Exon skipping compositions for treating muscular dystrophy
Inventors
Bestwick, Richard K. • FRANK, Diane Elizabeth
Assignees
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Publication Number
US-11932851-B2
Publication Date
2024-03-19
Expiration Date
Abstract
Antisense molecules capable of binding to a selected target site in the human dystrophin gene to induce exon 44 skipping are described.
Core Innovation
The invention relates to antisense morpholino oligonucleotides for Duchenne/Becker muscular dystrophy. The oligonucleotides induce exon skipping of human dystrophin exon 44. The content describes antisense oligonucleotides comprising an oligonucleotide base sequence and optional thymine to uracil substitution, including antisense sequences identified by SEQ ID NOs 1–7.
The morpholino oligonucleotides are described with morpholinos replacing the sugar moieties of the oligonucleotide backbone. The content further covers phosphorus-containing intersubunit linkages and optional designs related to RNase H non-activation. Terminal modifications and conjugation concepts are also described, including morpholino constructs and related variants that target exon skipping.
Conjugated antisense morpholino oligonucleotides are described with an arginine-rich cell penetrating peptide (CPP), including CPP examples identified by SEQ ID NOs 19–34 and additional structural options such as glycine linkers. The content also describes expression vectors, including AAV, pharmaceutical formulations, and kits that incorporate the described antisense conjugates for exon skipping.
Claims Coverage
The provided claim content centers on one independent claim and dependent limitations. It covers a 28-base antisense morpholino construct defined by SEQ ID NO: 6 with optional thymine/uracil substitution, conjugation to an arginine-rich cell penetrating peptide, and pharmaceutically acceptable salt forms, with additional dependent features for CPP sequence limits, a glycine linker, and a pharmaceutical composition.
28-base antisense morpholino base sequence SEQ ID NO: 6 with optional thymine/uracil substitution
An antisense oligonucleotide of 28 bases comprising the base sequence of SEQ ID NO: 6, in which thymine bases are optionally uracil bases.
Morpholino backbone replacing sugar moieties
The sugar moieties of the oligonucleotide backbone are replaced with morpholinos.
Conjugation to an arginine-rich cell penetrating peptide
The antisense oligonucleotide is conjugated to an arginine-rich cell penetrating peptide or a pharmaceutically acceptable salt thereof.
Arginine-rich cell penetrating peptide limited to SEQ ID NOs 19–34
The arginine-rich cell penetrating peptide consists of a sequence selected from SEQ ID NOS: 19–34.
Glycine linker between the CPP and the antisense oligonucleotide
The arginine-rich cell penetrating peptide utilizes glycine as the linker between the arginine-rich cell penetrating peptide and the antisense oligonucleotide.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising the antisense oligonucleotide and a pharmaceutically acceptable carrier.
Protection centers on a 28-base antisense morpholino defined by SEQ ID NO: 6 with optional uracil substitution, morpholino sugar replacement, and conjugation to an arginine-rich CPP. Additional dependent features further limit the CPP sequence to SEQ ID NOS: 19–34, introduce a glycine linker option, and include pharmaceutical compositions with a pharmaceutically acceptable carrier.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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