SNCA-targeted miRNA compositions for the treatment of SNCA-associated disease

Claims

1. A double-stranded ribonucleic acid (dsRNA)-based agent for inhibiting the expression of SNCA, wherein the dsRNA agent comprises a sense strand having a 5'-end and a 3'-end, and an antisense strand having a 5'-end and a 3'-end, wherein the sense strand and the antisense strand form a double-stranded region, wherein: the sense strand comprises a nucleotide sequence selected from the group consisting of SEQ ID NO: 150, SEQ ID NO: 157, SEQ ID NO: 164, and SEQ ID NO: 142-149, 151-156, 158-163, and 165-184 from Table 3, with 0 or 1 non-complementary base; the sense strand of the dsRNA agent includes a lipophilic group attached at position 6 or 16, measured from the 5' end of the sense strand; the antisense strand comprises a nucleotide sequence selected from the group consisting of SEQ ID NO: 193, SEQ ID NO: 200, SEQ ID NO: 207, and SEQ ID NO: 185-192, 194-199, 201-206, and 208-227 from Table 3, with 0 or 1 non-complementary base; the dsRNA agent does not include GalNAc modification; and The dsRNA vehicle comprises eight phosphorothioate internucleotide linkages located as the penultimate and terminal internucleotide linkages from the respective 3' and 5' ends of each sense and antisense strand of the dsRNA vehicle.

2. The dsRNA agent according to claim 1, wherein the lipophilic group is an aliphatic, alicyclic or polyalicyclic compound.

3. The dsRNA agent according to claim 1 or 2, wherein the lipophilic group is a lipid, cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-bis-O(hexadecyl)glycerol, geranyloxyhexanol, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, dimethoxytrityl or phenoxazine.

4. A dsRNA agent according to any of the preceding claims, wherein the lipophilic group comprises a saturated or unsaturated C4-C 30 a hydrocarbon chain and an optional functional group selected from the group consisting of hydroxyl, amine, carboxyl, sulfonate, phosphate, thiol, azide and alkyne.

5. The dsRNA agent according to any of the preceding claims, wherein the lipophilic group comprises a saturated or unsaturated C6-C 18 hydrocarbon chain.

6. A dsRNA agent according to any of the preceding claims, wherein the lipophilic group comprises a saturated or unsaturated C 16 hydrocarbon chain.

7. A dsRNA agent according to any of the preceding claims, wherein the lipophilic group is: where B is a nucleotide base or a nucleotide base analogue, where B is optionally selected from the group consisting of adenine, guanine, cytosine, thymine and uracil.

8. The dsRNA agent according to any of the preceding claims, wherein the lipophilic group is attached via a linker or carrier.

9. A dsRNA agent according to any of the preceding claims, wherein the lipophilic group is conjugated via a carrier that replaces a nucleotide at position 6 or 16 of the sense strand.

10. The dsRNA agent of claim 9, wherein the carrier is a cyclic group selected from the group consisting of pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, [1,3]-dioxolanyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, tetrahydrofuranyl, and decalinyl; or an acyclic group based on a serinol skeleton or a diethanolamine skeleton.

11. The dsRNA agent of any one of claims 1-8, wherein the lipophilic group is conjugated to the dsRNA agent via a linker comprising an ether, a thioether, a urea, a carbonate, an amine, an amide, a maleimide-thioether, a disulfide, a phosphodiester, a sulfonamide linkage, a click reaction product, or a carbamate.

12. The dsRNA agent of any one of claims 1-8 and 11, wherein the lipophilic group is conjugated to the dsRNA agent via a biodegradable linker selected from the group consisting of DNA, RNA, disulfide, amide, functionalized monosaccharides or oligosaccharides of galactosamine, glucosamine, glucose, galactose, mannose and combinations thereof.

13. The dsRNA agent of any of the preceding claims, wherein substantially all of the nucleotides of the sense strand are modified nucleotides.

14. The dsRNA agent of any one of the preceding claims, wherein substantially all of the nucleotides of the antisense strand are modified nucleotides.

15. The dsRNA agent of any of the preceding claims, wherein all nucleotides of the sense strand are modified nucleotides.

16. The dsRNA agent of any of the preceding claims, wherein all nucleotides of the antisense strand are modified nucleotides.

17. The dsRNA agent of any of the preceding claims, wherein all nucleotides of the sense strand and all nucleotides of the antisense strand are modified nucleotides.

18. The dsRNA agent of any one of the preceding claims having one or more modified nucleotides, and wherein at least one of the more modified nucleotides is selected from the group consisting of a deoxynucleotide, a 3'-terminal deoxythymidine (dT) nucleotide, a 2'-O-methyl-modified nucleotide, a 2'-fluoro-modified nucleotide, a 2'-deoxy-modified nucleotide, a closed nucleotide, an unclosed nucleotide, a conformationally constrained nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2'-amino-modified nucleotide, a 2'-O-allyl-modified nucleotide, a 2'-C-alkyl-modified nucleotide, a 2'-hydroxy-modified nucleotide, a 2'-methoxyethyl-modified nucleotide, a 2'-O-alkyl-modified nucleotide, morpholine nucleotide, phosphoramidate, non-natural base nucleotide, tetrahydropyran-modified nucleotide, 1,5-anhydrohexite-modified nucleotide,a cyclohexenyl-modified nucleotide, a nucleotide comprising a 5'-phosphorothioate group, a nucleotide comprising a 5'-methylphosphonate group, a nucleotide comprising a 5'-phosphate or a 5'-phosphate mimetic, a nucleotide comprising a vinyl phosphate, a nucleotide comprising adenosine glycol nucleic acid (GNA), a nucleotide comprising the S-isomer of thymidine glycol nucleic acid (GNA), a nucleotide comprising 2-hydroxymethyl-tetrahydrofuran-5-phosphate, a nucleotide comprising 2'-deoxythymidine-3'phosphate, a nucleotide comprising 2'-deoxyguanosine-3'-phosphate, and a terminal nucleotide linked to a cholesterol derivative and a dodecanoic acid bisdecylamide group.

19. The dsRNA agent according to any one of the preceding claims, wherein the dsRNA agent comprises at least one modified nucleotide selected from the group consisting of a 2'-O-methyl-modified nucleotide, a 2'-fluoro-modified nucleotide, a 2'-C16 (2'-O-hexadecyl) modified nucleotide, and a nucleotide comprising vinyl phosphate, wherein the dsRNA agent optionally comprises at least one of each of the following modifications: a 2'-O-methyl-modified nucleotide, a 2'-fluoro-modified nucleotide, a 2'-C16 (2'-O-hexadecyl) modified nucleotide, and a nucleotide comprising vinyl phosphate.

20. The dsRNA agent of any one of the preceding claims, further comprising a phosphate or phosphate mimetic at the 5' end of the antisense strand.

21. The dsRNA agent according to claim 20, wherein the phosphate mimetic is 5'-vinyl phosphonate (VP).

22. The dsRNA agent of any one of the preceding claims, comprising a pattern of modified nucleotides as shown in Table 2 (wherein the positions of the 2'-C16, 2'-(O-methyl, 2'-deoxy, HNK, phosphorothioate, vinyl phosphonate, and 2'-fluoro modifications are shown in Table 2, regardless of the individual nucleotide base sequences of the dsRNA agents shown).

23. The dsRNA agent of any one of the preceding claims, having a nucleotide sequence of a sense strand and an antisense nucleotide sequence of one duplex selected from the group consisting of AD-1804698, AD-1804699, AD-1747575, AD-1747576, AD-1804700, AD-1747577, AD-1747578, AD-1747579, AD-1747580, AD-1747581, AD-1804701, AD-1747582, AD-1804702, AD-1804703, AD-1804704, AD-1747583, AD-1804705, AD-1804706, AD-1804707, AD-1804708, AD-1804709, AD-1747591, AD-1747585, AD-1804710, AD-1804711, AD-1747586, AD-1804712, AD-1747587, AD-1804713, AD-1804714, AD-1747588, AD-1804715, AD-1804716, AD-1804717, AD-1804718, AD-1804719, AD-1804720, AD-1804721, AD-1804722, AD-1804723, AD-1804724, AD-1804725 and AD-1804726, optionally having a nucleotide sequence of a sense and an antisense nucleotide sequence of one duplex selected from the group consisting of AD-1747580, AD-1747583 and AD-1747585.

24. The dsRNA agent of any one of the preceding claims, wherein the sense strand of the dsRNA agent has a modification pattern selected from the group consisting of 5'-nsnsnnn(Nhd)NfnNfNfNfnnnnnnnnsnsn-3' and 5'-nsnsnnnnnnNfNfNfnnnn(Nhd)nnnsnsn-3', wherein n is a 2'-O-methyl nucleotide, s is a phosphorothioate internucleotide linkage, Nf is a 2'-fluoro nucleotide, and (Nhd) is a 2'-O-hexadecyl nucleotide.

25. The dsRNA agent of any one of the preceding claims, wherein the antisense strand of the dsRNA agent has a modification pattern selected from the group consisting of 5'-VPnsdNsnndNndNnnnndNnNfnnnnnnnsnsn-3' and 5'-VPnsNfsnndNn(Ngn)nnnnnnNfnNfnnnnnsnsn-3', wherein VP is vinyl phosphonate, n is 2'-O-methyl nucleotide, s is a phosphorothioate internucleotide linkage, dN is 2'-deoxy nucleotide, Nf is 2'-fluoro nucleotide, and (Ngn) is the S-isomer of glycol nucleic acid.

26. A double-stranded ribonucleic acid (dsRNA)-based agent for inhibiting the expression of SNCA, wherein the dsRNA agent comprises a sense strand having a 5' end and a 3' end, and an antisense strand having a 5' end and a 3' end, wherein the sense strand and the antisense strand form a double-stranded region, wherein: the sense strand comprises the nucleotide sequence and modifications from Table 2 (SEQ ID NO: 13-55), with 0 or 1 non-complementary base; and The antisense strand comprises the nucleotide sequence and modifications from Table 2 (SEQ ID NO: 56-98), with 0 or 1 non-complementary base.

27. The dsRNA agent according to any one of the preceding claims, having a nucleotide sequence of the sense strand selected from the group consisting of 5'-asasgug(Chd)ucAfGfUfuccaaugusgsa-3' (SEQ ID NO: 35), 5'-uscsuuugcuCfCfCfaguu(Uhd)cuusgsa-3' (SEQ ID NO: 28), 5'-gsasgca(Ahd)guGfAfCfaaauguugsgsa-3' (SEQ ID NO: 21), 5'-gsusaca(Ahd)GfuGfCfUfcaguuccasasa-3' (SEQ ID NO: 34), 5'-cscsauc(Ahd)gcAfGfUfgauugaagsusa-3' (SEQ ID NO: 43), 5'-uscsccag(Uhd)uUfCfUfugagaucusgsa-3' (SEQ ID NO: 261) and 5'-uscsaug(Ahd)aaGfGfAfcuuucaaasgsa-3' (SEQ ID NO: 19), where a is 2'-O-methyladenosine-3'-phosphate, a is 2'-O-methyluridine-3'-phosphate, g is 2'-O-methylguanosine-3'-phosphate, c is 2'-O-methylcytidine-3'-phosphate, s is a phosphorothioate internucleotide linkage, Af is 2'-fluoroadenosine-3'-phosphate, Gf is 2'-fluoroguanosine-3'-phosphate, Uf is 2'-fluorouridine-3'-phosphate, Cf is 2'-fluorocytidine-3'-phosphate,(Ahd) is 2'-O-hexadecyl-adenosine-3'-phosphate, (Uhd) is 2'-O-hexadecyl-uridine-3'-phosphate, and (Chd) is 2'-O-hexadecyl-cytidine-3'-phosphate.

28. The dsRNA agent according to any one of the preceding claims, having a nucleotide sequence of the antisense strand selected from the group consisting of 5'-VPusdCsacdAudTggaadCuGfagcacuusgsu-3' (SEQ ID NO: 78), 5'-VPusdCsaadGadAacugdGgAfgcaaagasusa-3' (SEQ ID NO: 71), 5'-VPusdCscadAcdAuuugdTcAfcuugcucsusu-3' (SEQ ID NO: 64), 5'-VPusUfsugdGa(Agn)cugagcAfcUfuguacsasg-3' (SEQ ID NO: 77), 5'-VPusdAscudTcdAaucadCuGfcugauggsasa-3' (SEQ ID NO: 86), 5'-VPusdCsagdAudCucaadGaAfacugggasgsc-3' (SEQ ID NO: 262) and 5'-VPusdCsuudTgdAaagudCcUfuucaugasasu-3' (SEQ ID NO: 62), where VP is vinyl phosphonate, a is 2'-O-methyladenosine-3'-phosphate, a is 2'-O-methyluridine-3'-phosphate, g is 2'-O-methylguanosine-3'-phosphate, c is 2'-O-methylcytidine-3'-phosphate, s is a phosphorothioate internucleotide linkage, Af is 2'-fluoroadenosine-3'-phosphate, Gf is 2'-fluoroguanosine-3'-phosphate,Uf is 2'-fluorouridine-3'-phosphate, Cf is 2'-fluorocytidine-3'-phosphate, dA is 2'-deoxyadenosine-3'-phosphate, dC is 2'-deoxycytidine-3'-phosphate, dG is 2'-deoxyguanosine-3'-phosphate, dT is 2'-deoxythymidine-3'-phosphate, and (Agn) is the S-isomer of adenosine glycol nucleic acid (GNA).

29. The dsRNA agent according to any one of the preceding claims, having a duplex nucleotide sequence selected from the group consisting of: (i) a sense strand: 5'-asasgug(Chd)ucAfGfUfuccaaugusgsa-3' (SEQ ID NO: 35) and an antisense strand: 5'-VPusdCsacdAudTggaadCuGfagcacuusgsu-3' (SEQ ID NO: 78); (ii) a sense strand: 5'-uscsuuugcuCfCfCfaguu(Uhd)cuusgsa-3' (SEQ ID NO: 28) and an antisense strand: 5'-VPusdCsaadGadAacugdGgAfgcaaagasusa-3' (SEQ ID NO: 71); (iii) sense strand: 5'-gsasgca(Ahd)guGfAfCfaaauguugsgsa-3' (SEQ ID NO: 21) and antisense strand: 5'-VPusdCscadAcdAuuugdTcAfcuugcucsusu-3' (SEQ ID NO: 64); (iv) sense strand: 5'-gsusaca(Ahd)GfuGfCfUfcaguuccasasa-3' (SEQ ID NO: 34) and antisense strand: 5'-VPusUfsugdGa(Agn)cugagcAfcUfuguacsasg-3' (SEQ ID NO: 77); (v) sense strand: 5'-cscsauc(Ahd)gcAfGfUfgauugaagsusa-3' (SEQ ID NO: 43) and antisense strand: 5'-VPusdAscudTcdAaucadCuGfcugauggsasa-3' (SEQ ID NO: 86); (vi) sense strand: 5'-uscsccag(Uhd)uUfCfUfugagaucusgsa-3' (SEQ ID NO:261) and antisense strand: 5'-VPusdCsagdAudCucaadGaAfacugggasgsc-3' (SEQ ID NO: 262); and (vii) a sense strand: 5'-uscsaug(Ahd)aaGfGfAfcuuucaaasgsa-3' (SEQ ID NO: 19) and an antisense strand: 5'-VPusdCsuudTgdAaagudCcUfuucaugasasu-3' (SEQ ID NO: 62), wherein VP is vinyl phosphonate, a is 2'-O-methyladenosine-3'-phosphate, a is 2'-O-methyluridine-3'-phosphate, g is 2'-O-methylguanosine-3'-phosphate, c is 2'-O-methylcytidine-3'-phosphate, s is a phosphorothioate internucleotide linkage, Af is 2'-fluoroadenosine-3'-phosphate, Gf is 2'-fluoroguanosine-3'-phosphate, Uf is 2'-fluorouridine-3'-phosphate, Cf is 2'-fluorocytidine-3'-phosphate, dA is 2'-deoxyadenosine-3'-phosphate, dC is 2'-deoxycytidine-3'-phosphate, dG is 2'-deoxyguanosine-3'-phosphate, dT is 2'-deoxythymidine-3'-phosphate, (Agn) is the S-isomeradenosine glycol nucleic acid (GNA), (Ahd) is 2'-O-hexadecyl-adenosine-3'-phosphate, (Uhd) is 2'-O-hexadecyl-uridine-3'-phosphate, and (Chd) is 2'-O-hexadecyl-cytidine-3'-phosphate.

30. A double-stranded ribonucleic acid (dsRNA)-based agent for inhibiting the expression of SNCA, having a sense strand sequence of 5'-asasgug(Chd)ucAfGfUfuccaaugusgsa-3' (SEQ ID NO: 35) and an antisense strand sequence of 5'-VPusdCsacdAudTggaadCuGfagcacuusgsu-3' (SEQ ID NO: 78), wherein VP is vinyl phosphonate, a is 2'-O-methyladenosine-3'-phosphate, and is 2'-O-methyluridine-3'-phosphate, g is 2'-O-methylguanosine-3'-phosphate, c is 2'-O-methylcytidine-3'-phosphate, s is a phosphorothioate internucleotide linkage, Af is 2'-fluoroadenosine 3'-phosphate, Gf is 2'-fluoroguanosine 3'-phosphate, Uf is 2'-fluorouridine 3'-phosphate, dA is 2'-deoxyadenosine 3'-phosphate, dC is 2'-deoxycytidine 3'-phosphate, dT is 2'-deoxythymidine 3'-phosphate, and (Chd) is 2'-O-hexadecyl-cytidine 3'-phosphate.

31. A double-stranded ribonucleic acid (dsRNA)-based agent for inhibiting the expression of SNCA, having a sense strand sequence of 5'-uscsuuugcuCfCfCfaguu(Uhd)cuusgsa-3' (SEQ ID NO: 28) and an antisense strand sequence of 5'-VPusdCsaadGadAacugdGgAfgcaaagasusa-3' (SEQ ID NO: 71), wherein VP is vinyl phosphonate, a is 2'-O-methyladenosine-3'-phosphate, a is 2'-O-methyluridine-3'-phosphate, g is 2'-O-methylguanosine-3'-phosphate, c is 2'-O-methylcytidine-3'-phosphate, s is a phosphorothioate internucleotide linkage, Af is 2'-fluoroadenosine 3'-phosphate, Cf is 2'-fluorocytidine 3'-phosphate, dA is 2'-deoxyadenosine 3'-phosphate, dC is 2'-deoxycytidine 3'-phosphate, dG is 2'-deoxyguanosine 3'-phosphate, and (Uhd) is 2'-O-hexadecyl uridine 3'-phosphate.

32. A double-stranded ribonucleic acid (dsRNA)-based agent for inhibiting the expression of SNCA, having a sense strand sequence of 5'-gsasgca(Ahd)guGfAfCfaaauguugsgsa-3' (SEQ ID NO: 21) and an antisense strand sequence of 5'-VPusdCscadAcdAuuugdTcAfcuugcucsusu-3' (SEQ ID NO: 64), wherein VP is vinyl phosphonate, a is 2'-O-methyladenosine-3'-phosphate, a is 2'-O-methyluridine-3'-phosphate, g is 2'-O-methylguanosine-3'-phosphate, c is 2'-O-methylcytidine-3'-phosphate, s is a phosphorothioate internucleotide linkage, Af is 2'-fluoroadenosine 3'-phosphate, Gf is 2'-fluoroguanosine 3'-phosphate, Cf is 2'-fluorocytidine 3'-phosphate, dA is 2'-deoxyadenosine 3'-phosphate, dC is 2'-deoxycytidine 3'-phosphate, dT is 2'-deoxythymidine 3'-phosphate, and (Ahd) is 2'-O-hexadecyl-adenosine 3'-phosphate.

33. A cell comprising a dsRNA agent according to any one of claims 1-32.

34. A pharmaceutical composition for use in inhibiting the expression of α-synuclein, comprising a dsRNA agent according to any one of claims 1-32.

35. The pharmaceutical composition according to claim 34, wherein the dsRNA agent is administered in a buffer-free solution.

36. The pharmaceutical composition according to claim 35, wherein said unbuffered solution is a sodium chloride solution or water.

37. The pharmaceutical composition according to claim 34, wherein said dsRNA agent is administered with a buffer solution.

38. The pharmaceutical composition of claim 37, wherein said buffer solution comprises acetate, citrate, protamine, carbonate, or phosphate, or any combination thereof.

39. The pharmaceutical composition according to claim 37, wherein said buffer solution is phosphate buffered saline (PBS).

40. A pharmaceutical composition comprising a dsRNA agent according to any one of claims 1-32 and a lipid composition.

41. The pharmaceutical composition of claim 40, wherein the lipid composition comprises LNP.

42. A method for inhibiting the expression of the alpha-synuclein gene (SNCA) in a cell and / or preventing the formation of alpha-synuclein aggregates in a cell or the body of a subject, comprising: (a) contacting the cell or subject with the dsRNA agent of any one of claims 1-32 or with the pharmaceutical composition of any one of claims 34-41; and (b) maintaining the cell or subject obtained in step (a) for a time sufficient to cleave the mRNA transcript of the SNCA gene, thereby inhibiting the expression of the SNCA gene in the cell and / or preventing the formation of alpha-synuclein aggregates in the cell or subject.

43. The method according to claim 42, wherein said cell is present in the subject's body.

44. The method according to paragraph 43, where the subject is a human being.

45. The method of claim 43, wherein the subject is selected from the group consisting of a rhesus macaque, a cynomolgus macaque, a mouse, and a rat.

46. ​​The method of claim 44, wherein the human subject suffers from an SNCA-associated disease.

47. The method of claim 46, wherein the SNCA-associated disease is a synucleinopathy, optionally the disease is selected from the group consisting of PD, multiple system atrophy (MSA), dementia with Lewy bodies (DLB), primary autonomic failure (PAF), Pick's syndrome, progressive supranuclear palsy, dementia of the boxers, chromosome 17 parkinsonism, Lytico-Bodig disease, dementia with predominant neurofibrillary tangles, argyrophilic grain disease, ganglioglioma, gangliocytoma, meningoangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, corticobasal degeneration, frontotemporal dementia, frontotemporal lobar degeneration, Alzheimer's disease, Huntington's disease, Down syndrome, psychosis, schizophrenia and Creutzfeldt-Jakob disease.

48. The method of any one of claims 42-47, wherein the expression of SNCA in the cell or subject is inhibited by the dsRNA agent by at least about 50%, at least about 40%, at least about 30%, at least about 20%, or at least about 10% compared to a control cell or control subject.

49. A method of treating a subject diagnosed with a SNCA-associated neurodegenerative disease, comprising administering to the subject a therapeutically effective amount of the dsRNA agent of any one of claims 1-32 or the pharmaceutical composition of any one of claims 34-42, wherein the subject is optionally re-administered a dose of the therapeutically effective amount of the dsRNA agent of any one of claims 1-32 or the pharmaceutical composition of any one of claims 34-42, thereby treating said subject.

50. The method according to paragraph 49, where the subject is a human being.

51. The method of claim 49 or 50, wherein the treatment comprises alleviating at least one sign or symptom of an SNCA-associated neurodegenerative disease.

52. The method according to any one of paragraphs 49-51, wherein the treatment comprises preventing the progression of the disease.

53. The method according to any of paragraphs. 49-52, wherein the SNCA-associated neurodegenerative disease is characterized by one or more symptoms selected from the group consisting of tremor, slow movement (bradykinesia), muscle rigidity, postural and balance disturbances, loss of automatic movements, speech changes, writing changes, visual, auditory, olfactory, or tactile hallucinations, poor regulation of body functions (autonomic nervous system) such as dizziness, falls, and bowel problems, cognitive impairment such as confusion, decreased attention, optical-spatial agnosia, and memory loss, difficulty falling asleep such as rapid eye movement (REM) sleep behavior disorder (in which dreams are physically re-enacted by the patient while asleep), fluctuations in attention including episodes of drowsiness, prolonged periods of fixed gaze, prolonged sleep during the day, or disorganized speech, depression, and apathy,Orthostatic hypotension (a sudden drop in blood pressure that occurs when the patient stands up, causing dizziness and lightheadedness, and the need to sit, squat, or lie down to prevent loss of consciousness), clumsiness or loss of coordination, problems with bladder control, contractures (chronic shortening of the muscles or tendons around the joints that prevents the joints from moving freely) in the arms or limbs, Leaning Tower syndrome (a postural disorder in which the body appears to be tilted to one side), antecollis (in which the neck is tilted forward and the head is drooping), and / or involuntary and uncontrollable sighing or shortness of breath.

54. The method according to any of paragraphs. 49-53, wherein the SNCA-associated neurodegenerative disease is selected from the group consisting of a synucleinopathy such as PD, multiple system atrophy (MSA), dementia with Lewy bodies (DLB), primary autonomic failure (PAF), Pick's syndrome, progressive supranuclear palsy, dementia of the boxers, chromosome 17 parkinsonism, Lytico-Bodig disease, dementia with predominant neurofibrillary tangles, argyrophilic grain disease, ganglioglioma, gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, corticobasal degeneration, frontotemporal dementia, Frontotemporal lobar degeneration, Alzheimer's disease, Huntington's disease, Down syndrome, psychosis, schizophrenia, and Creutzfeldt-Jakob disease.

55. The method of any one of paragraphs 49-54, wherein the dsRNA agent is administered to the subject at a dose of from about 0.01 mg / kg to about 50 mg / kg.

56. The method according to any one of paragraphs 49-55, wherein the dsRNA agent is administered to the subject intrathecally.

57. The method of any one of claims 49-56, further comprising administering to the subject an additional agent or therapy suitable for the treatment or prevention of an SNCA-associated neurodegenerative disease or disorder.

58. The method according to any one of claims 49-57, wherein the SNCA-associated neurodegenerative disease is Parkinson's disease (PD).

59. The method according to any one of claims 49-58, wherein the SNCA-associated neurodegenerative disease is selected from the group consisting of dementia with Lewy bodies (DLB) and multiple system atrophy (MSA).

60. The method according to any one of claims 49-59, wherein the expression of SNCA is inhibited by at least about 30%.

61. The method according to any one of paragraphs 49-60, further comprising administering an additional therapeutic agent to the subject.

62. The method according to any one of paragraphs 49-61, wherein the dsRNA agent is administered to the subject intrathecally.

63. The method of claim 62, wherein the method reduces the expression of SNCA in brain or spinal cord tissue.

64. The method of claim 63, wherein the brain or spinal cord tissue is selected from the group consisting of the cerebral cortex, cerebellum, basal ganglia, hippocampus, amygdala, thalamus, brainstem, cervical spinal cord, lumbar spinal cord, and thoracic spinal cord.

65. A method for inhibiting the expression of SNCA in a subject, comprising: administering to said subject a therapeutically effective amount of the dsRNA agent of any one of claims 1-32 or the pharmaceutical composition of any one of claims 34-41, thereby inhibiting the expression of SNCA in said subject.

66. A method for treating or preventing a SNCA-associated disease in a subject, comprising: administering to said subject a therapeutically effective amount of a dsRNA agent according to any one of claims 1-32 or a pharmaceutical composition according to any one of claims 34-41, thereby treating or preventing a SNCA-associated disease in the subject.

67. The method of claim 66, wherein the SNCA-associated disease is selected from the group consisting of a synucleinopathy such as PD, multiple system atrophy (MSA), dementia with Lewy bodies (DLB), primary autonomic failure (PAF), Pick's syndrome, progressive supranuclear palsy, dementia of the boxers, chromosome 17 parkinsonism, Lytico-Bodig disease, dementia with predominant neurofibrillary tangles, argyrophilic grain disease, ganglioglioma, gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, corticobasal degeneration, frontotemporal dementia, Frontotemporal lobar degeneration, Alzheimer's disease, Huntington's disease, Down syndrome, psychosis, schizophrenia, and Creutzfeldt-Jakob disease.

68. The method of claim 66, wherein the step of administering causes at least a 60% knockdown of SNCA mRNA or α-synuclein protein in one or more tissues of the subject, wherein the one or more tissues of the subject are optionally selected from the group consisting of CSF, prefrontal cortex, midbrain, thoracic spinal cord, hippocampus, medulla oblongata, pons, caudate nucleus of the striatum, and cerebellum.

69. A kit for performing the method according to any one of paragraphs 42-67, including a) dsRNA agent, b) instructions for use, and c) optionally, a means for administering the dsRNA agent to the subject.