[Summary] In this report, we conducted a pilot study to confirm whether repeated intravenous administration of autologous adipose-derived stem cells (ADSCs) for Parkinson's disease can be safely performed in a clinical setting. The subjects were 3 individuals, and 5 to 6 administrations were given at intervals of approximately one month. Evaluations were conducted using the Hoehn & Yahr scale and MDS-UPDRS, in addition to examinations by neurologists and interviews with patients and caregivers. We reported that no adverse events were observed throughout the observation period (from the start of treatment to 6 months after the final administration), and improvements in MDS-UPDRS were observed in all 3 individuals. While acknowledging the small number of cases, we presented the feasibility of repeated administration and basic findings for future research.

[Summary] In this report, we documented a case where autologous adipose-derived mesenchymal stem cells (ADSCs) were administered for ALS (Amyotrophic Lateral Sclerosis), and the subsequent long-term course was followed. The case was a 46-year-old male who was diagnosed with ALS in 2009, triggered by weakness in his lower limbs and choking while swallowing. His ALSFRS-R was initially 43, and his symptoms progressed rapidly, making choking during meals and conversation a problem. Intravenous administration of ADSCs began in 2013, with a total of 6 administrations. We noted that after the administration, the patient himself recognized a decrease in choking during conversation and meals, and progressed in a state where dysphagia and dysarthria were not prominent. We also reported that the ALSFRS-R showed changes up to a maximum of 45, and there was a period when fasciculation potentials were not detected on electromyography. After clearly stating that this is a single case and does not establish a causal relationship with the treatment, we indicated the possibility of safe administration and the need for further study.

[Summary] In this report, as part of our initiative of repeated intravenous infusion of autologous adipose-derived stem cells (ADSCs), we focused on and evaluated cognitive function. As research background, we noted that a total of 182 administrations were given to 39 individuals with ALS, COPD, PD, MSA (including SCD), and Alzheimer's disease, and no side effects were observed observationally. In this study, 9 individuals with cognitive impairment were evaluated through examinations by neurologists, interviews with caregivers, and MoCA. Administrations were given 5 to 6 times at intervals of approximately one month, and 5.0×10^7 to 1.2×10^8 cells were administered intravenously per session. We reported that the MoCA changed from an average of 10.3 to 19.6, and no cases of deterioration were observed among the 9 evaluated subjects. We also noted that amyloid PET was performed before and after administration in 3 individuals with Alzheimer's disease, suggesting a decrease in deposition in 1 case. As a consideration of the mechanism of action, we showed that the administered cells were positive for CD10 (neprilysin), reinforcing the hypothesis related to amyloid degradation. However, we also added that since this is not a comparative trial with a control group, clinical conclusions require future verification.

[Summary] In this report, we examined the intravenous administration of ADSCs to ALS patients with the aim of confirming safety and exploring efficacy. To 6 individuals, 4.3 to 8.7×10^7 ADSCs were administered 3 times at intervals of 1 to 2 months, and they were followed up for up to 3 months post-administration through examinations by multiple doctors including neurologists and interviews with patients and caregivers. We noted that while no adverse events were observed, 1 individual died due to disease progression. The transition of ALSFRS varied from case to case, with maintenance or decline mixed. After clearly stating that it was an open-label study without a control group and that caution is necessary in judging efficacy, we presented the possibility of safely performing repeated intravenous administration and the fact that the maintenance/improvement of ALSFRS suggested in some cases could serve as a rationale for future trials.

[Summary] In this report, regarding a case previously reported where "skin amyloid deposition may have improved after stem cell administration," we followed up on the same area 5 years later and summarized the long-term progress. The subject was a dermatology professor, and we noted that he expressed strong satisfaction that the deposition, which had been progressing over decades, receded after the administration. On the other hand, considering the possibility of other factors such as natural course, we made it clear that it is difficult to conclude that the improvement is the effect of ADSCs. Based on that, and against the background that the improvement continued for 2 months post-administration in a situation where other interventions were scarce, and that enzyme activities related to abnormal protein degradation have been reported in ADSCs, we presented the possibility of a connection between the two as a hypothesis. We also stated that the point of discussion regarding how long the effect might last could be important when discussing the applicability not only to skin amyloidosis but also to progressive neurodegenerative diseases.

[Summary] In this paper, we presented the treatment strategy of intravenously administering autologous adipose-derived stem cells for Alzheimer's disease as a hypothesis. The core idea is whether the administered stem cells might secrete neprilysin in the brain, breaking down and removing amyloid deposits. As one of the grounds, we cited a case where skin amyloid deposition resolved after stem cell administration, and noted that neprilysin activity was confirmed in the administered cells at that time. Furthermore, we organized the point that multiple mechanisms of action, such as nerve regeneration/repair, growth factor secretion, anti-inflammatory action, and angiogenesis, might be simultaneously involved. While touching on the characteristics that adipose-derived stem cells are relatively minimally invasive to harvest and can be repeatedly administered intravenously, we summarized from the standpoint that efficacy should be confirmed through future verification.

[Summary] In this paper, starting from the discussion that stem cells have neprilysin activity that breaks down amyloid β, we expanded it to a more generalized property and presented the hypothesis that there might be an activity that "solubilizes and removes abnormal proteins that have become insoluble and deposited." We pointed out the possibility that skin amyloid deposition and amyloid β in the Alzheimer's disease brain may not be identical, and developed the argument while avoiding a simple equation of the two. We stated that if this property is confirmed, it could be a theoretical suggestion not only for amyloidosis of the skin, heart, liver, and kidneys, but also for groups of diseases characterized by abnormal protein deposition, such as ALS (TDP-43) and Parkinson's disease (α-synuclein). We also mentioned verification methods, such as observing whether insoluble substances are broken down by stem cells in vitro.

[Summary] In this paper, we positioned the intravenous administration of ADSCs for ALS as a treatment hypothesis and organized the assumed mechanisms of action. We cited nerve repair, secretion of cytokines and nerve growth factors, and homing to the site of injury as background. Furthermore, focusing on caspase-4 as an enzyme that may be involved in the breakdown of TDP-43, which accumulates in ALS, we noted that we demonstrated the presence of caspase-4 activity in ADSCs via ELISA. We also clearly stated that a double-blind randomized controlled trial (RCT) is necessary to verify the hypothesis, and concluded with the expectation that this proposal would lead to the design and promotion of clinical trials.

[Summary] In this paper, we viewed neurodegenerative diseases as "proteinopathies" characterized by the accumulation of abnormal proteins, and organized the discussion with the aim of reinforcing the hypothesis that stem cells may be involved in the removal of abnormal proteins with additional experimental data. Following the previously reported neprilysin (amyloid β) and caspase activity (TDP-43), we evaluated reelin activity, which is discussed in relation to phosphorylated tau, by ELISA using ADSCs derived from Alzheimer's disease patients. All 5 cases showed positive, and we presented the measured values. Based on these results, we stated the possibility that the hypothesis that ADSCs may be broadly involved in the removal of abnormal protein deposits would be strengthened. At the same time, we mentioned future research developments combining characteristics such as homing, neuroprotection, and anti-inflammation.

[Summary] In this review, we provided an overview of stem cells used in regenerative medicine (iPS cells, ES cells, MSCs), and organized in particular the characteristics, current status of clinical application, and future prospects of mesenchymal stem cells (MSCs). In addition to MSCs' multi-lineage differentiation potential, we took up points of discussion such as tissue repair, anti-inflammatory action, secretion of growth factors, and potential involvement in abnormal proteins (amyloid, etc.). While citing bone marrow, dental pulp, etc., as sources, we described the clinical advantages of adipose-derived stem cells (ADSCs), which are minimally invasive to harvest and relatively easy to culture in sufficient quantities. We also touched on the point that the property of easily accumulating at lesions via intravenous administration (homing) could be important for clinical application. Furthermore, we outlined the system for implementing stem cell therapy in Japan (the Act on the Safety of Regenerative Medicine, review by a Certified Special Committee for Regenerative Medicine, submission of plans to the Ministry of Health, Labour and Welfare, institutional ethical review, etc.), and organized it including requirements regarding the medical care provision system.

[Summary] In this letter, we provided supplements and organized discussion points from an academic perspective in response to a previous report on the intravenous administration of autologous MSCs to spinal cord injury patients (13 cases). We mainly stated perspectives on research methodology, such as how to read case accumulations and what kind of verification is desirable in the future, and made it clear that the content does not conclude the effectiveness of individual treatments.