bims-limsir Biomed News
on Lipophilic modified siRNAs
Issue of 2022–11–13
two papers selected by
Ivan V. Chernikov, Institute of Сhemical Biology and Fundamental Medicine of the SB RAS
  1. Biodistribution and delivery of oligonucleotide therapeutics to the central nervous system: ADVANCES, CHALLENGES, AND FUTURE PERSPECTIVES.
  2. In vivo delivery of CRISPR-Cas9 genome editing components for therapeutic applications.
  1. Biopharm Drug Dispos. 2022 Nov 05.
    Biodistribution and delivery of oligonucleotide therapeutics to the central nervous system: ADVANCES, CHALLENGES, AND FUTURE PERSPECTIVES.
    Akihiko Goto, Syunsuke Yamamoto, Shinji Iwasaki.
      Considerable advances have been made in the research and development of oligonucleotide therapeutics (OTs) for treating central nervous system (CNS) diseases, such as psychiatric and neurodegenerative disorders, because of their promising mode of action. However, due to the tight barrier function and complex physiological structure of the CNS, the efficient delivery of OTs to target the brain has been a major challenge, and intensive efforts have been made to overcome this limitation. In this review, we summarize the representative methodologies and current knowledge of biodistribution, along with the pharmacokinetic/pharmacodynamic (PK/PD) relationship of OTs in the CNS, which are critical elements for the successful development of OTs for CNS diseases. First, quantitative bioanalysis methods and imaging-based approaches for the evaluation of OT biodistribution are summarized. Next, information available on the biodistribution profile, distribution pathways, quantitative PK/PD modeling, and simulation of OTs following intrathecal or intracerebroventricular administration are reviewed. Finally, the latest knowledge on the drug delivery systems to the brain via intranasal or systemic administration as non-invasive routes for improved patient quality of life is reviewed. The aim of this review is to enrich research on the successful development of OTs by clarifying OT distribution profiles and pathways to the target brain regions or cells, and by identifying points that need further investigation for a mechanistic approach to generate efficient OTs. This article is protected by copyright. All rights reserved.
    Keywords:  biodistribution; central nervous systems; drug delivery system; oligonucleotide therapeutics
    DOI:  https://doi.org/10.1002/bdd.2338
  2. Biomaterials. 2022 Oct 28. pii: S0142-9612(22)00516-6. [Epub ahead of print]291 121876
    In vivo delivery of CRISPR-Cas9 genome editing components for therapeutic applications.
    Kun Huang, Daniel Zapata, Yan Tang, Yong Teng, Yamin Li.
      Since its mechanism discovery in 2012 and the first application for mammalian genome editing in 2013, CRISPR-Cas9 has revolutionized the genome engineering field and created countless opportunities in both basic science and translational medicine. The first clinical trial of CRISPR therapeutics was initiated in 2016, which employed ex vivo CRISPR-Cas9 edited PD-1 knockout T cells for the treatment of non-small cell lung cancer. So far there have been dozens of clinical trials registered on ClinicalTrials.gov in regard to using the CRISPR-Cas9 genome editing as the main intervention for therapeutic applications; however, most of these studies use ex vivo genome editing approach, and only a few apply the in vivo editing strategy. Compared to ex vivo editing, in vivo genome editing bypasses tedious procedures related to cell isolation, maintenance, selection, and transplantation. It is also applicable to a wide range of diseases and disorders. The main obstacles to the successful translation of in vivo therapeutic genome editing include the lack of safe and efficient delivery system and safety concerns resulting from the off-target effects. In this review, we highlight the therapeutic applications of in vivo genome editing mediated by the CRISPR-Cas9 system. Following a brief introduction of the history, biology, and functionality of CRISPR-Cas9, we showcase a series of exemplary studies in regard to the design and implementation of in vivo genome editing systems that target the brain, inner ear, eye, heart, liver, lung, muscle, skin, immune system, and tumor. Current challenges and opportunities in the field of CRISPR-enabled therapeutic in vivo genome editing are also discussed.
    Keywords:  CRISPR-Cas9; Genome editing; Nanomaterial; Organ targeting; Viral vector
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121876
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