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Publication Number
US-11591600-B2
Publication Date
2023-02-28
Expiration Date
Abstract
The present technology relates, in part, to long double-stranded RNA (dsRNA) (e.g., 30 or more base pairs) that inhibits gene expression.
Core Innovation
The invention provides a composition comprising long double-stranded RNA (ldRNA) capable of triggering gene silencing via an RNA interference (RNAi) mechanism. The ldRNA consists of two substantially complementary RNA strands and comprises at least one guide sequence complementary to one or more target mRNAs. Each RNA strand is in the range of 40 to 80 nucleotides and has an overhang on a 3′ end, and the ldRNA comprises one or more phosphorothioate linkages.
The invention addresses activation of innate immune response pathways associated with RNAi by enabling ldRNA that inhibits gene expression while avoiding significant antiviral/innate immune activation. Long double-stranded RNA of at least 40 nucleotides is described as inhibiting gene expression in mammalian cells via RNAi, while unexpectedly avoiding significant antiviral/innate immune activation. Increasing length reduces interferon response versus a shorter blunt dsRNA, and optional 3′ dinucleotide (2-nt) overhangs further eliminate innate immune activation by preventing RIG-I recognition.
The invention defines preferred structural features for the ldRNA, including substantially complementary strands, blunt ends or 3′ overhangs, and possible non-canonical base pairing such as G:U wobble, along with modified backbones and phosphorothioate linkages to stabilize the RNA. Guide sequences (≤8 bp) target single or multiple mRNA regions/mRNAs, including viral and cancer-relevant targets, with reported control of innate immune signaling supported by RIG-I/MDAS knockout settings.
Claims Coverage
The independent claim covers a long double-stranded RNA (ldRNA) composition that triggers gene silencing via RNAi while incorporating specific structural length, 3′ overhang, phosphorothioate linkage, and guide-sequence targeting features. Dependent claims further refine target scope and immune-response performance and may further specify structural and formulation/use aspects.
Long double-stranded RNA triggering RNA interference with guide-sequence targeting
The ldRNA is a composition in which two substantially complementary RNA strands include at least one guide sequence complementary to one or more target mRNAs, where each strand is 40 to 80 nucleotides with a 3′ end overhang and the ldRNA comprises one or more phosphorothioate linkages.
Across the claim family, the core inventive concept is an ldRNA composition with two substantially complementary strands, RNAi-mediated gene-silencing capability, guide-sequence complementarity to one or more target mRNAs, strand length in the 40–80 nt range with a 3′ overhang, and phosphorothioate linkages; dependent claims refine targeting and add constraints related to antiviral response activation and other structural/formulation details.
Stated Advantages
Unexpectedly avoids significant antiviral/innate immune activation while inhibiting gene expression via RNAi in mammalian cells.
Increasing ldRNA length reduces interferon response versus a shorter blunt dsRNA.
3′ dinucleotide (2-nt) overhangs further eliminate innate immune activation by preventing RIG-I recognition.
Induces little or no activation of an antiviral response.
Enables target mRNA knockdown comparable to conventional 19+2 siRNA while maintaining low ISG induction (as described for survivin-targeting examples).
Documented Applications
Inhibiting gene expression by using the ldRNA composition in mammalian cells, tissues, or animals.
Therapeutic use framing for ldRNA administration to cells/tissues/animals with non-limiting disease area examples.
Formulation and administration routes are described as topical, oral, and inhalation, including use of carriers and liposomes and controlled-release depots.
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