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CN-122003498-A - Compositions and methods for inhibiting Amyloid Precursor Protein (APP) expression

CN122003498ACN 122003498 ACN122003498 ACN 122003498ACN-122003498-A

Abstract

The present invention provides compositions and methods useful for reducing Amyloid Precursor Protein (APP) gene expression and treating APP-related diseases and conditions. The present invention provides APPdsRNA agents, APP antisense polynucleotide agents, compositions comprising APPdsRNA agents, and compositions comprising APP antisense polynucleotide agents useful for reducing APP expression in cells and subjects.

Inventors

  • SHU DONGXU
  • SHAO PENGCHENG
  • XIA SHIWEI

Assignees

  • 上海舶望制药有限公司

Dates

Publication Date
20260508
Application Date
20241009
Priority Date
20231010

Claims (20)

  1. 1. A double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of an Amyloid Precursor Protein (APP), wherein said dsRNA agent comprises a sense strand and an antisense strand, wherein said sense strand comprises at least 15 contiguous nucleotides differing by NO more than 3 nucleotides from the nucleotide sequence of SEQ ID No. 1 and said antisense strand comprises at least 15 contiguous nucleotides differing by NO more than 3 nucleotides from the nucleotide sequence of SEQ ID No. 2, wherein said sense strand and said antisense strand may be partially, substantially or fully complementary.
  2. 2. The dsRNA agent of claim 1, wherein the antisense strand comprises a region complementary to an mRNA encoding APP comprising at least 15 consecutive nucleotides differing by no more than 1,2 or 3 nucleotides from one of the antisense sequences listed in any one of tables 1-3.
  3. 3. The dsRNA agent of claim 1, wherein the antisense strand comprises a region complementary to mRNA encoding APP comprising at least 15 contiguous nucleotides from any one of the antisense sequences listed in any one of tables 1-3.
  4. 4. A double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of an Amyloid Precursor Protein (APP), wherein the dsRNA agent comprises a sense strand and an antisense strand, nucleotide positions 2 to 18 in the antisense strand comprising a region of complementarity to an APP RNA transcript, wherein the region of complementarity comprises at least 15 contiguous nucleotides differing by 0, 1,2 or 3 nucleotides from one of the antisense sequences listed in one of tables 1-3, and optionally comprising a targeting ligand.
  5. 5. The dsRNA agent of claim 4, wherein the region complementary to the APP RNA transcript comprises at least 15, 16, 17, 18 or 19 consecutive nucleotides differing by no more than 3 nucleotides from one of the antisense sequences listed in one of tables 1-3.
  6. 6. The dsRNA agent of any one of claims 1-5, wherein the antisense strand of dsRNA is substantially or fully complementary to any one of the target regions of SEQ ID NO: 1, and preferably the dsRNA agent comprises an antisense strand sequence of any one of tables 1-3.
  7. 7. The dsRNA agent of any one of claims 1-6, wherein the sense strand sequence is at least substantially complementary or fully complementary to an antisense strand sequence in the dsRNA agent, preferably wherein the dsRNA agent comprises a sense strand sequence of any one of tables 1-3.
  8. 8. The dsRNA agent of any one of claims 1-7, wherein the dsRNA agent comprises a sequence listed as a duplex sequence in any one of tables 1-3.
  9. 9. The dsRNA agent of any one of claims 1-8, wherein the dsRNA agent comprises at least one modified nucleotide.
  10. 10. The dsRNA agent of any one of claims 1-9, wherein all or substantially all of the nucleotides of the sense strand and/or the antisense strand are modified nucleotides.
  11. 11. A double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of an Amyloid Precursor Protein (APP), wherein the dsRNA agent comprises a sense strand and an antisense strand, wherein the sense strand is complementary to the antisense strand, wherein the antisense strand comprises a region of complementarity to a portion of an mRNA encoding APP, wherein each strand is from about 15 to about 30 nucleotides in length, wherein the sense strand sequence can be represented by formula (I): Wherein each N ' F represents a 2' -fluoro modified nucleotide; Each of N ' N1 、N' N2 、N' N3 、N' N4 、N' N5 and N' N6 independently represents a modified or unmodified nucleotide; each N ' L independently represents a modified or unmodified nucleotide, but not a 2' -fluoro modified nucleotide; And m 'and n' are each independently integers of 0 to 7.
  12. 12. A double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of an Amyloid Precursor Protein (APP), wherein the dsRNA agent comprises a sense strand and an antisense strand, wherein the sense strand is complementary to the antisense strand, wherein the antisense strand comprises a region of complementarity to a portion of an mRNA encoding APP, wherein each strand is about 18 to about 30 nucleotides in length, wherein the antisense strand sequence is represented by formula (II): wherein each N F represents a 2' -fluoro modified nucleotide; Each of N M1 、N M2 、N M3 、N M4 、N M5 、N M6 、N M7 and N M8 independently represents a modified or unmodified nucleotide; Each N L independently represents a modified or unmodified nucleotide, but not a 2' -fluoro modified nucleotide; and n is an integer of 0 to 7.
  13. 13. A double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of an Amyloid Precursor Protein (APP), wherein the dsRNA agent comprises a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a dsRNA duplex, wherein the sense strand is complementary to the antisense strand, wherein the antisense strand comprises a region of complementarity to an mRNA encoding APP, wherein the region of complementarity comprises at least 15 contiguous nucleotides, wherein the dsRNA duplex is represented by formula (III): Wherein: each strand is independently about 17 to about 30 nucleotides in length; Each of N F and N ' F independently represents a 2' -fluoro modified nucleotide; Each N M1 、N M2 、N M3 、N M4 、N M5 、N M6 、N M7 、N M8 、N' N1 、N' N2 、N' N3 、N' N4 、N' N5 and N' N6 independently represents a modified or unmodified nucleotide; Each N L and N ' L independently represents a modified or unmodified nucleotide, but not a 2' -fluoro modified nucleotide; And m ', n' and n are each independently integers from 0 to 7.
  14. 14. The dsRNA agent of any one of claims 9-13, wherein the one or more modified nucleotides are independently selected from the group consisting of a2 '-O-methyl nucleotide, a 2' -fluoro nucleotide, a2 '-deoxy nucleotide, a 2'3'-seco nucleotide mimetic, a locked nucleotide, an unlocked nucleic acid nucleotide (UNA), a ethylene glycol nucleic acid nucleotide (GNA), a 2' -F-arabinose nucleotide, a2 '-methoxyethyl nucleotide, an abasic nucleotide, a ribonol, an inverted nucleotide, an inverted abasic nucleotide, an isomannide nucleotide, an inverted 2' -OMe nucleotide, an inverted 2 '-deoxy nucleotide, a 2' -amino modified nucleotide, a2 '-alkyl modified nucleotide, a morpholino nucleotide, a 3' -OMe nucleotide, a nucleotide comprising a5 '-phosphorothioate group, a 5' -phosphate or 5 '-phosphate mimetic modified nucleotide, a terminal nucleotide linked to a sterol derivative or dodecanodicarboxamide group, a 2' -amino modified nucleotide, a phosphoramidate or a non-natural comprising nucleotide.
  15. 15. The dsRNA agent of any one of claims 1 to 14, comprising an E-vinylphosphonate nucleotide at the 5 ́ terminus of the guide strand.
  16. 16. The dsRNA agent of any one of claims 1-15, wherein the dsRNA agent comprises at least one phosphorothioate internucleoside linkage.
  17. 17. The dsRNA agent of any one of claims 1 to 15, wherein the sense strand comprises at least one phosphorothioate internucleoside linkage.
  18. 18. The dsRNA agent of any one of claims 1 to 15, wherein the antisense strand comprises at least one phosphorothioate internucleoside linkage.
  19. 19. The dsRNA agent of any one of claims 1 to 15, wherein the sense strand comprises 1, 2, 3,4, 5 or 6 phosphorothioate internucleoside linkages.
  20. 20. The dsRNA agent of any one of claims 1-15, wherein the antisense strand comprises 1, 2, 3, 4,5, or 6 phosphorothioate internucleoside linkages.

Description

Compositions and methods for inhibiting Amyloid Precursor Protein (APP) expression Field of the invention The present invention relates in part to compositions and methods useful for inhibiting the expression of Amyloid Precursor Protein (APP) genes. Technical Field The Amyloid Precursor Protein (APP) gene encodes an integral membrane protein expressed in neurons and glial cells. Although the primary function of APP is not yet clear, APP is one of the major interests in current Alzheimer's Disease (AD) studies, as aberrant processing of APP can lead to the production and accumulation of the neurotoxic peptide amyloid- β (aβ). Aβ is produced from a β -Amyloid Precursor Protein (APP), which is first cleaved sequentially by β -secretase and then by the γ -secretase complex. In addition to being closely related to the pathogenesis of AD, APP is also involved in a variety of cellular activities that promote brain development and function. Inhibition of APP expression and/or activity blocks or inhibits the production and/or level of aβ -cleaved forms of APP, and is useful for preventing or treating various APP-related diseases and conditions, such as AD, cerebral Amyloid Angiopathy (CAA), and early-onset familial alzheimer's disease (EOFAD or eFAD), and the like. Current treatment options for APP-related diseases and conditions are limited and largely ineffective. For example, many aβ -directed immunotherapy is in different stages of development, while many human gamma-secretase inhibitor programs are stopped due to toxicity. To date, approved drug therapies for APP-related diseases or disorders are only used to treat symptoms, not to prevent or cure, and the efficacy of such therapies is limited, especially as APP-related diseases or disorders develop in affected individuals. Thus, novel therapies directed against APP represent a new approach to reduce APP levels and to treat APP-related diseases (such as alzheimer's disease). Disclosure of Invention In general, the present disclosure provides novel APP gene-specific RNAi agents, compositions comprising APP RNAi agents, and methods of inhibiting APP gene expression in vitro and/or in vivo using APP RNAi agents and compositions comprising APP RNAi agents described herein. The APP RNAi agents described herein can selectively and effectively reduce, inhibit, or silence the expression of APP gene in a subject (e.g., a human or animal subject). According to one aspect of the present invention there is provided a double stranded ribonucleic acid (dsRNA) agent for inhibiting the expression of Amyloid Precursor Protein (APP), wherein said dsRNA agent comprises a sense strand and an antisense strand, wherein said sense strand comprises at least 15 consecutive nucleotides differing by NO more than 1, 2 or 3 nucleotides from the nucleotide sequence of SEQ ID No. 1, 3 or 5, and said antisense strand comprises at least 15 consecutive nucleotides differing by NO more than 1, 2 or 3 nucleotides from the nucleotide sequence of SEQ ID No. 2, 4 or 6, wherein said sense strand and said antisense strand may be partially, substantially or fully complementary. In some embodiments, the APP mRNA transcript is SEQ ID NO. 1. In some embodiments, the target region of the APP mRNA transcript is any one of the following nucleotide sequences ：378-398、383-403、391-411、472-492、499-519、535-555、536-556、537-557、539-559、542-562、561-581、684-704、723-743、724-744、725-745、808-828、809-829、810-830、811-831、812-832、813-833、814-834、817-837、868-888、1264-1284、1368-1388、1405-1425、1406-1426、1407-1427、1416-1436、1417-1437、1426-1446、1427-1447、1428-1448、1434-1454、1456-1476、1458-1478、1461-1481、1462-1482、1463-1483、1465-1485、1529-1549、1608-1628、1609-1629、1611-1631、1612-1632、1675-1695、1744-1764、1818-1838、1819-1839、1820-1840、1821-1841、1822-1842、1833-1853、1854-1874、1856-1876、1857-1877、1861-1881、1862-1882、1876-1896、1877-1897、1878-1898、1879-1899、1885-1905、1893-1913、1895-1915、1899-1919、1900-1920、1901-1921、1934-1954、1935-1955、2038-2058、2039-2059、2111-2131、2115-2135、2116-2136、2138-2158、2139-2159、2302-2322、2335-2355、2422-2442、2437-2457、2443-2463、2444-2464、2471-2491、2473-2493、2488-2508、2492-2512、2495-2515、2518-2538、2521-2541、2562-2582、2571-2591、2587-2607、2590-2610、2594-2614、2608-2628、2614-2634、2682-2702、2686-2706、2710-2730、2711-2731、2712-2732、2714-2734、2715-2735、2716-2736、2720-2740、2731-2751、2732-2752、2733-2753、2737-2757、2742-2762、2743-2763、2744-2764、2745-2765、2746-2766、2750-2770、2782-2802、1178-1198、1220-1240、1969-1989、2186-2206、2329-2349、373-393、384-404、385-405、390-410、392-412、393-413、428-448、498-518、501-521、519-539、520-540、540-560、541-561、543-563、544-564、633-653、634-654、635-655、643-663、695-715、720-740、721-741、726-746、728-748、804-824、805-825、871-891、895-915、996-1016、1315-1335、1374-1394、1408-1428、1411-1431、1415-1435、1423-1443、1424-1444、1425-1445、1432-1452、1457-1477、1459-1479、1460-1480、1761-1781、1779-1799、1816-1836、1825-1845、1841-1861、1849-1869、1852-1872、1853-1873、1869-1889、1879-1899、1881-1901、1882-1902、1892-1912、1894-1914、1896-1