bims-muscge Biomed News
on Muscle stem cells and gene therapy
Issue of 2023–08–20
twelve papers selected by
Chance Bowman, Dartmouth College
  1. Recombinant adeno-associated virus 8 vector in gene therapy: Opportunities and challenges.
  2. Development of a novel purification method for AAV vectors using tangential flow filtration.
  3. Clinical applications of the CRISPR/Cas9 genome-editing system: Delivery options and challenges in precision medicine.
  4. Unveiling the intricacies of gene delivery: Caveolae-mediated endocytosis induces efficient mRNA delivery in slow-dividing cells.
  5. Emerging non-viral vectors for gene delivery.
  6. In vivo imaging of skeletal muscle form and function: 50 years of insight.
  7. Gene therapy for monogenic disorders: challenges, strategies, and perspectives.
  8. Bioorthogonal Engineered Virus-Like Nanoparticles for Efficient Gene Therapy.
  9. Muscle wasting: emerging pathways and potential drug targets.
  10. Impaired skeletal muscle health in Parkinsonian syndromes: clinical implications, mechanisms and potential treatments.
  11. Autophagy and exercise: current insights and future research directions.
  12. CRISPR/Cas9-based application for cancer therapy: Challenges and solutions for non-viral delivery.
  1. Genes Dis. 2024 Jan;11(1): 283-293
    Recombinant adeno-associated virus 8 vector in gene therapy: Opportunities and challenges.
    Liyuan Zhao, Zixuan Yang, Minhui Zheng, Lei Shi, Mengyun Gu, Gang Liu, Feng Miao, Yan Chang, Fanghua Huang, Naping Tang.
      In recent years, significant breakthroughs have been made in the field of gene therapy. Adeno-associated virus (AAV) is one of the most promising gene therapy vectors and a powerful tool for delivering the gene of interest. Among the AAV vectors, AAV serotype 8 (AAV8) has attracted much attention for its efficient and stable gene transfection into specific tissues. Currently, recombinant AAV8 has been widely used in gene therapy research on a variety of diseases, including genetic diseases, cancers, autoimmune diseases, and viral diseases. This paper reviewed the applications and challenges of using AAV8 as a vector for gene therapy, with the aim of providing a valuable resource for those pursuing the application of viral vectors in gene therapy.
    Keywords:  AAV8; Adeno-associated virus; Gene therapy; Primates; Recombinant; Rodents
    DOI:  https://doi.org/10.1016/j.gendis.2023.02.010
  2. Biotechnol Bioeng. 2023 Aug 16.
    Development of a novel purification method for AAV vectors using tangential flow filtration.
    Rimi Miyaoka, Yuji Tsunekawa, Yae Kurosawa, Takako Sasaki, Azusa Onodera, Kenji Sakamoto, Yuko Kakiuchi, Mikako Wada, Yuko Nitahara-Kasahara, Hiromi Hayashita-Kinoh, Takashi Okada.
      Adeno-associated virus (AAV) vector can efficiently transduce therapeutic genes in various tissue types with less side effects; however, owing to complex multistep processes during manufacture, there have been surges in the pricing of recently approved AAV vector-based gene therapy products. This study aimed to develop a simple and efficient method for high-quality purification of AAV vector via tangential flow filtration (TFF), which is commonly used for concentration and diafiltration of solutions during AAV vector purification. We established a novel purification method using TFF and surfactants. Treatment with two classes of surfactants (anionic and zwitterionic) successfully inhibited the aggregation of residual proteins separated from the AAV vector in the crude product by TFF, obtaining a clearance of 99.5% residual proteins. Infectivity of the AAV vector purified using the new method was confirmed both in vitro and in vivo, and no remarkable inflammation or tissue damage was observed in mouse skeletal muscle after local administration. Overall, our proposed method could be used to establish a platform for the purification of AAV vector.
    Keywords:  adeno-associated virus; purification; surfactant; tangential flow filtration; ultrafiltration
    DOI:  https://doi.org/10.1002/bit.28524
  3. Genes Dis. 2024 Jan;11(1): 268-282
    Clinical applications of the CRISPR/Cas9 genome-editing system: Delivery options and challenges in precision medicine.
    Mohadeseh Khoshandam, Hossein Soltaninejad, Marziyeh Mousazadeh, Amir Ali Hamidieh, Saman Hosseinkhani.
      CRISPR/Cas9 is an effective gene editing tool with broad applications for the prevention or treatment of numerous diseases. It depends on CRISPR (clustered regularly interspaced short palindromic repeats) as a bacterial immune system and plays as a gene editing tool. Due to the higher specificity and efficiency of CRISPR/Cas9 compared to other editing approaches, it has been broadly investigated to treat numerous hereditary and acquired illnesses, including cancers, hemolytic diseases, immunodeficiency disorders, cardiovascular diseases, visual maladies, neurodegenerative conditions, and a few X-linked disorders. CRISPR/Cas9 system has been used to treat cancers through a variety of approaches, with stable gene editing techniques. Here, the applications and clinical trials of CRISPR/Cas9 in various illnesses are described. Due to its high precision and efficiency, CRISPR/Cas9 strategies may treat gene-related illnesses by deleting, inserting, modifying, or blocking the expression of specific genes. The most challenging barrier to the in vivo use of CRISPR/Cas9 like off-target effects will be discussed. The use of transfection vehicles for CRISPR/Cas9, including viral vectors (such as an Adeno-associated virus (AAV)), and the development of non-viral vectors is also considered.
    Keywords:  CRISPR/Cas9; Clinical trials; Gene therapy; Non-viral vectors; Viral vectors
    DOI:  https://doi.org/10.1016/j.gendis.2023.02.027
  4. Mol Ther Nucleic Acids. 2023 Sep 12. 33 545-547
    Unveiling the intricacies of gene delivery: Caveolae-mediated endocytosis induces efficient mRNA delivery in slow-dividing cells.
    Sabine den Roover, Joeri L Aerts.
      
    DOI:  https://doi.org/10.1016/j.omtn.2023.07.024
  5. J Nanobiotechnology. 2023 Aug 17. 21(1): 272
    Emerging non-viral vectors for gene delivery.
    Chenfei Wang, Chaolan Pan, Haiyang Yong, Feifei Wang, Tao Bo, Yitong Zhao, Bin Ma, Wei He, Ming Li.
      Gene therapy holds great promise for treating a multitude of inherited and acquired diseases by delivering functional genes, comprising DNA or RNA, into targeted cells or tissues to elicit manipulation of gene expression. However, the clinical implementation of gene therapy remains substantially impeded by the lack of safe and efficient gene delivery vehicles. This review comprehensively outlines the novel fastest-growing and efficient non-viral gene delivery vectors, which include liposomes and lipid nanoparticles (LNPs), highly branched poly(β-amino ester) (HPAE), single-chain cyclic polymer (SCKP), poly(amidoamine) (PAMAM) dendrimers, and polyethyleneimine (PEI). Particularly, we discuss the research progress, potential development directions, and remaining challenges. Additionally, we provide a comprehensive overview of the currently approved non-viral gene therapeutics, as well as ongoing clinical trials. With advances in biomedicine, molecular biology, materials science, non-viral gene vectors play an ever-expanding and noteworthy role in clinical gene therapy.
    Keywords:  Gene delivery process; Gene therapy; Lipid nanoparticles; Nanomaterials; Non-viral gene vectors
    DOI:  https://doi.org/10.1186/s12951-023-02044-5
  6. J Biomech. 2023 Jul 29. pii: S0021-9290(23)00315-9. [Epub ahead of print]158 111745
    In vivo imaging of skeletal muscle form and function: 50 years of insight.
    Silvia S Blemker.
      Skeletal muscle form and function has fascinated scientists for centuries. Our understanding of muscle function has long been driven by advancements in imaging techniques. For example, the sliding filament theory of muscle, which is now widely leveraged in biomechanics research, stemmed from observations made possible by scanning electron microscopy. Over the last 50 years, advancing in medical imaging, combined with ingenuity and creativity of biomechanists, have provide a wealth of new and important insights into in vivo human muscle function. Incorporation of in vivo imaging has also advanced computational modeling and allowed our research to have an impact in many clinical populations. While this review does not provide a comprehensive or meta-analysis of the all the in vivo muscle imaging work over the last five decades, it provides a narrative about the past, present, and future of in vivo muscle imaging.
    Keywords:  Imaging; In vivo; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.jbiomech.2023.111745
  7. J Genet Genomics. 2023 Aug 14. pii: S1673-8527(23)00164-9. [Epub ahead of print]
    Gene therapy for monogenic disorders: challenges, strategies, and perspectives.
    Yi Zhang, Zhi-Ying Wu.
      Monogenic disorders refer to a group of human diseases caused by mutations in single genes. While disease-modifying therapies have offered some relief to symptoms and delayed progression for some monogenic diseases, most of these diseases still lack effective treatments. In recent decades, gene therapy has emerged as a promising therapeutic strategy for genetic disorders. Researchers have developed various gene manipulation tools and gene delivery systems to treat monogenic diseases. Despite this progress, concerns about inefficient delivery, persistent expression, immunogenicity, toxicity, capacity limitation, genomic integration, and limited tissue specificity still need to be addressed. This review gives an overview of commonly used gene therapy and delivery tools, along with the challenges they face and the potential strategies to counter them.
    Keywords:  Challenges; Gene delivery; Gene editing; Gene therapy; Monogenic diseases
    DOI:  https://doi.org/10.1016/j.jgg.2023.08.001
  8. Nanomicro Lett. 2023 Aug 12. 15(1): 197
    Bioorthogonal Engineered Virus-Like Nanoparticles for Efficient Gene Therapy.
    Chun-Jie Bao, Jia-Lun Duan, Ying Xie, Xin-Ping Feng, Wei Cui, Song-Yue Chen, Pei-Shan Li, Yi-Xuan Liu, Jin-Ling Wang, Gui-Ling Wang, Wan-Liang Lu.
      Gene therapy offers potentially transformative strategies for major human diseases. However, one of the key challenges in gene therapy is developing an effective strategy that could deliver genes into the specific tissue. Here, we report a novel virus-like nanoparticle, the bioorthgonal engineered virus-like recombinant biosome (reBiosome), for efficient gene therapies of cancer and inflammatory diseases. The mutant virus-like biosome (mBiosome) is first prepared by site-specific codon mutation for displaying 4-azido-L-phenylalanine on vesicular stomatitis virus glycoprotein of eBiosome at a rational site, and the reBiosome is then prepared by clicking weak acid-responsive hydrophilic polymer onto the mBiosome via bioorthogonal chemistry. The results show that the reBiosome exhibits reduced virus-like immunogenicity, prolonged blood circulation time and enhanced gene delivery efficiency to weakly acidic foci (like tumor and arthritic tissue). Furthermore, reBiosome demonstrates robust therapeutic efficacy in breast cancer and arthritis by delivering gene editing and silencing systems, respectively. In conclusion, this study develops a universal, safe and efficient platform for gene therapies for cancer and inflammatory diseases.
    Keywords:  Bioorthogonal chemistry; Gene therapy; Recombinant biosome; Site-specific codon mutation; Virus-like nanoparticle
    DOI:  https://doi.org/10.1007/s40820-023-01153-y
  9. Trends Pharmacol Sci. 2023 Aug 16. pii: S0165-6147(23)00168-2. [Epub ahead of print]
    Muscle wasting: emerging pathways and potential drug targets.
    Aylin Domaniku, Sevval Nur Bilgic, Serkan Kir.
      Muscle wasting is a serious comorbidity associated with many disorders, including cancer, kidney disease, heart failure, and aging. Progressive loss of skeletal muscle mass negatively influences prognosis and survival, and is often accompanied by frailty and poor quality of life. Clinical trials testing therapeutics against muscle wasting have yielded limited success. Some therapies improved muscle mass in patients without appreciable differences in physical performance. This review article discusses emerging pathways that regulate muscle atrophy, including oncostatin M (OSM) and ectodysplasin A2 (EDA2) receptor (EDA2R) signaling, outcomes of recent clinical trials, and potential drug targets for future therapies.
    Keywords:  cachexia; skeletal muscle atrophy; wasting
    DOI:  https://doi.org/10.1016/j.tips.2023.07.006
  10. J Cachexia Sarcopenia Muscle. 2023 Aug 13.
    Impaired skeletal muscle health in Parkinsonian syndromes: clinical implications, mechanisms and potential treatments.
    Kate T Murphy, Gordon S Lynch.
      There is increasing evidence that neurodegenerative disorders including the Parkinsonian syndromes are associated with impaired skeletal muscle health, manifesting as wasting and weakness. Many of the movement problems, lack of muscle strength and reduction in quality of life that are characteristic of these syndromes can be attributed to impairments in skeletal muscle health, but this concept has been grossly understudied and represents an important area of unmet clinical need. This review describes the changes in skeletal muscle health in idiopathic Parkinson's disease and in two atypical Parkinsonian syndromes, the most aggressive synucleinopathy multiple system atrophy, and the tauopathy progressive supranuclear palsy. The pathogenesis of the skeletal muscle changes is described, including the contribution of impairments to the central and peripheral nervous system and intrinsic alterations. Pharmacological interventions targeting the underlying molecular mechanisms with therapeutic potential to improve skeletal muscle health in affected patients are also discussed. Although little is known about the mechanisms underlying these conditions, current evidence implicates multiple pathways and processes, highlighting the likely need for combination therapies to protect muscle health and emphasizing the merit of personalized interventions for patients with different physical capacities at different stages of their disease. As muscle fatigue is often experienced by patients prior to diagnosis, the identification and measurement of this symptom and related biomarkers to identify early signs of disease require careful interrogation, especially for multiple system atrophy and progressive supranuclear palsy where diagnosis is often made several years after onset of symptoms and only confirmed post-mortem. We propose a multidisciplinary approach for early diagnosis and implementation of personalized interventions to preserve muscle health and improve quality of life for patients with typical and atypical Parkinsonian syndromes.
    Keywords:  Multiple system atrophy; Parkinson's disease; Progressive supranuclear palsy; Skeletal muscle; Wasting; Weakness
    DOI:  https://doi.org/10.1002/jcsm.13312
  11. Int J Sports Med. 2023 Aug 15.
    Autophagy and exercise: current insights and future research directions.
    Javier Botella, Chris Shaw, David Bishop.
      Autophagy is a cellular process by which proteins and organelles are degraded inside the lysosome. Exercise is known to influence the regulation of autophagy in skeletal muscle. However, as gold standard techniques to assess autophagy flux in vivo are restricted to animal research, important gaps remain in our understanding of how exercise influences autophagy activity in humans. Using available datasets, we show how the gene expression profile of autophagy receptors and ATG8 family members differ between human and mouse skeletal muscle, providing a potential explanation for their differing exercise-induced autophagy responses. Furthermore, we provide a comprehensive view of autophagy regulation following exercise in humans by summarising human transcriptomic and phosphoproteomic datasets that provide novel targets of potential relevance. These newly identified phosphorylation sites may provide an explanation as to why both endurance and resistance exercise lead to an exercise-induced reduction in LC3B-II, while possibly divergently regulating autophagy receptors, and, potentially, autophagy flux. We also provide recommendations to use ex vivo autophagy flux assays to better understand the influence of exercise, and other stimuli, on autophagy regulation in humans. This review provides a critical overview of the field and points towards novel research areas of autophagy regulation following exercise in humans.
    DOI:  https://doi.org/10.1055/a-2153-9258
  12. J Control Release. 2023 Aug 15. pii: S0168-3659(23)00526-6. [Epub ahead of print]
    CRISPR/Cas9-based application for cancer therapy: Challenges and solutions for non-viral delivery.
    Ying-Qi Lin, Ke-Ke Feng, Jie-Ying Lu, Jing-Qing Le, Wu-Ling Li, Bing-Chen Zhang, Cheng-Lei Li, Xun-Huan Song, Ling-Wu Tong, Jing-Wei Shao.
      CRISPR/Cas9 genome editing is a promising therapeutic technique, which makes precise and rapid gene editing technology possible on account of its high sensitivity and efficiency. CRISPR/Cas9 system has been proved to able to effectively disrupt and modify genes, which shows great potential for cancer treatment. Current researches proves that virus vectors are capable of effectively delivering the CRISPR/Cas9 system, but immunogenicity and carcinogenicity caused by virus transmission still trigger serious consequences. Therefore, the greatest challenge of CRISPR/Cas9 for cancer therapy lies on how to deliver it to the target tumor site safely and effectively. Non-viral delivery systems with specific targeting, high loading capacity, and low immune toxicity are more suitable than viral vectors, which limited by uncontrollable side effects. Their medical advances and applications have been widely concerned. Herein, we present the molecule mechanism and different construction strategies of CRISPR/Cas9 system for editing genes at the beginning of this research. Subsequently, several common CRISPR/Cas9 non-viral deliveries for cancer treatment are introduced. Lastly, based on the main factors limiting the delivery efficiency of non-viral vectors proposed in the existing researches and literature, we summarize and discuss the main methods to solve these limitations in the existing tumor treatment system, aiming to introduce further optimization and innovation of the CRISPR/Cas9 non-viral delivery system suitable for cancer treatment.
    Keywords:  CRISPR/Cas9; Non-viral vectors; cancer therapy; editing efficient
    DOI:  https://doi.org/10.1016/j.jconrel.2023.08.028
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