Stem Cell Transplantation in Amyotrophic Lateral Sclerosis Patients: Methodological Approach, Safety, and Feasibility

Abstract

We previously reported the therapeutic potential of human peripheral blood (hPB) CD34(+) cells for bone fracture healing via vasculogenesis/angiogenesis and osteogenesis. Transplantation of not only hPB CD34(+) cells but also hPB total mononuclear cells (MNCs) has shown their therapeutic efficiency for enhancing ischemic neovascularization. Compared with transplantation of purified hPB CD34(+) cells, transplantation of hPB MNCs is more attractive due to its simple method of cell isolation and inexpensive cost performance in the clinical setting. Thus, in this report, we attempted to test a hypothesis that granulocyte colony-stimulating factor-mobilized (GM) hPB MNC transplantation could also contribute to fracture healing via vasculogenesis/angiogenesis and osteogenesis. Nude rats with unhealing fractures received local administration of the following materials with atelocollagen: 1 × 10(7) GM hPB MNCs (Hi group), 1 × 10(6) GM hPB MNCs (Lo group), or PBS (PBS group). Immunohistochemistry and real-time reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated human cell-derived vasculogenesis and osteogenesis in the Hi and Lo groups, but not in the PBS group at week 1. Intrinsic angiogenesis and osteogenesis assessed by rat capillary, osteoblast density, and real-time RT-PCR analysis was significantly enhanced in the Hi group compared to the other groups. Blood flow assessment by laser doppler perfusion imaging showed a significantly higher blood flow ratio at week 1 in the Hi group compared with the other groups. Morphological fracture healing was radiographically and histologically confirmed in about 30% of animals in the Hi group at week 8, whereas all animals in the other groups resulted in nonunion. Local transplantation of GM hPB MNCs contributes to fracture healing via vasculogenesis/angiogenesis and osteogenesis.

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

“…An early study tested 3 patients using a protocol of subcutaneous G-CSF therapy and isolation of CD34+ stem cells followed by intrathecal administration of the collected stem cells and showed minimal adverse effects [66]. Alternatively, a separate group focused on CD133+ cells mobilized by G-CSF followed by direct injection of the cells into cortical motor areas of the brain utilizing a frame-based or frame-less stereotactically guided needle [68,69]. In the initial study, 10 patients were enrolled and compared with 10 control patients not accepting treatment or who applied after the study period [68].…”

“…The treatment group showed an improvement in baseline ALSFRS-R scores; however, the control group had a higher ALSFRS-R score at baseline limiting a comparison. An additional 67 patients were then evaluated after having undergone the same procedure [69]. Two postoperative deaths were reported, and no outcome data were reported, but these serious adverse events suggest that further use of frontal cortex injection should be approached cautiously to minimize patient risk.…”

Increase of Pyramidal Tract Fractional Anisotropy on MRI after Stem Cell Transplantation in ALS Patients

“…Mesenchymal stem cell transplantation into the spinal cords of ALS patients has been described, and the authors reported this method as safe [41]. Recently it has also been described that CD133+ stem cells transplantation into the frontal motor cortices in ALS patients is a safe and well−tolerated procedure [43,44,47].…”

“…Therefore some researchers have attempted stem-cell-based approaches for the treatment of ALS patients. Current clinical trials are based principally on two main transplantation strategies: the systemic [39,40] and the local approaches [22,[41][42][43][44][45][46]. Mesenchymal stem cell transplantation into the spinal cords of ALS patients has been described, and the authors reported this method as safe [41].…”

“…The aim of this uncontrolled, open-label non-randomized clinical trial was to assess a possible improvement of UMN status through FA changes in the PT. and (e) evidence of cervical spondylotic myelopathy or structural abnormalities on MRI, as previously described [43,44].…”