Exploring dose and downregulation dynamics in lipid nanoparticles based siRNA therapy: Systematic review and
Anil Kumar1, Bakr Ahmed2, Indu Pal Kaur2
1Department of Pharmacology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh 160012, India.
Abstract:
Small interfering RNA (siRNA) holds promise as a therapeutic approach for various diseases, yet challenges persist in achieving efficient delivery, biodistribution, and minimizing off-target effects. Lipidic nanoformulations are being developed to address these hurdles, but the optimal dose for preclinical investigations remains unclear. This systematic review and meta-analysis aims to determine the optimal dose of nanoformulated siRNA and explore factors influencing dose and biodistribution, informing future research in this field. A comprehensive search across four electronic databases identified 25 potential studies, with 15 selected for meta-analysis after screening. Quality assessment was conducted using SYRCLE's risk of bias tool modified for animal studies based on research question. Study found an average siRNA dose of 1.513 ± 0.377 mg/kg with mean downregulation of 65.79 % achieved, with siRNA-LNPs mainly accumulating in the liver. While individual factors showed no significant correlation, a positive association between dose and downregulation was observed, alongside other influencing factors. Extrapolating intravenous doses to potential oral doses, we suggest an initial oral dose range of 1.5 to 8 mg/kg, considering siRNA-LNPs bioavailability. These findings contribute to advancing RNA interference research and encourage further exploration of siRNA-based treatments in personalized medicine.
Insights
This study determined the optimal dose for nanoformulated small interfering RNA (siRNA) in preclinical research. An average dose of 1.513 mg/kg achieved 65.79% gene downregulation, primarily in the liver.
Area of Science:
- Biotechnology
- Pharmacology
- Genetics
Background:
- Small interfering RNA (siRNA) offers therapeutic potential but faces delivery and safety challenges.
- Lipidic nanoformulations are emerging solutions, yet optimal preclinical dosing is undefined.
Purpose of the Study:
- To establish the optimal dose of nanoformulated siRNA for preclinical studies.
- To investigate factors affecting siRNA dose, biodistribution, and efficacy.
Main Methods:
- Systematic review and meta-analysis of 15 preclinical studies.
- Quality assessment using SYRCLE's risk of bias tool.
- Analysis of dose-response and biodistribution data.
Main Results:
- Average effective siRNA dose identified as 1.513 ± 0.377 mg/kg, yielding 65.79% gene downregulation.
- siRNA-lipid nanoparticles (LNPs) predominantly accumulated in the liver.
- A positive correlation between dose and downregulation was observed.
Conclusions:
- The findings provide crucial dosing guidance for nanoformulated siRNA preclinical research.
- Suggests an initial oral dose range of 1.5-8 mg/kg based on intravenous data and bioavailability.
- Supports advancement of RNA interference therapeutics and personalized medicine.
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