bims-muscge 2023-08-27 papers

bims-muscge

Biomed News

on Muscle stem cells and gene therapy

Issue of 2023–08–27
nine papers selected by
Chance Bowman, Dartmouth College

Exploring the Role of Oxidative Stress in Skeletal Muscle Atrophy: Mechanisms and Implications.
Liposome-Based Carriers for CRISPR Genome Editing.
Selection of appropriate non-clinical animal models to ensure translatability of novel AAV-gene therapies to the clinic.
Gene therapy for Duchenne muscular dystrophy: an update on the latest clinical developments.
Biopolymers in Drug and Gene Delivery Systems.
Regenerating Myofibers after an Acute Muscle Injury: What Do We Really Know about Them?
Thrown for a Loop: Fibro-Adipogenic Progenitors in Skeletal Muscle Fibrosis.
Progress and Prospects of Gene Editing in Pluripotent Stem Cells.
Extracellular Vesicles for Muscle Atrophy Treatment.

Cureus. 2023 Jul;15(7): e42178

Exploring the Role of Oxidative Stress in Skeletal Muscle Atrophy: Mechanisms and Implications.

Suyash Agrawal, Swarupa Chakole, Nidhi Shetty, Roshan Prasad, Tejaswee Lohakare, Mayur Wanjari.

  Skeletal muscle atrophy is a complex physiological process characterized by progressive muscle mass and strength loss. It is associated with various health conditions, including aging, disease, and certain diseases. Emerging research has indicated that oxidative stress plays a significant role in developing and progressing skeletal muscle atrophy. This review article explores the mechanisms by which oxidative stress influences skeletal muscle atrophy and its implications for potential therapeutic interventions. The review begins by providing an overview of skeletal muscle atrophy and the current understanding of its underlying mechanisms, highlighting the intricate balance between protein degradation and synthesis pathways. Subsequently, the concept of oxidative stress is introduced, discussing its sources and the intricate redox signaling pathways present in skeletal muscle cells. This review's main focus is exploring the multifaceted role of oxidative stress in skeletal muscle atrophy. The detrimental effects of excessive reactive oxygen species (ROS) production on cellular components, including proteins, lipids, and deoxyribonucleic acid (DNA), are discussed. In addition, the impact of oxidative stress on key signaling pathways involved in muscle wasting, such as the ubiquitin-proteasome system and autophagy, is examined. Furthermore, the review highlights the implications of oxidative stress in modulating muscle regeneration and the importance of redox balance in maintaining muscle health. Potential therapeutic strategies targeting oxidative stress, such as antioxidant supplementation, exercise interventions, and pharmacological approaches, are also discussed. In conclusion, this review comprehensively explains the intricate relationship between oxidative stress and skeletal muscle atrophy. By elucidating the underlying mechanisms and discussing potential therapeutic interventions, this review aims to contribute to the development of novel strategies for mitigating muscle wasting and improving overall muscle health.

Keywords:  antioxidant supplementation; muscle regeneration; oxidative stress; protein degradation; reactive oxygen species (ros); redox signaling; skeletal muscle atrophy; therapeutic interventions

DOI:  https://doi.org/10.7759/cureus.42178
Int J Mol Sci. 2023 Aug 16. pii: 12844. [Epub ahead of print]24(16):

Liposome-Based Carriers for CRISPR Genome Editing.

Xing Yin, Romain Harmancey, David D McPherson, Hyunggun Kim, Shao-Ling Huang.

  The CRISPR-based genome editing technology, known as clustered regularly interspaced short palindromic repeats (CRISPR), has sparked renewed interest in gene therapy. This interest is accompanied by the development of single-guide RNAs (sgRNAs), which enable the introduction of desired genetic modifications at the targeted site when used alongside the CRISPR components. However, the efficient delivery of CRISPR/Cas remains a challenge. Successful gene editing relies on the development of a delivery strategy that can effectively deliver the CRISPR cargo to the target site. To overcome this obstacle, researchers have extensively explored non-viral, viral, and physical methods for targeted delivery of CRISPR/Cas9 and a guide RNA (gRNA) into cells and tissues. Among those methods, liposomes offer a promising approach to enhance the delivery of CRISPR/Cas and gRNA. Liposomes facilitate endosomal escape and leverage various stimuli such as light, pH, ultrasound, and environmental cues to provide both spatial and temporal control of cargo release. Thus, the combination of the CRISPR-based system with liposome delivery technology enables precise and efficient genetic modifications in cells and tissues. This approach has numerous applications in basic research, biotechnology, and therapeutic interventions. For instance, it can be employed to correct genetic mutations associated with inherited diseases and other disorders or to modify immune cells to enhance their disease-fighting capabilities. In summary, liposome-based CRISPR genome editing provides a valuable tool for achieving precise and efficient genetic modifications. This review discusses future directions and opportunities to further advance this rapidly evolving field.

Keywords:  CRISPR/Cas9; gRNA; gene delivery; gene editing; liposome; single-guide RNA

DOI:  https://doi.org/10.3390/ijms241612844
Gene Ther. 2023 Aug 23.

Selection of appropriate non-clinical animal models to ensure translatability of novel AAV-gene therapies to the clinic.

Mark Singh, Andrew Brooks, Parto Toofan, Keith McLuckie.

Gene Therapy Medicinal Products consist of a recombinant nucleic acid intended for the modulation or manipulation of a genetic sequence. A single administration of a novel gene therapy has the potential to be curative, with a durable long-term benefit to patients. Adeno-associated viral vectors have become the viral vector of choice for in vivo delivery of therapeutic transgenes as they are mildly immunogenic, can effectively transduce a variety of human tissues and cells, and have low levels of genomic integration. Central to the effective translation of data generated in discovery studies to the clinic is the selection of appropriate animal species for pivotal non-clinical studies. This review aims to support the selection of appropriate animal models for non-clinical studies to advance the development of novel adeno-associated virus gene therapies.

DOI: https://doi.org/10.1038/s41434-023-00417-x
Expert Rev Neurother. 2023 Aug 21. 1-16

Gene therapy for Duchenne muscular dystrophy: an update on the latest clinical developments.

Cedric Happi Mbakam, Jacques P Tremblay.

   INTRODUCTION: Duchenne muscular dystrophy (DMD) is one of the most severe and devastating neuromuscular hereditary diseases with a male newborn incidence of 20 000 cases each year. The disease caused by mutations (exon deletions, nonsense mutations, intra-exonic insertions or deletions, exon duplications, splice site defects, and deep intronic mutations) in the DMD gene, progressively leads to muscle wasting and loss of ambulation. This situation is painful for both patients and their families, calling for an emergent need for effective treatments.
AREAS COVERED: In this review, the authors describe the state of the gene therapy approach in clinical trials for DMD. This therapeutics included gene replacement, gene substitution, RNA-based therapeutics, readthrough mutation, and the CRISPR approach.
EXPERT OPINION: Only a few drug candidates have yet been granted conditional approval for the treatment of DMD. Most of these therapies have only a modest capability to restore the dystrophin or improve muscle function, suggesting an important unmet need in the development of DMD therapeutics. Complementary genes and cellular therapeutics need to be explored to both restore dystrophin, improve muscle function, and efficiently reconstitute the muscle fibers in the advanced stage of the disease.

Keywords:  Asos; DMD; Gene therapy; dystrophin; gene substitution; gene transfer; readthrough mutation; snRNA

DOI:  https://doi.org/10.1080/14737175.2023.2249607
Int J Mol Sci. 2023 Aug 14. pii: 12763. [Epub ahead of print]24(16):

Biopolymers in Drug and Gene Delivery Systems.

Yury A Skorik.

Recent years have seen remarkable advances in the field of drug and gene delivery systems, revolutionizing the way we approach therapeutic treatments [...].

DOI: https://doi.org/10.3390/ijms241612763
Int J Mol Sci. 2023 Aug 08. pii: 12545. [Epub ahead of print]24(16):

Regenerating Myofibers after an Acute Muscle Injury: What Do We Really Know about Them?

Francis X Pizza, Kole H Buckley.

  Injury to skeletal muscle through trauma, physical activity, or disease initiates a process called muscle regeneration. When injured myofibers undergo necrosis, muscle regeneration gives rise to myofibers that have myonuclei in a central position, which contrasts the normal, peripheral position of myonuclei. Myofibers with central myonuclei are called regenerating myofibers and are the hallmark feature of muscle regeneration. An important and underappreciated aspect of muscle regeneration is the maturation of regenerating myofibers into a normal sized myofiber with peripheral myonuclei. Strikingly, very little is known about processes that govern regenerating myofiber maturation after muscle injury. As knowledge of myofiber formation and maturation during embryonic, fetal, and postnatal development has served as a foundation for understanding muscle regeneration, this narrative review discusses similarities and differences in myofiber maturation during muscle development and regeneration. Specifically, we compare and contrast myonuclear positioning, myonuclear accretion, myofiber hypertrophy, and myofiber morphology during muscle development and regeneration. We also discuss regenerating myofibers in the context of different types of myofiber necrosis (complete and segmental) after muscle trauma and injurious contractions. The overall goal of the review is to provide a framework for identifying cellular and molecular processes of myofiber maturation that are unique to muscle regeneration.

Keywords:  embryonic myogenesis; muscle regeneration; muscle repair; postnatal myogenesis

DOI:  https://doi.org/10.3390/ijms241612545
Am J Physiol Cell Physiol. 2023 Aug 21.

Thrown for a Loop: Fibro-Adipogenic Progenitors in Skeletal Muscle Fibrosis.

Taryn Loomis, Lucas R Smith.

  Fibro-adipogenic progenitors (FAPs) are key regulators of skeletal muscle regeneration and homeostasis. However, dysregulation of these cells leads to fibro-fatty infiltration across various muscle diseases. FAPs are the key source of extracellular matrix (ECM) deposition in muscle, and disruption to this process leads to a pathological accumulation of ECM, known as fibrosis. The replacement of contractile tissue with fibrotic ECM functionally impairs the muscle and increasing muscle stiffness. FAPs and fibrotic muscle form a progressively degenerative feedback loop where, as a muscle becomes fibrotic, it induces a fibrotic FAP phenotype leading to further development of fibrosis. In this review we summarize FAPs' role in fibrosis in terms of their activation, heterogeneity, contributions to fibrotic degeneration, and role across musculoskeletal diseases. We also discuss current research on potential therapeutic avenues to attenuate fibrosis by targeting FAPs.

Keywords:  Fibro-adipogenic progenitors (FAPs); extracellular matrix (ECM); fibrosis; skeletal muscle; stem cells

DOI:  https://doi.org/10.1152/ajpcell.00245.2023
Biomedicines. 2023 Aug 01. pii: 2168. [Epub ahead of print]11(8):

Progress and Prospects of Gene Editing in Pluripotent Stem Cells.

Zhenwu Zhang, Xinyu Bao, Chao-Po Lin.

  Applying programmable nucleases in gene editing has greatly shaped current research in basic biology and clinical translation. Gene editing in human pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), is highly relevant to clinical cell therapy and thus should be examined with particular caution. First, since all mutations in PSCs will be carried to all their progenies, off-target edits of editors will be amplified. Second, due to the hypersensitivity of PSCs to DNA damage, double-strand breaks (DSBs) made by gene editing could lead to low editing efficiency and the enrichment of cell populations with defective genomic safeguards. In this regard, DSB-independent gene editing tools, such as base editors and prime editors, are favored due to their nature to avoid these consequences. With more understanding of the microbial world, new systems, such as Cas-related nucleases, transposons, and recombinases, are also expanding the toolbox for gene editing. In this review, we discuss current applications of programmable nucleases in PSCs for gene editing, the efforts researchers have made to optimize these systems, as well as new tools that can be potentially employed for differentiation modeling and therapeutic applications.

Keywords:  CRISPR-Cas9; base editor; gene editing; induced pluripotent stem cell; pluripotent stem cell; prime editor

DOI:  https://doi.org/10.3390/biomedicines11082168
Adv Exp Med Biol. 2023 ;1418 119-126

Extracellular Vesicles for Muscle Atrophy Treatment.

Xuan Su, Yan Shen, Il-Man Kim, Neal L Weintraub, Mark Hamrick, Yaoliang Tang.

  Skeletal muscle atrophy is a progressive chronic disease associated with various conditions, such as aging, cancer, and muscular dystrophy. Interleukin-6 (IL-6) is highly correlated with or plays a crucial role in inducing skeletal muscle atrophy. Extracellular vehicles (EVs), including exosomes, mediate cell-cell communication, and alterations in the genetic material contained in EVs during muscle atrophy may impair muscle cell signaling. Transplantation of muscle progenitor cell-derived EVs (MPC-EVs) is a promising approach for treating muscle diseases such as Duchenne muscular dystrophy (DMD). Moreover, stem cell-derived EVs with modification of microRNAs (e.g., miR-26 and miR-29) have been reported to attenuate muscle atrophy. Unbiased RNA-Seq analysis suggests that MPC-EVs may exert an inhibitory effect on IL-6 pathway. Here, we review the latest advances concerning the mechanisms of stem cell/progenitor cell-derived EVs in alleviating muscle atrophy, including anti-inflammatory and anti-fibrotic effects. We also discuss the clinical application of EVs in the treatment of muscle atrophy.

Keywords:  Bioengineering; Extracellular vesicles; IL-6; Muscle atrophy; Myogenic progenitor cells

DOI:  https://doi.org/10.1007/978-981-99-1443-2_8