Modulation of dystrophia myotonica-protein kinase (DMPK) expression
Inventors
Freier, Susan M. • Thornton, Charles A. • Wheeler, Thurman • Cheng, Seng H. • Leger, Andrew • Wentworth, Bruce M.
Assignees
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Publication Number
US-12480126-B2
Publication Date
2025-11-25
Expiration Date
Abstract
Provided herein are methods, compounds, and compositions for reducing expression of a DMPK mRNA and protein in an animal. Also provided herein are methods, compounds, and compositions for preferentially reducing CUGexp DMPK RNA, reducing myotonia or reducing spliceopathy in an animal. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate type 1 myotonic dystrophy, or a symptom thereof.
Core Innovation
The invention is directed to modified oligonucleotide compounds consisting of 20 to 30 linked nucleosides. The nucleobase sequence is at least 90% complementary to at least 20 contiguous nucleobases of an equal length portion of nucleobases 2077-2099 of SEQ ID NO:1, or at least 90% identical to the nucleobase sequences recited in SEQ ID NOs: 590-594. The modified oligonucleotide includes at least one modified sugar moiety and/or at least one modified internucleoside linkage.
The disclosed invention relates to therapeutic approaches for type 1 myotonic dystrophy (DM1) by reducing DMPK mRNA and protein in animals, with preferential reduction of expanded CUG-repeat (CUGexp) DMPK RNA. The disclosed mechanism is antisense-based and targets mutant/CUGexp DMPK RNA to promote RNA cleavage in the nucleus using nuclear ribonucleases, including RNase H1. The approach is directed to non-repeat regions of mutant/CUGexp DMPK RNA in order to address CUGexp nuclear foci and RNA dominance.
The disclosed embodiments further specify sugar surrogates and internucleoside linking group chemistry, including THP nucleoside analogs with internucleoside linkers T3/T4, cyclohexenyl nucleoside analogs, and general sugar surrogates such as HNA/ANA/MNA. The disclosure includes gapmer motifs, 2′-MOE, phosphorothioate, and 5-methylcytosine, together with complementarity criteria to DMPK sequences using multiple SEQ ID NOs and target windows.
Claims Coverage
The provided claim set contains two independent claim types, both directed to modified oligonucleotide compounds defined by size, sequence or complementarity requirements, and the presence of at least one modified sugar moiety and/or at least one modified internucleoside linkage.
Modified oligonucleotide with defined complementarity to SEQ ID NO:1 nucleobases 2077-2099
A compound comprising a modified oligonucleotide consisting of 20 to 30 linked nucleosides, wherein the nucleobase sequence is at least 90% complementary to at least 20 contiguous nucleobases of an equal length portion of nucleobases 2077-2099 of SEQ ID NO:1, and wherein the modified oligonucleotide comprises at least one modified sugar moiety and/or at least one modified internucleoside linkage.
Modified oligonucleotide with defined sequence identity to SEQ ID NOs: 590-594
A compound comprising a modified oligonucleotide consisting of 20 to 30 linked nucleosides, wherein the nucleobase sequence is at least 90% identical to any of the nucleobase sequences recited in SEQ ID NOs: 590-594, and wherein the modified oligonucleotide comprises at least one modified sugar moiety and/or at least one modified internucleoside linkage.
Across the claim coverage, the core inventive features are modified oligonucleotide compounds of 20 to 30 linked nucleosides with specified complementarity or sequence identity requirements and at least one modified sugar moiety and/or at least one modified internucleoside linkage; dependent claims further specify chemistries such as phosphorothioate, 2′-O-methoxyethyl, and 5-methylcytosine, and include DMPK-related disease contexts.
Stated Advantages
Transcript normalization with no evidence for off-target effects as described in the document.
In vivo reductions in target transcripts and associated functional outcomes, including electromyography myotonia grade reductions and normalization of alternative splicing of Serca1 and other splicing targets.
Preferential reduction of expanded CUG-repeat (CUGexp) DMPK RNA.
Reduction of DMPK mRNA and protein in animals.
Activation of nuclear ribonucleases for RNA cleavage in the nucleus, including RNase H1.
Documented Applications
Treating DMPK-related diseases or symptoms described as myotonia or spliceopathy, including correction or normalization of alternative splicing of Serca1 and additional splicing targets in transgenic mouse models.
ASO evaluation in murine DMPK contexts, including quantitative RT-PCR inhibition and cross-reactivity tracking, with dose-response inhibition data described in mouse primary hepatocytes and HepG2 cells.
Transcriptome microarray analysis in HSA LR mice showing broad transcript normalization and reversal upon ISIS treatment, used as an off-target assessment described in the document.
Therapeutic treatment of type 1 myotonic dystrophy (DM1) by reducing DMPK mRNA and protein in animals, with preferential reduction of CUGexp DMPK RNA.
Cell-based inhibition context described for in vitro inhibition of human DMPK transcripts in human skeletal muscle cells using modified oligonucleotides.
Spliceopathy correction biomarkers described, including splice outcomes such as Serca1/m-Titin/Clen1/Zasp splicing outcomes.
DMPK-related disease treatment contexts including myotonia and spliceopathy, including type 1 myotonic dystrophy and MBNL-dependent spliceopathy, as described in the disclosure and dependent claim context.
In vitro and in vivo testing context involving inhibition of DMPK mRNA, including percent inhibition results using described gapmer architectures, and reference to DMPK/DM1 and an HSA LR mouse model.
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