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US-20260125687-A1 - RNA THERAPEUTICS FOR FIBRODYSPLASIA OSSIFICANS PROGRESSIVA AND USES THEREOF

US20260125687A1US 20260125687 A1US20260125687 A1US 20260125687A1US-20260125687-A1

Abstract

Aspects of the disclosure relate to compositions and methods for treating Fibrodysplasia ossificans progressiva (FOP). The disclosure is based, in part, on muscle-targeting, chemically-modified interfering nucleic acids (e.g., siRNAs) that bind to and inhibit an ACVR1 R206H allele or an Inhba allele of a subject.

Inventors

  • Jae-Hyuck Shim
  • Julia Alterman
  • Yeon-Suk Yang
  • David Cooper
  • Nozomi Yamada
  • Katherine Gross
  • Jillian Caiazzi

Assignees

  • UNIVERSITY OF MASSACHUSETTS

Dates

Publication Date
20260507
Application Date
20251006

Claims (20)

  1. 1 . An isolated nucleic acid comprising a sense strand and an antisense strand, wherein the antisense strand comprises a sequence that is at least 80% complementary to at least 18 consecutive nucleotides of an activin receptor type 1 (ACVR1) R206H (ACVR1 R206H ) sequence of SEQ ID NO: 675.
  2. 2 . (canceled)
  3. 3 . The isolated nucleic acid of claim 1 , wherein: the antisense strand is at least 80% complementary to a sequence as set forth in any one of SEQ ID NOs: 676-721; the antisense strand comprises a nucleic acid sequence of any one of SEQ ID NOs: 768-813; and/or the sense strand comprises a nucleic acid sequence of any one of SEQ ID NOs: 722-767.
  4. 4 - 14 . (canceled)
  5. 15 . The isolated nucleic acid of claim 1 , wherein: the sense strand comprises a chemical modification pattern set forth in Table 1 or 2; the antisense strand comprises a chemical modification pattern set forth in Table 1 or 2; the sense strand comprises a sequence set forth in any one of SEQ ID NOs: 1-16, and 33-62; and/or the antisense strand comprises a sequence set forth in any one of SEQ ID NOs: 17-32 and 63-92.
  6. 16 - 18 . (canceled)
  7. 19 . An isolated nucleic acid comprising a sense strand and an antisense strand, wherein the antisense strand comprises a sequence that is at least 80% complementary to at least 18 consecutive nucleotides of an inhibitin beta A (INHBA) sequence of any one of SEQ ID NOs: 817-912.
  8. 20 . (canceled)
  9. 21 . The isolated nucleic acid of claim 19 , wherein: the antisense strand is at least 80% complementary to a sequence as set forth in any one of SEQ ID NOs: 913-1007; the antisense strand comprises a nucleic acid sequence of any one of SEQ ID NOs: 1008-1103; and/or the sense strand comprises a nucleic acid sequence of any one of SEQ ID NOs: 1104-1199.
  10. 22 - 32 . (canceled)
  11. 33 . The isolated nucleic acid of claim 19 , wherein: the sense strand comprises a chemical modification pattern set forth in Table 3; the antisense strand comprises a chemical modification pattern set forth in Table 3; the sense strand comprises a sequence set forth in any one of SEQ ID NOs: 93-188; and/or the antisense strand comprises a sequence set forth in any one of SEQ ID NOs: 189-284.
  12. 34 - 36 . (canceled)
  13. 37 . An isolated nucleic acid comprising a sense strand and an antisense strand, wherein the antisense strand comprises a sequence that is at least 80% complementary to at least 18 consecutive nucleotides of a myostatin (MSTN) sequence of any one of SEQ ID NOs: 1376-1472 and 1200-1287.
  14. 38 . (canceled)
  15. 39 . The isolated nucleic acid of claim 37 , wherein: the antisense strand is at least 80% complementary to a sequence as set forth in any one of SEQ ID NOs: 1473-1569 and 1288-1375; the antisense strand comprises a nucleic acid sequence of any one of SEQ ID NOs: 1570-1657 and 1746-1842; and/or the sense strand comprises a nucleic acid sequence of any one of SEQ ID NOs: 1658-1745 and 1843-1939.
  16. 40 - 50 . (canceled)
  17. 51 . The isolated nucleic acid of claim 37 , wherein: the sense strand comprises a chemical modification pattern set forth in Table 4 or 5; the antisense strand comprises a chemical modification pattern set forth in Table 4 or 5; the sense strand comprises a sequence set forth in any one of SEQ ID NOs: 285-372 and 481-577; and/or the antisense strand comprises a sequence set forth in any one of SEQ ID NOs: 373-480 and 578-674.
  18. 52 - 54 . (canceled)
  19. 55 . A bi-specific nucleic acid molecule comprising: (i) a first siRNA targeting a first RNA transcript selected from activin receptor type 1 (ACVR1) R206H (ACVR1 R206H ), INHBA, IL-1β, TNF, and myostatin (MSTN); linked to (ii) a second siRNA targeting a second RNA transcript selected from ACVR1 R206H , INHBA, IL-1β, TNF, and myostatin (MSTN), wherein the first RNA transcript and the second RNA transcript are not transcribed from a same gene.
  20. 56 . (canceled)

Description

RELATED APPLICATIONS This application is a continuation of International Patent Application No. PCT/US2024/025492, filed Apr. 19, 2024, which claims priority to U.S. Provisional Patent Application Ser. No. 63/497,292, filed Apr. 20, 2023, the entire contents of which are incorporated herein by reference. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML file, created on Oct. 6, 2025, is named 769944_UM9-323PCCON_ST26.xml and is 3,016,367 bytes in size. BACKGROUND Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by progressive, disabling heterotopic ossification (HO) that forms within skeletal muscle, tendons, ligaments, fascia, and aponeuroses. HO develops during flare-ups that occur spontaneously or are triggered by minor trauma, injury, intramuscular injection, or inflammation. Approximately 97% of FOP patients carry a mutation (c.617G>A; R206H) in the ACVR1 gene. SUMMARY Aspects of the disclosure relate to compositions and methods for treating Fibrodysplasia ossificans progressiva (FOP). The disclosure is based, in part, on muscle-targeting, chemically-modified interfering nucleic acids (e.g., siRNAs) that bind to and inhibit an ACVR1R206H allele or an Inhba allele of a subject. In some aspects, the disclosure relates to muscle-targeting, chemically-modified bi-specific siRNAs that bind to and inhibit combinations of genes associated with FOP, for example ACVR1206H, Inhba, IL-1β, TNF, and myostatin (Mstn). In some aspects, the present disclosure provide an isolated nucleic acid comprising a sense strand and an antisense strand, wherein the antisense strand comprises a sequence that is at least 80% complementary to at least 18 consecutive nucleotides of a ACVR1R206H sequence of SEQ ID NO: 675. In some embodiments, the antisense strand is at least 80% complementary to at least 20 consecutive nucleotide of SEQ ID NO: 675. In some embodiments, antisense strand is at least 80% complementary to the sequence as set forth in any one of SEQ ID NOs: 676-721. In some embodiments, the antisense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 768-813. 15. In some embodiments, the sense strand comprises the chemical modification pattern set forth in Table 1 or 2. In some embodiments, the antisense strand comprises the chemical modification pattern set forth in Table 1 or 2. In some embodiments, the sense strand comprises the sequence set forth in any one of SEQ ID NOs: 1-16, and 33-62. In some embodiments, the antisense strand comprises the sequence set forth in any one of SEQ ID NOs: 17-32 and 63-92. In some aspects, the present disclosure provides an isolated nucleic acid comprising a sense strand and an antisense strand, wherein the antisense strand comprises a sequence that is at least 80% complementary to at least 18 consecutive nucleotides of a INHBA sequence of any one of SEQ ID NOs: 817-912. In some embodiments, the antisense strand is at least 80% complementary to at least 20 consecutive nucleotide of any one of SEQ ID NOs: 817-912. In some embodiments, antisense strand is at least 80% complementary to the sequence as set forth in any one of SEQ ID NOs: 913-1007. In some embodiments, the antisense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 1008-1103. In some embodiments, the sense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 1104-1199. In some embodiments, the sense strand comprises the chemical modification pattern set forth in Table 3. In some embodiments, the antisense strand comprises the chemical modification pattern set forth in Table 3. In some embodiments, the sense strand comprises the sequence set forth in any one of SEQ ID NOs: 93-188. In some embodiments, the antisense strand comprises the sequence set forth in any one of SEQ ID NOs: 189-284. In some aspects, the present disclosure provides an isolated nucleic acid comprising a sense strand and an antisense strand, wherein the antisense strand comprises a sequence that is at least 80% complementary to at least 18 consecutive nucleotides of a MSTN sequence of any one of SEQ ID NOs: 1376-1472, and 1200-1287. In some embodiments, the antisense strand is at least 80% complementary to at least 20 consecutive nucleotide of any one of SEQ ID NOs: 1376-1472, and 1200-1287. In some embodiments, antisense strand is at least 80% complementary to the sequence as set forth in any one of SEQ ID NOs: 1473-1569, and 1288-1375. In some embodiments, the antisense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 1570-1657, and 1746-1842. In some embodiments, the sense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 1658-1745, and 1843-1939. In some embodiments, the sense strand comprises the chemical modification pattern set forth in Table 4 or 5. In some embodiments, the antis