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Acceleration of Translational Mesenchymal Stromal Cell Therapy Through Consistent Quality GMP Manufacturing.

ABSTRACT: Human mesenchymal stromal cell (hMSC) therapy has been gaining immense interest in regenerative medicine and quite recently for its immunomodulatory properties in COVID-19 treatment. Currently, the use of hMSCs for various diseases is being investigated in >900 clinical trials. Despite the huge effort, setting up consistent and robust scalable manufacturing to meet regulatory compliance across various global regions remains a nagging challenge. This is in part due to a lack of definitive consensus for quality control checkpoint assays starting from cell isolation to expansion and final release criterion of clinical grade hMSCs. In this review, we highlight the bottlenecks associated with hMSC-based therapies and propose solutions for consistent GMP manufacturing of hMSCs starting from raw materials selection, closed and modular systems of manufacturing, characterization, functional testing, quality control, and safety testing for release criteria. We also discuss the standard regulatory compliances adopted by current clinical trials to broaden our view on the expectations across different jurisdictions worldwide.

SUBMITTER: Jayaraman P

PROVIDER: S-EPMC8076909 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHuman adipose stromal cells-derived extracellular vesicles (haMSC-EVs) have been shown to alleviate inflammation in acute lung injury (ALI) animal models. However, there are few systemic studies on clinical-grade haMSC-EVs. Our study aimed to investigate the manufacturing, quality control (QC) and preclinical safety of clinical-grade haMSC-EVs.MethodshaMSC-EVs were isolated from the conditioned medium of human adipose MSCs incubated in 2D containers. Purification was performed by PEG precipitation and differential centrifugation. Characterizations were conducted by nanoparticle tracking analysis, transmission electron microscopy (TEM), Western blotting, nanoflow cytometry analysis, and the TNF-α inhibition ratio of macrophage [after stimulated by lipopolysaccharide (LPS)]. RNA-seq and proteomic analysis with liquid chromatography tandem mass spectrometry (LC-MS/MS) were used to inspect the lot-to-lot consistency of the EV products. Repeated toxicity was evaluated in rats after administration using trace liquid endotracheal nebulizers for 28 days, and respiratory toxicity was evaluated 24 h after the first administration. In vivo therapeutic effects were assessed in an LPS-induced ALI/ acute respiratory distress syndrome (ARDS) rat model.ResultsThe quality criteria have been standardized. In a stability study, haMSC-EVs were found to remain stable after 6 months of storage at - 80°C, 3 months at - 20 °C, and 6 h at room temperature. The microRNA profile and proteome of haMSC-EVs demonstrated suitable lot-to-lot consistency, further suggesting the stability of the production processes. Intratracheally administered 1.5 × 108 particles/rat/day for four weeks elicited no significant toxicity in rats. In LPS-induced ALI/ARDS model rats, intratracheally administered haMSC-EVs alleviated lung injury, possibly by reducing the serum level of inflammatory factors.ConclusionhaMSC-EVs, as an off-shelf drug, have suitable stability and lot-to-lot consistency. Intratracheally administered haMSC-EVs demonstrated excellent safety at the tested dosages in systematic preclinical toxicity studies. Intratracheally administered haMSC-EVs improved the lung function and exerted anti-inflammatory effects on LPS-induced ALI/ARDS model rats.

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Acceleration of Translational Mesenchymal Stromal Cell Therapy Through Consistent Quality GMP Manufacturing.

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