Neurotrophic Bone Marrow Cellular Nests Prevent Spinal Motoneuron Degeneration in Amyotrophic Lateral Sclerosis Patients: A Pilot Safety Study

Abstract

The objective of this article is to assess the safety of intraspinal infusion of autologous bone marrow mononuclear cells (BMNCs) and, ultimately, to look for histopathological signs of cellular neurotrophism in amyotrophic lateral sclerosis (ALS) patients. We conducted an open single arm phase I trial. After 6 months observation, autologous BMNCs were infused into the posterior spinal cord funiculus. Safety was the primary endpoint and was defined as the absence of serious transplant-related adverse events. In addition, forced vital capacity (FVC), ALS-functional rating scale (ALS-FRS), Medical Research Council scale for assessment of muscle power (MRC), and Norris scales were assessed 6 and 3 months prior to the transplant and quarterly afterward for 1 year. Pathological studies were performed in case of death. Eleven patients were included. We did not observe any severe transplant-related adverse event, but there were 43 nonsevere events. Twenty-two (51%) resolved in ≤2 weeks and only four were still present at the end of follow-up. All were common terminology criteria for adverse events grade ≤2. No acceleration in the rate of decline of FVC, ALS-FRS, Norris, or MRC scales was observed. Four patients died on days 359, 378, 808, and 1,058 post-transplant for reasons unrelated to the procedure. Spinal cord pathological analysis showed a greater number of motoneurons in the treated segments compared with the untreated segments (4.2 ± 0.8 motoneurons per section [mns per sect] and 0.9 ± 0.3 mns per sect, respectively). In the treated segments, motoneurons were surrounded by CD90+ cells and did not show degenerative ubiquitin deposits. This clinical trial confirms not only the safety of intraspinal infusion of autologous BMNC in ALS patients but also provides evidence strongly suggesting their neurotrophic activity.

Point-Of-Care Stem Cell Therapy (POCST): Multisite transplantation of autologous bone marrow-derived mononuclear cells in 85 patients with Amyotrophic Lateral Sclerosis improves survival

“…These confirms and reassure the previous findings by other groups about the safety of the IT infusion of SCs [52,53,[68][69][70]72,77].…”

“…Our results support the safety of the method and add unique information about the effectiveness of autologous stem cells to treat ALS supporting previous reports that described safety, feasibility and in some cases stop of the functional declination [52,53,[68][69][70]72,77].…”

“…Furthermore, other models point-out that BM-MNCs infusion via IT [50] or IM [51] have major beneficial effects in ALS. Therefore, and together with safety profiles described by other authors infusing SCs IT in ALS and other diseases [52,53,[62][63][64][65][66][67][68][69][70][71][72]] the use of BM-MNCs via IT, IM and IV in humans with ALS is rational.…”

Rethinking on ethics and regulations in cell therapy as part of neurorestoratology

“…There have been ten studies thus far evaluating the effects of cellular therapy in 203 patients. [24][25][26][27][28][29][30][31][32] These studies have demonstrated beneficial effects on survival, motor function, and in stabilizing the progressive deterioration in the forced vital capacity of ALS patients. Some of the notable results are found in the following studies: 1) Prabhakar et al conducted a pilot study of ten patients receiving adult autologous BMMNCs intrathecal transplantation.…”

Recent Advances and the Future of Stem Cell Therapies in Amyotrophic Lateral Sclerosis

“…Thus, the authors suggested that slowing of the disease course in these subjects may have been a reflection of the disease phenotype and not the therapy. Another group, in Spain, evaluated 11 patients following injection of autologous bone marrow-derived MSCs into the spinal cord [77,78]. No serious adverse events were reported nor were there any reported changes in the disease course; however, MNs near the areas of grafting showed fewer degenerative signs on histopathology.…”