Kinetics of HTT lowering in brain of YAC 128 mice following single and repetitive intranasal dosing of siRNA packaged in chitosan-based nanoparticle

V Sava; O Fihurka; A Khvorova; J Sanchez-Ramos

doi:10.1016/j.jddst.2021.102517

Kinetics of HTT lowering in brain of YAC 128 mice following single and repetitive intranasal dosing of siRNA packaged in chitosan-based nanoparticle

J Drug Deliv Sci Technol. 2021 Jun:63:102517. doi: 10.1016/j.jddst.2021.102517. Epub 2021 Apr 6.

Authors

V Sava¹, O Fihurka¹, A Khvorova², J Sanchez-Ramos¹

Affiliations

¹ Department of Neurology, University of South Florida.
² RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts.

Abstract

This report describes the kinetics of Huntington's Disease (HD) gene (HTT) lowering in brains of YAC 128 mice. Lowering (or "knock-down") of HTT mRNA expression was achieved by intranasal administration of specially designed siRNA loaded into chitosan nanoparticles. Kinetic patterns of HTT lowering observed in different brain regions allowed calculation of cumulative lowering effects that result from multiple consecutive administrations. Mathematical modeling generated dosing schedules for approaching a steady knock-down effect and for prediction of magnitude and duration of HTT lowering. Kinetic modeling of HTT lowering with our algorithm will be useful in determining intranasal dosing schedules to produce chronic, therapeutically significant lowering effect of gene expression.

Keywords: Lowering brain HTT; intranasal administration; kinetics of gene lowering; repetitive dosing; siRNA loaded nanoparticles.

Abstract

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