RNAi-based drug design: considerations and future directions

Tang, Qi; Khvorova, Anastasia

doi:10.1038/s41573-024-00912-9

Cited by 39 publications

(2 citation statements)

References 270 publications

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“…Oligonucleotides (ASOs and siRNAs) have become an increasingly popular therapeutic modality, with the CNS being one of the areas of intense preclinical and clinical development. 54 , 55 Oligonucleotides do not cross the blood-brain barrier and must be delivered through direct cerebral spinal fluid (CSF) administration via intracerebroventricular (ICV) or intrathecally (IT) injections. 13 While there are different types of toxicity associated with oligonucleotides 47 , 48 , 50 , CSF administration will likely impose additional limitations.…”

Section: Discussionmentioning

confidence: 99%

Preventing acute neurotoxicity of CNS therapeutic oligonucleotides with the addition of Ca2+ and Mg2+ in the formulation

Miller,

Paquette,

Barker

et al. 2024

Preprint

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Oligonucleotide therapeutics (ASOs and siRNAs) have been explored for modulation of gene expression in the central nervous system (CNS), with several drugs approved and many in clinical evaluation. Administration of highly concentrated oligonucleotides to the CNS can induce acute neurotoxicity. We demonstrate that delivery of concentrated oligonucleotides to the CSF in awake mice induces acute toxicity, observable within seconds of injection. Electroencephalography (EEG) and electromyography (EMG) in awake mice demonstrated seizures. Using ion chromatography, we show that siRNAs can tightly bind Ca2+ and Mg2+ up to molar equivalents of the phosphodiester (PO)/phosphorothioate (PS) bonds independently of the structure or phosphorothioate content. Optimization of the formulation by adding high concentrations (above biological levels) of divalent cations (Ca2+ alone, Mg2+ alone, or Ca2+ and Mg2+) prevents seizures with no impact on the distribution or efficacy of the oligonucleotide. The data here establishes the importance of adding Ca2+ and Mg2+ to the formulation for the safety of CNS administration of therapeutic oligonucleotides.

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Section: Discussionmentioning

confidence: 99%

Preventing acute neurotoxicity of CNS therapeutic oligonucleotides with the addition of Ca2+ and Mg2+ in the formulation

Miller,

Paquette,

Barker

et al. 2024

Preprint

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“…13,17–19 Therefore, a number of siRNA medicines conjugated with different GalNAc ligands have been approved by the U.S. Food and Drug Administration (FDA) or have shown positive results in recent clinical investigations. 20 For example, inclisiran (ALN-PCSsc), an siRNA conjugated to the GalNAc ligand L96, reduces low-density lipoprotein (LDL) cholesterol by directly inhibiting the synthesis of proprotein convertase subtilisin 9 (PCSK9) in hepatocytes. 21,22…”

Section: Introductionmentioning

confidence: 99%

Novel diamine-scaffold based N-acetylgalactosamine (GalNAc)–siRNA conjugate: synthesis and in vivo activities

Li,

Dong,

Chen

2024

RSC Adv.

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Unlocking the Potential of Chemically Modified Nucleic Acid Therapeutics

Gao,

Nutan,

Gargouri

et al. 2024

Advanced Therapeutics

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Nucleic acid therapeutics have demonstrated tremendous potential for treating diseases by targeting the genetic underpinnings at the transcriptomic level. However, their efficacy hinges on robust strategies to protect nucleic acids from degradation during circulation and to facilitate precise delivery to diseased tissues and cells. Here the critical roles of chemical modification and bioconjugation in advancing nucleic acid therapeutics for improved binding affinity, enhanced stability, and targeted delivery are reviewed. Commencing diverse applications, the significance of different chemical modifications is discussed based on recent literature and clinical products, on oligonucleotides. These modifications encompass backbone, ribose, base alterations and bioconjugation techniques such as N‐acetylgalactosamine (GAlNac), aptamers, antibodies, and cell‐penetrating peptides (CPPs). Supported by a clinical perspective, diverse applications and ongoing developments are highlighted. Furthermore, the current landscape of nucleic acid therapeutics and their potential in addressing genetic disorders with multiple cellular/organelle targeting is discussed. Here the promising prospect of combining chemical innovation and bioconjugation strategies is underscored to propel the development of more effective nucleic acid therapeutics.

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RNAi-based drug design: considerations and future directions

Cited by 39 publications

References 270 publications

Preventing acute neurotoxicity of CNS therapeutic oligonucleotides with the addition of Ca2+ and Mg2+ in the formulation

Preventing acute neurotoxicity of CNS therapeutic oligonucleotides with the addition of Ca2+ and Mg2+ in the formulation

Novel diamine-scaffold based N-acetylgalactosamine (GalNAc)–siRNA conjugate: synthesis and in vivo activities

Unlocking the Potential of Chemically Modified Nucleic Acid Therapeutics

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