Targeted inhibition using engineered oligonucleotides
Inventors
PLACE, Robert • SALEH, Anthony • WILLIAMS, Tishan
Assignees
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Publication Number
US-11795459-B2
Publication Date
2023-10-24
Expiration Date
Abstract
Disclosed herein are engineered oligonucleotides for selective inhibition of polypeptide expression and activity. Also disclosed herein are methods of selectively inhibiting polypeptide expression and activity contacting an engineered oligonucleotide with a polynucleotide encoding the polypeptide.
Core Innovation
The invention relates to an antisense oligonucleotide or salt thereof comprising a polynucleotide sequence. The antisense oligonucleotide is at least partially complementary to at least a portion of a first RNA and a second RNA originating from two genetic loci associated with a disease or condition, and at least a portion of the first or the second RNA is encoded in an IRX5 gene.
In binding to the first RNA, a first region comprising at least seven contiguous bases in the antisense oligonucleotide is complementary to contiguous nucleic acids contained within the first RNA, and a second region comprising at least five contiguous bases in the antisense oligonucleotide is complementary to contiguous nucleic acids contained within the first RNA. In binding to the second RNA, the antisense oligonucleotide similarly includes a first region of at least seven contiguous bases complementary to contiguous nucleotides contained within the second RNA and a second region of at least five contiguous bases complementary to contiguous nucleotides contained within the second RNA.
The binding performance is further constrained by a predicted Gibbs free energy of binding of the antisense oligonucleotide to the first and the second RNA, each ranging from about minus 17 to about minus 36 kcal mol-1 at about 37 degrees Celsius and at a pH ranging from about 7.2 to about 7.6. The antisense oligonucleotide or salt also comprises at least one chemically modified nucleotide, and the construct scope includes chemically modified nucleotides and backbone modifications, including phosphorothioate backbones and sugar modifications.
Claims Coverage
The independent claim covers one antisense oligonucleotide or salt concept with dual-RNA complementarity, IRX5 gene RNA inclusion, contiguous match lengths, a predicted Gibbs free energy binding range at specified temperature and pH, and at least one chemically modified nucleotide. Dependent claims further refine oligonucleotide length, functional performance upon mRNA contact, neuromuscular disorder treatment scope, and an antibody-conjugate covalent linker configuration.
Dual-RNA antisense complementarity with IRX5 locus RNA
An antisense oligonucleotide or salt thereof is at least partially complementary to at least a portion of a first and a second RNA originating from two genetic loci associated with a disease or condition, wherein at least a portion of the first or the second RNA is encoded in an IRX5 gene.
Defined seven- and five-contiguous-base complementary regions
When the antisense oligonucleotide or salt thereof at least partially binds to the first RNA, a first region of at least seven contiguous bases in the antisense oligonucleotide are complementary to contiguous nucleic acids contained within the first RNA, and a second region of at least five contiguous bases in the antisense oligonucleotide are complementary to contiguous nucleic acids contained within the first RNA; and when the antisense oligonucleotide or salt thereof at least partially binds to the second RNA, a first region of at least seven contiguous bases in the antisense oligonucleotide are complementary to contiguous nucleotides contained within the second RNA, and a second region of at least five contiguous bases in the antisense oligonucleotide are complementary to contiguous nucleotides contained within the second RNA.
Predicted delta G binding range at 37 degrees Celsius and pH 7.2-7.6
A predicted Gibbs free energy of binding of the antisense oligonucleotide to the first and the second RNA ranges, individually, from about minus 17 to about minus 36 kcal mol-1 at about 37 degrees Celsius and at a pH ranging from about 7.2 to about 7.6.
Chemically modified nucleotides
The antisense oligonucleotide or salt thereof comprises at least one chemically modified nucleotide.
mRNA-contacted expression reduction criterion
The antisense oligonucleotide or salt thereof, when contacted with an mRNA sequence, yields at least about a 1.2-fold lower expression of the mRNA-encoded polypeptide than an otherwise comparable ncRNA tested under matched transfection in the same type of mammalian cells, determined by transfecting into two isolated mammalian cells and measuring the expressed polypeptide levels.
Neuromuscular disorder treatment use including muscular dystrophy or myopathy
The antisense oligonucleotide or salt thereof is for treating a neuromuscular disorder, specifically including muscular dystrophy or myopathy.
Antibody-conjugated covalent linker
The antisense oligonucleotide or salt thereof comprises a covalent linker conjugated to an antibody.
Overall, the claims cover an antisense oligonucleotide or salt that binds two disease-associated RNAs, including an IRX5-encoded RNA, with defined seven- and five-contiguous-base complementarity and a specified Gibbs free energy binding range at about 37 degrees Celsius and pH 7.2-7.6, while including chemically modified nucleotides. Dependent claim refinements further restrict functional reduction, disease indication, and construct features such as antibody-conjugated covalent linkers.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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