Polynucleotide molecules and uses thereof
Inventors
Fraley, Andrew W. • Roy, Atanu • Stanton, Matthew
Assignees
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Publication Number
US-10385088-B2
Publication Date
2019-08-20
Expiration Date
Abstract
The present disclosure provides alternative sugar moieties and polynucleotides comprising such sugar moieties, and methods of use thereof.
Core Innovation
The invention relates to an mRNA 30 to 5000 nucleotides in length encoding a polypeptide, where the mRNA comprises at least one backbone moiety having a nucleobase-defined structure (B) or a salt thereof. The nucleobase options include uracil, pseudouracil, 1-methylpseudouracil, 5-methoxyuracil, cytosine, 5-methylcytosine, guanine, and adenine, and the disclosure includes backbone and heteroatom configurations defined by Formula IA, Formula IIA, and corresponding general structures for polynucleotide backbone moieties.
In addition to the backbone moiety, the polynucleotides may include a 5′ untranslated region, a 3′ untranslated region, a 5′ cap structure, and a poly-A tail. The disclosure also describes 5′ UTR and 3′ UTR elements, Kozak sequence, 5′ cap structures, cap analogs, and post-transcriptional capping concepts, including cap0, cap1, cap2, cap4, anti-reverse cap analog (ARCA), and mCAP.
The subject matter also discusses reduced innate immune response, altered protein:Cytokine (PC) ratio evaluation, improved expression/stability, and avoidance or reduction of sensing pathways associated with TLR7, TLR8, RIG-I, MDA5, LGP2, TLRs, PRRs, and DEX(D/H) helicases. It further includes terminal architecture modifications such as histone stem loop and stabilization strategies, 3′ triple helix elements, and poly-A tail length ranges.
Claims Coverage
The claim coverage centers on an mRNA 30 to 5000 nucleotides in length encoding a polypeptide and comprising at least one backbone moiety having a nucleobase-defined structure B or a salt thereof. The independent claim is supported by dependent features that add 5′ untranslated region, 3′ untranslated region, and 5′ cap structure elements, and that further specify the 3′ poly-A tail length range and chemical definitions of B.
Polypeptide-encoding mRNA with nucleobase-defined backbone moiety
An mRNA 30 to 5000 nucleotides in length encoding a polypeptide, the mRNA comprising at least one backbone moiety having the structure wherein B is a nucleobase, or a salt thereof.
RNA-region inclusion of 5′ UTR, 3′ UTR, and 5′ cap structure
The mRNA further includes a 5′ untranslated region, a 3′ untranslated region, and a 5′ cap structure.
3′ poly-A tail of specified length in the 3′ UTR terminus
The mRNA further includes a poly-A tail 100 to 250 nucleotides in length at the 3′-terminus of the 3′ untranslated region.
Nucleobase B defined by specific chemical structures
The mRNA is further narrowed by specific chemical structures for the nucleobase component B, including listed nucleobase options and salt forms.
Overall, the claims define an mRNA encoding a polypeptide and including at least one backbone moiety defined by a nucleobase B or a salt thereof, and they further narrow the construct by RNA-region features, a specified 3′ poly-A tail length, and particular nucleobase chemical structures.
Stated Advantages
Reduced innate immune response.
Improved expression/stability.
Altered protein:Cytokine (PC) ratio evaluation.
Documented Applications
Not explicitly described in patent.
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