bims-limsir Biomed News
on Lipophilic modified siRNAs
Issue of 2023–08–06
two papers selected by
Ivan V. Chernikov, Institute of Сhemical Biology and Fundamental Medicine of the SB RAS
  1. The endosomal escape vehicle platform enhances delivery of oligonucleotides in preclinical models of neuromuscular disorders.
  2. From barriers to novel strategies: smarter CAR T therapy hits hard to tumors.
  1. Mol Ther Nucleic Acids. 2023 Sep 12. 33 273-285
    The endosomal escape vehicle platform enhances delivery of oligonucleotides in preclinical models of neuromuscular disorders.
    Xiang Li, Mahboubeh Kheirabadi, Patrick G Dougherty, Kimberli J Kamer, Xiulong Shen, Nelsa L Estrella, Suresh Peddigari, Anushree Pathak, Sara L Blake, Emmanuelle Sizensky, Carmen Del Genio, Arti B Gaur, Mohanraj Dhanabal, Mahasweta Girgenrath, Natarajan Sethuraman, Ziqing Qian.
      Biological therapeutic agents are highly targeted and potent but limited in their ability to reach intracellular targets. These limitations often necessitate high therapeutic doses and can be associated with less-than-optimal therapeutic activity. One promising solution for therapeutic agent delivery is use of cell-penetrating peptides. Canonical cell-penetrating peptides, however, are limited by low efficiencies of cellular uptake and endosomal escape, minimal proteolytic stability, and toxicity. To overcome these limitations, we designed a family of proprietary cyclic cell-penetrating peptides that form the core of our endosomal escape vehicle technology capable of delivering therapeutic agent-conjugated cargo intracellularly. We demonstrated the therapeutic potential of this endosomal escape vehicle platform in preclinical models of muscular dystrophy with distinct disease etiology. An endosomal escape vehicle-conjugated, splice-modulating oligonucleotide restored dystrophin protein expression in striated muscles in the mdx mouse, a model for Duchenne muscular dystrophy. Furthermore, another endosomal escape vehicle-conjugated, sterically blocking oligonucleotide led to knockdown of aberrant transcript expression levels in facioscapulohumeral muscular dystrophy patient-derived skeletal muscle cells. These findings suggest a significant therapeutic potential of our endosomal escape vehicle conjugated oligonucleotides for targeted upregulation and downregulation of gene expression in neuromuscular diseases, with possible broader application of this platform for delivery of intracellular biological agents.
    Keywords:  Duchenne muscular dystrophy; MT: Oligonucleotides: Therapies and Applications; antisense oligonucleotides; cell-penetrating peptides; endosomal escape; facioscapulohumeral muscular dystrophy; neuromuscular disorders
    DOI:  https://doi.org/10.1016/j.omtn.2023.06.022
  2. Front Immunol. 2023 ;14 1203230
    From barriers to novel strategies: smarter CAR T therapy hits hard to tumors.
    Muhammad Babar Khawar, Fei Ge, Ali Afzal, Haibo Sun.
      Chimeric antigen receptor (CAR) T cell therapy for solid tumors shows promise, but several hurdles remain. Strategies to overcome barriers such as CAR T therapy-related toxicities (CTT), immunosuppression, and immune checkpoints through research and technology are needed to put the last nail to the coffin and offer hope for previously incurable malignancies. Herein we review current literature and infer novel strategies for the mitigation of CTT while impeding immune suppression, stromal barriers, tumor heterogeneity, on-target/off-tumor toxicities, and better transfection strategies with an emphasis on clinical research and prospects.
    Keywords:  CAR T; immune checkpoints; immunosuppression; stromal barrier; transfection strategies
    DOI:  https://doi.org/10.3389/fimmu.2023.1203230
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