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Biomedicines
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New Insights in Gene and Cell Therapy
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New Insights in Gene and Cell Therapy

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Gene and Cell Therapy".

Deadline for manuscript submissions: closed (15 November 2022) | Viewed by 51072

Special Issue Editor

Prof. Dr. Bart De Geest

E-Mail Website
Guest Editor
Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Campus Gasthuisberg, Herestraat 49 bus 911, 3000 Leuven, Belgium
Interests: lipoproteins; atherosclerosis; coronary heart disease; familial hypercholesterolemia; low-density lipoprotein (LDL) receptor; heart failure; gene therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Advanced therapy medicinal products (ATMPs) represent a major class of innovative therapies, differing substantially from classic therapeutic agents. ATMPs include gene therapy medicinal products (GTMPs), somatic cell therapy medicinal products (sCTMPs), tissue-engineered products (TEPs), and combined ATMPs. The global cell and gene therapy market reached a value of nearly USD 4.4 billion in 2020 and is expected to grow to USD 15.5 billion in 2025. These numbers remain small compared to the global pharmaceuticals market of USD 1.3 trillion in 2020. In addition, the complexity of these therapies is substantially higher than that of classical pharmaceutical approaches and results in a significant number of hurdles that limit widespread applications. Marketing authorization is essentially dependent on clinical efficacy and safety. Pharmacodynamic evaluation in adequate preclinical models should provide robust evidence for potential clinical efficacy. Safety evaluation comprises immunogenicity and immunotoxicity studies, analysis of non-immune toxicity, determination of genotoxicity, biodistribution analysis, expression targeting, etc. This Special Issue is dedicated to all dimensions of preclinical research evaluating gene and cell therapy strategies, potentially leading to ATMPs.

Prof. Dr. Bart De Geest
Guest Editor

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • gene transfer
  • gene therapy
  • cell therapy
  • preclinical models
  • targeting

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Published Papers (8 papers)

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Research

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17 pages, 1544 KiB  
Article
Brain Gene Silencing with Cationic Amino-Capped Poly(ethylene glycol) Polyplexes
by Abdullah A. Alamoudi, Paula A. Méndez, David Workman, Andreas G. Schätzlein and Ijeoma F. Uchegbu
Biomedicines 2022, 10(9), 2182; https://doi.org/10.3390/biomedicines10092182 - 3 Sep 2022
Cited by 4 | Viewed by 1872
Abstract
Therapeutic gene silencing in the brain is usually achieved using highly invasive intracranial administration methods and/or comparatively toxic vectors. In this work, we use a relatively biocompatible vector: poly(ethylene glycol) star-shaped polymer capped with amine groups (4APPA) via the nose to brain route. [...] Read more.
Therapeutic gene silencing in the brain is usually achieved using highly invasive intracranial administration methods and/or comparatively toxic vectors. In this work, we use a relatively biocompatible vector: poly(ethylene glycol) star-shaped polymer capped with amine groups (4APPA) via the nose to brain route. 4APPA complexes anti- itchy E3 ubiquitin protein ligase (anti-ITCH) siRNA to form positively charged (zeta potential +15 ± 5 mV) 150 nm nanoparticles. The siRNA-4APPA polyplexes demonstrated low cellular toxicity (IC50 = 13.92 ± 6 mg mL−1) in the A431 cell line and were three orders of magnitude less toxic than Lipofectamine 2000 (IC50 = 0.033 ± 0.04 mg mL−1) in this cell line. Cell association and uptake of fluorescently labelled siRNA bound to siRNA-4APPA nanoparticles was demonstrated using fluorescent activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), respectively. Gene silencing of the ITCH gene was observed in vitro in the A431 cell line (65% down regulation when compared to the use of anti-ITCH siRNA alone). On intranasal dosing with fluorescently labelled siRNA-4APPA polyplexes, fluorescence was seen in the cells of the olfactory bulb, cerebral cortex and mid-brain regions. Finally, down regulation of ITCH was seen in the brain cells (54 ± 13% ITCH remaining compared to untreated controls) in a healthy rat model, following intranasal dosing of siRNA-4APPA nanoparticles (0.15 mg kg−1 siRNA twice daily for 3 days). Gene silencing in the brain may be achieved by intranasal administration of siRNA- poly(ethylene glycol) based polyplexes. Full article
(This article belongs to the Special Issue New Insights in Gene and Cell Therapy)
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14 pages, 3273 KiB  
Article
Preventive Effects of a Human Hematopoietic Mesenchymal Stem Cell (hHMSC) Therapy in Ovalbumin-Induced Food Allergy
by Dong-Geon Lee, Yu-Jin Lee, Song-Hee Park, Hye-Ree Park, Hoon Kang and Jung-Eun Kim
Biomedicines 2022, 10(2), 511; https://doi.org/10.3390/biomedicines10020511 - 21 Feb 2022
Cited by 1 | Viewed by 2651
Abstract
No effective therapeutic strategies have been developed against food allergies. Immunomodulation during early infant period could prevent the development of food allergies. We investigated the preventive effects of human hematopoietic mesenchymal stem cells (hHMSCs) in mice with ovalbumin (OVA)-induced food allergy. BALB/c mice [...] Read more.
No effective therapeutic strategies have been developed against food allergies. Immunomodulation during early infant period could prevent the development of food allergies. We investigated the preventive effects of human hematopoietic mesenchymal stem cells (hHMSCs) in mice with ovalbumin (OVA)-induced food allergy. BALB/c mice with OVA-induced food allergy were divided into 3 groups, and each group was treated with hHMSCs or hHMSC culture medium (hHMSC-CM) or saline. Ear thickness, allergy score, rectal temperature, and diarrhea occurrence were checked. Total IgE, OVA-specific IgE, and mucosal mast cell protease-1 (mMCP-1) were measured by ELISA. Other allergic parameters were analyzed using histology specimens, RT-PCR, and flow cytometry. Treatment with hHMSCs or hHMSC-CM significantly suppressed the frequency of anaphylactic response and rectal temperature decline, reduced diarrhea, total IgE, OVA-specific IgE, and mMCP-1. While the treatment decreased the level of Th2 cytokines, it enhanced IL-10 and TGF-β1 mRNA. Exposure to hHMSC or hHMSC-CM did not generate regulatory T cells, but reduced mast cells. The immunomodulatory effect on the Th2 cytokines was greater in hHMSC-CM than in hHMSCs. hHMSC treatment may be a promising preventive intervention against food allergy. Further studies are needed to elucidate the key substances released from hHMSC to induce immune tolerance. Full article
(This article belongs to the Special Issue New Insights in Gene and Cell Therapy)
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34 pages, 10203 KiB  
Article
Optimized Manufacture of Lyophilized Dermal Fibroblasts for Next-Generation Off-the-Shelf Progenitor Biological Bandages in Topical Post-Burn Regenerative Medicine
by Alexis Laurent, Corinne Scaletta, Philippe Abdel-Sayed, Murielle Michetti, Marjorie Flahaut, Jeanne-Pascale Simon, Anthony de Buys Roessingh, Wassim Raffoul, Nathalie Hirt-Burri and Lee Ann Applegate
Biomedicines 2021, 9(8), 1072; https://doi.org/10.3390/biomedicines9081072 - 23 Aug 2021
Cited by 9 | Viewed by 3169
Abstract
Cultured fibroblast progenitor cells (FPC) have been studied in Swiss translational regenerative medicine for over two decades, wherein clinical experience was gathered for safely managing burns and refractory cutaneous ulcers. Inherent FPC advantages include high robustness, optimal adaptability to industrial manufacture, and potential [...] Read more.
Cultured fibroblast progenitor cells (FPC) have been studied in Swiss translational regenerative medicine for over two decades, wherein clinical experience was gathered for safely managing burns and refractory cutaneous ulcers. Inherent FPC advantages include high robustness, optimal adaptability to industrial manufacture, and potential for effective repair stimulation of wounded tissues. Major technical bottlenecks in cell therapy development comprise sustainability, stability, and logistics of biological material sources. Herein, we report stringently optimized and up-scaled processing (i.e., cell biobanking and stabilization by lyophilization) of dermal FPCs, with the objective of addressing potential cell source sustainability and stability issues with regard to active substance manufacturing in cutaneous regenerative medicine. Firstly, multi-tiered FPC banking was optimized in terms of overall quality and efficiency by benchmarking key reagents (e.g., medium supplement source, dissociation reagent), consumables (e.g., culture vessels), and technical specifications. Therein, fetal bovine serum batch identity and culture vessel surface were confirmed, among other parameters, to largely impact harvest cell yields. Secondly, FPC stabilization by lyophilization was undertaken and shown to maintain critical functions for devitalized cells in vitro, potentially enabling high logistical gains. Overall, this study provides the technical basis for the elaboration of next-generation off-the-shelf topical regenerative medicine therapeutic products for wound healing and post-burn care. Full article
(This article belongs to the Special Issue New Insights in Gene and Cell Therapy)
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Review

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27 pages, 1632 KiB  
Review
Enhanced Chimeric Antigen Receptor T Cell Therapy through Co-Application of Synergistic Combination Partners
by Sophia Stock, Anna-Kristina Kluever, Stefan Endres and Sebastian Kobold
Biomedicines 2022, 10(2), 307; https://doi.org/10.3390/biomedicines10020307 - 28 Jan 2022
Cited by 14 | Viewed by 5931
Abstract
Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable response rates and revolutionized the treatment of patients suffering from defined hematological malignancies. However, many patients still do not respond to this therapy or relapse after an initial remission, underscoring the need for [...] Read more.
Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable response rates and revolutionized the treatment of patients suffering from defined hematological malignancies. However, many patients still do not respond to this therapy or relapse after an initial remission, underscoring the need for improved efficacy. Insufficient in vivo activity, persistence, trafficking, and tumor infiltration of CAR T cells, as well as antigen escape and treatment-associated adverse events, limit the therapeutic success. Multiple strategies and approaches have been investigated to further improve CAR T cell therapy. Besides genetic modification of the CAR itself, the combination with other treatment modalities has the potential to improve this approach. In particular, combining CAR T cells with clinically approved compounds such as monoclonal antibodies and small molecule inhibitors might be a promising strategy. Combination partners could already be applied during the production process to influence the cellular composition and immunophenotype of the final CAR T cell product. Alternatively, simultaneous administration of clinically approved compounds with CAR T cells would be another feasible avenue. In this review, we will discuss current strategies to combine CAR T cells with compounds to overcome recent limitations and further enhance this promising cancer therapy, potentially broadening its application beyond hematology. Full article
(This article belongs to the Special Issue New Insights in Gene and Cell Therapy)
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26 pages, 1711 KiB  
Review
Gene Therapy Developments for Pompe Disease
by Zeenath Unnisa, John K. Yoon, Jeffrey W. Schindler, Chris Mason and Niek P. van Til
Biomedicines 2022, 10(2), 302; https://doi.org/10.3390/biomedicines10020302 - 28 Jan 2022
Cited by 27 | Viewed by 9503
Abstract
Pompe disease is an inherited neuromuscular disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). The most severe form is infantile-onset Pompe disease, presenting shortly after birth with symptoms of cardiomyopathy, respiratory failure and skeletal muscle weakness. Late-onset Pompe disease is [...] Read more.
Pompe disease is an inherited neuromuscular disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). The most severe form is infantile-onset Pompe disease, presenting shortly after birth with symptoms of cardiomyopathy, respiratory failure and skeletal muscle weakness. Late-onset Pompe disease is characterized by a slower disease progression, primarily affecting skeletal muscles. Despite recent advancements in enzyme replacement therapy management several limitations remain using this therapeutic approach, including risks of immunogenicity complications, inability to penetrate CNS tissue, and the need for life-long therapy. The next wave of promising single therapy interventions involves gene therapies, which are entering into a clinical translational stage. Both adeno-associated virus (AAV) vectors and lentiviral vector (LV)-mediated hematopoietic stem and progenitor (HSPC) gene therapy have the potential to provide effective therapy for this multisystemic disorder. Optimization of viral vector designs, providing tissue-specific expression and GAA protein modifications to enhance secretion and uptake has resulted in improved preclinical efficacy and safety data. In this review, we highlight gene therapy developments, in particular, AAV and LV HSPC-mediated gene therapy technologies, to potentially address all components of the neuromuscular associated Pompe disease pathology. Full article
(This article belongs to the Special Issue New Insights in Gene and Cell Therapy)
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21 pages, 2602 KiB  
Review
CAR-T Regulatory (CAR-Treg) Cells: Engineering and Applications
by Motahareh Arjomandnejad, Acadia L. Kopec and Allison M. Keeler
Biomedicines 2022, 10(2), 287; https://doi.org/10.3390/biomedicines10020287 - 26 Jan 2022
Cited by 51 | Viewed by 16069
Abstract
Regulatory T cells are critical for maintaining immune tolerance. Recent studies have confirmed their therapeutic suppressive potential to modulate immune responses in organ transplant and autoimmune diseases. However, the unknown and nonspecific antigen recognition of polyclonal Tregs has impaired their therapeutic potency in [...] Read more.
Regulatory T cells are critical for maintaining immune tolerance. Recent studies have confirmed their therapeutic suppressive potential to modulate immune responses in organ transplant and autoimmune diseases. However, the unknown and nonspecific antigen recognition of polyclonal Tregs has impaired their therapeutic potency in initial clinical findings. To address this limitation, antigen specificity can be conferred to Tregs by engineering the expression of transgenic T-cell receptor (TCR) or chimeric antigen receptor (CAR). In contrast to TCR Tregs, CAR Tregs are major histocompatibility complex (MHC) independent and less dependent on interleukin-2 (IL-2). Furthermore, CAR Tregs maintain Treg phenotype and function, home to the target tissue and show enhanced suppressive efficacy compared to polyclonal Tregs. Additional development of engineered CAR Tregs is needed to increase Tregs’ suppressive function and stability, prevent CAR Treg exhaustion, and assess their safety profile. Further understanding of Tregs therapeutic potential will be necessary before moving to broader clinical applications. Here, we summarize recent studies utilizing CAR Tregs in modulating immune responses in autoimmune diseases, transplantation, and gene therapy and future clinical applications. Full article
(This article belongs to the Special Issue New Insights in Gene and Cell Therapy)
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19 pages, 840 KiB  
Review
Non-Integrating Lentiviral Vectors in Clinical Applications: A Glance Through
by Narmatha Gurumoorthy, Fazlina Nordin, Gee Jun Tye, Wan Safwani Wan Kamarul Zaman and Min Hwei Ng
Biomedicines 2022, 10(1), 107; https://doi.org/10.3390/biomedicines10010107 - 5 Jan 2022
Cited by 24 | Viewed by 7082
Abstract
Lentiviral vectors (LVs) play an important role in gene therapy and have proven successful in clinical trials. LVs are capable of integrating specific genetic materials into the target cells and allow for long-term expression of the cDNA of interest. The use of non-integrating [...] Read more.
Lentiviral vectors (LVs) play an important role in gene therapy and have proven successful in clinical trials. LVs are capable of integrating specific genetic materials into the target cells and allow for long-term expression of the cDNA of interest. The use of non-integrating LVs (NILVs) reduces insertional mutagenesis and the risk of malignant cell transformation over integrating lentiviral vectors. NILVs enable transient expression or sustained episomal expression, especially in non-dividing cells. Important modifications have been made to the basic human immunodeficiency virus (HIV) structures to improve the safety and efficacy of LVs. NILV-aided transient expression has led to more pre-clinical studies on primary immunodeficiencies, cytotoxic cancer therapies, and hemoglobinopathies. Recently, the third generation of self-inactivating LVs was applied in clinical trials for recombinant protein production, vaccines, gene therapy, cell imaging, and induced pluripotent stem cell (iPSC) generation. This review discusses the basic lentiviral biology and the four systems used for generating NILV designs. Mutations or modifications in LVs and their safety are addressed with reference to pre-clinical studies. The detailed application of NILVs in promising pre-clinical studies is also discussed. Full article
(This article belongs to the Special Issue New Insights in Gene and Cell Therapy)
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15 pages, 887 KiB  
Review
Role of Oxidative Stress in Heart Failure: Insights from Gene Transfer Studies
by Bart De Geest and Mudit Mishra
Biomedicines 2021, 9(11), 1645; https://doi.org/10.3390/biomedicines9111645 - 9 Nov 2021
Cited by 15 | Viewed by 3223
Abstract
Under physiological circumstances, there is an exquisite balance between reactive oxygen species (ROS) production and ROS degradation, resulting in low steady-state ROS levels. ROS participate in normal cellular function and in cellular homeostasis. Oxidative stress is the state of a transient or a [...] Read more.
Under physiological circumstances, there is an exquisite balance between reactive oxygen species (ROS) production and ROS degradation, resulting in low steady-state ROS levels. ROS participate in normal cellular function and in cellular homeostasis. Oxidative stress is the state of a transient or a persistent increase of steady-state ROS levels leading to disturbed signaling pathways and oxidative modification of cellular constituents. It is a key pathophysiological player in pathological hypertrophy, pathological remodeling, and the development and progression of heart failure. The heart is the metabolically most active organ and is characterized by the highest content of mitochondria of any tissue. Mitochondria are the main source of ROS in the myocardium. The causal role of oxidative stress in heart failure is highlighted by gene transfer studies of three primary antioxidant enzymes, thioredoxin, and heme oxygenase-1, and is further supported by gene therapy studies directed at correcting oxidative stress linked to metabolic risk factors. Moreover, gene transfer studies have demonstrated that redox-sensitive microRNAs constitute potential therapeutic targets for the treatment of heart failure. In conclusion, gene therapy studies have provided strong corroborative evidence for a key role of oxidative stress in pathological remodeling and in the development of heart failure. Full article
(This article belongs to the Special Issue New Insights in Gene and Cell Therapy)
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