Methods for alleviating facioscapulohumeral dystrophy (FSHD) by an antisense nucleic acid molecule inhibiting the expression of double homeobox 4 (DUX4)
Inventors
van der Maarel, Silvere M. • Tapscott, Stephen J. • Tawil, Rabi • Lemmers, Richard J.L.F. • Geng, Linda • Snider, Lauren
Assignees
Leiden University Medical Center • University of Rochester • Fred Hutchinson Cancer Center
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Publication Number
US-12624396-B2
Publication Date
2026-05-12
Expiration Date
Abstract
In one aspect, the invention provides a method of screening a human subject to determine if said subject has a genetic predisposition to develop, or is suffering from Facioscapulohumeral Dystrophy (FSHD), said method comprising: (a) providing a biological sample comprising genomic DNA from the subject; and (b) analyzing the portion of the genomic DNA in the sample corresponding to the distal D4Z4-pLAM region on chromosome 4 and determining the presence or absence of a polymorphism resulting in a functional polyadenylation sequence operationally linked to exon 3 of the DUX4 gene.
Core Innovation
The invention relates to alleviating Facioscapulohumeral Dystrophy (FSHD) in a subject having FSHD by administering a Double homeobox, 4 full length (DUX4-fl) inhibitor agent. The DUX4-fl inhibitor agent comprises a DUX4 antisense nucleic acid molecule that is identical to a portion of the DUX4 gene and hybridizes to DUX4 mRNA, thereby inhibiting production of DUX4.
The disclosure further grounds the DUX4-fl target context in the presence of a functional polyadenylation sequence operationally linked to exon 3 of the DUX4 gene at the distal D4Z4-pLAM genomic region. A polymorphism in the distal D4Z4-pLAM region creates a canonical polyadenylation signal, enabling stable DUX4-fl mRNA production when combined with chromatin relaxation from D4Z4 contraction.
The document also reports DUX4-fl versus DUX4-s expression in FSHD and controls, using iPS cell-derived embryoid bodies and iPS/primary cells, nested RT-PCR, and ChIP-qPCR assessing repressive H3K9me3 at the DUX4 5′ region. It further describes human testis as showing highly expressed DUX4 transcripts with polyadenylation-site dependent contributions from chromosomes 4 and 10, and links D4Z4-associated chromatin repression to alternative splicing and polyadenylation of DUX4 transcripts.
Claims Coverage
The identified independent claims are centered on alleviating FSHD by inhibiting DUX4-fl production through a DUX4 antisense nucleic acid molecule. Across the provided claims content, the inventive features further specify a fatty-acid-containing composition administered parenterally and dependent limitations relating to a functional polyadenylation sequence and antisense nucleic acid format.
Administration of a DUX4-fl inhibitor agent comprising a DUX4 antisense nucleic acid
Administering to a subject having FSHD a Double homeobox, 4 full length (DUX4-fl) inhibitor agent comprising a Double homeobox, 4 (DUX4) antisense nucleic acid molecule identical to a portion of the DUX4 gene and hybridizing to DUX4 mRNA, wherein the DUX4 antisense nucleic acid molecule inhibits production of DUX4.
Parenteral fatty-acid composition with a DUX4-fl inhibitor agent
Administering to a subject having FSHD a composition comprising a Double homeobox, 4 full length (DUX4-fl) inhibitor agent and a fatty acid, wherein the DUX4-fl inhibitor agent comprises a DUX4 antisense nucleic acid molecule identical to a portion of the DUX4 gene and hybridizes to DUX4 mRNA, wherein the DUX4 antisense nucleic acid molecule inhibits production of DUX4, and wherein the composition is administered parenterally.
Functional polyadenylation sequence linked to DUX4 exon 3 at distal D4Z4-pLAM
A functional polyadenylation sequence is operationally linked to exon 3 of the DUX4 gene at the distal D4Z4-pLAM genomic region.
Antisense nucleic acid molecule as an antisense oligonucleotide
The DUX4 antisense nucleic acid molecule is an antisense oligonucleotide.
Antisense nucleic acid identity of at least 8 nucleotides of the DUX4 gene
The DUX4 antisense nucleic acid molecule is identical to at least 8 nucleotides of the DUX4 gene.
Overall, the independent claim coverage is directed to methods for alleviating FSHD using a DUX4-fl inhibitor agent defined by a DUX4 antisense nucleic acid that hybridizes to DUX4 mRNA and inhibits DUX4 production, with one independent claim additionally requiring a fatty-acid-containing composition administered parenterally. Dependent claims further narrow genomic context and antisense nucleic acid specifics, including a functional polyadenylation sequence linked to DUX4 exon 3 in the distal D4Z4-pLAM region and antisense oligonucleotide identity constraints.
Stated Advantages
Alleviating Facioscapulohumeral Dystrophy (FSHD) in a subject having FSHD.
Documented Applications
Screening/detection concepts for assessing genomic DNA for functional polyadenylation sequence presence or absence and measuring DUX4-fl polypeptide and/or polyadenylated DUX4-fl mRNA using assays with nucleic-acid probes/primers.
Treatment/alleviation use case by administering DUX4-fl inhibitor agents comprising DUX4 antisense nucleic acid molecules to subjects having FSHD.
Characterizing DUX4-fl versus DUX4-s expression in FSHD versus controls using iPS cell-derived embryoid bodies and iPS/primary cells, and assessing repressive H3K9me3 at the DUX4 5′ region.
Using a differentiation-associated framework in which DUX4-fl and DUX4-s expression is analyzed in pluripotent/FSHD iPS and after embryoid body differentiation in controls.
Describing DUX4 transcript expression in human testis and contributions dependent on polyadenylation site, including alternative splicing and polyadenylation as part of a mechanistic model.
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