Abstract
Mesenchymal stromal cells (MSCs) are multipotent cells with anti-inflammatory properties. Here we tested the safety of MSCs in patients with progressive supranuclear palsy (PSP; ClinicalTrials.gov: NCT01824121; Eudract No. 2011-004051-39). Seven patients were treated. To improve the safety, protocol adjustments were made during the performance of the study. The objectives of our work were: (1) to assess the safety of MSCs and (2) to identify critical issues in cell therapies for neurodegenerative diseases. Autologous MSCs from the bone marrow of PSP patients were administered through the internal carotid arteries. 1-year survival and number of severe adverse events were considered as safety endpoints. Clinical rating scales, neuropsychological assessments, gait and posture analysis, single-photon emission computed tomography, positron emission tomography, and brain magnetic resonance (BMR) were performed at different follow-up times. Peripheral blood levels of inflammatory cytokines were measured before and after cell infusion. Six of the seven treated patients were living 1 year after cell infusion. Asymptomatic spotty lesions were observed at BMR after 24 h in six of the seven treated patients. The last patient in the preliminary cohort (Case 5) exhibited transiently symptomatic BMR ischemic alterations. No severe adverse events were recorded in the last two treated patients. Interleukin-8 serum concentrations decreased in three patients (Case 2, 3, and 4). An adaptive study design, appropriate and up-to-date efficacy measures, adequate sample size estimation, and, possibly, the use of a cellular and/or allogeneic cell sources may help in performing phase II trials in the field.
Highlights
Progressive supranuclear palsy (PSP) is a sporadic neurodegenerative disease, characterized by ocular motor dysfunction, postural instability, akinesia, cognitive dysfunction, dysarthria, and dysphagia (Steele et al, 1964)
The main reason for failure in obtaining a conform final product was insufficient cell growth and it was unjustified to repeat the production since the same growing capacity is expected from starting material obtained from the same subject
Gender Age Disease duration mesenchymal stromal cells (MSCs) dosage and purity Total MSCs (×106) Cell dose (×106)/kg Purity Survival Alive/total treated after 1 year from treatment Adverse events Number of adverse events (N = 8) Hematoma at the injection site Asymptomatic spotty lesion Left hemiparesis Urticaria Phosphenes Hallucinosis MMSE Baseline (n = 8) 1-month (n = 5) 12-month (n = 4) Hoehn and Yahr (H&Y) score ≥ 4 Baseline (n = 8) 1-month (n = 6) 3-month (n = 7) 6-month (n = 4) 12-month (n = 4) Unified Parkinson’s Disease Rating Scale (UPDRS) III Baseline (n = 8) 1-month (n = 6) 3-month (n = 7) 6-month (n = 4) 12-month (n = 4) PSP rating scale (PSP-RS) Baseline (n = 8) 1-month (n = 6) 3-month (n = 7) 6-month (n = 4) 12-month (n = 4)
Summary
Progressive supranuclear palsy (PSP) is a sporadic neurodegenerative disease, characterized by ocular motor dysfunction, postural instability, akinesia, cognitive dysfunction, dysarthria, and dysphagia (Steele et al, 1964). Neuroinflammation is an important factor in PSP progression (Bevan-Jones et al, 2019; Inci et al, 2020; Malpetti et al, 2021). Immunomodulatory disease-modifying therapies may be extremely useful in controlling PSP. Cell-based, advanced therapy medicinal products (ATMPs) have shown encouraging results in different clinical contexts. Mesenchymal stromal cells (MSCs) are currently being used as immunomodulatory drugs in several phase III clinical trials on graft-versus-host disease (GvHD) after bone marrow (BM) transplantation (Gay et al, 2021). MSCs have been granted conditional market approval in Canada and New Zealand for the treatment of children with GvHD refractory to steroids (Cyranoski, 2012)
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