Compounds and methods for modulating alpha-synuclein expression

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Compounds and pharmaceutical compositions targeting SNCA mRNA and α-synuclein reduce levels in cells, addressing the inadequacies of current treatments for synucleinogenic disorders and offering therapeutic relief.

HK40134704APending Publication Date: 2026-07-10IONIS PHARMACEUTICALS INC

Patent Information

Authority / Receiving Office: HK · HK
Patent Type: Applications
Current Assignee / Owner: IONIS PHARMACEUTICALS INC
Filing Date: 2026-04-20
Publication Date: 2026-07-10

AI Technical Summary

Technical Problem

Current treatments for synucleinogenic disorders such as Parkinson's disease, Lewy body dementia, Parkinson's dementia, multiple system atrophy, neurogenic Gaucher disease, and Alzheimer's disease are inadequate in effectively reducing α-synuclein levels, leading to unaddressed symptoms and progression of the diseases.

Method used

Compounds and pharmaceutical compositions that reduce SNCA mRNA levels and α-synuclein amounts in cells, thereby alleviating symptoms of these disorders.

Benefits of technology

The compounds and compositions effectively decrease α-synuclein levels, providing therapeutic benefits for synucleinogenic disorders.

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Abstract

Provided herein are compounds, pharmacal compositions, and methods of use for reducing the amount or activity of SNCA mRNA in a cell or subject, and in certain instances reducing the amount of alpha-synuclein protein in a cell or subject. Such compounds, pharmaceutical compositions, and methods of use are useful to ameliorate at least one symptom or hallmark of a synucleinopathy. Such synucleinopathies include Parkinson's disease, dementia with Lewy bodies (DLB), diffuse Lewy body disease, Parkinson's disease dementia (PDD), pure autonomic failure, multiple system atrophy (MSA), neuronopathic Gaucher's disease, and Alzheimer's disease.

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Description

538589\45910499_1.docx IRN: 538589 Title: Compounds and Methods for Regulating α-Synnuclein Expression Abstract: This article provides compounds, pharmaceutical compositions, and methods of use for reducing the amount or activity of SNCA mRNA in cells or subjects, and in some cases, reducing the amount of α-synuclein in cells or subjects. These compounds, pharmaceutical compositions, and methods of use can be used to improve at least one symptom or marker of synucleinogenic disorders. These synucleinogenic disorders include Parkinson's disease, Lewy body dementia (DLB), diffuse Lewy body disease, Parkinson's dementia (PDD), pure autonomic failure, multiple system atrophy (MSA), neurogenic Gaucher disease, and Alzheimer's disease.

Claims

WHAT IS CLAIMED:

1. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to an equal length portion of a SNCA nucleic acid, and wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar and a modified intemucleoside linkage.

2. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides and having a nucleobase sequence comprising at least 12, at least 13, at least 14, at least 15, at least 16, at least 17. at least 18. at least 19, or 20 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 13-3334, wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified intemucleoside linkage.

3. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides and having a nucleobase sequence comprising at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14. at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases complementary to: an equal length portion of nucleobases 16,692-16,716 of SEQ ID NO: 1 or nucleobases 18,758-18,782 of SEQ ID NO: 2; an equal length portion of nucleobases 18,568-18,593 of SEQ ID NO: 1 or nucleobases 20,634-20,659 of SEQ ID NO: 2; an equal length portion of nucleobases 18.621-18,649 of SEQ ID NO: 1 or nucleobases 20,687-20,715 of SEQ ID NO: 2; an equal length portion of nucleobases 18.721-18,752 of SEQ ID NO: 1 or nucleobases 20,787-20,818 of SEQ ID NO: 2; an equal length portion of nucleobases 19.423-19,443 of SEQ ID NO: 1 or nucleobases 21,489-21,509 of SEQ ID NO: 2; an equal length portion of nucleobases 19.555-19,575 of SEQ ID NO: 1 or nucleobases 21,621-21,641 of SEQ ID NO: 2; an equal length portion of nucleobases 21.457-21,501 of SEQ ID NO: 1 or nucleobases 23,523-23,567 of SEQ ID NO: 2; an equal length portion of nucleobases 22.008-22,030 of SEQ ID NO: 1 or nucleobases 24,074-24,096 of SEQ ID NO: 2; an equal length portion of nucleobases 22.507-22,529 of SEQ ID NO: 1 or nucleobases 24.573-24,595 of SEQ ID NO: 2; an equal length portion of nucleobases 22.614-22,637 of SEQ ID NO: 1 or nucleobases 24,680-24,703 of SEQ ID NO: 2; an equal length portion of nucleobases 25,049-25,090 of SEQ ID NO: 1 or nucleobases 27,115-27.156 of SEQ ID NO: 2:an equal length portion of nucleobases 26.367-26,388 of SEQ ID NO: 1 or nucleobases 28,433-28,454 of SEQ ID NO: 2; an equal length portion of nucleobases 26.508-26,531 of SEQ ID NO: 1 or nucleobases 28,574-28,597 of SEQ ID NO: 2; an equal length portion of nucleobases 30.207-30,226 of SEQ ID NO: 1 or nucleobases 32.273-32,292 of SEQ ID NO: 2; an equal length portion of nucleobases 31.412-31,438 of SEQ ID NO: 1 or nucleobases 33.478-33,504 of SEQ ID NO: 2; an equal length portion of nucleobases 33,027-33,057 of SEQ ID NO: 1 or nucleobases 35,093-35.123 of SEQ ID NO: 2; or an equal length portion of nucleobases 48,460-48,489 of SEQ ID NO: 1 or nucleobases 50,526-50.555 of SEQ ID NO: 2: wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified intemucleoside linkage.

4. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides and having a nucleobase sequence comprising at least 8, at least 9. at least 10, at least 11, at least 12, at least 13, at least 14. at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases of:SEQ ID NO: 78, 2564, 2697, 2747. 2789, 2936, 3063, 3081, 3142, 3189, or 3271;SEQ ID NO:

206. 231, 270, 316, 2486, 2558, 3041, 3076, 3137, 3184. or 3266;SEQ ID NO: 64, 128, 289. 921, 2744, 2853. 2922, 3031, 3057, 3099, 3123, 3132, 3160. 3207, 3231, 3289, or 3313;SEQ ID NO: 227, 427, 545, 1214, 1279, 1385, 1401, 1476, 1616, 3048, 3115, 3176, or 3305;SEQ ID NO: 203, 285, 1974, 2044, 2949, 3021, 3090, 3151, 3198, or 3280;SEQ ID NO: 205, 2594, 2686, 3028, 3097, 3158, 3205, or 3287;SEQ ID NO: 214, 247, 865, 1887, 1948, 3067, 3085, 3146, 3193, or 3275;SEQ ID NO: 167, 208, 248, 304, 1930, 3054, 3120, 3129, 3228, or 3310;SEQ ID NO: 196, 1814, 1909, 3042, 3109, 3170, 3217, or 3299;SEQ ID NO: 171, 207, 245, 489, 2390, 3053, 3119, 3128, 3227, or 3309;SEQ ID NO: 24, 133, 199, 228, 230, 276, 314, 946, 2759, 2818. 2873, 3069, 3087, 3148, 3195, or 3277;SEQ ID NO: 168, 193, 236, 313, 2446, 3049, 3116, 3177, 3224. or 3306;SEQ ID NO: 210, 223, 272, 273, 274. 1026, 1143, 3020, 3089, 3150, 3197, or 3279;SEQ ID NO: 287, 964, 1040. 1154, 3050, 3117, 3178, 3225, or 3307;SEQ ID NO: 119, 980, 1085. 1166, 3051, 3118, 3127, 3226, or 3308;SEQ ID NO: 194, 277, 1113. 1185, 1309, 3024, 3093, 3154, 3201, or 3283; orSEQ ID NO: 310, 803. 919, 1582, 1674. 3032. 3032, 3032, 3100, 3161, 3208, 3290. or 3290; wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified intemucleoside linkage.

5. The oligomeric compound of any of claims 1-4, wherein the modified oligonucleotide has a nucleobase sequence that is at least 85%, at least 90%. at least 95%. or 100% complementary to the nucleobase sequence of any one of SEQ ID NOs: 1-9 when measured across the entire nucleobase sequence of the modified oligonucleotide.

6. The oligomeric compound of any of claims 1-5, wherein the modified oligonucleotide consists of 12 to 20, 12 to 25. 12 to 30, 12 to 50, 13 to 20. 13 to 25. 13 to 30, 13 to 50, 14 to 20. 14 to 25, 14 to 30, 14 to 50. 15 to 20, 15 to 25, 15 to 30, 15 to 50, 16 to 18.16 to 20. 16 to 25, 16 to 30, 16 to 50. 17 to 20, 17 to 25, 17 to 30. 17 to 50. 18 to 20, 18 to 25, 18 to 30, 18 to 50, 19 to 20, 19 to 25, 19 to 30, 19 to 50, 20 to 25, 20 to 30, or 20 to 50 linked nucleosides.

7. The oligomeric compound of any of claims 1-6, wherein at least one nucleoside of the modified oligonucleotide is a modified nucleoside.

8. The oligomeric compound of claim 7. wherein the modified nucleoside comprises a modified sugar moiety.

9. The oligomeric compound of claim 8. wherein the modified sugar moiety comprises a bicyclic sugar moiety.

10. The oligomeric compound of claim 9. wherein the bicyclic sugar moiety comprises a 2’-4’ bridge selected from-O-CH2-; and -O-CH(CH3)-.

11. The oligomeric compound of any of claims 7-10, wherein the modified nucleoside comprises a non-bicyclic modified sugar moiety.

12. The oligomeric compound of claim 11, wherein the non-bicyclic modified sugar moiety is a 2’-M0E sugar moiety, a 2'-OMc sugar moiety, a 2’-p-D-deoxyxylosyl sugar moiety, or a 2’-a-L-deoxyribosyl sugar moiety.

13. The oligomeric compound of any of claims 7-12, wherein the modified nucleoside comprises a sugar surrogate.

14. The oligomeric compound of claim 13, wherein the sugar surrogate is any of morpholino, modified morpholino, glycol nucleic acid (GNA), six-membered tetrahydropyran (THP), and F-hexitol nucleic acid (F-HNA).

15. The oligomeric compound of any of claims 1-14, wherein the modified oligonucleotide is a gapmer.

16. The oligomeric compound of any of claims 1-15, wherein the modified oligonucleotide comprises at least one modified intemucleoside linkage.

17. The oligomeric compound of claim 16, wherein at least one intemucleoside linkage is a phosphodiester intemucleoside linkage.

18. The oligomeric compound of claim 16 or claim 17, wherein at least one modified intemucleoside linkage is a phosphorothioatc intemucleoside linkage.

19. The oligomeric compound of any of claims 16-18, wherein at least one modified intemucleoside linkage is a mesyl phosphoramidate intemucleoside linkage.

20. The oligomeric compound of any of claims 16-19, wherein each intemucleoside linkage is independently selected from a phosphodiester intemucleoside linkage, a phosphorothioate intemucleoside linkage, and a mesyl phosphoramidate intemucleoside linkage.

21. The oligomeric compound of any of claims 16, 18, or 19, wherein each intemucleoside linkage is independently selected from a phosphorothioate intemucleoside linkage and a mesyl phosphoramidate intemucleoside linkage.

22. The oligomeric compound of any of claims 16-18, wherein each intemucleoside linkage is independently selected from a phosphodiester intemucleoside linkage and a phosphorothioate intemucleoside linkage.

23. The oligomeric compound of any of claims 16-22, wherein at least 4. at least 5, at least 6, at least 7. at least 8, at least 9, at least 10. at least 11. at least 12, at least 13, at least 14, at least 15. at least 16. at least 17, at least 18, or 19 intemucleoside linkages of the modified oligonucleotide are phosphorothioate intemucleoside linkages.

24. The oligomeric compound of any of claims 16-21, wherein at least 1. at least 2, at least 3, at least 4. at least 5, at least 6, at least 7, or at least 8 intemucleoside linkages of the modified oligonucleotide are mesyl phosphoramidate intemucleoside linkages.

25. The oligomeric compound of any of claims 16-20, wherein the modified oligonucleotide has an intemucleoside linkage motif selected from 5’- soossssssssssos -3’. 5’- soossssssssssoos -3’, 5’- sooossssssssssos -3’. 5’- sooossssssssssoos -3’, 5’- soooossssssssssooos -3’. 5’- soossssssssssooos -3’. 5’- soossssssssssssss -3’, 5’- sssssssssssssssssss -3’. 5’- sooooossssssssssoss -3’. 5’- ssssszzzzssssssssss -3’, 5’- soooszzzzssssssooss -3’, 5’- sooosssssssssssooss -3’, 5’- sosssssssssssssooss -3’, 5’- sooosszzsssssoss -3’. 5’- sossssssssssssssoss -3’, 5’- soosszzzzssssssooss -3’, 5’- sossszzzzssssssooss -3’, 5’- sossszzzzsssssssoss -3’, 5’- sssssszsszzszssssss -3’. 5’- ssssssssszzsssssoss -3’, 5’- ssooszsssssszsssoss -3’. 5’- ssosszsssssszzssoss -3’, 5’- sssoszzzsssssssssss -3’, 5’- ssoosszzsssssssosss -3’, 5’- ssssszzsssszzssssss -3’. 5’- sssssszssssszsssoss -3’, 5’- soossssssssssssooss -3’, 5’- sossszzsssszzssosss -3’, 5’- sossszzsssszzsssoss -3’, 5’- sossszzsssszzssssss -3’, 5’- ssssszzsssszzssooss -3’, 5’- ssssszssssszzssssss -3’, 5’ - sssssszsssszzssssss -3’, 5’- ssssszzssssszssssss -3’. 5’- ssssszzsssszsssssss -3’, 5’- sossszssssszzssosss -3’, 5’- sosssszsssszzssosss -3’, 5’- sossszzssssszssosss -3’, 5’- sossszzsssszsssosss -3’, 5’- sossszssssszzsssoss -3’, 5’- sosssszsssszzsssoss -3’, 5’- sossszzssssszsssoss -3’, 5’- sossszzsssszssssoss -3’, 5’- szssszzsssszzsszzss -3', 5’- zzssszzsssszzsssszz -3‘, 5’- zsssszzsssszzsssssz -3’, 5‘- ssooszsssssszzssoss -3’, 5‘- sssoszsssssszzssoss -3', 5’- ssooszsssssszzsssss -3‘, 5’- ssssszsssssszzssoss -3’, 5‘- sssszzsssssszzsssss -3‘, 5’- soooszzssssszssooss -3’, 5‘- soooszzssssszzsooss -3’, 5’- ssooszzssssszssooss -3’, 5'- ssooszzssssszzsooss -3’, 5’- sssoszzssssszssooss -3’, 5’- sssoszzssssszzsooss -3’, 5’- sssoszzssssszssosss -3‘, and 5’- sssoszzssssszzsosss -3’, wherein each “s” represents a phosphorothioate intemucleoside linkage, each “o” represents a phosphodiester intemucleoside linkage, and each “z” represents a mesyl phosphoramidate intemucleoside linkage.

26. The oligomeric compound of any of claims 1-25, wherein at least one nucleoside of tire modified oligonucleotide comprises a modified nucleobase.

27. The oligomeric compound of claim 26, wherein the modified nucleobase is a 5-mcthylcytosinc.

28. The oligomeric compound of claim 27, wherein each cytosine is a 5-mcthylcytosinc.

29. The oligomeric compound of any of claims 1-28, wherein each nucleoside of the modified oligonucleotide is unmodified adenine, unmodified guanine, unmodified thymine, unmodified cytosine, or 5-methylcytosine.

30. The oligomeric compound of any of claims 1-29. wherein the modified oligonucleotide comprises a deoxy region.

31. The oligomeric compound of claim 30, wherein each nucleoside of the deoxy region is a 2’-0-D- deoxynucleoside.

32. The oligomeric compound of claim 30 or claim 31, wherein the deoxy region consists of 6, 7, 8, 9, 10, or 6-10 linked nucleosides.

33. The oligomeric compound of any of claims 30-32, wherein each nucleoside immediately adjacent to the deoxy region comprises a modified sugar moiety.

34. The oligomeric compound of any of claims 30-33, wherein the deoxy region is flanked on the 5’-side by a 5’- region consisting of 1-6 linked 5’-region nucleosides and on the 3’-side by a 3’-region consisting of 1-6 linked 3’-region nucleosides; wherein at least one nucleoside of the 5 ’-region comprises a modified sugar moiety; and at least one nucleoside of the 3’-region comprises a modified sugar moiety.

35. The oligomeric compound of claim 34, wherein each nucleoside of the 5’-region comprises a modified sugar moiety.

36. The oligomeric compound of claim 34 or claim 35, wherein each nucleoside of the 3 ’-region comprises a modified sugar moiety.

37. The oligomeric compound of any of claims 1-36, wherein the modified oligonucleotide consists of 12-30. 12- 22. 12-20,14-18, 14-20, 15-17, 15-25. 16-20, 18-22 or 18-20 linked nucleosides.

38. The oligomeric compound of any of claims 1-37, wherein tire modified oligonucleotide consists of 20 linked nucleosides.

39. The oligomeric compound of any of claims 1-38, wherein the modified oligonucleotide comprises; a 5 ’-region consisting of 1-6 linked 5 ’-region nucleosides; a central region consisting of 6-10 linked central region nucleosides; and a 3 ’-region consisting of 1-6 linked 3 ’-region nucleosides; wherein each of the 5’-region nucleosides and each of the 3’-region nucleosides comprises a modified sugar moiety and each of the central region nucleosides comprises a 2 ’-p-D-deoxy ribosyl sugar moiety.

40. The oligomeric compound of any of claims 1-39, wherein the modified oligonucleotide lias a sugar motif comprising; a 5 ’-region consisting of 5 linked 5 ’-region nucleosides; a central region consisting of 10 linked central region nucleosides; and a 3 ’ -region consisting of 5 linked 3 ’ -region nucleosides; wherein each of the 5‘-region nucleosides and each of the 3’-region nucleosides comprises a modified sugar moiety and each of the central region nucleosides comprises a 2 ’-p-D-deoxy ribosyl sugar moiety.

41. The oligomeric compound of claim 40, wherein the modified oligonucleotide lias a 5 ’-region consisting of 5 linked 5 ’-region nucleosides; a central region consisting of 10 linked central region nucleosides; and a 3 ’-region consisting of 5 linked 3 ’-region nucleosides; wherein each of the 5’-region nucleosides and each of the 3’-region nucleosides comprises a 2’-MOE sugar moiety and each of the central region nucleosides comprises a 2 ’-P-D-deoxy ribosyl sugar moiety.

42. The oligomeric compound of any of claims 1-39. wherein the modified oligonucleotide has a sugar motif comprising: a 5 ’-region consisting of 6 linked 5 ’-region nucleosides; a central region consisting of 10 linked central region nucleosides; and a 3 ’-region consisting of 4 linked 3 ’-region nucleosides; wherein each of the 5’-region nucleosides and each of the 3’-region nucleosides comprises a modified sugar moiety and each of the central region nucleosides comprises a 2 ’-P-D-deoxy ribosyl sugar moiety.

43. The oligomeric compound of claim 42, wherein the modified oligonucleotide hasa 5 ’-region consisting of 6 linked 5 ’-region nucleosides; a central region consisting of 10 linked central region nucleosides; and a 3’-region consisting of 4 linked 3’-region nucleosides; wherein each of the 5’-region nucleosides and each of the 3’-region nucleosides comprises a 2’-M0E sugar moiety and each of the central region nucleosides comprises a 2 ’-P-D-deoxy ribosyl sugar moiety.

44. The oligomeric compound of any of claims 1-43. consisting of the modified oligonucleotide.

45. The oligomeric compound of any of claims 1-43. wherein the oligomeric compound comprises a conjugate group.

46. The oligomeric compound of claim 45, wherein the conjugate group comprises a conjugate moiety and a conjugate linker.

47. The oligomeric compound of claim 46, wherein the conjugate linker is a phosphodiester linker.

48. The oligomeric compound of claim 46, wherein the conjugate linker consists of a single bond.

49. The oligomeric compound of any of claims 46 - 48, wherein the conjugate linker is cleavable.

50. The oligomeric compound of any of claims 46, 47. or 49. wherein the conjugate linker comprises 1-3 linker- nucleosides, wherein at least one linker nucleoside is linked to the conjugate moiety, to the modified oligonucleotide, or to another linker-nucleoside by a phosphodiester bond.

51. The oligomeric compound of any of claims 45-50, wherein the conjugate group is attached to the modified oligonucleotide at the 5 ’-end of the modified oligonucleotide.

52. The oligomeric compound of any of claims 45-50, wherein the conjugate group is attached to the modified oligonucleotide at the 3 ’-end of the modified oligonucleotide.

53. The oligomeric compound of any of claims 1-49 or 51-52, wherein the oligomeric compound does not comprise linker-nucleo sides.

54. The oligomeric compound of any of claims 1-53, comprising a terminal group.

55. The oligomeric compound of claim 54, wherein the terminal group is an abasic sugar moiety.

56. The oligomeric compound of any of claims 1-55, wherein the oligomeric compound is an RNase H agent.

57. An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation: AeSmCeSAeSGeSAeSTdzAdzTdzTdZTdSTdST*GdSTdSTdSmCeSTeSGeSraCeSmCe (SEQ ID NO: 3335), wherein:A = an adenine nuclcobasc, mC = a 5-methylcytosine nucleobase.G = a guanine nucleobase,T = a thymine nucleobase, e = a 2 ’-MOE sugar moiety, d = a 2 ’-P-D-deoxy ribosyl sugar moiety, s = a phosphorothioate intemucleoside linkage, and z = a mesyl phosphoramidate intemucleoside linkage; and wherein the oligomeric compound optionally comprises a conjugate group or a terminal group.

58. An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation: AeSmCeSGeoAeomCeSAdzTdsTdsTdsT*mCdsTdsTdzGdsmCdsmCeSTeomCesTesTe (SEQ ID NO: 3336), wherein:A = an adenine nucleobase,mC = a 5-methylcytosine nucleobase.G = a guanine nucleobase.T = a thymine nucleobase. e = a 2’-MOE sugar moiety, d = a 2’-P-D-deoxyribosyl sugar moiety, s = a phosphorothioate intemucleoside linkage, z = a mesyl phosphoramidate intemucleoside linkage, and o = a phosphodiester intemucleoside linkage; and wherein the oligomeric compound optionally comprises a conjugate group or a terminal group.

59. An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation: AeSmCesAeSGeSAesTdzAdzTdsTdsTdsTdsTdzGdzTdsTdsmCesTeSGesmCesinCe (SEQ ID NO: 3337), wherein:A = an adenine nucleobase. mC = a 5-methylcytosine nucleobase,G = a guanine nucleobase,T = a thymine nucleobase, e = a 2 ’-MOE sugar moiety, d = a 2’-p-D-deoxyribosyl sugar moiety, s = a phosphorothioate intemucleoside linkage, and z = a mesyl phosphoramidate intemucleoside linkage; and wherein the oligomeric compound optionally comprises a conjugate group or a terminal group.

60. An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation: AeSTeomCeoAeOmCeoGeoAdslnCdsAdsTdsTdsTdsTdsmCdsTdsTdsGeomCeSlnCeSTe (SEQ ID NO: 3338), wherein:A = an adenine nucleobase, mC = a 5-methylcytosine nucleobase,G = a guanine nucleobase,T = a thymine nucleobase, c = a 2 ’-MOE sugar moiety , d = a 2 ’-p-D-dcoxy ribosyl sugar moiety’, s = a phosphorothioate intemucleoside linkage, and o = a phosphodiester intemucleoside linkage; and wherein the oligomeric compound optionally comprises a conjugate group or a terminal group.

61. The oligomeric compound of any of claims 57-60, wherein the modified oligonucleotide is a pharmaceutically acceptable salt.

62. The oligomeric compound of claim 61, which is a pharmaceutically acceptable salt comprising one or more cations selected from sodium, potassium, calcium, and magnesium.

63. The oligomeric compound of any of claims 1-62. wherein the oligomeric compound is a singled-stranded oligomeric compound.

64. An oligomeric compound according to the following chemical notation: N1esmCesAesGesAesTdzAdzTdzTdzTdsTdsTdsGdsTdsTdsmCesTesGesmCesN2e(SEQ ID NO: 3346), wherein:A = an adenine nucleobase, mC = a 5-methylcytosine nucleobase.G = a guanine nucleobase.T = a thymine nucleobase.N1= an adenine nucleobase. a modified adenine, a hypoxanthine, an abasic sugar moiety, a terminal group, or is absent, wherein when N1is absent its sugar and intemucleoside linkage are also absent,N2= a cytosine nucleobase, a modified cytosine, an abasic sugar moiety, a terminal group, or is absent, wherein when N2is absent its sugar is also absent, e = a 2’-M0E sugar moiety. d = a 2’-P-D-deoxyribosyl sugar moiety. s = a phosphorothioate intemucleoside linkage, and z = a mesyl phosphoramidate intemucleoside linkage; and wherein the oligomeric compound optionally comprises a conjugate group.

65. An oligomeric compound according to the following chemical notation:N1eSmCesGeoAeomCesAdzTdsTdsTdsTdsn’CdsTdsTdzGdsniCdsniCesTeoniCeSTesN3e (SEQ ID NO: 3347), wherein:A = an adenine nucleobase, mC = a 5-methylcytosine nucleobase,G = a guanine nucleobase,T = a thymine nucleobase,N1= an adenine nucleobase, a modified adenine, a hypoxanthine, an abasic sugar moiety, a terminal group, or is absent, wherein when N1is absent its sugar and intemucleoside linkage are also absent,N3= a thymine nucleobase, a modified thymine, an abasic sugar moiety, a terminal group, or is absent, wherein when N3is absent its sugar is also absent, e = a 2 ’-MOE sugar moiety, d = a 2’-p-D-deoxyribosyl sugar moiety, s = a phosphorothioate intemucleoside linkage, z = a mesyl phosphoramidate intemucleoside linkage, and o = a phosphodicstcr intemucleoside linkage; and wherein the oligomeric compound optionally comprises a conjugate group.

66. An oligomeric compound according to the following chemical notation:N1eSmCeSAesGeSAesTdzAdzTdSTdsTdSTdSTdzGdzTdSTdSmCeSTesGeSmCeSN2e(SEQ ID NO: 3348), wherein:A = an adenine nucleobase, mC = a 5-methylcytosine nucleobase.G = a guanine nucleobase,T = a thymine nucleobase,N1= an adenine nucleobase. a modified adenine, a hypoxanthine, an abasic sugar moiety, a terminal group, or is absent, wherein when N1is absent its sugar and intemucleoside linkage are also absent,N2= a cytosine nucleobase, a modified cytosine, an abasic sugar moiety, a terminal group, or is absent, wherein when N2is absent its sugar is also absent,e = a 2’-MOE sugar moiety, d = a 2 ’-P-D-deoxj ribosyl sugar moiety, s = a phosphorothioate intemucleoside linkage, and z = a mesyl phosphoramidate intemucleoside linkage; and wherein the oligomeric compound optionally comprises a conjugate group.

67. An oligomeric compound according to the following chemical notation:N1esTeoniCeoAeomCeoGeoAdsinCdsAdsTdsTdsTdsTdsmCdsT*TrisGeomCesmCesN3e(SEQ ID NO: 3349), wherein:A = an adenine nucleobase. mC = a 5-methylcytosine nucleobase,G = a guanine nucleobase,T = a thymine nucleobase,N1= an adenine nucleobase, a modified adenine, a hypoxanthine, an abasic sugar moiety, a terminal group, or is absent, wherein when N1is absent its sugar and intemucleoside linkage are also absent,N3= a thymine nucleobase, a modified thymine, an abasic sugar moiety, a terminal group, or is absent, wherein when N3is absent its sugar is also absent, e = a 2 ’-MOE sugar moiety. d = a 2’-p-D-deoxyribosyl sugar moiety, s = a phosphorothioate intemucleoside linkage, and o = a phosphodiester intemucleoside linkage; and wherein the oligomeric compound optionally comprises a conjugate group.

68. The oligomeric compound of any of claims 64-67, wherein N1is an adenine nucleobase.

69. The oligomeric compound of any of claims 64-67, wherein N1is an unmodified adenine.

70. The oligomeric compound of any of claims 64-67, wherein N1is a modified adenine.

71. The oligomeric compound of any of claims 64-67, wherein N1is a hypoxanthine.

72. The oligomeric compound of any of claims 64-67, wherein N1is an abasic sugar moiety.

73. The oligomeric compound of any of claims 64-67, wherein N1is a terminal group.

74. The oligomeric compound of any of claims 64-67, wherein N1is absent.

75. The oligomeric compound of any of claims 64-74, wherein N2is a modified cytosine.

76. The oligomeric compound of any of claims 64-74, wherein N2is 5-methylcytosine.

77. The oligomeric compound of any of claims 64-74, wherein N2is an unmodified cytosine.

78. The oligomeric compound of any of claims 64-74, wherein N2is an abasic sugar moiety.

79. The oligomeric compound of any of claims 64-74, wherein N2is a terminal group.

80. The oligomeric compound of any of claims 64-74, wherein N2is absent.

81. The oligomeric compound of any of claims 64-74, wherein N3is a modified thymine.

82. The oligomeric compound of any of claims 64-74, wherein N3is an unmodified thymine.

83. The oligomeric compound of any of claims 64-74, wherein N3is an abasic sugar moiety.

84. The oligomeric compound of any of claims 64-74, wherein N3is a terminal group.

85. The oligomeric compound of any of claims 64-74, wherein N3is absent.

86. The oligomeric compound of any of claims 64-80, wherein N1is an adenine nucleobase and N2is a cytosine nucleobase, a modified cytosine, an abasic sugar moiety, a terminal group, or is absent.

87. The oligomeric compound of any of claims 64-80 or 86, wherein N1is an adenine nucleobase and N2is a modified cytosine.

88. The oligomeric compound of any of claims 64-80 or 86. wherein N1is an adenine nucleobase and N2is an abasic sugar moiety.

89. The oligomeric compound of any of claims 64-80 or 86, wherein N1is an adenine nucleobase and N2is a terminal group.

90. The oligomeric compound of any of claims 64-80 or 86, wherein N1is an adenine nucleobase and N2is absent.

91. The oligomeric compound of any of claims 64-80. wherein N1is a modified adenine and N2is a cytosine nucleobase. a modified cytosine, an abasic sugar moiety, a terminal group, or is absent.

92. The oligomeric compound of any of claims 64-80 or 91, wherein N1is a modified adenine and N2is a modified cytosine.

93. The oligomeric compound of any of claims 64-80 or 91, wherein N1is a modified adenine and N2is 5- methylcytosine.

94. The oligomeric compound of any of claims 64-80 or 91, wherein N1is a modified adenine and N2is an abasic sugar moiety.

95. The oligomeric compound of any of claims 64-80 or 91 , wherein N1is a modified adenine and N2is a terminal group.

96. The oligomeric compound of any of claims 64-80 or 91, wherein N1is a modified adenine and N2is absent.

97. The oligomeric compound of any of claims 64-80 or 91, wherein N1is a hypoxanthine and N2is a cytosine nucleobase, a modified cytosine, an abasic sugar moiety, a terminal group, or is absent.

98. The oligomeric compound of any of claims 64-80 or 97, wherein N1is a hypoxanthine and N2is a modified cytosine.

99. The oligomeric compound of any of claims 64-80 or 97, wherein N1is a hypoxanthine and N2is 5- methylcytosine.

100. The oligomeric compound of any of claims 64-80 or 97, wherein N1is a hypoxanthine and N2is an abasic sugar moiety.

101. The oligomeric compound of any of claims 64-80 or 97, wherein N1is a hy poxanthine and N2is a terminal group.

102. The oligomeric compound of any of claims 64-80 or 97, wherein N1is a hypoxanthine and N2is absent.

103. The oligomeric compound of any of claims 64-80, wherein N1is an abasic sugar moiety' and N2is a cytosine nucleobase, a modified cytosine, an abasic sugar moiety, a terminal group, or is absent.

104. The oligomeric compound of any of claims 64-80, wherein N1is a terminal group and N2is a cytosine nucleobase, a modified cytosine, an abasic sugar moiety, a terminal group, or is absent.

105. The oligomeric compound of any of claims 64-80, wherein N1is absent and N2is a cytosine nucleobase. a modified cytosine, an abasic sugar moiety, a terminal group, or is absent.

106. The oligomeric compound of any of claims 64-80, wherein N1is absent and N2is absent.

107. The oligomeric compound of any of claims 64-74 or 81-85, wherein N1is an adenine nucleobase and N3is a thymine nucleobase, a modified thymine, an abasic sugar moiety, a terminal group, or is absent.

108. The oligomeric compound of any of claims 64-74, 81-85, or 107, wherein N1is an adenine nucleobase and N3is a thymine nucleobase.

109. The oligomeric compound of any of claims 64-74, 81-85, or 107, wherein N1is an adenine nucleobase and N3is a modified thymine.

110. The oligomeric compound of any of claims 64-74, 81-85, or 107, wherein N1is an adenine nucleobase and N3is an abasic sugar moiety.

111. The oligomeric compound of any of claims 64-74. 81-85. or 107, wherein N1is an adenine nucleobase and N3is a terminal group.

112. The oligomeric compound of any of claims 64-74, 81-85. or 107, wherein N1is an adenine nucleobase and N3is absent.

113. The oligomeric compound of any of claims 64-74 or 81-85. wherein N1is a modified adenine and N3is a thymine nucleobase. a modified thymine, an abasic sugar moiety, a terminal group, or is absent.

114. The oligomeric compound of any of claims 64-74, 81-85. or 113, wherein N1is a modified adenine and N3is an unmodified thymine.

115. The oligomeric compound of any of claims 64-74, 81-85. or 113, wherein N1is a modified adenine and N3is an abasic sugar moiety.

116. The oligomeric compound of any of claims 64-74, 81-85. or 113, wherein N1is a modified adenine and N3is a terminal group.

117. The oligomeric compound of any of claims 64-74, 81-85, or 113, wherein N1is a modified adenine and N3is absent.

118. The oligomeric compound of any of claims 64-74 or 81-85, wherein N1is a hypoxanthine and N3is a thymine nucleobase, a modified thymine, an abasic sugar moiety, a terminal group, or is absent.

119. The oligomeric compound of any of claims 64-74, 81-85, or 118, wherein N1is a hypoxanthine and N3is an unmodified thymine.

120. The oligomeric compound of any of claims 64-74, 81-85, or 118, wherein N1is a hypoxanthine and N3is an abasic sugar moiety.

121. The oligomeric compound of any of claims 64-74, 81-85, or 118, wherein N1is a hypoxanthine and N3is a terminal group.

122. The oligomeric compound of any of claims 64-74, 81-85, or 118, wherein N1is a hypoxanthine and N3is absent.

123. The oligomeric compound of any of claims 64-74 or 81-85, wherein N1is an abasic sugar moiety and N3is a thymine nucleobase, a modified thymine, an abasic sugar moiety, a terminal group, or is absent.

124. The oligomeric compound of any of claims 64-74 or 81-85, wherein N1is a terminal group and N3is a thymine nucleobase, a modified thymine, an abasic sugar moiety, a terminal group, or is absent.

125. The oligomeric compound of any of claims 64-74 or 81-85, wherein N1is absent and N3is a thymine nucleobase, a modified thymine, an abasic sugar moiety, a terminal group, or is absent.

126. The oligomeric compound of any of claims 64-74 or 81-85, wherein N1is absent and N3is absent.

127. The oligomeric compound of any of claims 64-126. wherein the conjugate group comprises a conjugate moiety and a conjugate linker.

128. The oligomeric compound of claim 127. wherein the conjugate linker is a phosphodiester linker.

129. The oligomeric compound of claim 127. wherein the conjugate linker consists of a single bond.

130. The oligomeric compound of any of claims 127-129, wherein the conjugate linker is cleavable.

131. The oligomeric compound of any of claims 127, 128, or 130, wherein the conjugate linker comprises 1-3 linker-nucleosides. wherein at least one linker nucleoside is linked to the conjugate moiety, to the oligomeric compound, or to another linker-nucleoside by a phosphodiester bond.

132. The oligomeric compound of any of claims 64-131, wherein the conjugate group is attached to the oligomeric compound at the 5 ’-end of the oligomeric compound.

133. The oligomeric compound of any of claims 64-131, wherein the conjugate group is attached to the oligomeric compound at the 3 ’-end of the oligomeric compound.

134. The oligomeric compound of any of claims 64-133, wherein the oligomeric compound is a pharmaceutically acceptable salt.

135. The oligomeric compound of claim 133, wherein the pharmaceutically acceptable salt comprises one or more cations selected from sodium, potassium, calcium, and magnesium.

136. An oligomeric duplex, comprising a first oligomeric compound and a second oligomeric compound comprising a second modified oligonucleotide, wherein the first oligomeric compound is an oligomeric compound of any of claims 1-135.

137. The oligomeric duplex of claim 136, wherein the second modified oligonucleotide consists of 12 to 50 linked nucleosides, and wherein the nucleobase sequence of the second modified oligonucleotide comprises a complementary region of at least 8 nucleobases that is at least 90% complementary to an equal length portion of tire first modified oligonucleotide.

138. The oligomeric duplex of claim 136 or claim 137, wherein the modified oligonucleotide of the first oligomeric compound comprises a 5 ’-stabilized phosphate group.

139. The oligomeric duplex of claim 138, wherein the stabilized phosphate group comprises a cyclopropyl phosphonatc or a vinyl phosphonatc.

140. The oligomeric duplex of any of claims 136-139, wherein at least one nucleoside of the second modified oligonucleotide comprises a modified sugar moiety.

141. The oligomeric duplex of claim 140, wherein the modified sugar moiety’ of tire second modified oligonucleotide comprises a bicyclic sugar moiety.

142. The oligomeric duplex of claim 141, wherein the bicyclic sugar moiety of the second modified oligonucleotide comprises a 2’-4’ bridge selected from -O-CH2-; and -O-CH(CH3)-.

143. The oligomeric duplex of claim 140, wherein the modified sugar moiety of the second modified oligonucleotide comprises a non-bicyclic modified sugar moiety.

144. The oligomeric duplex of claim 143, wherein the non-bicyclic modified sugar moiety of the second modified oligonucleotide is a 2’-MOE sugar moiety’, a 2’-F modified sugar moiety, or 2’-OMe modified sugar moiety.

145. The oligomeric duplex of any of claims 136-144. wherein at least one intemucleoside linkage of the second modified oligonucleotide is a modified intemucleoside linkage.

146. The oligomeric duplex of claim 145, wherein at least one modified intemucleoside linkage of the second modified oligonucleotide is a phosphorothioate intemucleoside linkage.

147. The oligomeric duplex of any of claims 136-146. wherein at least one intemucleoside linkage of the second modified oligonucleotide is a phosphodiester intemucleoside linkage.

148. The oligomeric duplex of any of claims 145-147. wherein at least one intemucleoside linkage of the second modified oligonucleotide is a mesyl phosphoramidate intemucleoside linkage.

149. The oligomeric duplex of any of claims 136-148. wherein each intemucleoside linkage of the second modified oligonucleotide is independently selected from a phosphodiester intemucleoside linkage, a phosphorothioate intemucleoside linkage, or a mesyl phosphoramidate intemucleoside linkage.

150. The oligomeric duplex of any of claims 136-149, wherein tire second modified oligonucleotide comprises at least one modified nucleobase.

151. The oligomeric duplex of claim 150, wherein the at least one modified nucleobase of the second modified oligonucleotide is 5-methylcytosine.

152. The oligomeric duplex of any of claims 136-151, wherein the second modified oligonucleotide comprises a conjugate group.

153. The oligomeric duplex of claim 152, wherein the conjugate group comprises a conjugate moiety and a conjugate linker.

154. The oligomeric duplex of claim 153, wherein tire conjugate linker consists of a single bond.

155. The oligomeric duplex of claim 153 or claim 154, wherein the conjugate linker is cleavable.

156. The oligomeric duplex of claim 153 or claim 155, wherein the conjugate linker comprises 1-3 linker- nucleosides, wherein at least one linker nucleoside is linked to the conjugate moiety, to the modified oligonucleotide, or to another linker-nucleoside by a phosphodiester bond.

157. The oligomeric duplex of any of claims 153-156, wherein the conjugate linker is a phosphodiester linker.

158. The oligomeric duplex of any of claims 152-157, wherein the conjugate group is attached to the 5’-end of the second modified oligonucleotide.

159. The oligomeric duplex of any of claims 152-157, wherein the conjugate group is attached to the 3 ’-end of the second modified oligonucleotide.

160. The oligomeric duplex of any of claims 152-157, wherein the conjugate group is attached via the 2’ position of a ribosyl sugar moiety at an internal position of the second modified oligonucleotide.

161. The oligomeric duplex of any of claims 152-160, wherein the conjugate group comprises a C22 alky l, C20 alkyl. C16 alkyl, CIO alkyl, C21 alkyd, C19 alky l, C18 alky l, C17 alky l, C15 alky l, C14 alkyl, C13 alkyl, C12 alkyl, CH alkyl. C9 alky l, C8 alkyl, C7 alky l, C6 alkyl, C5 alky l, C22 alkeny l, C20 alkenyl, C16 alkenyl, CIO alkenyl, C21 alkenyl. C19 alkeny l, C18 alkeny l, C17 alkenyl, C15 alkenyl, C14 alkenyl, C13 alkenyl, C12 alkenyl. Cl l alkenyl, C9 alkenyl. C8 alkeny l, C7 alkenyl, C6 alkenyl, or C5 alkenyl.

162. The oligomeric duplex of any of claims 152-161. wherein the conjugate group comprises a cell-targeting moiety.

163. The oligomeric duplex of any of claims 136-162. wherein the second modified oligonucleotide comprises a terminal group.

164. The oligomeric duplex of claim 163, wherein the terminal group is an abasic sugar moiety.

165. An antisense agent comprising or consisting of an antisense compound, wherein the antisense compound is the oligomeric compound of any of claims 1-135.

166. An antisense agent, wherein the antisense agent is the oligomeric duplex of any of claims 136-164.

167. The antisense agent of claim 165 or claim 166. wherein the antisense agent is: i) an RNase H agent capable of reducing the amormt of SNCA nucleic acid through the activation ofRNase H; or ii) an RNAi agent capable of reducing the amount of SNCA nucleic acid through the activation of RISC / Ago2.

168. The antisense agent of any of claims 165-167. wherein the antisense agent comprises a conjugate group, and wherein the conjugate group comprises a cell-targeting moiety.

169. A modified oligonucleotide according to the following chemical structure:(SEQ ID NO: 3335). or a pharmaceutically acceptable salt thereof.

170. A modified oligonucleotide according to the following chemical structure:(SEQ ID NO: 3336), or a pharmaceutically acceptable salt thereof.

171. A modified oligonucleotide according to the following chemical structure: NH2N N H172. A modified oligonucleotide according to the following chemical structure:(SEQ ID NO: 3338). or a pharmaceutically acceptable salt thereof.

173. The modified oligonucleotide of any of claims 169-172, which is a pharmaceutically acceptable salt comprising one or more cations selected from sodium, potassium, calcium, and magnesium.

177. A modified oligonucleotide according to the following chemical structure:(SEQ ID NO: 3338).

178. A population of oligomeric compounds of any of claims 1-135 or a population of modified oligonucleotides of any of claims 169-177, wherein the population is chirally enriched for modified oligonucleotides comprising at least one particular phosphorothioate intemucleoside linkage having a particular stereochemical configuration.

179. The population of claim 178. wherein the population is chirally enriched for modified oligonucleotides comprising at least one particular phosphorothioate intemucleoside linkage having the (Sp) configuration.

180. The population of claim 178. wherein the population is chirally enriched for modified oligonucleotides comprising at least one particular phosphorothioate intemucleoside linkage having the (Ap) configuration.

181. The population of claim 178. wherein the population is chirally enriched for modified oligonucleotides having a particular, independently selected stereochemical configuration at each phosphorothioate intemucleoside linkage.

182. The population of claim 178. wherein the population is chirally enriched for modified oligonucleotides having the (S'p) configuration at each phosphorothioate intemucleoside linkage or for modified oligonucleotides having the (Ap) configuration at each phosphorothioate intemucleoside linkage.

183. The population of claim 178. wherein the population is chirally enriched for modified oligonucleotides having the (Ap) configuration at one particular phosphorothioate intemucleoside linkage and the (Sp) configuration at each of the remaining phosphorothioate intemucleoside linkages.

184. The population of claim 178, wherein the population is chirally enriched for modified oligonucleotides having at least 3 contiguous phosphorothioate intemucleoside linkages in the .S'p. .Sp. and Rp configurations, in the 5’ to 3’ direction.

185. A population of oligomeric compounds of any of claims 1-135, modified oligonucleotides of any of claims 169-177, oligomeric duplexes of any of claims 136-164. or antisense agents of any of claims 165-168. wherein all of the phosphorothioate intemucleoside linkages of the modified oligonucleotide are stereorandom.

186. A population of oligomeric compounds of any of claims 1-135, modified oligonucleotides of any of claims 169-177. oligomeric duplexes of any of claims 136-164, or antisense agents of any of claims 165-168, wherein all of the mesyl phosphoramidate intemucleoside linkages of the modified oligonucleotide are stereorandom.

187. A pharmaceutical composition comprising an oligomeric compound of any of claims 1-135. a modified oligonucleotide of any of claims 169-177. an oligomeric duplex of any of claims 136-164. an antisense agent of any of claims 165-168. or a population of any of claims 178-186, and a pharmaceutically acceptable diluent.

188. The pharmaceutical composition of claim 187. wherein the pharmaceutically acceptable diluent is artificial cerebral spinal fluid (aCSF) or phosphate-buffered saline (PBS).

189. The pharmaceutical composition of claim 188. wherein the pharmaceutical composition consists essentially of the oligomeric compound of any of claims 1-135, the modified oligonucleotide of any of claims 169-177, the oligomeric duplex of any of claims 136-164, the antisense agent of any of claims 165-168, or the population of any of claims 178- 186, and aCSF.

190. The pharmaceutical composition of claim 188. wherein the pharmaceutical composition consists essentially of the oligomeric compound of any of claims 1-135, the modified oligonucleotide of any of claims 169-177, the oligomeric duplex of any of claims 136-164, the antisense agent of any of claims 165-168, or the population of any of claims 178- 186, and PBS.

191. A method comprising administering to a subject an oligomeric compound of any of claims 1-135, a modified oligonucleotide of any of claims 169-177, an oligomeric duplex of any of claims 136-164, an antisense agent of any of claims 165-168, a population of any of claims 178-186, or a pharmaceutical composition of any of claims 187-190.

192. The method of claim 191, wherein the subject has or is at risk of developing a synucleinopathy.

193. The method of claim 191, wherein the subject has or is at risk of developing Parkinson’s disease.

194. The method of claim 191, wherein the subject has or is at risk of developing multiple system atrophy (MSA).

195. The method of claim 191, wherein the subject has or is at risk of developing dementia with Lewy bodies(DLB), diffuse Lewy body disease, Parkinson’s disease dementia (PDD), pure autonomic failure, neuronopathic Gaucher's disease, or Alzheimer’s disease.

196. A method of treating a synucleinopathy comprising administering to a subject having or at risk of developing a synucleinopathy a therapeutically effective amount of an oligomeric compound of any of claims 1-135, a modified oligonucleotide of any of claims 169-177, an oligomeric duplex of any of claims 136-164, an antisense agent of any of claims 165-168, a population of any of claims 178-186, or a pharmaceutical composition of any of claims 187-190.

197. The method of claim 196, wherein the synucleinopathy is Parkinson’s disease, dementia with Lewy bodies (DLB), diffuse Lewy body disease, Parkinson’s disease dementia (PDD), pure autonomic failure, multiple system atrophy (MSA), neuronopathic Gaucher's disease, or Alzheimer’s disease.

198. The method of claim 196, wherein the synucleinopathy is Parkinson’s disease.

199. The method of claim 196, wherein the synucleinopathy is multiple system atrophy (MSA).

200. The method of any of claims 196-199. wherein at least one symptom or hallmark of synucleinopathy is ameliorated.

201. The method of claim 200, wherein the symptom or hallmark is motor dysfunction, aggregation of alpha- synuclein. neurodegeneration, cognitive decline, dementia, sleep disorders, hyposmia, autonomic failure, ataxia, hallucination, or seizures.

202. The method of any of claims 196-201, wherein administering the oligomeric compound of any of claims 1-135, the modified oligonucleotide of any of claims 169-177. the oligomeric duplex of any of claims 136-164, the antisense agent of any of claims 165-168, the population of any of claims 178-186. or the pharmaceutical composition of any of claims 187-190 reduces or delays the onset or progression of motor dysfunction, aggregation of alpha-synuclein. neurodegeneration, cognitive decline, dementia, sleep disorders, hyposmia. autonomic failure, ataxia, hallucination, or seizures.

203. The method of any of claims 191-202, wherein tire oligomeric compound of any of claims 1-135, tire modified oligonucleotide of any of claims 169-177, the oligomeric duplex of any of claims 136-164, tire antisense agent of any of claims 165-168. the population of any of claims 178-186. or the pharmaceutical composition of any of claims 187-190 is administered to the central nervous system or systemically.

204. The method of any of claims 191-203, wherein tire oligomeric compound of any of claims 1-135, tire modified oligonucleotide of any of claims 169-177, the oligomeric duplex of any of claims 136-164, tire antisense agent of any of claims 165-168, the population of any of claims 178-186, or the pharmaceutical composition of any of claims 187-190 is administered intrathecally.

205. The method of any of claims 191-204, wherein the subject is a human.

206. A method of reducing expression of SNCA in a cell comprising contacting the cell with oligomeric compound of any of claims 1-135, a modified oligonucleotide of any of claims 169-177, an oligomeric duplex of any of claims 136- 164, an antisense agent of any of claims 165-168, a population of any of claims 178-186, or a pharmaceutical composition of any of claims 187-190.

207. The method of claim 206, wherein the cell is a brain cell.

208. The method of claim 206 or claim 207, wherein the cell is a neuron or an oligodendrocyte.

209. The method of any of claims 206-208, wherein the cell is a human cell.

210. Use of oligomeric compound of any of claims 1-135, a modified oligonucleotide of any of claims 169-177, an oligomeric duplex of any of claims 136-164, an antisense agent of any of claims 165-168, a population of any of claims 178-186, or a pharmaceutical composition of any of claims 187-190 for treating a synucleinopathy.

211. Use of oligomeric compound of any of claims 1-135, a modified oligonucleotide of any of claims 169-177, an oligomeric duplex of any of claims 136-164, an antisense agent of any of claims 165-168, a population of any of claims 178-186, or a pharmaceutical composition of any of claims 187-190 for the manufacture of a medicament for treating a synucleinopathy.

212. The use of claim 210 or claim 211, wherein the synucleinopathy is Parkinson’s disease, dementia with Lewy bodies (DLB). diffuse Lewy body disease, Parkinson’s disease dementia (PDD), pure autonomic failure, multiple system atrophy (MSA), neuronopathic Gaucher's disease, or Alzheimer’s disease.

213. The use of claim 210 or claim 21 1, wherein the synucleinopathy is Parkinson’s disease.

214. The use of claim 210 or claim 211, wherein the synucleinopathy is multiple system atrophy (MSA).