bims-limsir 2022-10-23 papers

on Lipophilic modified siRNAs

Issue of 2022–10–23
seven papers selected by
Ivan V. Chernikov, Institute of Сhemical Biology and Fundamental Medicine of the SB RAS

Small interfering RNA (siRNA): discovery, pharmacology and clinical development - an introductory review.
Clinical pharmacology of siRNA therapeutics: current status and future prospects.
Efficient Downregulation of Alk4 in Skeletal Muscle After Systemic Treatment with Conjugated siRNAs in a Mouse Model for Duchenne Muscular Dystrophy.
Investigation of the ionic conditions in SiRNA-mediated delivery through its carriers in the cell membrane: a molecular dynamic simulation.
RNA interference (RNAi)-based therapeutics for treatment of rare neurologic diseases.
CAR-T cell therapy for hematological malignancies: Limitations and optimization strategies.
B cell deficiency promotes the initiation and progression of lung cancer.

Br J Pharmacol. 2022 Oct 17.

Small interfering RNA (siRNA): discovery, pharmacology and clinical development - an introductory review.

Priyanga Ranasinghe, Melisande Addison, James W Dear, David J Webb.

  Post-transcriptional gene silencing targets and degrades mRNA transcripts, silencing the expression of specific genes. RNA interference using synthetic structurally well-defined short dsRNA (small interfering RNA [siRNA]), is a technology that has advanced rapidly in recent years. This introductory review describes utility of siRNA, by exploring the underpinning biology, pharmacology, recent advances and clinical developments, alongside potential limitations and ongoing challenges. Mediated by the RNA-induced silencing complex, siRNAs bind to specific complementary mRNAs, that are subsequently degraded. siRNA therapy offers advantages over other therapeutic approaches, including ability of specifically designed siRNAs to potentially target any mRNA and improved patient adherence through infrequent administration associated with a very long duration of action. Key pharmacokinetic and pharmacodynamic challenges include targeted administration, poor tissue penetration, nuclease inactivation, rapid renal elimination, immune activation and off-target effects. These have been overcome by chemical modification of siRNA and/or by utilising a range of delivery systems, increasing bioavailability and stability, allowing successful clinical translation. Patisiran (hereditary transthyretin-mediated amyloidosis) was the first licensed siRNA, since joined by givosiran (acute hepatic porphyria), lumasiran (primary hyperoxaluria type-1]) and inclisiran (familial hypercholesterolaemia) all use N-acetylgalactosamine (GalNAc) linkage for effective liver-directed delivery. Others are currently under development for indications varying from rare genetic diseases to common chronic non-communicable diseases (hypertension and cancer). Technological advances are overcoming pharmacological barriers, paving way for broader clinical use. Ongoing challenges remain in targeting organs beyond liver and reaching special sites (e.g. brain). By overcoming these barriers, siRNA therapy has the potential to substantially widen its therapeutic impact.

Keywords:  RNA interference; medication adherence; post-transcriptional gene silencing; siRNA; therapeutics

DOI:  https://doi.org/10.1111/bph.15972
Expert Rev Clin Pharmacol. 2022 Oct 17.

Clinical pharmacology of siRNA therapeutics: current status and future prospects.

Ahmed Khaled Abosalha, Jacqueline Boyajian, Waqar Ahmad, Paromita Islam, Merry Ghebretatios, Sabrina Schaly, Rahul Thareja, Karan Arora, Satya Prakash.

   INTRODUCTION: Small interfering RNA (siRNA) has emerged as a powerful tool for post-transcriptional downregulation of multiple genes for various therapies. Naked siRNA molecules are surrounded by several barriers that tackle their optimum delivery to target tissues such as limited cellular uptake, short circulation time, degradation by endonucleases, glomerular filtration, and capturing by the reticuloendothelial system (RES).
AREAS COVERED: This review provides insights into studies that investigate various siRNA-based therapies, focusing on the mechanism, delivery strategies, bioavailability, pharmacokinetic, and pharmacodynamics of naked and modified siRNA molecules. The clinical pharmacology of currently approved siRNA products is also discussed.
EXPERT OPINION: Few siRNA-based products have been approved recently by the Food and Drug Administration (FDA) and other regulatory agencies after approximately twenty years following its discovery due to the associated limitations. The absorption, distribution, metabolism, and excretion of siRNA therapeutics are highly restricted by several obstacles, resulting in rapid clearance of siRNA-based therapeutic products from systemic circulation before reaching the cytosol of targeted cells. The siRNA therapeutics however are very promising in many diseases, including gene therapy and SARS-COV-2 viral infection. The design of suitable delivery vehicles and developing strategies toward better pharmacokinetic parameters may solve the challenges of siRNA therapies.

Keywords:  Small interfering RNA (siRNA); bioavailability; bioconjugation; givosiran; lumasiran; patisiran; pharmacodynamic

DOI:  https://doi.org/10.1080/17512433.2022.2136166
Nucleic Acid Ther. 2022 Oct 20.

Efficient Downregulation of Alk4 in Skeletal Muscle After Systemic Treatment with Conjugated siRNAs in a Mouse Model for Duchenne Muscular Dystrophy.

Sarah Engelbeen, Svetlana Pasteuning-Vuhman, Joke Boertje-van der Meulen, Rubina Parmar, Klaus Charisse, Laura Sepp-Lorenzino, Muthiah Manoharan, Annemieke Aartsma-Rus, Maaike van Putten.

  Downregulation of genes involved in the secondary pathology of Duchenne muscular dystrophy, for example, inflammation, fibrosis, and adiposis, is an interesting approach to ameliorate degeneration of muscle and replacement by fibrotic and adiposis tissue. Small interfering RNAs (siRNAs) are able to downregulate target genes, however, delivery of siRNAs to skeletal muscle still remains a challenge. We investigated delivery of fully chemically modified, cholesterol-conjugated siRNAs targeting Alk4, a nontherapeutic target that is expressed highly in muscle. We observed that a single intravenous or intraperitoneal (IP) injection of 10 mg/kg resulted in significant downregulation of Alk4 mRNA expression in skeletal muscles in both wild-type and mdx mice. Treatment with multiple IP injections of 10 mg/kg led to an overall reduction of Alk4 expression, reaching significance in tibialis anterior (39.7% ± 6.2%), diaphragm (32.7% ± 5.8%), and liver (41.3% ± 29.9%) in mdx mice. Doubling of the siRNA dose did not further increase mRNA silencing in muscles of mdx mice. The chemically modified conjugated siRNAs used in this study are very promising for delivery to both nondystrophic and dystrophic muscles and could have major implications for treatment of muscular dystrophy pathology.

Keywords:  delivery; dystrophin; mdx mouse; pathology

DOI:  https://doi.org/10.1089/nat.2022.0021
Sci Rep. 2022 Oct 20. 12(1): 17520

Investigation of the ionic conditions in SiRNA-mediated delivery through its carriers in the cell membrane: a molecular dynamic simulation.

Mohammad Hasan Darvishi, Abdollah Allahverdi, Hadi Hashemzadeh, Hamid Reza Javadi.

SiRNA is a new generation of drug molecules and a new approach for treating a variety of diseases such as cancer and viral infections. SiRNA delivery to cells and translocation into cytoplasm are the main challenges in the clinical application of siRNA. Lipid carriers are one of the most successful carriers for siRNA delivery. In this study, we investigated the interaction of siRNA with a zwitterionic bilayer and how ion concentration and lipid conjugation can affect it. The divalent cation such as Mg2+ ions could promote the siRNA adsorption on the bilayer surface. The cation ions can bind to the head groups of lipids and the grooves of siRNA molecules and form bridges between the siRNA and bilayer surface. Our findings demonstrated the bridges formed by divalent ions could facilitate the attachment of siRNA to the membrane surface. We showed that the divalent cations can regulate the bridging-driven membrane attachment and it seems the result of this modulation can be used for designing biomimetic devices. In the following, we examined the effect of cations on the interaction between siRNA modified by cholesterol and the membrane surface. Our MD simulations showed that in the presence of Mg2+, the electrostatic and vdW energy between the membrane and siRNA were higher compared to those in the presence of NA+. We showed that the electrostatic interaction between membrane and siRNA cannot be facilitated only by cholesterol conjugated. Indeed, cations are essential to create coulomb repulsion and enable membrane attachment. This study provides important insight into liposome carriers for siRNA delivery and could help us in the development of siRNA-based therapeutics. Due to the coronavirus pandemic outbreak, these results may shed light on the new approach for treating these diseases and their molecular details.

DOI: https://doi.org/10.1038/s41598-022-22509-1
Mol Aspects Med. 2022 Oct 15. pii: S0098-2997(22)00093-0. [Epub ahead of print] 101148

RNA interference (RNAi)-based therapeutics for treatment of rare neurologic diseases.

Noelle D Germain, Wendy K Chung, Patrick D Sarmiere.

  Advances in genome sequencing have greatly facilitated the identification of genomic variants underlying rare neurodevelopmental and neurodegenerative disorders. Understanding the fundamental causes of rare monogenic disorders has made gene therapy a possible treatment approach for these conditions. RNA interference (RNAi) technologies such as small interfering RNA (siRNA), microRNA (miRNA), and short hairpin RNA (shRNA), and other oligonucleotide-based modalities such as antisense oligonucleotides (ASOs) are being developed as potential therapeutic approaches for manipulating expression of the genes that cause a variety of neurological diseases. Here, we offer a brief review of the mechanism of action of these RNAi approaches; provide deeper discussion of the advantages, challenges, and specific considerations related to the development of RNAi therapeutics for neurological disease; and highlight examples of rare neurological diseases for which RNAi therapeutics hold great promise.

Keywords:  Gene therapy; Neurological disorders; RNA interference; RNA-targeting therapeutics

DOI:  https://doi.org/10.1016/j.mam.2022.101148
Front Immunol. 2022 ;13 1019115

CAR-T cell therapy for hematological malignancies: Limitations and optimization strategies.

Jiawen Huang, Xiaobing Huang, Juan Huang.

  In the past decade, the emergence of chimeric antigen receptor (CAR) T-cell therapy has led to a cellular immunotherapy revolution against various cancers. Although CAR-T cell therapies have demonstrated remarkable efficacy for patients with certain B cell driven hematological malignancies, further studies are required to broaden the use of CAR-T cell therapy against other hematological malignancies. Moreover, treatment failure still occurs for a significant proportion of patients. CAR antigen loss on cancer cells is one of the most common reasons for cancer relapse. Additionally, immune evasion can arise due to the hostile immunosuppressive tumor microenvironment and the impaired CAR-T cells in vivo persistence. Other than direct antitumor activity, the adverse effects associated with CAR-T cell therapy are another major concern during treatment. As a newly emerged treatment approach, numerous novel preclinical studies have proposed different strategies to enhance the efficacy and attenuate CAR-T cell associated toxicity in recent years. The major obstacles that impede promising outcomes for patients with hematological malignancies during CAR-T cell therapy have been reviewed herein, along with recent advancements being made to surmount them.

Keywords:  CAR-T cell therapy; hematological malignancies; immune evasion; toxicity; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2022.1019115
Front Oncol. 2022 ;12 1006477

B cell deficiency promotes the initiation and progression of lung cancer.

Han Wu, Chen Chen, Lixing Gu, Jiapeng Li, Yunqiang Yue, Mengqing Lyu, Yeting Cui, Xiaoyu Zhang, Yu Liu, Haichuan Zhu, Xinghua Liao, Tongcun Zhang, Fan Sun, Weidong Hu.

  Currently commercialized CAR-T cell therapies targeting CD19 and BCMA show great efficacy to cure B cell malignancies. However, intravenous infusion of these CAR-T cells severely destroys both transformed and normal B cells in most tissues and organs, in particular lung, leading to a critical question that what the impact of normal B cell depletion on pulmonary diseases and lung cancer is. Herein, we find that B cell frequency is remarkably reduced in both smoking carcinogen-treated lung tissues and lung tumors, which is associated with advanced cancer progression and worse patient survival. B cell depletion by anti-CD20 antibody significantly accelerates the initiation and progression of lung tumors, which is mediated by repressed tumor infiltration of T cells and macrophage elimination of tumor cells. These findings unveil the overall antitumor activity of B cells in lung cancer, providing novel insights into both mechanisms underlying lung cancer pathogenesis and clinical prevention post CAR-T cell therapy.

Keywords:  B cell; CAR-T; initiation; lung cancer; progression

DOI:  https://doi.org/10.3389/fonc.2022.1006477