Pharmaceutical compositions and methods for potentiating gene silencing
Inventors
Lee, Dong Ki • SON, Da Seul • Kim, Yang Hee
Assignees
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Publication Number
US-11040057-B2
Publication Date
2021-06-22
Expiration Date
Abstract
In various aspects and embodiments, the invention provides compounds or agents that potentiate siRNA cellular entry or activity, and provides methods for identifying such compounds or agents. Exemplary agents that act as L-type calcium channel blockers are described herein, and are shown to potentiate gene silencing with cp-asiRNAs.
Core Innovation
The document describes a technology for potentiating RNA interference by administering a cell penetrating asymmetric small interfering RNA (cp-asiRNA) or a long-antisense asiRNA (lasiRNA) together with an L-type calcium channel blocker. The approach is directed to increasing siRNA cellular entry and/or gene-silencing activity. The L-type calcium channel blocker is defined using dihydropyridine (DHP) and non-dihydropyridine L-type calcium channel blockers including cilnidipine, nicardipine, nifedipine, or amlodipine.
The document further describes administering the cp-asiRNA or lasiRNA in combination with the L-type calcium channel blocker either in a single pharmaceutical composition or as co-administered agents. Delivery routes described include topical, pulmonary, and parenteral administration. The asiRNA forms and chemistries described include asymmetric siRNA concepts for cp-asiRNA and lasiRNA, with optional nucleotide and backbone modifications and lipophilic conjugates.
A screening method is described to identify candidate compounds that increase siRNA cellular entry or gene-silencing activity. The examples presented support the use of L-type calcium channel blockers to enhance cp-asiRNA gene silencing and increase cellular uptake, including a comparison where T-type blockers do not provide the same effect. The document provides exemplary L-type blocker classes/agents and associates the RNAi approach with multiple target genes and disease contexts.
Claims Coverage
The partial claim set provided contains one independent claim directed to gene silencing by administering cp-asiRNA or lasiRNA with an L-type calcium channel blocker. No additional independent claims are provided in the supplied list.
Gene silencing with cp-asiRNA or lasiRNA plus an L-type calcium channel blocker
A method of gene silencing in a subject comprising administering an effective amount of a cell penetrating asymmetric small interfering RNA (cp-asiRNA) or a long-antisense asiRNA (lasiRNA) and an L-type calcium channel blocker comprising cilnidipine, nicardipine, nifedipine, or amlodipine.
Based on the independent claim provided, the core inventive concept is administering effective amounts of cp-asiRNA or lasiRNA together with an L-type calcium channel blocker containing cilnidipine, nicardipine, nifedipine, or amlodipine to achieve gene silencing.
Stated Advantages
Potentiation of RNA interference by increasing siRNA cellular entry and/or gene-silencing activity.
Enhanced cp-asiRNA gene silencing and increased cellular uptake with L-type calcium channel blockers, while T-type blockers do not provide the same effect.
Documented Applications
CTGF-associated disorders, including keloid, kidney fibrosis, pulmonary fibrosis, hepatic fibrosis, arthritis, renal failure, vasculogenesis-related disorder, and dermatofibrosis.
Age-related macular degeneration (AMD) via MyD88/TLR3 targeting.
Melanin reduction via tyrosinase targeting, including skin whitening and darkening-related outcomes.
Skin conditions including keloid, atopic dermatitis, psoriasis, scleroderma, hair loss, wrinkled skin, scarring, and skin whitening/darkening contexts.
Pulmonary fibrosis.
Hepatic fibrosis.
Kidney fibrosis.
Hair loss.
Wrinkled skin.
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