Compositions and methods for modulating MECP2 expression
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Publication Number
US-12343357-B2
Publication Date
2025-07-01
Expiration Date
Abstract
Disclosed herein are compounds and methods for decreasing MECP2 mRNA and protein expression. Such compounds and methods are useful to treat, prevent, or ameliorate MECP2 associated disorders and syndromes. Such MECP2 associated disorders include MECP2 duplication syndrome.
Core Innovation
The invention relates to modified antisense oligonucleotides targeting human Methyl CpG Binding Protein 2 (MECP2), including a nucleobase sequence selected from SEQ ID NO: 2 context and other selected SEQ ID NOs. The antisense oligonucleotides comprise 5-methylcytosine, modified nucleosides and linkages, and a gapmer architecture with a central gap of 2'-deoxynucleotides and wings using modified nucleosides, including 2'-methoxyethyl modified nucleosides.
The invention further relates to substituted tetrahydropyran nucleoside analogs, including tetrahydropyran nucleoside analogs of Formula VII. The analogs include a heterocyclic base moiety, internucleoside linking groups that may be H or may include hydroxyl protecting group, linked conjugate group, or 5′/3′-terminal group, and substituent sets q1–q7 and R1/R2.
The disclosure connects these nucleoside analogs to modified antisense oligonucleotides and describes MECP2-targeted antisense oligonucleotides evaluated by in vitro and in vivo testing. The document reports in vitro inhibition of MECP2 mRNA, reduction of MECP2 mRNA and MECP2 protein, and in vivo effects after brain infusion, including behavioral phenotypes, seizure, and EEG readouts.
Claims Coverage
The independent claim coverage centers on modified antisense oligonucleotide compounds defined by length, consecutive nucleobase runs from selected SEQ ID NOs, and complementarity to reference sequences. Across the provided claim sets, inventive features further specify 5-methylcytosine, 2′-MOE, and a gap/wing segment architecture with a deoxynucleoside gap between modified-sugar wings.
Modified antisense oligonucleotide length and consecutive nucleobase run
A modified antisense oligonucleotide consisting of 13 to 30 linked nucleosides, or 16 to 30 linked nucleosides, with at least 13 or at least 16 consecutive nucleobases of a nucleobase sequence selected from SEQ ID NOs: 16-24, 112, 190, and 268.
High complementarity to specified reference sequences
The modified antisense oligonucleotide has a nucleobase sequence at least 95% complementary to SEQ ID NO: 1 or SEQ ID NO: 2.
5-methylcytosine as the modified nucleobase
The modified nucleobase is 5-methylcytosine.
2'-MOE as a modified sugar moiety
At least one modified sugar moiety is a 2'-MOE modified sugar moiety.
Gap/wing gapmer architecture with deoxynucleoside gap and modified-sugar wings
A modified antisense oligonucleotide includes a 10-deoxynucleoside gap segment positioned between 5'-2' and 3'-2' wing segments of 5 linked nucleosides each, with each wing-segment nucleoside having a modified sugar.
Coverage centers on MECP2-targeted modified antisense oligonucleotide compounds defined by constrained length and sequence content, with dependent refinements specifying high complementarity, 5-methylcytosine, 2′-MOE, and a gap/wing segment architecture.
Stated Advantages
In vitro dose-dependent inhibition of MECP2 mRNA in HepG2 cells.
Reduction of MECP2 mRNA and MECP2 protein (human isoforms) in MECP2 duplication transgenic mice.
No effect on mouse MECP2 mRNA after antisense treatment.
Improved behavioral phenotypes associated with the most potent candidate Isis No. 628785.
Patient lymphoblast dose-response inhibition of MECP2 expression.
In vivo seizure/EEG improvements with Isis No. 628785 treatment.
Treating MECP2 duplication syndrome by reducing MECP2 expression.
Reducing MECP2 expression without causing Rett syndrome symptoms.
Documented Applications
In vitro MECP2 mRNA inhibition in HepG2 cells using selected Isis Numbers, including a dose-response effect.
In vivo assessment in MECP2 duplication transgenic mice, including reductions in MECP2 mRNA and MECP2 protein (human isoforms) and behavioral phenotype improvements after brain infusion.
Use of Isis No. 628785 for patient lymphoblast dose-response inhibition of MECP2 expression.
In vivo seizure activity and EEG improvements associated with Isis No. 628785 treatment.
Treating MECP2 duplication syndrome by reducing MECP2 expression using antisense compositions.
Applications include assays and endpoints described for functional and neurological readouts such as motor function, anxiety, social interaction, seizures, and EEG.
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