Therapeutic splice-switching oligonucleotides
Inventors
Merico, Daniele • Goncalves, Joao Antonio Lourenco • Wienholds, Erno • Sun, Mark George Ford
Assignees
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Publication Number
US-11427821-B2
Publication Date
2022-08-30
Expiration Date
Abstract
The present disclosure provides compositions and methods for treating a disorder associated with mutations in the CEP290 gene. The disclosure includes synthetic polynucleotides for skipping a reading-frame of a CEP290 pre-RNA, yielding a CEP290 translated product that lacks one or more exons. The disclosure also provides methods of treating patients with the synthetic polynucleotides disclosed herein.
Core Innovation
The invention relates to therapeutic splice-switching synthetic polynucleotides targeting CEP290 pre-mRNA to induce exon skipping, thereby producing translated products lacking one or more exons. The specification frames the problem as treating CEP290 mutation-associated disorders by modulating pre-mRNA splicing to create exon-skipped translated products.
The document describes compositions and targeting of CEP290 by using splice-switching synthetic polynucleotides configured to skip selected CEP290 exons. Exemplary target exons explicitly mentioned include exons 7, 31, 34, 36, 41, and 46, and the patent includes tables listing synthetic polynucleotides tested to skip these CEP290 exons.
The synthetic polynucleotides include modified internucleoside linkages selected from phosphorothioate, phosphoroamidate, and phosphorodiamidate linkages, including phosphorodiamidate morpholino oligomers. The document also describes modified sugar moieties including 2′-O-methyl, 2′-O-MOE, 2′-fluoro, LNA, and morpholino-based internucleoside linkages, and possible conjugation to cell-penetrating peptides, intended to support nuclease resistance and transport while functioning as splice-switching agents.
Claims Coverage
The partial content includes one independent claim with one inventive feature set, with dependent claims further constraining sequence subset selection, length ranges, linkage type selection, and adding formulation/admin context and molecular conjugation features.
Synthetic polynucleotide composition with defined SEQ ID sequences and modified internucleoside linkage
A composition comprising a synthetic polynucleotide having the nucleobase sequence of any one of SEQ ID NOS: 270-276, and 282-298, with a length from about 20 nucleotides to about 30 nucleotides, or the nucleobase sequence of any one of SEQ ID NOS: 277, 281, 299, and 303, with a length of 20 nucleotides, wherein the synthetic polynucleotide comprises a modified internucleoside linkage selected from phosphorothioate internucleoside linkage, phosphoroamidate internucleoside linkage, and phosphorodiamidate internucleoside linkage.
The claim coverage centers on defined therapeutic splice-switching synthetic polynucleotides characterized by specified nucleobase sequences tied to enumerated SEQ ID NOS, defined length constraints, and inclusion of modified internucleoside linkages selected from phosphorothioate, phosphoroamidate, and phosphorodiamidate linkages.
Stated Advantages
Treating CEP290 mutation-associated disorders by inducing exon skipping in CEP290 pre-mRNA to produce translated products lacking one or more exons.
Provides nuclease protection by reducing nuclease degradation, including endo-/exonuclease degradation.
Described cell-uptake enhancement via conjugation concepts using cell-penetrating peptides.
Documented Applications
Treating Leber Congenital Amaurosis (LCA).
Treating Senior-Locken Syndrome (SLS).
Treating Joubert syndrome (JS).
Treating Meckel Syndrome (MS).
Exon skipping targeting CEP290 (centrosomal protein 290) pre-mRNA, including embodiments related to diseases described as Leber Congenital Amaurosis, Senior-Locken Syndrome, Joubert syndrome, and Meckel Syndrome.
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