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Current Molecular Progress on Cell and Gene Therapies

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 May 2025 | Viewed by 7098

Special Issue Editor


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Guest Editor
Laboratory of Experimental Virology, Department of Medical Microbiology, Amsterdam UMC, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Interests: CRISPR-Cas methods; HIV; DNA; gene therapy; antiviral mechanism; cell therapy

Special Issue Information

Dear Colleagues,

Gene and cell therapy have emerged as promising approaches for the treatment of various diseases. This special issue aims to provide a comprehensive overview of the recent advancements and challenges in the field of gene and cell therapy. This special issue aims to provide a comprehensive overview of the recent advancements and challenges in the field of gene and cell therapy, with a particular focus on molecular-level insights. The issue will cover a wide range of topics, including novel gene delivery systems, gene editing techniques, stem cell-based therapies, with an emphasis on molecular mechanisms underlying their efficacy and ssafety. The use of viral and non-viral vectors for gene delivery has significantly improved the efficiency and specificity of gene therapy. Understanding the molecular interactions between the vectors and the target cells is crucial for optimizing their delivery and enhancing therapeutic outcomes. Additionally, the advent of gene editing technologies, such as CRISPR/Cas9, has revolutionized the field by enabling precise modifications of the genome. Moreover, stem cells have demonstrated tremendous potential in regenerative medicine, with their ability to differentiate into various cell types and promote tissue repair. Elucidating the molecular signaling pathways and epigenetic modifications involved in stem cell differentiation and therapeutic effects is essential for harnessing their full therapeutic potential. This special issue invites original research articles, reviews, and perspectives that provide molecular-level insights into gene and cell therapy. Contributions focusing on molecular mechanisms underlying the safety and efficacy of these therapies are particularly encouraged. Moreover, studies highlighting the molecular basis of the preclinical and clinical applications of gene and cell therapies for specific diseases will be of great interest. This special issue aims to advance our understanding of the intricate molecular processes involved in gene and cell therapy facilitating the translation of gene and cell therapies into effective clinical interventions.

Dr. Elena Herrera Carrillo
Guest Editor

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Keywords

  • gene therapy
  • cell therapy
  • gene delivery
  • gene editing
  • stem cells
  • regenerative medicine
  • CRISPR-Cas
  • viral vectors
  • non-viral vectors
  • immunotherapies

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Published Papers (4 papers)

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Research

11 pages, 1786 KiB  
Communication
Tolerization with a Novel Dual-Acting Liposomal Tim Agonist Prepares the Immune System for the Success of Gene Therapy
by Abdulraouf Ramadan, Pushpa Rao, Saleh Allababidi, Raed Khashan and Anas M. Fathallah
Int. J. Mol. Sci. 2025, 26(8), 3830; https://doi.org/10.3390/ijms26083830 - 18 Apr 2025
Viewed by 197
Abstract
Gene therapy holds great promise for treating various congenital rare diseases. However, immunogenicity against viral vectors used in gene therapy remains a challenge, impacting both the safety and efficacy of gene therapy products. Neutralizing antibodies against the vector capsid proteins impact the ability [...] Read more.
Gene therapy holds great promise for treating various congenital rare diseases. However, immunogenicity against viral vectors used in gene therapy remains a challenge, impacting both the safety and efficacy of gene therapy products. Neutralizing antibodies against the vector capsid proteins impact the ability to re-dose patients, which a growing body of evidence suggests might be required for some indications and certain younger patient populations. In this communication, we report a novel dual-acting liposomal formulation that induces immune tolerance toward adeno-associated virus 9null (AAV9null) capsid proteins. We present in silico data on our first- and second-generation Tim agonist molecules as well as in vitro and in vivo data supporting the generation of antigen-specific regulatory T cells (Tregs) as well as abrogation of antibody response to AAV9null capsid in our animal models. These early data are encouraging and may offer a new solution to mitigate the immunogenicity induced by gene therapy products. Full article
(This article belongs to the Special Issue Current Molecular Progress on Cell and Gene Therapies)
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19 pages, 3396 KiB  
Article
A Snapshot of Early Transcriptional Changes Accompanying the Pro-Neural Phenotype Switch by NGN2, ASCL1, SOX2, and MSI1 in Human Fibroblasts: An RNA-Seq Study
by Ekaterina M. Samoilova, Daria A. Chudakova, Erdem B. Dashinimaev, Anastasiya V. Snezhkina, Olga M. Kudryashova, Anastasia V. Lipatova, Alesya V. Soboleva, Pavel O. Vorob’yev, Vladimir T. Valuev-Elliston, Natalia F. Zakirova, Alexander V. Ivanov and Vladimir P. Baklaushev
Int. J. Mol. Sci. 2024, 25(22), 12385; https://doi.org/10.3390/ijms252212385 - 18 Nov 2024
Viewed by 1137
Abstract
Direct pro-neural reprogramming is a conversion of differentiated somatic cells to neural cells without an intermediate pluripotency stage. It is usually achieved via ectopic expression (EE) of certain transcription factors (TFs) or other reprogramming factors (RFs). Determining the transcriptional changes (TCs) caused by [...] Read more.
Direct pro-neural reprogramming is a conversion of differentiated somatic cells to neural cells without an intermediate pluripotency stage. It is usually achieved via ectopic expression (EE) of certain transcription factors (TFs) or other reprogramming factors (RFs). Determining the transcriptional changes (TCs) caused by particular RFs in a given cell line enables an informed approach to reprogramming initiation. Here, we characterized TCs in the human fibroblast cell line LF1 on the 5th day after EE of the single well-known pro-neural RFs NGN2, ASCL1, SOX2, and MSI1. As assessed by expression analysis of the bona fide neuronal markers nestin and beta-III tubulin, all four RFs initiated pro-neuronal phenotype conversion; analysis by RNA-seq revealed striking differences in the resulting TCs, although some pathways were overlapping. ASCL1 and SOX2 were not sufficient to induce significant pro-neural phenotype switches using our EE system. NGN2 induced TCs indicative of cell phenotype changes towards neural crest cells, neural stem cells, mature neurons, as well as radial glia, astrocytes, and oligodendrocyte precursors and their mature forms. MSI1 mainly induced a switch towards early stem-like cells, such as radial glia. Full article
(This article belongs to the Special Issue Current Molecular Progress on Cell and Gene Therapies)
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19 pages, 2775 KiB  
Article
A Customizable Platform to Integrate CAR and Conditional Expression of Immunotherapeutics in T Cells
by Huong T. X. Nguyen, Yabin Song, Satendra Kumar and Fu-Sen Liang
Int. J. Mol. Sci. 2024, 25(19), 10568; https://doi.org/10.3390/ijms251910568 - 30 Sep 2024
Viewed by 1816
Abstract
The potential of chimeric antigen receptor (CAR)-based immunotherapy as a promising therapeutic approach is often hindered by the presence of highly immunosuppressive tumor microenvironments (TME). Combination therapies with either co-administration or built-in expression of additional TME-modulating therapeutic molecules to potentiate the functions of [...] Read more.
The potential of chimeric antigen receptor (CAR)-based immunotherapy as a promising therapeutic approach is often hindered by the presence of highly immunosuppressive tumor microenvironments (TME). Combination therapies with either co-administration or built-in expression of additional TME-modulating therapeutic molecules to potentiate the functions of CAR-T cells can cause systemic toxicities due to the lack of control over the delivery of biologics. Here, we present a proof-of-concept engineered platform in human Jurkat T cells that combines CAR with a therapeutic gene circuit capable of sensing β-galactosidase (a reported cancer-associated signal) and subsequently activate the production of customized therapeutic gene products. We have demonstrated the integration of the chemically induced proximity (CIP) and associated signal sensing technologies with CAR in this study. A β-galactosidase-activatable prodrug was designed by conjugating a galactose moiety with a CIP inducer abscisic acid (ABA). We showed that Jurkat T cells engineered with CAR and the ABA-inducible genetic circuits can respond to recombinant β-galactosidase to drive the production and secretion of various immunotherapeutics including an anti-cancer agent, an immunomodulatory cytokine, and immune checkpoint inhibitors. Our design is highly modular and could be adapted to sense different cancer-related signals to locally produce antitumor therapeutics that can potentially boost CAR-T efficacy and persistence. Full article
(This article belongs to the Special Issue Current Molecular Progress on Cell and Gene Therapies)
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15 pages, 4222 KiB  
Article
CRISPR-Cas12a for Highly Efficient and Marker-Free Targeted Integration in Human Pluripotent Stem Cells
by Ruba Hammad, Jamal Alzubi, Manuel Rhiel, Kay O. Chmielewski, Laura Mosti, Julia Rositzka, Marcel Heugel, Jan Lawrenz, Valentina Pennucci, Birgitta Gläser, Judith Fischer, Axel Schambach, Thomas Moritz, Nico Lachmann, Tatjana I. Cornu, Claudio Mussolino, Richard Schäfer and Toni Cathomen
Int. J. Mol. Sci. 2024, 25(2), 985; https://doi.org/10.3390/ijms25020985 - 12 Jan 2024
Viewed by 3450
Abstract
The CRISPR-Cas12a platform has attracted interest in the genome editing community because the prototypical Acidaminococcus Cas12a generates a staggered DNA double-strand break upon binding to an AT-rich protospacer-adjacent motif (PAM, 5′-TTTV). The broad application of the platform in primary human cells was enabled [...] Read more.
The CRISPR-Cas12a platform has attracted interest in the genome editing community because the prototypical Acidaminococcus Cas12a generates a staggered DNA double-strand break upon binding to an AT-rich protospacer-adjacent motif (PAM, 5′-TTTV). The broad application of the platform in primary human cells was enabled by the development of an engineered version of the natural Cas12a protein, called Cas12a Ultra. In this study, we confirmed that CRISPR-Cas12a Ultra ribonucleoprotein complexes enabled allelic gene disruption frequencies of over 90% at multiple target sites in human T cells, hematopoietic stem and progenitor cells (HSPCs), and induced pluripotent stem cells (iPSCs). In addition, we demonstrated, for the first time, the efficient knock-in potential of the platform in human iPSCs and achieved targeted integration of a GFP marker gene into the AAVS1 safe harbor site and a CSF2RA super-exon into CSF2RA in up to 90% of alleles without selection. Clonal analysis revealed bi-allelic integration in >50% of the screened iPSC clones without compromising their pluripotency and genomic integrity. Thus, in combination with the adeno-associated virus vector system, CRISPR-Cas12a Ultra provides a highly efficient genome editing platform for performing targeted knock-ins in human iPSCs. Full article
(This article belongs to the Special Issue Current Molecular Progress on Cell and Gene Therapies)
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