A paper published in the journal of the Alzheimer’s Association has revealed the results of a Phase 1 clinical trial of stem cells for Alzheimer’s disease.
Using stem cells for their signals
While stem cells, including the mesenchymal stem cells (MSCs) of which Lomecel-B consists, are well-known for their ability to differentiate into other cells, this approach does not involve that ability. Instead, this clinical trial focused on their attraction to damage and inflammation [1] along with their signaling abilities, a combination that gives them the ability to recruit microglia in order to reduce amyloid beta deposits, as has been shown in preclinical animal studies [2].
However, despite their effectiveness being shown in cell culture and animals, it has not previously been shown to be effective or even safe in people, which was the purpose of this trial.
Shown to be safe in this placebo-controlled study
In this Phase 1 study of people with mild Alzheimer’s disease, 8 people were given placebo, 15 people were given 20 million MSCs, and 10 people were given 100 million MSCs. As a Phase 1 trial is focused on safety rather than effectiveness, the primary endpoint was treatment-emergent serious adverse events (TE-SAEs) within 30 days of infusion.
Only one person had a TE-SAE: a person who had received 100 million cells had back pain that was determined to be unrelated to the treatment. One person, who had withdrawn from the low-dose group, died in an assisted living facility 144 days after infusion, presumably of age-related diseases.
Adverse events occurred more often in the placebo group than the treatment groups. No adverse events, serious or otherwise, were determined to be related to the infusion.
Mechanisms of action
The researchers analyzed multiple biomarkers related to neurodegenerative disease, including vascular endothelial growth factor (VEGF), interleukin-4 (IL-4), and IL-6.
VEGF is known to have positive and protective effects on the nervous system [3], and while it degrades with Alzheimer’s disease, it was maintained in the low-dose group and actually increased in the high-dose group. IL-4, which has anti-inflammatory effects and known positive effects in the context of Alzheimer’s disease [4], was maintained in the treatment arms but decreased in the placebo group. IL-6, a cytokine that protects against glucose toxicity [5], was significantly higher in the high-dose group than the placebo group.
Perhaps most importantly, the volume of the hippocampus, the part of the brain associated with memory, was significantly higher in the high-dose treatment group than either of the other groups.
Effects on cognition
Unfortunately, the effects on cognitive decline were less clear than the biomarker studies. The high-dose group performed akin to placebo on the Mini-Mental State Examination and a quality of life test; only the low-dose group saw improvement there. Another test, ADAS-cog, showed positive results that were not statistically significant. In a different quality of life study, ADCS-ADL, the placebo group performed much worse than either of the treatment groups.
Conclusion
In total, these results are very positive for a Phase 1 clinical trial. While the cognitive effects are unclear, the mechanisms of action appear to work as expected, it has been shown to be safe at both doses, and future phases with more participants will better prove or disprove the effectiveness of Lomecel-B for Alzheimer’s disease.
Literature
[1] Oliva, A. A., McClain-Moss, L., Pena, A., Drouillard, A., & Hare, J. M. (2019). Allogeneic mesenchymal stem cell therapy: A regenerative medicine approach to geroscience. Aging Medicine, 2(3), 142-146.
[2] Lee, J. K., Schuchman, E. H., Jin, H. K., & Bae, J. S. (2012). Soluble CCL5 derived from bone marrow-derived mesenchymal stem cells and activated by amyloid ß ameliorates Alzheimer’s disease in mice by recruiting bone marrow-induced microglia immune responses. Stem cells, 30(7), 1544-1555.
[3] Hohman, T. J., Bell, S. P., Jefferson, A. L., & Alzheimer’s Disease Neuroimaging Initiative. (2015). The role of vascular endothelial growth factor in neurodegeneration and cognitive decline: exploring interactions with biomarkers of Alzheimer disease. JAMA neurology, 72(5), 520-529.
[4] Shimizu, E., Kawahara, K., Kajizono, M., Sawada, M., & Nakayama, H. (2008). IL-4-induced selective clearance of oligomeric ß-amyloid peptide1–42 by rat primary type 2 microglia. The Journal of Immunology, 181(9), 6503-6513.
[5] Villar-Fincheira, P., Sanhueza-Olivares, F., Norambuena-Soto, I., Cancino-Arenas, N., Hernandez-Vargas, F., Troncoso, R., … & Chiong, M. (2021). Role of interleukin-6 in vascular health and disease. Frontiers in Molecular Biosciences, 8, 79.
