Genome-edited adult stem cells: Next-generation advanced therapy medicinal products

Benabdellah, Karim; Sánchez‐Hernández, Sabina; Aguilar-González, Araceli; Maldonado‐Pérez, Noelia; Gutiérrez‐Guerrero, Alejandra; Cortijo-Gutierréz, Marina; Ramos-Hernández, Iris; Tristán‐Manzano, María; Galindo‐Moreno, Pablo; Herrera, Concha; Martín, Francisco

doi:10.1002/sctm.19-0338

Cited by 10 publications

(10 citation statements)

References 106 publications

(125 reference statements)

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“…Recently, gene editing has emerged as a powerful alternative approach ( 157 ). Moghadan and associates developed a CRISPR-based system that could effectively modulate the immune responses of the host ( 158 ).…”

Section: Enhancement Of the Immunomodulatory Functions Of Mscsmentioning

confidence: 99%

From Mesenchymal Stromal/Stem Cells to Insulin-Producing Cells: Immunological Considerations

Refaie

Elbassiouny²,

Kloc

et al. 2021

Front. Immunol.

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Mesenchymal stem cell (MSC)-based therapy for type 1 diabetes mellitus (T1DM) has been the subject matter of many studies over the past few decades. The wide availability, negligible teratogenic risks and differentiation potential of MSCs promise a therapeutic alternative to traditional exogenous insulin injections or pancreatic transplantation. However, conflicting arguments have been reported regarding the immunological profile of MSCs. While some studies support their immune-privileged, immunomodulatory status and successful use in the treatment of several immune-mediated diseases, others maintain that allogeneic MSCs trigger immune responses, especially following differentiation or in vivo transplantation. In this review, the intricate mechanisms by which MSCs exert their immunomodulatory functions and the influencing variables are critically addressed. Furthermore, proposed avenues to enhance these effects, including cytokine pretreatment, coadministration of mTOR inhibitors, the use of Tregs and gene manipulation, are presented. As an alternative, the selection of high-benefit, low-risk donors based on HLA matching, PD-L1 expression and the absence of donor-specific antibodies (DSAs) are also discussed. Finally, the necessity for the transplantation of human MSC (hMSC)-derived insulin-producing cells (IPCs) into humanized mice is highlighted since this strategy may provide further insights into future clinical applications.

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Section: Enhancement Of the Immunomodulatory Functions Of Mscsmentioning

confidence: 99%

From Mesenchymal Stromal/Stem Cells to Insulin-Producing Cells: Immunological Considerations

Refaie

Elbassiouny²,

Kloc

et al. 2021

Front. Immunol.

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“…It is pivotal to collect strong evidence proving the safety and hypoimmunogenicity of cells prior to clinical applications. 85 …”

Section: Challenges and Future Perspectivesmentioning

confidence: 99%

Neuronal Cell-based Medicines from Pluripotent Stem Cells: Development, Production, and Preclinical Assessment

Sun

Lin

Liang

et al. 2021

Stem Cells Translational Medicine

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Brain degeneration and damage is difficult to cure due to the limited endogenous repair capability of the central nervous system. Furthermore, drug development for treatment of diseases of the central nervous system remains a major challenge. However, it now appears that using human pluripotent stem cell-derived neural cells to replace degenerating cells provides a promising cell-based medicine for rejuvenation of brain function. Accordingly, a large number of studies have carried out preclinical assessments, which have involved different neural cell types in several neurological diseases. Recent advances in animal models identify the transplantation of neural derivatives from pluripotent stem cells as a promising path toward the clinical application of cell therapies [Stem Cells Transl Med 2019;8:681-693; Drug Discov Today 2019;24:992-999; Nat Med 2019;25:1045-1053]. Some groups are moving toward clinical testing in humans. However, the difficulty in selection of valuable critical quality criteria for cell products and the lack of functional assays that could indicate suitability for clinical effect continue to hinder neural cell-based medicine development [Biologicals 2019;59:68-71]. In this review, we summarize the current status of preclinical studies progress in this area and outline the biological characteristics of neural cells that have been used in new developing clinical studies. We also discuss the requirements for translation of stem cell-derived neural cells in examples of stem cell-based clinical therapy.

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“…The use of viral vectors has major limitations due to possible oncogene transactivation and the lack of physiological expression that allows monitoring. Recently, gene therapy researchers have focused on gene editing technologies as an alternative approach [76]. The breakthrough in genome editing started in 2013, when the first CRISPR/Cas9 system was engineered to work in mammalian cells [77,78].…”

Section: Gene Editingmentioning

confidence: 99%

From Mesenchymal Stromal/Stem Cells to Insulin-Producing Cells: Progress and Challenges

Ghoneim

Refaie

Elbassiouny

et al. 2020

Stem Cell Rev and Rep

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Mesenchymal stromal cells (MSCs) are an attractive option for cell therapy for type 1 diabetes mellitus (DM). These cells can be obtained from many sources, but bone marrow and adipose tissue are the most studied. MSCs have distinct advantages since they are nonteratogenic, nonimmunogenic and have immunomodulatory functions. Insulin-producing cells (IPCs) can be generated from MSCs by gene transfection, gene editing or directed differentiation. For directed differentiation, MSCs are usually cultured in a glucose-rich medium with various growth and activation factors. The resulting IPCs can control chemically-induced diabetes in immune-deficient mice. These findings are comparable to those obtained from pluripotent cells. PD-L1 and PD-L2 expression by MSCs is upregulated under inflammatory conditions. Immunomodulation occurs due to the interaction between these ligands and PD-1 receptors on T lymphocytes. If this function is maintained after differentiation, life-long immunosuppression or encapsulation could be avoided. In the clinical setting, two sites can be used for transplantation of IPCs: the subcutaneous tissue and the omentum. A 2-stage procedure is required for the former and a laparoscopic procedure for the latter. For either site, cells should be transplanted within a scaffold, preferably one from fibrin. Several questions remain unanswered. Will the transplanted cells be affected by the antibodies involved in the pathogenesis of type 1 DM? What is the functional longevity of these cells following their transplantation? These issues have to be addressed before clinical translation is attempted.

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Genome-edited adult stem cells: Next-generation advanced therapy medicinal products

Cited by 10 publications

References 106 publications

From Mesenchymal Stromal/Stem Cells to Insulin-Producing Cells: Immunological Considerations

From Mesenchymal Stromal/Stem Cells to Insulin-Producing Cells: Immunological Considerations

Neuronal Cell-based Medicines from Pluripotent Stem Cells: Development, Production, and Preclinical Assessment

From Mesenchymal Stromal/Stem Cells to Insulin-Producing Cells: Progress and Challenges

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