5′-cap-trinucleotide- or higher oligonucleotide compounds and their use in stabilizing RNA, expressing proteins in therapy
Inventors
Kuhn, Andreas • MURAMATSU, HIROMI • Kariko, Katalin • Fesser, Stephanie • Sahin, Ugur
Assignees
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Publication Number
US-12281138-B2
Publication Date
2025-04-22
Expiration Date
Abstract
The present invention relates to 5′-cap compounds, in particular the stabilization of RNA by such 5′-cap compounds, and provides compositions, such as pharmaceutical compositions, and cells comprising an RNA which is modified with such a 5′-cap compound, as well as methods for producing a peptide or protein of interest using the compositions or cells according to the present invention. Furthermore, the present invention provides the RNA, compositions, or cells for use in therapy, in particular for use in a method of treating a disease or disorder by protein replacement therapy, genome engineering, genetic reprogramming, and immunotherapy; a method for increasing the stability of RNA in cells; a method for increasing the expression of RNA in cells; and a method for providing an RNA with a 5′-cap structure.
Core Innovation
The invention provides 5′-cap compounds having a 5′-cap structure according to formula (I) or formula (III), with defined selections for R1, R2 and R3, R4 and R6, R5, R7, R8, n, and a purine or pyrimidine base moiety B. The compound is capable of co-transcriptional incorporation into an RNA strand.
The disclosure links co-transcriptional incorporation of the 5′-cap compound into RNA with increased RNA stability in cells, increased RNA expression in cells, increased mRNA translation, and reduced IFIT1/cap0 recognition. It also describes increased antigen presentation, including a fraction of MHC molecules presenting antigen, in the context of RNA delivery and targeting of antigen-presenting cells such as dendritic cells.
A further embodiment defines a formula (III) 5′-cap compound with constrained substituent patterns, including R1 as methyl or ethyl; one of R2 and R3 as OCH3 and the other as OH; n = 1; R7 as *pGpN or *pG; R8 as methoxy; and B as a purine or pyrimidine base moiety. The disclosure also describes compositions and kits, RNA modified with the 5′-cap, compositions and cells containing that RNA, and methods to treat disease or disorder by administering the capped RNA.
Claims Coverage
Two independent claim families are identified: a 5′-cap compound of formula (I) and a 5′-cap compound of formula (III). Each independent claim is centered on a specifically defined cap structure and its capability for co-transcriptional incorporation into an RNA strand.
Formula (I) 5′-cap compound capable of co-transcriptional incorporation
A 5′-cap compound having the 5′-cap structure according to formula (I), with defined selections for R1; R2 and R3 arrangements; R4 and R6 and R5 selections from O, S, Se, and BH3; R7 as a mononucleotide or an oligonucleotide having 2 to 9 bases; R8; n as 1, 2, or 3; and B as a purine or pyrimidine base moiety, wherein the 5′-cap compound is capable of co-transcriptional incorporation into an RNA strand.
Formula (III) 5′-cap compound capable of co-transcriptional incorporation
A 5′-cap compound having a structure according to formula (III), with R1 as methyl or ethyl; one of R2 and R3 as OCH3 and the other as OH; n = 1; R7 as *pGpN or *pG; R8 as methoxy; and B as a purine or pyrimidine base moiety, wherein the 5′-cap compound is capable of co-transcriptional incorporation into an RNA strand.
The inventive coverage is directed to specifically defined 5′-cap compounds of formula (I) and formula (III), each limited by constrained substituent and base selections and by capability for co-transcriptional incorporation into an RNA strand.
Stated Advantages
Increased RNA stability and translation.
Reduced IFIT1/cap0 recognition.
Improved immune response when antigen-encoding RNA is used.
Increased RNA stability in cells.
Increased RNA expression in cells.
Increased antigen presentation, expressed as a portion of MHC molecules presenting antigen.
Increased mRNA translation / translation of an mRNA encoded by the co-transcriptionally incorporated 5′-cap-containing RNA.
Documented Applications
RNA use in contexts where increased RNA stability and translation, reduced IFIT1/cap0 recognition, and improved immune response are described, including antigen-encoding RNA.
Therapeutic/vaccine use cases described as extensive uses for the capped RNA.
Protein expression examples described for luciferase and mEPO, including reduced dosing frequency.
Protein replacement therapy using capped RNA.
Genome engineering using capped RNA.
Genetic reprogramming using capped RNA or in somatic cells using RNA containing a 5′-cap structure.
Immunotherapy using capped RNA, including immature antigen-presenting cells such as dendritic cells, MHC molecule presentation, and vaccination contexts.
RNA vaccination / RNA administration framework involving delivery and targeting of antigen-presenting cells such as dendritic cells.
Treating a disease or disorder by administering the capped RNA, or a composition or cell containing that RNA.
Vaccination involving viral antigens including influenza A/B/C, CMV, and RSV.
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