USP10 targeted self-deliverable siRNA compositions and methods for preventing or inhibiting fibrosis and/or scarring
The present disclosure provides compositions and methods for using self-deliverable siRNA (sdRNAi) directed against USP-10 for the treatment of various medical conditions, including skin scaring due to trauma wounds and surgery, corneal and retina scaring due to injury and surgery, internal organ scaring due to injury and surgery, heart tissue scaring due to heart attack and surgery, and lung, liver, and kidney fibrosis due to inflammation and injury. In embodiments, compositions including self-deliverable siRNA (sdRNAi) directed against USP-10 are suitable for use in pharmaceutical formulations and treatments resulting in significant less scar formation, and include synthetic nucleic acids such as sense and antisense oligonucleotides.
1 . A composition comprising a synthetic nucleic acid comprising a polynucleotide sequence of one of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20, wherein the synthetic nucleic acid comprises one or more modifications.
2 . The composition of claim 1 , wherein the synthetic nucleic acid is an antisense oligonucleotide.
3 . A composition comprising a synthetic nucleic acid comprising a polynucleotide sequence of one of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19, wherein the synthetic nucleic acid comprises one or more modifications.
4 . The composition of claim 3 , wherein the synthetic nucleic acid is a sense oligonucleotide.
5 . A composition comprising a double-stranded self-deliverable siRNA (sdRNAi) comprising a first synthetic nucleic acid and a second synthetic nucleic acid, wherein:
the first synthetic nucleic acid comprises a polynucleotide sequence of one of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20;
the second synthetic nucleic acid comprises a polynucleotide sequence of one of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19;
and the sdRNAi is directed against Ubiquitin-Specific Peptidase 10 (USP-10).
6 . A composition comprising a double-stranded self-deliverable SiRNA (sdRNAi) comprising a first synthetic nucleic acid and a second synthetic nucleic acid, wherein:
the first synthetic nucleic acid comprises a polynucleotide sequence of SEQ ID NO: 12; and the second synthetic nucleic acid comprises a polynucleotide sequence of SEQ ID NO: 11 and the sdRNAi is directed against Ubiquitin-Specific Peptidase 10 (USP-10).
7 . The composition of claim 6 , wherein the sdRNAi further comprises a one or more modifications, cholesterol moieties and/or vinyl-phosphonate moieties.
8 . The composition of claim 6 , wherein:
the first synthetic nucleic acid comprises or consists of 20 nucleotides, and
the second synthetic nucleic acid comprises or consists of 15 nucleotides.
9 . A pharmaceutical composition comprising the sdRNAi of claim 6 and a pharmaceutically acceptable carrier.
10 . The pharmaceutical composition of claim 9 , wherein the pharmaceutical composition is formulated for topical administration, intravitreal administration, or transscleral administration.
11 . The pharmaceutical composition of claim 9 , wherein the pharmaceutical composition further comprises one or more modifications, cholesterol moieties and/or vinyl-phosphonate moieties.
12 . A method of treating or alleviating fibrosis in a subject comprising administering to the fibrotic tissue or wounded tissue in a therapeutically effective amount of the pharmaceutical composition of claim 9 to the subject.
13 . The method of claim 12 , wherein the method fully or substantially eliminates an upregulation of USP10 after wounding.
14 . A method of eliminating or reducing fibrosis in a subject after a tissue wound comprising administering to the tissue wound a therapeutically effective amount of the pharmaceutical composition of claim 9 to the subject.
15 . The method of claim 14 , wherein the method fully or substantially eliminates an upregulation of USP10 after wounding.
16 . A method of eliminating or reducing ocular scarring in an eye of a subject after an ocular wound comprising administering to the ocular wound a therapeutically effective amount of the pharmaceutical composition of claim 9 to the subject.
17 . The method of claim 16 , wherein the method fully or substantially eliminates an upregulation of USP10 after wounding.
18 . The method of claim 16 , wherein the ocular scarring occurs on a cornea.