Translational and clinical development of therapeutic siRNA and ASOs: current industry practices, perspectives, and recommendations

RNA-based therapies, particularly small interfering RNA (siRNA) and antisense oligonucleotides (ASOs), represent a promising modality class with the potential to target previously "undruggable" proteins, and with potential for precision medicine approach. The successful development of these therapeutics relies on a comprehensive understanding of several key factors, including bioconjugation, bioanalytical techniques, biotransformation, tissue distribution, computational modeling and simulation, and clinical pharmacology. Bioconjugation strategies are essential for enhancing metabolic stability, facilitating cellular uptake, and targeting specific tissues, thereby improving efficacy and minimizing dosing. Tailored bioanalytical methods are crucial for assessing pharmacokinetics (PK) and pharmacodynamics, with particular emphasis on tissue PK in cases where plasma PK does not reflect therapeutic activity. Biotransformation and tissue distribution studies are essential, although a less comprehensive package may be adequate for well-established chemistry. Given the unique properties of oligonucleotides, computational modeling plays a critical role in predicting drug behavior in target tissues, supporting dose optimization. Clinical pharmacology for oligonucleotides is less complex than for small molecules, as they are less likely to interact with common drug metabolizing enzymes or transporter proteins. This white paper, developed by the Innovation and Quality (IQ) Consortium Nucleic Acids Working Group, consolidates industry insights and recommendations to inform best practices and regulatory guidelines, ensuring the safe and efficient development of siRNA and ASO therapies.

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Publication Details

Journal
Nucleic Acids Research
Published
2025-08-15
DOI
https://doi.org/10.1093/nar/gkaf778
Citations
7
Primary Topic
RNA Interference and Gene Delivery
Type
article
Field-Weighted Citation Impact
5.64
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article

Translational and clinical development of therapeutic siRNA and ASOs: current industry practices, perspectives, and recommendations

Linzhi Chen, Swati Gupta, Darshana Jani, Jingxian Chen et al.
7 citations
Nucleic Acids Research
RNA Interference and Gene Delivery
5.64
article

Translational and clinical development of therapeutic siRNA and ASOs: current industry practices, perspectives, and recommendations

Linzhi Chen, Swati Gupta, Darshana Jani, Jingxian Chen, Amir S. Youssef, Jesper Kammersgaard Christensen, Xien Yu Chua, Felix Huth, Guangnong Zhang, Vibha Jawa, Shirin Hooshfar, Christophe Husser, Barent DuBois, Katharina Root, Carol Kuo, Nicholas Colletti, Bertil Lindmark, Jeffrey C. Kurz, Wenying Jian, Sara C. Humphreys, V. Ravikanth, Matthew E. Albertolle, Helle Linnebjerg, Francis D. Gibbons, Girish R. Chopda, Sumeet Singla, Steve R. Hood, Chenxiao Tang, Krishna Aluri, Annie Lumen, Thomas N. Kakuda, Steven Zhang, Pedro Morais, Rongrong Jiang, Sabine Lohmann, Tao Niu, Jing Liu, Shyam Kumar Gudey
article en
7 citations

Abstract

RNA-based therapies, particularly small interfering RNA (siRNA) and antisense oligonucleotides (ASOs), represent a promising modality class with the potential to target previously "undruggable" proteins, and with potential for precision medicine approach. The successful development of these therapeutics relies on a comprehensive understanding of several key factors, including bioconjugation, bioanalytical techniques, biotransformation, tissue distribution, computational modeling and simulation, and clinical pharmacology. Bioconjugation strategies are essential for enhancing metabolic stability, facilitating cellular uptake, and targeting specific tissues, thereby improving efficacy and minimizing dosing. Tailored bioanalytical methods are crucial for assessing pharmacokinetics (PK) and pharmacodynamics, with particular emphasis on tissue PK in cases where plasma PK does not reflect therapeutic activity. Biotransformation and tissue distribution studies are essential, although a less comprehensive package may be adequate for well-established chemistry. Given the unique properties of oligonucleotides, computational modeling plays a critical role in predicting drug behavior in target tissues, supporting dose optimization. Clinical pharmacology for oligonucleotides is less complex than for small molecules, as they are less likely to interact with common drug metabolizing enzymes or transporter proteins. This white paper, developed by the Innovation and Quality (IQ) Consortium Nucleic Acids Working Group, consolidates industry insights and recommendations to inform best practices and regulatory guidelines, ensuring the safe and efficient development of siRNA and ASO therapies.

Nucleic Acids ResearchVol. 53(18)
Roche (Switzerland) (CH), Novartis (Switzerland) (CH), Biogen (United States) (US), Amgen (United States) (US), Johnson & Johnson (United States) (US), Boehringer Ingelheim (Germany) (DE), Alnylam Pharmaceuticals (United States) (US), Bristol-Myers Squibb (Germany) (DE), Eli Lilly (United States) (US), Pfizer (United States) (US), Novo Nordisk (Denmark) (DK), Age UK (GB), AbbVie (United States) (US), AstraZeneca (South Korea) (KR), Bioanalytica (Switzerland) (CH), Electronic BioSciences (United States) (US), Novo Nordisk (United States) (US), Novo Nordisk (Switzerland) (CH), Moderna Therapeutics (United States) (US), Simulation Technologies (United States) (US), Bristol-Myers Squibb (Sweden) (SE), AstraZeneca (Finland) (FI), Boehringer Ingelheim (France) (FR), EpiVax (United States) (US), Sarepta Therapeutics (United States) (US), Bristol-Myers Squibb (Japan) (JP), AstraZeneca (United States) (US), Tris Pharma (United States) (US), Takeda (Japan) (JP), Eisai (Japan) (JP), Bayer (Germany) (DE)
Openalex Percentile: Top 4%
RNA Interference and Gene Delivery
5.64
DOIOpen Access PDFOpenAlex
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