Abstract
Due to their immune suppressive pharmacology, regenerative capacity, and immune privileged status, mesenchymal stromal cells (MSCs) are an attractive cell type to treat a variety of diseases. Genetically engineered MSCs are currently in non-clinical and clinical development for a wide range of applications including the delivery of pro-drugs and therapeutic proteins or modified to enhance their regenerative potential. Unmodified MSCs have been shown to have good safety profiles in clinical development. The introduction of exogenous transgenes introduces possible additional risks that need to be assessed in non-clinical studies prior to initiating clinical studies. The use of ex vivo non-viral genetic modification approaches potentially reduces the risks associated with viral vector transfection approaches, including the potential for cell transformation. This review provides an overview of the regulatory-compliant non-clinical proof-of-concept and safety studies required to take MSC-based gene therapy products from the bench to the clinic.
Highlights
Mesenchymal stromal cells (MSCs) are a heterogenous population of cells that can be isolated from various supportive stromal tissues and expanded in culture
Whilst we recognise that components of the Chemistry-Manufacturing-Control (CMC) activities contribute to the understanding of both the safety profiles and quality attributes of these and other advanced therapy medicinal products (ATMPs), we intend to limit the scope of this manuscript to a description of the main considerations related to the non-clinical aspects of MSC-based non-viral gene therapy product development
Of the 21 genetically modified MSC trials identified in a GlobalData extract performed on the 15 March 2021, oncology (10) was the largest therapeutic area accounting for approximately half of the genetically modified MSC clinical trials
Summary
Mesenchymal stromal cells (MSCs) are a heterogenous population of cells that can be isolated from various supportive stromal tissues and expanded in culture. Pharmaceutics 2021, 13, 823 produce anti-inflammatory mediators, including indoleamine 2,3-dioxygenase (IDO), TNFstimulated gene 6 (TSG-6), and the transforming growth factor-β (TGF-β), which induce anti-inflammatory M2 macrophages and regulatory T cells (Tregs), inhibit the extravasation of leukocytes, and negatively regulate the activation and proliferation of T cells [2,11,12,13] In addition to their immunomodulatory role, MSCs have been shown to induce pro-regenerative effects, mainly related to their paracrine ability and their secretion of microvesicles, exosomes, and growth factors, including hepatocyte growth factor (HGF), fibroblast growth factor (FGF), and vascular endothelial growth factor (VEGF) [14,15]. Whilst we recognise that components of the Chemistry-Manufacturing-Control (CMC) activities contribute to the understanding of both the safety profiles and quality attributes of these and other advanced therapy medicinal products (ATMPs), we intend to limit the scope of this manuscript to a description of the main considerations related to the non-clinical aspects of MSC-based non-viral gene therapy product development
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