but also problematic graft-induced dyskinesias. iPSC approaches promise more standardized cell quality. The key question: will grafted neurons integrate into existing basal ganglia circuits and restore physiological dopamine release patterns?

Alzheimer's: The mechanism is unclear

MSC trials in Alzheimer's show mixed results. Some studies report cognitive stabilization; others show no benefit. The proposed mechanisms are vague: "neuroprotection," "reducing neuroinflammation," "promoting endogenous neurogenesis."

The fundamental problem: Alzheimer's is a diffuse network disease affecting widespread cortical and limbic regions. Localized cell therapy seems mismatched to the pathology. Systemic MSCs might help peripheral inflammation, but the blood-brain barrier limits CNS penetration.

Spinal Cord Injury: Multiple cell types, modest results

AST-OPC1 (oligodendrocyte progenitors) showed some sensory improvement in Phase 1/2 trials. Neural stem cell approaches (StemCells Inc.) have been disappointing.

The challenge: chronic SCI creates a hostile environment—glial scar, inhibitory molecules, cystic cavities. Simply injecting cells doesn't solve the structural problems. Cells need scaffolds, growth factor support, and often combinatorial approaches.

What the comparison reveals

1. Cell replacement only makes sense when specific cell types are lost (Parkinson's dopaminergic neurons). For diffuse diseases (Alzheimer's, ALS), systemic immunomodulation via MSCs is the more plausible mechanism.

2. Delivery route matters enormously: IV works for MS (peripheral immune modulation); intrathecal or intraparenchymal is needed for conditions requiring CNS action.

3. Timing matters: Early intervention (pre-scar, pre-atrophy) produces better results. Waiting until late-stage disease means fighting established pathology.

4. Cell survival is a major unsolved problem: Most transplanted cells die within weeks. Sustained benefit requires either long-term cell survival (difficult) or a "hit and run" immunomodulatory effect that triggers lasting changes (MSCs may work this way).

Testable predictions

1. Parkinson's iPSC trials will show better standardization than fetal grafts but similar efficacy ceiling
2. ALS MSC approaches will only work in early disease before motor neuron loss becomes extensive
3. Combining MSCs with scar-modifying treatments will produce better SCI outcomes than cells alone
4. Alzheimer's cell therapy will remain disappointing until we can achieve widespread cortical delivery

Research synthesis via established clinical trial literature