Expanding RNAi to Kidneys, Lungs, and Spleen via Selective ORgan Targeting (SORT) siRNA Lipid Nanoparticles
Amogh Vaidya1, Stephen Moore1, Sumanta Chatterjee1
1Department of Biomedical Engineering, Department of Biochemistry, Simmons Comprehensive Cancer Center, Program in Genetic Drug Engineering, The University of Texas Southwestern Medical Center, Dallas, TX, 75235, USA.
Abstract:
Inhibition of disease-causing mutations using RNA interference (RNAi) has resulted in clinically approved medicines with additional candidates in late stage trials. However, targetable tissues currently in preclinical development are limited to liver following systemic intravenous (IV) administration because predictable delivery of siRNA to non-liver tissues remains an unsolved challenge. Here, evidence of durable extrahepatic gene silencing enabled by siRNA Selective ORgan Targeting lipid nanoparticles (siRNA SORT LNPs) to the kidneys, lungs, and spleen is provided. LNPs excel at dose-dependent silencing of tissue-enriched endogenous targets resulting in 60%-80% maximal knockdown after a single IV injection and up to 88% downregulation of protein expression in mouse lungs after two doses. To examine knockdown potency and unbiased organ targeting, B6.129TdTom/EGFP mice that constitutively express the TdTomato transgene across all cell types are utilized to demonstrate 58%, 45%, and 15% reduction in TdTomato fluorescence in lungs, spleen, and kidneys, respectively. Finally, physiological relevance of siRNA SORT LNP-mediated gene silencing is established via acute suppression of endogenous Tie2 which induces lung-specific phenotypic alteration of vascular endothelial barrier. Due to plethora of extrahepatic diseases that may benefit from RNAi interventions, it is anticipated that the findings will expand preclinical landscape of therapeutic targets beyond the liver.
Insights
RNA interference (RNAi) using novel lipid nanoparticles achieves durable gene silencing in non-liver organs like the kidneys, lungs, and spleen. This breakthrough expands RNAi therapeutic potential for treating extrahepatic diseases.
Area of Science:
- Biotechnology
- Molecular Biology
- Pharmacology
Background:
- RNA interference (RNAi) therapies have yielded approved drugs, but delivery to non-liver tissues remains a challenge.
- Current RNAi preclinical development is largely confined to liver-targeted therapies via systemic administration.
- Developing effective siRNA delivery to extrahepatic tissues is crucial for expanding RNAi therapeutic applications.
Purpose of the Study:
- To demonstrate the efficacy of siRNA Selective ORgan Targeting lipid nanoparticles (siRNA SORT LNPs) for extrahepatic gene silencing.
- To evaluate the biodistribution and gene silencing potency of siRNA SORT LNPs in non-liver organs.
- To establish the physiological relevance of siRNA SORT LNP-mediated gene silencing in a disease model.
Main Methods:
- Systemic intravenous (IV) administration of siRNA SORT LNPs in mouse models.
- Quantification of gene knockdown using fluorescence reduction in TdTomato reporter mice.
- Assessment of protein expression changes and physiological outcomes following gene silencing.
Main Results:
- siRNA SORT LNPs achieved dose-dependent gene silencing in kidneys, lungs, and spleen.
- Maximal knockdown ranged from 60%-80% after a single IV injection, with up to 88% protein downregulation in lungs after two doses.
- Significant reduction in TdTomato fluorescence observed in lungs (58%), spleen (45%), and kidneys (15%).
- Suppression of endogenous Tie2 demonstrated physiologically relevant, lung-specific vascular effects.
Conclusions:
- siRNA SORT LNPs enable durable, extrahepatic gene silencing in multiple organs.
- These findings validate siRNA SORT LNPs as a promising platform for RNAi therapeutics beyond the liver.
- The study significantly expands the preclinical landscape for RNAi interventions targeting extrahepatic diseases.
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