bims-limsir 2023-06-11 papers

on Lipophilic modified siRNAs

Issue of 2023–06–11
two papers selected by
Ivan V. Chernikov, Institute of Сhemical Biology and Fundamental Medicine of the SB RAS

Extended Nucleic Acid (exNA): A Novel, Biologically Compatible Backbone that Significantly Enhances Oligonucleotide Efficacy in vivo.
Combination of CAR‑T cell therapy and radiotherapy: Opportunities and challenges in solid tumors (Review).

bioRxiv. 2023 May 26. pii: 2023.05.26.542506. [Epub ahead of print]

Extended Nucleic Acid (exNA): A Novel, Biologically Compatible Backbone that Significantly Enhances Oligonucleotide Efficacy in vivo.

Ken Yamada, Vignesh Narayan Hariharan, Jillian Caiazzi, Rachael Miller, Chantal Furguson, Ellen Sapp, Hassan Fakih, Qi Tan, Nozomi Yamada, Raymond C Furgal, Joseph Paquette, Brianna Bramato, Nicholas McHugh, Ashley Summers, Clemens Lochmann, Bruno M D C Godinho, Samuel Hildebrand, Dimas Echeverria, Matthew R Hassler, Julia F Alterman, Marian DiFiglia, Neil Aronin, Anastasia Khvorova.

Metabolic stabilization of therapeutic oligonucleotides requires both sugar and backbone modifications, where phosphorothioate (PS) is the only backbone chemistry used in the clinic. Here, we describe the discovery, synthesis, and characterization of a novel biologically compatible backbone, extended nucleic acid (exNA). Upon exNA precursor scale up, exNA incorporation is fully compatible with common nucleic acid synthetic protocols. The novel backbone is orthogonal to PS and shows profound stabilization against 3'- and 5'-exonucleases. Using small interfering RNAs (siRNAs) as an example, we show exNA is tolerated at most nucleotide positions and profoundly improves in vivo efficacy. A combined exNA-PS backbone enhances siRNA resistance to serum 3'-exonuclease by ∼32-fold over PS backbone and >1000-fold over the natural phosphodiester backbone, thereby enhancing tissue exposure (∼6-fold), tissues accumulation (4- to 20-fold), and potency both systemically and in brain. The improved potency and durability imparted by exNA opens more tissues and indications to oligonucleotide-driven therapeutic interventions.

DOI: https://doi.org/10.1101/2023.05.26.542506
Oncol Lett. 2023 Jul;26(1): 281

Combination of CAR‑T cell therapy and radiotherapy: Opportunities and challenges in solid tumors (Review).

Liqiang Zhong, Yi Li, Tobias Achu Muluh, Yongsheng Wang.

  Chimeric antigen receptor (CAR) T cell therapy has emerged as a new and breakthrough cancer immunotherapy. Although CAR-T cell therapy has made significant progress clinically in patients with refractory or drug-resistant hematological malignancies, there are numerous challenges in its application to solid tumor therapy, including antigen escape, severe toxic reactions, abnormal vascularization, tumor hypoxia, insufficient infiltration of CAR-T cells and immunosuppression. As a conventional mode of anti-tumor therapy, radiotherapy has shown promising effects in combination with CAR-T cell therapy by enhancing the specific immunity of endogenous target antigens, which promoted the infiltration and expansion of CAR-T cells and improved the hypoxic tumor microenvironment. This review focuses on the obstacles to the application of CAR-T technology in solid tumor therapy, the potential opportunities and challenges of combined radiotherapy and CAR-T cell therapy, and the review of recent literature to evaluate the best combination for the treatment of solid tumors.

Keywords:  CAR-T cell therapy; immunotherapy; radiotherapy; solid tumor clinical trials

DOI:  https://doi.org/10.3892/ol.2023.13867