First-in-man use of a cardiovascular cell-derived secretome in heart failure. Case report.

BACKGROUND: There is increased evidence that the effects of stem cells can mostly be duplicated by administration of their secretome which might streamline the translation towards the clinics. METHODS: The 12-patient SECRET-HF phase 1 trial has thus been designed to determine the feasibility and safety of repeated intravenous injections of the extracellular vesicle (EV)-enriched secretome of cardiovascular progenitor cells differentiated from pluripotent stem cells in severely symptomatic patients with drug-refractory left ventricular (LV) dysfunction secondary to non-ischemic dilated cardiomyopathy. Here we report the case of the first treated patient (baseline NYHA class III; LV Ejection Fraction:25%) in whom a dose of 20 × 109 particles/kg was intravenously infused three times three weeks apart. FINDINGS: In addition to demonstrating the feasibility of producing a cardiac cell secretome compliant with Good Manufacturing Practice standards, this case documents the excellent tolerance of its repeated delivery, without any adverse events during or after infusions. Six months after the procedure, the patient is in NYHA Class II with improved echo parameters, a reduced daily need for diuretics (from 240 mg to 160 mg), no firing from the previously implanted automatic internal defibrillator and no alloimmunization against the drug product, thereby supporting its lack of immunogenicity. INTERPRETATION: The rationale underlying the intravenous route is that the infused EV-enriched secretome may act by rewiring endogenous immune cells, both circulating and in peripheral organs, to take on a reparative phenotype. These EV-modified immune cells could then traffic to the heart to effect tissue repair, including mitigation of inflammation which is a hallmark of cardiac failure. FUNDING: This trial is funded by the French Ministry of Health (Programme Hospitalier de Recherche CliniqueAOM19330) and the "France 2030" National Strategy Program (ANR-20-F2II-0003). It is sponsored by Assistance Publique-Hôpitaux de Paris.

Treatment of COVID-19-associated ARDS with umbilical cord-derived mesenchymal stromal cells in the STROMA-CoV-2 multicenter randomized double-blind trial: long-term safety, respiratory function, and quality of life.

BACKGROUND: The STROMA-CoV-2 study was a French phase 2b, multicenter, double-blind, randomized, placebo-controlled clinical trial that did not identify a significant efficacy of umbilical cord-derived mesenchymal stromal cells in patients with SARS-CoV-2-induced acute respiratory distress syndrome. Safety on day 28 was found to be good. The aim of our extended study was to assess the 6- and 12-month safety of UC-MSCs administration in the STROMA-CoV-2 cohort. METHODS: A detailed multi-domain assessment was conducted at 6 and 12 months following hospital discharge focusing on adverse events, lung computed tomography-scan, pulmonary and muscular functional status, and quality of life in the STROMA-CoV-2 cohort including SARS-CoV-2-related early (< 96 h) mild-to-severe acute respiratory distress syndrome. RESULTS: Between April 2020 and October 2020, 47 patients were enrolled, of whom 19 completed a 1-year follow-up. There were no significant differences in any endpoints or adverse effects between the UC-MSCs and placebo groups at the 6- and 12-month assessments. Ground-glass opacities persisted at 1 year in 5 patients (26.3%). Furthermore, diffusing capacity for carbon monoxide remained altered over 1 year, although no patient required oxygen or non-invasive ventilatory support. Quality of life revealed declines in mental, emotional and physical health throughout the follow-up period, and the six-minute walking distance remained slightly impaired at the 1-year patient assessment. CONCLUSIONS: This study suggests a favorable safety profile for the use of intravenous UC-MSCs in the context of the first French wave of SARS-CoV-2-related moderate-to-severe acute respiratory distress syndrome, with no adverse effects observed at 1 year.

The transplant of cardiac cells and myoblast skeletal cells in myocardial infarction

OBJETIVO:Comparar o resultado funcional e anátomo-patológico entre o transplante de células mioblásticas e cardíacas no infarto do miocárdio. MÉTODO: Realizado infarto da parede ântero-lateral do ventrículo esquerdo em 26 ratos Wistar, com ligadura da artéria coronária esquerda. Após cinco dias, os animais foram submetidos a ecocardiografia transtorácica para cálculo dos volumes sistólico (VSFVE) e diastólico (VDFVE) finais e da fraçäo de ejeçäo do ventrículo esquerdo (FEVE). Os animais foram divididos em três grupos: 1) controle (n=10), 2) células cardíacas adultas (n=8) e 3) células musculares esqueléticas adultas (n=8). Sete dias após o infarto do miocárdio, os animais foram reoperados por esternotomia mediana, sendo identificada a regiäo de fibrose no ventrículo esquerdo e nela, injetado 0.15ml de meio de cultura no grupo I, 8.5x106/0.15ml de células cardíacas heterólogas no grupo II e 8.5x106/0.15ml de células musculares esqueléticas heterólogas no grupo III. Todos os animais receberam ciclosporina (15mg/kg/dia). Após dois meses do transplante, realizou-se nova ecocardiografia avaliando os mesmos parâmetros. RESULTADOS: Após dois meses do transplante celular, o grupo I apresentou um decréscimo da FEVE (48.18 porcento vs. 33.25 porcento p=0.0003), sendo que houve um acréscimo dos VSFVE e VDFVE (0.308ml vs. 0.536ml p=0.026 e 0.597ml vs. 0.776ml p=0.054, respectivamente). No grupo II houve uma estabilizaçäo da FEVE (42.48 porcento vs. 41.31 porcento p=0.4968, respectivamente) e um discreto aumento do VDFVE (0.602ml vs. 0.771ml p=0.0711). O VSFVE variou de 0.358ml a 0.450ml p=0.0400. O grupo III apresentou um acréscimo da FEVE, VDFVE e VSFVE (40 porcento vs. 47.35 porcento p=0.0142, 0.643ml vs. 0.931ml p=0.0026 e 0.388ml vs. 0.491ml p=0.0557 (sem significância), respectivamente. O GIII apresentou um maior valor, considerado estatisticamente significativo, da fraçäo de ejeçäo do ventrículo esquerdo, em comparaçäo ao GI e ao GII (47.35 porcento + 6.89 porcento vs. 41.31 porcento + 8.46 porcento vs. 33.25 porcento + 12.41 porcento p=0.0200, respectivamente). Identificou-se uma diferença estatisticamente significativa da fraçäo de ejeçäo do ventrículo esquerdo entre o GIII e o GI, após dois meses do transplante (47.35 porcento + 6.891 porcento vs. 33.25 porcento + 12.41 porcento p=0.0213, respectivamente)...