IL305668A

IL305668A - Antisense oligonucleotides for inhibiting alpha-synuclein expression

Info

Publication number: IL305668A
Application number: IL305668A
Authority: IL
Original assignee: Servier Lab
Priority date: 2021-03-08
Filing date: 2022-03-07
Publication date: 2023-11-01
Also published as: MX2023010535A; PE20240696A1; WO2022189363A1; CA3212650A1; AU2022234522A1; CL2023002644A1; EP4305168A1; JP2024508956A; TW202305132A

Description

WO 2022/189363 PCT/EP2022/055770 ANTISENSE OLIGONUCLEOTIDES FOR INHIBITING ALPHA-SYNUCLEIN EXPRESSION SEQUENCE LISTING [0001]The instant application contains a Sequence Listing that has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on March 6, 2021, is named 027628_W0002_SLf1nal.txt and is 718,5bytes in size.

BACKGROUND OF THE INVENTION [0002]Alpha-synuclein is a protein encoded by the SNCA gene that is predominantly expressed in the central nervous system, including the neocortex, hippocampus, substantia nigra, thalamus, and cerebellum. In neurons, the expression of alpha-synuclein is localized at presynaptic terminals, and the protein is thought to be a chaperone involved in the assembly and function of the SNARE complex. At least three different isoforms of alpha-synuclein are known, which result from alternative splicing of the SNCA gene transcript. Alpha-synuclein may be involved in modulating many different neuronal functions and properties, including synaptic transmission, synaptic vesicle density, and neuronal plasticity. [0003]In some cases, alpha-synuclein aggregates and forms insoluble fibrils. Alpha- synuclein aggregates are thought to be involved in the pathology of many different neurological diseases, including Parkinson’s disease, Lewy body dementia, Alzheimer’s disease, and multiple system atrophy. The pathogenic role of alpha-synuclein in the progression of disease has been genetically validated. For example, missense mutations in the SNCA gene lead to rare familial Parkinson’s disease. Duplication or triplication of the wildtype gene can also cause rare cases of Parkinson’s disease, and the overexpression of wildtype alpha-synuclein protein alone has been demonstrated to be sufficient to cause disease. [0004]Disorders caused by misfolding or aggregation of alpha-synuclein are collectively termed synucleinopathies. Multiple system atrophy (MSA), a synucleinopathy with a rapid clinical progression, arises from the misfolding and accumulation of alpha-synuclein, resulting in the formation of glial cytoplasmic inclusions (GUIs) in oligodendrocytes. GUIs WO 2022/189363 PCT/EP2022/055770 are widely distributed in the nervous system of MSA patients, but some regions, including the basal ganglia, cerebellum, pons, and spinal cord, are more affected than others. At the microscopic level, the neuropathological features of MSA include moderate gliosis, myelin deficiency, and neuronal loss and axonal degeneration within the striatonigral and olivopontocerebellar systems. [0005]The alpha-synuclein protein can be found in tissues in several different forms, including as a monomer, oligomer, or fibrillary complex, and may be phosphorylated. It is currently unknown which of these protein species is causative in synucleinopathies. It is therefore challenging to know which form of the protein to target in order to develop drugs that treat synucleinopathies at the protein level. [0006]Currently there is a lack of acceptable options for treating synucleinopathies.Thus, there remains a need for compounds, methods and pharmaceutical compositions for the treatment of these disorders.

SUMMARY OF THE INVENTION [0007]The present disclosure provides antisense oligonucleotides (ASOs) that reduce the abundance or activity of RNA transcribed from the SNCA gene. By reducing levels of SNCA RNA, the compounds of the present disclosure decrease the abundance of alpha-synuclein protein in the cell. The ASOs described herein therefore reduce alpha-synuclein proteins, their accumulation and aggregates which might alleviate the symptoms and/or delay disease progression. [0008]In some aspects, the present disclosure provides an oligonucleotide comprising a nucleotide sequence of 15 to 30 (e.g., 16 to 20) contiguous nucleotides, wherein the nucleotide sequence is complementary to a region of the same length found in nucleotides a) 16350-16450, b) 18926-19030, c) 22250-22471, d) 22933-23079, e) 23408-23700, f) 29753-29819, g) 38128-38158, h) 39852-39906, i) 53762-53799, or j) 59754-59865 WO 2022/189363 PCT/EP2022/055770 of SEQ ID NO: 1. In certain embodiments, the nucleotide sequence comprises no more than mismatches to said region. For example, the nucleotide sequence may comprise 0, 1, or mismatches to said region. In particular embodiments, the nucleotide sequence is single- stranded. The nucleotide sequence may be selected from, e.g., SEQ ID NOs: 18-40. [0009]In some embodiments, an oligonucleotide described herein may comprise one or more ribonucleotides, one or more deoxyribonucleotides, or a combination of both. [0010]In some embodiments, an oligonucleotide described herein may comprise one or more modified nucleotides. Such modified nucleotides may comprise, e.g., a 2’-O- methoxy ethyl (2’-MOE) nucleotide, a locked nucleic acid (LNA) nucleotide, a bridged nucleic acid (BNA) nucleotide, or any combination thereof. [0011]In some embodiments, all cytosines in an oligonucleotide described herein are 5- methyl cytosines. [0012]In some embodiments, an oligonucleotide described herein may comprise phosphodiester internucleoside linkages and/or phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide may comprise at least 1, 2, 3, 4, or phosphodiester internucleoside linkages. In certain embodiments, at least 1, 2, 3, 4, or 5, or all internucleoside linkages in the oligonucleotide are phosphorothioate internucleoside linkages. [0013]In some embodiments, an oligonucleotide described herein comprises:i) a 5-10-5 MOE gapmer;ii) a 4-10-4 MOE gapmer;iii) a 3-10-3 LNA gapmer;iv) a 3 -11 -3 LNA gapmer;v) a 3-2-10-2-3 LNA/MOE gapmer;vi) a 2-3-10-3-2 BNA/MOE gapmer;vii) a 3-2-10-2-3 BNA/MOE gapmer; orviii) a 2-3-10-3-2 LNA/MOE gapmer. [0014]In certain embodiments, the oligonucleotide comprises:i) a 3-2-10-2-3 LNA/MOE gapmer;ii) a 2-3-10-3-2 BNA/MOE gapmer;iii) a 3-2-10-2-3 BNA/MOE gapmer; oriv) a 2-3-10-3-2 LNA/MOE gapmer;wherein the internucleoside linkages between nucleosidesv) 2 and 3, 4 and 5, 16 and 17, and 18 and 19; WO 2022/189363 PCT/EP2022/055770 vi) 2 and 3, 4 and 5, and 16 and 17;vii) 2 and 3, 3 and 4, 4 and 5, 16 and 17 and 17 and 18; orviii) 3 and 4, 4 and 5, 16 and 17, and 17 and 18are phosphodiester internucleoside linkages; and the remainder of the internucleoside linkages are phosphorothioate internucleoside linkages. [0015]In certain embodiments, an oligonucleotide described herein comprises the following formula:i) Ais Tlo mCls Aeo mCes mCds Tds Tds mCds Ads Ads Ads mCds mCds mCds mCeo Tes Tlo TIs mCl (SEQ ID NO: 34),ii) Abs Tbs mCeo Aeo mCes mCds Tds Tds mCds Ads Ads Ads mCds mCds mCds mCeo Teo Tes Tbs mCb (SEQ ID NO: 20),iii) Ais Alo TIs Aeo Ges mCds Ads Tds mCds mCds Tds Tds mCds mCds Ads mCeo Aes mClo mCls Al (SEQ ID NO: 33),iv) Abs Abs Teo Aeo Ges mCds Ads Tds mCds mCds Tds Tds mCds mCds Ads mCeo Aeo mCes mCbs Ab (SEQ ID NO: 19),v) Gbs mCbs Aeo Geo Tes Tds mCds Tds Ads Tds mCds mCds mCds Ads mCds Teo mCeo Aes Tbs mCb (SEQ ID NO: 18),vi) mCbs mCbs Geo Geo Tes Gds mCds mCds Ads Tds Tds Ads mCds Tds mCds mCeo mCeo Tes Tbs Tb (SEQ ID NO: 21),vii) Tbs Tbs Geo mCeo Aes Gds Ads Tds Ads Ads Ads mCds mCds Ads Tds mCeo mCeo mCes Abs mCb (SEQ ID NO: 22),viii) Abs Gbs Teo Geo mCes mCds Ads Gds Ads mCds mCds mCds Tds Tds Tds mCeo Aeo Tes Tbs Ab (SEQ ID NO: 23),ix) mCbs mCbs Aeo Aeo Ges Tds Gds mCds mCds Ads Gds Ads mCds mCds mCds Teo Teo Tes mCbs Ab (SEQ ID NO: 24),x) Gbs mCbs Aeo Geo Aes Tds Ads Ads Ads mCds mCds Ads Tds mCds mCds mCeo Aeo mCes Tbs Tb (SEQ ID NO: 25),xi) mCbs Gbs Geo Teo Ges mCds mCds Ads Tds Tds Ads mCds Tds mCds mCds mCeo Teo Tes Tbs mCb (SEQ ID NO: 26),xii) Gbs Abs Aeo mCeo Tes Gds Ads Tds Gds mCds mCds Tds mCds Tds Ads mCeo mCeo Tes mCbs mCb (SEQ ID NO: 27),xiii) Abs mCbs Teo Geo Aes Ads mCds Tds Gds Ads Tds Gds mCds mCds Tds mCeo Teo Aes mCbs mCb (SEQ ID NO: 28), WO 2022/189363 PCT/EP2022/055770 xiv) Tbs Abs mCeo Aeo Tes Gds Gds mCds mCds Ads Gds Ads Ads Ads mCds mCeo Aeo mCes Tbs Tb (SEQ ID NO: 29),xv) Abs Abs Geo mCeo mCes Ads Ads Gds mCds mCds mCds Ads Ads Ads mCds Aeo mCeo Tes Abs Ab (SEQ ID NO: 30),xvi) Tbs mCbs mCeo Aeo Aes Ads Gds Gds Ads Gds mCds Ads mCds mCds Ads Aeo mCeo mCes Abs Ab (SEQ ID NO: 31),xvii) GIs mClo Ais Geo Tes Tds mCds Tds Ads Tds mCds mCds mCds Ads mCds Teo mCes Alo TIs mCl (SEQ ID NO: 32),xviii) mCls mClo GIs Geo Tes Gds mCds mCds Ads Tds Tds Ads mCds Tds mCds mCeo mCes Tlo TIs T1 (SEQ ID NO: 35),xix) TIs Tlo GIs mCeo Aes Gds Ads Tds Ads Ads Ads mCds mCds Ads Tds mCeo mCes mClo Ais mCl (SEQ ID NO: 36),xx) Ais Glo TIs Geo mCes mCds Ads Gds Ads mCds mCds mCds Tds Tds Tds mCeo Aes Tlo TIs Al (SEQ ID NO: 37),xxi) mCls mClo Ais Aeo Ges Tds Gds mCds mCds Ads Gds Ads mCds mCds mCds Teo Tes Tlo mCls Al (SEQ ID NO: 38),xxii) GIs mClo Ais Geo Aes Tds Ads Ads Ads mCds mCds Ads Tds mCds mCds mCeo Aes mClo TIs T1 (SEQ ID NO: 39),xxiii) mCls Glo GIs Teo Ges mCds mCds Ads Tds Tds Ads mCds Tds mCds mCds mCeo Tes Tlo TIs mCl (SEQ ID NO: 40),xxiv) GIs Alo Ais mCeo Tes Gds Ads Tds Gds mCds mCds Tds mCds Tds Ads mCeo mCes Tlo mCls mCl (SEQ ID NO: 41),xxv) Ais mClo TIs Geo Aes Ads mCds Tds Gds Ads Tds Gds mCds mCds Tds mCeo Tes Alo mCls mCl (SEQ ID NO: 42),xxvi) TIs Alo mCls Aeo Tes Gds Gds mCds mCds Ads Gds Ads Ads Ads mCds mCeo Aes mClo TIs TI (SEQ ID NO: 43),xxvii) Ais Alo GIs mCeo mCes Ads Ads Gds mCds mCds mCds Ads Ads Ads mCds Aeo mCes Tlo Ais Al (SEQ ID NO: 44),xxviii) TIs mClo mCls Aeo Aes Ads Gds Gds Ads Gds mCds Ads mCds mCds Ads Aeo mCes mClo Ais Al (SEQ ID NO: 45), whereinA is adenine,mC is a 5-methyl cytosine,G is guanine, WO 2022/189363 PCT/EP2022/055770 T is thymine,e is a 2’-MOE modified ribose,d is a 2’-deoxyribose,b is a BNA,1 is an LNA,o is a phosphodiester internucleoside linkage, and s is a phosphorothioate internucleoside linkage. [0016]In some embodiments, the present disclosure provides an oligonucleotide WO 2022/189363 PCT/EP2022/055770 id="p-17" id="p-17" id="p-17" id="p-17" id="p-17" id="p-17" id="p-17" id="p-17"

[0017]In some embodiments, the present disclosure provides an oligonucleotide comprising the structural formula: WO 2022/189363 PCT/EP2022/055770 id="p-18" id="p-18" id="p-18" id="p-18" id="p-18" id="p-18" id="p-18" id="p-18"

[0018]In some embodiments, the present disclosure provides an oligonucleotidecomprising the structural formula: WO 2022/189363 PCT/EP2022/055770 id="p-19" id="p-19" id="p-19" id="p-19" id="p-19" id="p-19" id="p-19" id="p-19"

[0019]In some embodiments, the present disclosure provides an oligonucleotide comprising the structural formula: id="p-20" id="p-20" id="p-20" id="p-20" id="p-20" id="p-20" id="p-20" id="p-20"

[0020]The present disclosure also provides an oligonucleotide conjugate comprising an oligonucleotide described herein. [0021]In some aspects, the present disclosure provides a pharmaceutical composition comprising an oligonucleotide described herein or an oligonucleotide conjugate as described herein, and a pharmaceutically acceptable excipient. [0022]Also provided is a method of reducing alpha-synuclein expression in amammalian cell, comprising contacting the cell with an oligonucleotide, oligonucleotide conjugate, or pharmaceutical composition described herein, thereby reducing alpha-synuclein expression in the cell. In some embodiments, the cell is a central nervous system cell, such as a cell in the human brain. In some embodiments, the present disclosure provides a method for treating a synucleinopathy in a subject in need thereof, comprising administering a WO 2022/189363 PCT/EP2022/055770 therapeutically effective amount of an oligonucleotide, oligonucleotide conjugate, or pharmaceutical composition described herein to the subject. In certain embodiments, the synucleinopathy is Parkinson’s disease, Lewy body dementia, Alzheimer’s disease, or multiple system atrophy. The oligonucleotide may be, e.g., injected intrathecally or intracranially to the subject. In certain embodiments, the oligonucleotide reduces SNCA mRNA levels by at least 25, 50, 75, or 80% in murine primary cortical neurons engineered to express human alpha-synuclein. [0023]It is understood that any of the oligonucleotides, oligonucleotide conjugates, and pharmaceutical compositions described herein may be used in any method of treatment as described herein, may be for use in any treatment as described herein, and/or may be for use in the manufacture of a medicament for any treatment as described herein. [0024]Other features, objectives, and advantages of the invention are apparent in the detailed description that follows. It should be understood, however, that the detailed description, while indicating embodiments and aspects of the invention, is given by way of illustration only, not limitation. Various changes and modification within the scope of the invention will become apparent to those skilled in the art from the detailed description.

BRIEF DESCRIPTION OF THE FIGURES [0025] FIG. 1is a diagram illustrating the knock-in of the human SNCA gene at the endogenous mouse SNCA locus in an hSNCA mouse model (hSNCA*!*y [0026] FIG. 2Ais a bar graph showing the quantification of human alpha-synuclein protein (hSNCA protein) in cortical tissue from hSNCA*1* (n=5), hSNCA*1־ (n=5), and hSNCA־ A (n=2) three-month-old mice. The level of alpha-synuclein protein was assessed by mass spectrometry and normalized against the level of GADPH protein. [0027] FIG. 2Bis a bar graph showing the quantification of murine alpha-synuclein protein (mSNCA protein) in the cortex of hSNCA*1* (n=5), hSNCA*1־ (n=5), and hSNCA ־ 1 ־ (n=2) three-month-old mice. The level of alpha-synuclein protein was assessed by mass spectrometry and normalized against the level of GADPH protein. [0028] FIG. 2Cis a bar graph showing the level of human alpha-synuclein protein (hSNCA protein) in different brain areas (cortex, cerebellum, hippocampus, striatum, spinal cord) and peripheral organs (liver, spleen, kidney) in three-month-old hSNCA*1* mice (n=5). The level of alpha synuclein protein was assessed by mass spectrometry and normalized against the level of GADPH protein.

WO 2022/189363 PCT/EP2022/055770 id="p-29" id="p-29" id="p-29" id="p-29" id="p-29" id="p-29" id="p-29" id="p-29"

[0029] FIG. 3is a table showing the tolerability scoring system for mice utilized in the in vivo assays described herein. [0030] FIG. 4is a bar graph showing the efficacy and tolerability of the given ASO in mice. The left Y axis and solid bars depict the expression level of SNCA mRNA expressed in mouse neurons in vivo two weeks after treatment with the given ASO relative to PBS treated samples. The right Y axis and black circles depict the functional observational battery (FOB) absolute score observed in mice one hour after treatment with the given ASO. [0031] FIG. 5is a bar graph showing the efficacy and tolerability of the given 3LNA- 2MOE-10DNA-2MOE-3LNA gapmer ASO. Axes are as described in FIG. 4. [0032] FIG. 6is a bar graph showing the efficacy and tolerability of the given 2BNA- 3MOE-10DNA-3MOE-2BNA gapmer ASO. Axes are as described in FIG. 4. [0033] FIG.7 is a bar graph showing the efficacy of SNCA_ASO_1613, SNCA_ASO_1617 and SNCA_ASO_1625 at doses of 1, 5, 10, 30 and 100 nmol. The left Y axis and solid bars depict the expression level of SNCA mRNA expressed in mouse neurons in vivo four weeks after treatment with the given ASO relative to PBS treated samples. [0034] FIG. 8is a bar graph showing the efficacy of SNCA_ASO_1613, SNCA_ASO_1617 and SNCA_ASO_1625 at doses of 1, 5, 10, 30 and 100 nmol. The left Y axis and solid bars depict the expression level of alpha synuclein protein expressed in mouse neurons in vivo four weeks after treatment with the given ASO relative to PBS treated samples. [0035] FIG. 9is a dot graph showing the concentration of SNCA ASO1613, SNCA AS01617 and SNCA ASO 1625 quantified by HPLC fluorescence in cortical tissue homogenate four weeks after a single injection at 1, 5, 10, 30 and lOOnmol on ASO. [0036] FIG. 10is a table showing the tolerability scoring system for rats utilized in the in vivo assays described herein. [0037] FIG. 11is a dot graph comparing SNCA_ASO_01617 and SNCA_ASO_01613 at doses of 10 nmol and 50 nmol in the cortex based on SNCA mRNA expression quantified by qRT-PCR. [0038] FIG. 12is a dot graph a dots graph comparing SNCA ASO01617 andSNCA ASO 01613 at doses of 10 nmol and 50 nmol in the cerebellum based on SNCA mRNA expression quantified by qRT-PCR. [0039] FIG. 13is a dot graph that compares the SNCA ASO01617 and SNCA_ASO_01613 at doses of 10 nmol and 50 nmol in the striatum based on SNCA mRNA expression quantified by qRT-PCR as described above.

WO 2022/189363 PCT/EP2022/055770 id="p-40" id="p-40" id="p-40" id="p-40" id="p-40" id="p-40" id="p-40" id="p-40"

[0040] FIG. 14is a diagram illustrating the experimental protocol for the measurement of alpha-synuclein pathology in neuronal culture treated with ASO. [0041] FIG. 15is a bar graph that shows the level of alpha-synuclein pathology (phosphorylated form) in primary neuronal culture treated with SNCA_ASO_01613, SNCAASO01617 and non-targeting control MalatlASO and measured using a TR-FRET based immunoassay. [0042] FIG.16is a bar graph that shows the level of alpha-synuclein pathology (phosphorylated form) in primary neuronal culture treated with SNCA ASO 01613 before, during and after PFF treatment and measured by using a TR-FRET based immunoassay (mean±SEM). PFFs: human alpha-synuclein preformed fibrils.

DETAILED DESCRIPTION OF THE INVENTION [0043]The present disclosure is based on the discovery that antisense oligonucleotides (ASOs) targeting RNAs transcribed from the SNCA gene can effectively reduce the abundance of target SNCA gene transcripts and/or translation of the alpha-synuclein polypeptide from the transcripts. The ASOs of the present disclosure comprise sequences that are complementary to SNCA transcripts and bind to defined nucleotide sequences within the transcripts. [0044]By decreasing the level or translational activity of SNCA target transcripts in a cell, the ASO mediates a decrease in the expression and accumulation of the alpha-synuclein protein in the cell, alleviating the severity or progression of neurodegenerative diseases. The ASOs of the present disclosure are expected to be particularly useful in the treatment of synucleinopathies, which are caused by the accumulation or aggregation of the alpha- synuclein protein. This protein can be expressed in cells as, e.g., a monomer or an oligomer, and may be phosphorylated or unphosphorylated. Because it is unclear which of these alpha- synuclein species is causative in disease, it has thus far been challenging to develop effective therapeutics that target alpha-synuclein expression or activity at the protein level. The ASOs of the present disclosure are highly advantageous in that they target alpha-synuclein expression at the SNCA transcript level and thus have the ability to decrease expression of all of the above forms of the alpha-synuclein protein. 1. The SNCA gene and Alpha-Synuclein Protein [0045]The ASOs of the present disclosure bind to transcripts of the SNCA gene, which encodes the alpha-synuclein protein also named SNCA protein. The SNCA gene is also known WO 2022/189363 PCT/EP2022/055770 as alpha-synuclein, NACP, nonA-beta component of AD amyloid, PARKI, PARKP or PDI gene. In some embodiments, an ASO described herein targets a transcript of a mammalian SNCA gene (e.g., a murine or human SNCA gene). [0046]The sequence for the human SNCA gene is publicly available under GenBank Accession Number NC_000004.12. The gene is 137,980 bps in length and located at chromosome 4:89700345..89838324 (SEQ ID NO: 2). A portion of the human genomic SNCA sequence is shown in SEQ ID NO: 1, and a partial sequence for the pre-mRNA transcript can be found at GenBank Accession Number NG_011851.1 (residues 6001-8400). A mature mRNA transcript is shown in SEQ ID NO: 3. In some embodiments, an ASO of the present disclosure binds to an SNCA sequence, or a transcript thereof, selected from Chromosome 4: 89,700,345-89,838,315 (reverse strand) and those under GenBank Accession Numbers NM_000345.3, NT_016354.20 TRUNC 30800000-30919000, JN709863.1, BC013293.2, NM_001146055.1, HQ830269.1, and NC_000004.12 (89724099..89838324, complement). In some embodiments, an ASO of the present disclosure binds to an SNCA transcript that encodes an alpha-synuclein protein, e.g., as found under UniProt Accession Number P37840, A8K2A4, Q13701, Q4JHI3, or Q6IAU6. In certain embodiments, an ASO of the present disclosure comprises a sequence that may be at least 60, 70, 80, 85, 90, or 95%, or 100% complementary to a same-length sequence in the target SNCA transcript. [0047]In some embodiments, an ASO of the present disclosure can bind to a transcript of a wildtype SNCA gene (e.g., a wildtype human, non-human primate, or murine gene). In some embodiments, an ASO of the present disclosure binds to a variant, such as a known variant, of the wildtype SNCA gene. Known variants include, for example, a version of the human SNCA gene in which a G209A substitution results in an A53T mutation in the alpha- synuclein protein encoded from that gene. Additional known variants have nucleotide mutations giving rise to mutant alpha-synuclein proteins comprising A30P, E46K, H50Q, and G51D amino acid substitutions. These substitutions may be found alone or in combination with other mutations. The present ASOs can be designed to reduce or inhibit expression of wildtype or variant SNCA transcripts. In certain embodiments, an ASO described herein may reduce or inhibit expression of an SNCA transcript encoding an alpha-synuclein protein with one or more mutations selected from A30P, E46K, H50Q, G51D, and A53T. [0048]The present ASOs comprise sequences that are complementary to a same-length sequence in a target transcript encoded by the SNCA gene (wherein the genomic SNCA sequence may comprise, e.g., SEQ ID NO: 1). In certain embodiments, an ASO described herein comprises a sequence that is complementary to a sequence in a hotspot region within WO 2022/189363 PCT/EP2022/055770 the target SNCA nucleic acid. The term "hotspot region" refers to a region of the target nucleotide sequence wherein binding of a sequence within the region by a complementary ASO tends to result in a reduction in the abundance or translational activity of the target RNA transcript. A hotspot region may be entirely within an intron, entirely within an exon, or may span an intron/exon junction; or be located in whole or in part in the 5’ or 3’ untranslated region (UTR) of an RNA transcript. [0049]In some embodiments, an ASO described herein may comprise a sequence that binds to a target sequence within or overlapping with any of several different hotspot regions of the SNCA gene transcript. Table Alists exemplary hotspots in the human SNCA gene and identifies ASOs of the present disclosure that are designed to be complementary to them. The table also shows the minimum reduction in the SNCA gene transcript observed in vitro when neurons from a humanized SNCA knock-in mouse are treated with the selected ASOs targeting this hotspot (see, e.g., the section titled "Materials and Methods of in vitro Assays" below). Throughout this disclosure, compounds are referred to interchangeably as SNCA_ASO_[compound number] and as [compound number]. For example, compound number SNCA ASO 01608 and compound number 01608 represent the same antisense oligonucleotide compound. In certain embodiments, binding of a sequence in a hotspot region by an ASO described herein reduces SNCA RNA levels by at least 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% in a cell (e.g., in an in vitro assay such as the one described below in the section titled "Materials and Methods of in vitro Assays"). In particular embodiments, an ASO of the present disclosure may be an ASO listed in Table A,or an ASO with a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.

Table A. Human SNCA Gene Hotspots Targeted by Antisense Oligonucleotides Hotspot Nucleotide positions in SEQ ID NO:1 Selected ASOs targeting the hotspot Minimum reduction in SNCA gene transcript 16350-16450 01529, 00838, 00537, 66%18926-1903000554,00555, 00556, 00557, 0055880% 3 22245-22471 01040,01179,01054,01009, 01018,01078, 01052, 01155, 01182, 01217, 01115, 01135, 01209,01315,01137,01125, 00568,00569, 00570, 00985 % 4 22932-2307900576,01001, 00993, 00577, 01002, 01021, 01096, 01081, 01152,01141, 01253, 01184, 01319,01351,01279,0126525% WO 2022/189363 PCT/EP2022/055770 Hotspot Nucleotide positions in SEQ ID NO:1 Selected ASOs targeting the hotspot Minimum reduction in SNCA gene transcript 23408-2370000578, 00579, 00580, 00581, 00582,00583, 00584, 00585, 00587,0058855% 6 29753-2981900615,00616,00617,01011, 01036,00618, 01014, 00619, 00994,01013, 01003, 01151, 0111754% 7 38127-3815801317,01195, 01357, 01355, 01346,01269,01244,01136, 01187,01261,01260,0127042% 8 39852-39906 00646,00647, 00648, 00649, 01027, 01066, 01247, 01268, 01289,01280, 01105, 01127, 00650,00651, 00652, 00653, 00998,01026, 01153, 01104, 01143,01041, 01037, 01060, 01000, 01016 41% 9 53762-5379901138, 01294, 01211, 01231, 01164,01306,01343,0133850%59754-59865 01248,01252,01275,01123 58% II. Antisense Oligonucleotides [0050]The term "antisense oligonucleotide" or "ASO" refers to an oligonucleotide capable of hybridizing to a sequence in a target transcript. It is understood by a personskilled in the art that the ASOs described herein do not occur in nature (i.e., they are "isolated" ASOs). [0051]The term "transcript" refers to any RNA transcribed from a gene (e.g., an SNCA gene). The gene may be wildtype or may be a mutated or variant (e.g., polymorphic) form. An RNA transcript may be a primary RNA transcript or precursor messenger RNA (pre-mRNA), or a messenger RNA (mRNA), and may include exons, introns, 5’ UTRs and 3’ UTRs. Unless otherwise indicated, the sequences of transcripts and ASOs provided herein denote the nucleotide sequence from 5’ end (left) to 3’ end (right). [0052]The term "oligonucleotide," as used in the present disclosure, refers to a compound comprising a strand of about 5 to 100 nucleosides, e.g., 5 to 50 nucleosides, e.g., 8to 30 nucleosides, connected via internucleoside linkages. Each nucleoside and internucleoside linkage of an oligonucleotide of the present disclosure may be modified or unmodified from naturally occurring nucleotides and linkages. A modified oligonucleotide may comprise one or more modified sugar moieties, one or more modified nucleobases, and/or one or more modified internucleoside linkages.

WO 2022/189363 PCT/EP2022/055770 id="p-53" id="p-53" id="p-53" id="p-53" id="p-53" id="p-53" id="p-53" id="p-53"

[0053] An ASOdescribed herein may comprise a sequence that is substantially or fully complementary to a same-length sequence in the target transcript. Full complementarity occurs when a first strand of contiguous nucleotides (modified or unmodified) and a second strand of contiguous nucleotides (modified or unmodified) are completely complementary to each other over the entire length of the shorter strand (or both strands, if they are of the same length). The two strands are considered substantially complementary to each other when they base-pair with each other over 80% or more (e.g., 90% or more) over the length of the shorter strand (or both strands, if they are of the same length), with no more than 20% (e.g., no more than 10%) of mismatching base-pairs (e.g., for a duplex of 20 nucleotides, no more than 4 or no more than 2 mismatched base-pairs). In some embodiments, a sequence in an ASO of the present disclosure is 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to a target RNA transcript. In some embodiments, the present ASO comprises no more than 1, 2, or 3 mismatches to its target sequence. [0054]The term "identical" or "identity" in the context of comparing two nucleotide sequences refers to identical nucleobases. The term "percent identity" in this context refers to the percentage of nucleobases that are the same when the two comparing sequences are aligned (introducing gaps, if necessary) for maximum correspondence, over the length of the shorter comparing sequence (or both sequences, if the comparing sequences are of the same length). [0055]In certain embodiments, reduced, inhibited, or abrogated expression or activity of the target transcript is observed compared to a control sample not treated with the ASO. In some embodiments, an ASO of the present disclosure reduces the abundance and/or translational activity of the target SNCA transcript in a treated sample, e.g., by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to a control sample not exposed to the ASO. In some cases, the ASO reduces the level of the target transcript in vivo by said percentage, and administration of the ASO optionally results in a tolerability score (Functional Observational Battery or FOB score) of less than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1, e.g., 0. The terms "reduce" and "inhibit" do not necessarily mean a total elimination of the entire amount and/or activity of the transcript. In some embodiments, ASOs are considered to be active when they reduce the amount or activity of the target RNA by 25% or more in an in vitro assay. The present ASO may cause a detectable or measurable change in the level or activity of the alpha-synuclein protein encoded by the target RNA. [0056]Without wishing to be bound by theory, it is believed that ASOs may inhibit expression of alpha-synuclein by recruiting an RNase Hl enzyme to the duplex formed WO 2022/189363 PCT/EP2022/055770 between an ASO and the target SNCA transcript. Enzymes of the RNase Hl family are endonucleases that typically target RNA:DNA duplexes and catalyze the hydrolytic cleavage of the RNA in the duplex. [0057]In some embodiments, the ASOhas minimal off-target effects, and does not hybridize to any non-SNCA transcript in a way that results in significant reduction in the abundance or activity of the non-kMN transcript. A. Lengths of Antisense Oligonucleotides [0058]In some embodiments, the present ASOs are between 8 and 30 nucleotides in length (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length). In some embodiments, an ASO described herein can comprise a sequence, complementary to a same-length SNCA transcript sequence, that is any of a range of nucleotide lengths having an upper limit of 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or and an independently selected lower limit of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. [0059]In certain embodiments, the complementary sequence in the ASOis between and 20 nucleotides in length. In particular embodiments, the complementary sequence in the ASOis 16, 17, 18, or 20 nucleobases in length. B. Modifications of Antisense Oligonucleotides [0060]In some embodiments, the ASOs of the present disclosure may comprise one or more modifications, e.g., to increase binding affinity to the target transcript, increase ASO stability (e.g., increase resistance to degradation, e.g., by nucleases), and/or increase ease of ASO transport into the cell. Modifications may include any modification known in the art, including, for example, end modifications, nucleobase modifications, sugar modifications or replacements, and backbone modifications. End modifications may include, for example, 5’ and/or 3’ end modifications (e.g., phosphorylation, conjugation, DNA nucleotides, and inverted linkages). Base modifications may include, e.g., replacement with stabilizing bases, removal of bases, or conjugated bases. Sugar modifications or replacements may include, e.g., modifications at the 2’ and/or 4’ position of the ribose moiety, or replacement of the ribose moiety. Backbone modifications or internucleoside linkage modifications may include, for example, modification or replacement of phosphodiester linkages, e.g., with one or more phosphorothioates, phosphorodithioates, phosphotriesters, methyl and other alkyl phosphonates, phosphinates, and phosphoramidates. [0061]In some embodiments, the present ASOs may have one or more modified nucleosides. The term "nucleoside" refers to a compound comprising a nucleobase and a WO 2022/189363 PCT/EP2022/055770 sugar moiety. Naturally occurring nucleosides include DNA and RNA nucleosides. In a non-naturally occurring nucleoside (also referred to as a "modified nucleoside" or a "nucleoside analog"), the base and/or the sugar have been modified. The modification of the nucleoside may be "silent," in which case the modified nucleoside has the same or equivalent function in the context of the oligonucleotide compared to a naturally occurring nucleoside. In other cases, a modified nucleoside may increase the efficacy of the ASO in decreasing the abundance or activity of a target transcript. The term efficacy encompasses the target engagement on SNCA mRNA. [0062]The term "nucleotide," as used herein, refers to a nucleoside covalently bonded to one or more modified or unmodified internucleoside linkages. Exemplary nucleotides include monophosphates, diphosphates, triphosphates, and thiophosphates. As used herein, the term "nucleotide" encompasses unmodified nucleotides (i.e., naturally occurring nucleotides) and modified nucleotides (i.e., nucleotide analogs). The term "nucleoside" encompasses unmodified nucleosides (i.e., naturally occurring nucleosides) and modified nucleosides (i.e., nucleoside analogs); and the term "nucleobases" encompasses unmodified nucleobases (i.e., naturally occurring nucleobases) and modified nucleobases (i.e., nucleobase analogs). [0063]In some embodiments, a modified nucleoside comprises a modified nucleobase. In certain embodiments, the modified nucleobase is a 5-methyl cytosine (5mC) nucleobase, as shown in the structure (I) below, wherein R represents the sugar moiety. id="p-64" id="p-64" id="p-64" id="p-64" id="p-64" id="p-64" id="p-64" id="p-64"

[0064]In some embodiments, a sugar moiety can be a modified or an unmodified sugar moiety. As used herein, an unmodified sugar moiety refers to a 2’-0H(H) ribosyl moiety as found in naturally occurring RNA, also referred to as an unmodified RNA sugar moiety. In some embodiments, a modified sugar moiety may be a 2’-H(H) deoxyribose sugar moiety. This moiety is found naturally in deoxyribonucleic acids, and may be referred to as an unmodified DNA sugar moiety or simply a DNA sugar moiety. The structure of a 2’- deoxynucleoside sugar moiety is shown in the structure (II) below, wherein R represents a WO 2022/189363 PCT/EP2022/055770 nucleobase, and each of the 5’-hydroxyl and 3’-hydroxyl groups of the sugar is optionally involved in internucleoside linkages. (11) id="p-65" id="p-65" id="p-65" id="p-65" id="p-65" id="p-65" id="p-65" id="p-65"

[0065]In some embodiments, a modified sugar moiety may comprise an O-methoxyethyl (MOE) moiety. In some embodiments, the O-methoxyethyl moiety is at the 2’ position of the sugar, as shown in the structure below (III). R in the structure below represents a nucleobase. Each of the 5’-hydroxyl and 3’-hydroxyl groups of the sugar is optionally involved in internucleoside linkages. A 2’-MOE modified sugar or 2’-MOE modified nucleoside, or simply an MOE sugar or nucleoside, is a ribose or nucleoside in which the 2’ hydroxyl group that naturally occurs in the ribose is replaced with a 2’OCH2CH2OCH3 group. id="p-66" id="p-66" id="p-66" id="p-66" id="p-66" id="p-66" id="p-66" id="p-66"

[0066]In some embodiments, a modified sugar moiety may comprise a bridged nucleic acid (BNA) moiety. A bridged nucleic acid comprises a bicyclic sugar moiety. The sugar moiety comprises a 4’-CH2-NH-O-2’ linkage. The nitrogen of the bridged nucleic acid is optionally substituted (e.g., methylated, alkylated, or modified with a phenyl group). The structure of a BNA moiety is shown below (IV), wherein R is a nucleobase, R’ is, for example, an H, Me, or Phenyl group, and each of the 5’-hydroxyl and 3’-hydroxyl groups of the sugar is optionally involved in internucleoside linkages. In the present ASOs, R’ is an Me group, unless otherwise specified. A BNA modified nucleoside, or simply a BNA nucleoside, is a nucleoside comprising a BNA sugar moiety.

WO 2022/189363 PCT/EP2022/055770 (IV) [0067]In some embodiments, a modified sugar moiety may comprise a locked nucleic acid (LNA) moiety. A locked nucleic acid comprises a bicyclic sugar moiety. The sugar moiety comprises a 4’-CH2-O-2’ linkage. An LNA moiety, as described herein, may be in the alpha-L configuration or the beta-D configuration. In particular embodiments, LNA moieties in the ASOs described herein are in the beta-D configuration. The structure of an LNA moiety is shown below (V), wherein R is a nucleobase and each of the 5’-hydroxyl and 3’-hydroxyl groups of the sugar is optionally involved in internucleoside linkages. An LNA modified nucleoside, or simply an LNA nucleoside, is a nucleoside comprising an LNA sugar moiety.

(V) [0068]In certain embodiments, an ASO described herein may include one or more modified nucleotides known in the art, including, e.g., 2’-O-methyl modified nucleotides, 2’- fluoro modified nucleotides, 2’-deoxy modified nucleotides, 2’-O-m ethoxy ethyl modified nucleotides, modified nucleotides allowing for alternative internucleoside linkages (e.g., nucleotides comprising thiophosphates, phosphorothioates, and phosphotriesters), modified nucleotides terminally linked to a cholesterol derivative or lipophilic moiety, peptide nucleic acids, inverted deoxy or dideoxy modified nucleotides, abasic modifications of nucleotides, 2’-amino modified nucleotides, phosphoramidate modified nucleotides, modified nucleotides comprising modifications at other sites of the sugar or base of an oligonucleotide, and non- natural base-containing modified nucleotides.

WO 2022/189363 PCT/EP2022/055770 id="p-69" id="p-69" id="p-69" id="p-69" id="p-69" id="p-69" id="p-69" id="p-69"

[0069]In some embodiments, the ASOmay include one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) modified nucleosides. In certain embodiments, all of the nucleosides in the ASO are modified nucleosides. In other embodiments, less than 100% of the nucleosides in the ASO (e.g., less than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10%) are modified nucleosides. [0070]The ASOs of the present disclosure may comprise naturally-occurring and/or non- naturally-occurring internucleoside linkages. The term "internucleoside linkage," as used in the present disclosure, refers to a covalent linkage between adjacent nucleosides in an oligonucleotide. In certain embodiments, an ASO described herein may include one or more modified nucleoside linkages known in the art, including, e.g., phosphate, phosphotriester, boranophosphate, methylphosphonate, phosphoramidate, phosphorothioate, phosphorodithioate linkage, methylenemethylimino (-CH2-N(CH3)-O-CH2-), thiodiester, thionocarbamate (-O-C(=O)(NH)-S-), siloxane (-O-SiH2-O-), dialkylsiloxane, N,N'- dimethylhydrazine (-CH2-N(CH3)-N(CH3)-), MMI (3'-CH2-N(CH3)-O-5'), amide-3 (3’-CH2- C(=O)-N(H)-5'), amide-4 (3’-CH2-N(H)-C(=O)-5'), amide-5 (3’-N(H)-C(=O)-CH2-5’), amide-6 (3’-C(=O)-N(H)-CH2-5’), formacetal (3’-0-CH2-0-5'), methoxypropyl, thioformacetal (3'-S-CH2-0-5'), carboxylate ester, carboxamide, sulfide, sulfonate ester, or amide linker. See, for example: Carbohydrate Modifications in Antisense Research; Y.S. Sanghvi and P.D. Cook, Eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65. [0071]In certain embodiments, an ASO described herein may include one or more modified nucleoside linkages known in the art, including, e.g., a phosphonoacetate (PACE, P(CR’R")nCOOR) or thiophosphonoacetate (thioPACE, (S)-P(CR’R")nCOOR) internucleoside linkage, wherein n is an integer from 0 to 6 and each of R’ and R" is independently selected from the group consisting of H, an alkyl and substituted alkyl. Examples of these internucleoside linkages include phosphonocarboxylate, phosphonocarboxylate, thiophosphonocarboxylate, and thiophosphonocarboxylate ester linkages, and in some embodiments are described in Yamada et al., J. Am. Chem. Soc. (2006) 128(15):5251-61, the contents of which are hereby incorporated by reference in its entirety. [0072]In certain embodiments, the internucleoside linkage of a nucleotide may be a phosphate group or a thiophosphate group. Methods of preparation of phosphorous- containing internucleoside linkages are well known to those skilled in the art. In particular embodiments, the ASOs described herein may have phosphodiester internucleoside linkages, phosphorothioate internucleoside linkages, or a combination thereof. The term "phosphodiester internucleoside linkage" refers to an internucleoside linkage between two WO 2022/189363 PCT/EP2022/055770 nucleosides formed by a phosphodiester group. The term "phosphorothioate internucleoside linkage" refers to a modified internucleoside linkage in which one of the non-bridging oxygen atoms of the phosphodiester internucleoside linkage is replaced with a sulfur atom. [0073]In certain embodiments, internucleoside linkages having a chiral atom can be prepared as a racemic mixture, or can be prepared as separate enantiomers. Representative intemucleoside linkages having a chiral center include, but are not limited to, alkylphosphonates and phosphorothioates. ASOs of the present disclosure comprising internucleoside linkages having one or more chiral center(s) can be prepared as populations of ASOs comprising stereorandom internucleoside linkages, or as populations of ASOs comprising stereodefined internucleoside linkages. [0074]The term "stereodefined internucleoside linkage," in the present disclosure, refers to an internucleoside linkage in which the stereochemical designation of the phosphorus atom is controlled such that a specific amount of Rp or Sp of the internucleoside linkage is present within an ASO strand. The stereochemical designation of a chiral linkage can be defined by, for example, asymmetric synthesis. An ASO having at least one stereodefined internucleoside linkage can be referred to as a stereodefined ASO. [0075]In some embodiments, the present ASOs are fully stereodefined. The term "fully stereodefined ASO," as used in the present disclosure, refers to an ASO sequence having a defined chiral center (Rp or Sp) in each internucleoside linkage in the ASO. The term "partially stereodefined ASO," as used in the present disclosure, refers to an ASO sequence having a defined chiral center (Rp or Sp) in at least one internucleoside linkage, but not in all of the internucleoside linkages of the ASO. Therefore, a partially stereodefined ASO can include linkages that are achiral or non-stereodefmed in addition to at least one stereodefined linkage. [0076]In certain embodiments, populations of modified oligonucleotides are enriched for modified oligonucleotides comprising one or more particular phosphorothioate internucleoside linkages in a particular stereochemical configuration. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 65%, 70%, 80%, 90%, or 99% of the molecules in the population. Such chirally enriched populations of modified oligonucleotides can be generated using synthetic methods known in the art such as, for example, the methods described in Oka et al., JACS (2003) 125:8307, Wan et al., Nue. Acid. Res. (2014) 42:13456, and PCT Patent Publication WO 2017/015555.

WO 2022/189363 PCT/EP2022/055770 id="p-77" id="p-77" id="p-77" id="p-77" id="p-77" id="p-77" id="p-77" id="p-77"

[0077]Unless otherwise indicated, chiral internucleoside linkages of modified oligonucleotides described herein can be stereorandom or in a particular stereochemical configuration. C. Antisense Oligonucleotide Conjugates [0078] The present disclosure also provides antisense oligonucleotide conjugates (ASO conjugates) comprising one or more ASOs described herein. The term "ASO conjugate," in the present disclosure, refers to an oligomeric compound comprising an antisense oligonucleotide that is covalently linked to one or more non-nucl eotide moieties (conjugate moieties). Conjugation of an oligonucleotide to one or more conjugate moieties may improve the pharmacology or pharmacokinetic properties of the ASO. For example, the conjugate moiety may affect the activity, cellular distribution, cellular uptake, binding, absorption, tissue distribution, cellular distribution, charge, clearance, bioavailability, metabolism, excretion, permeability, and/or or stability of the ASO. In particular, the conjugate moiety may help target the ASO to a specific region in the central nervous system. In some embodiments of an ASO described herein, the conjugate moiety may be a carbohydrate, a peptide (e.g., a cell surface receptor ligand), and/or a lipid (e.g., phospholipid). [0079]PCT Patent Publications WO 1993/07883 and WO 2013/033230 provide suitable conjugate moieties for use with the ASOs of the present disclosure. Certain conjugate groups and conjugate moieties have been described previously, for example, in the following references: thioether moiety, e.g., hexyl-S-tritylthiol (Manoharan et al., Ann. NY. Acad. Sci. (1992) 660:306-309; Manoharan et al., Bioorg. Med. Chern. Lett. (1993) 3:2765-70), phospholipid, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac- glycero-3-H-phosphonate (Manoharan et al., Tetrahedron Lett. (1995) 36:3651-4; Shea et al., Nucl. Acids Res. (1990) 18:3777-83), a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides & Nucleotides (1995) 14:969-73), or adamantane acetic acid, a tocopherol group (Nishina et al., Molecular Therapy Nucleic Acids (2015) 4:e220; and Nishina et al., Molecular Therapy (2008) 16:734-40), or a GalNAc moiety (e.g., PCT Patent Publications WO 2014/076196, WO 2014/207232, and WO 2014/179620).[0080] In certain embodiments, conjugation of an ASO of the present disclosure to a lipophilic moiety may increase the delivery of the ASO to cells of the central nervous system. The term "lipophilic moiety," in the present disclosure, broadly refers to any compound or chemical moiety having an affinity for lipids. The lipophilic moiety may generally comprise a saturated or unsaturated hydrocarbon chain, which may be cyclic or acyclic. The hydrocarbon chain may comprise various substituents and/or one or more heteroatoms, such WO 2022/189363 PCT/EP2022/055770 as an oxygen or a nitrogen atom. In certain embodiments, the lipophilic moiety is a(n) aliphatic, cyclic, alicyclic, polycyclic, aromatic, or polyalicyclic compound. In certain embodiments, the lipophilic moiety is a steroid (e.g., sterol). Steroids include, without limitation, bile acids (e.g., cholic acid, deoxycholic acid and dehydrocholic acid), cortisone, digoxigenin, testosterone, cholesterol, and cationic steroids, such as cortisone. [0081]Certain lipophilic conjugate groups and conjugate moieties have been described previously, for example, in the following references: cholesterol moiety (Letsinger et al., Proc. Natl. Acad. Set. USA (1989) 86:6553-6), cholic acid moiety (Manoharan et al., Bioorg. Med. Chern. Lett. (1994) 4:1053-60), thiocholesterol moiety (Oberhauser et al., Nucl. Acids Res. (1992) 20:533-8), aliphatic chain, e.g., do-decan-diol or undecyl residues (Saison- Behmoaras et al., (1991) 10:1111-8; Kabanov et al., FEES Lett. (1990) 259:327-30;Svinarchuk et al., Biochimie (1993) 75:49-54), a palmityl moiety (Mishra et al., Biochim. Biophys. Acta (1995) 1264:229-37), or an octadecylamine or hexylamino-5 carbonyl- oxycholesterol moiety (Crooke et al., J Pharmacol. Exp. Ther. (1996) 277:923-37) D. Exemplary Antisense Oligonucleotide Compounds [0082]Certain abbreviations are used in the present disclosure to describe the modifications of each of the nucleotides and internucleoside linkages of ASOs described herein that are modified oligonucleotides. Abbreviations are as follows: A is an adenine nucleobase; G is a guanine nucleobase; T is a thymine nucleobase; mC is a 5-methyl cytosine nucleobase; e is a 2’-MOE modified sugar; d is a 2’-deoxyribose sugar; 1 is a locked nucleic acid; b is a bridged nucleic acid; o is a phosphodiester internucleoside linkage; and s is a phosphorothioate internucleoside linkage. [0083]In certain embodiments, the ASOs of the present disclosure are gapmers. The term "gapmer," as used in the present disclosure, refers to an oligonucleotide comprising or consisting of an internal region positioned between two external regions, wherein the sugar moieties of the nucleosides comprising the internal region are chemically distinct from the sugar moieties of the nucleosides comprising the external region. The term "gap" refers to the internal region of the oligonucleotide, while the term "wing" refers to the external regions. A gapmer has a 5’-wing, a gap, and a 3’-wing. The three regions form a contiguous sequence. The sugar moieties of each of the wing nucleosides differ from at least some of the sugar moieties of the gap nucleosides. Unless otherwise noted, the nucleosides of the gap region of the ASOs of the present disclosure comprise entirely 2’-deoxy rib oxy l nucleosides. In some embodiments, a gapmer may comprise one or more modified internucleoside WO 2022/189363 PCT/EP2022/055770 linkages and/or modified nucleobases that do not necessarily follow the gapmer pattern of sugar modifications. [0084]In some embodiments, the oligonucleotides of the present disclosure are gapmers that comprise MOE, BNA, LNA, or DNA modifications, or any combination thereof. In some embodiments, the gapmers comprise MOE, DNA, and BNA, MOE, DNA, and LNA, or BNA, DNA, and LNA modified sugar moieties. In certain embodiments, the internucleoside linkages between the oligonucleosides are phosphodiester or phosphorothioate internucleoside linkages, or a combination thereof. [0085]The lengths of the three gapmer regions may be notated using the notation [# of nucleosides in the 5’ wing]-[number of nucleosides in the gap]-[number of nucleosides in the 3’ wing]. Thus, a 4-10-4 gapmer comprises 4 linked nucleosides in each wing and linked nucleosides in the gap. [0086]In some embodiments, an ASO of the present disclosure is a 3-10-3 LNA gapmer. 3-10-3 LNA gapmers are 16 nucleobases in length, wherein the central gap segment comprises ten 2’- deoxynucleosides and each of the 5’ and 3’ wing segments comprises three LNA nucleosides. In some embodiments, all cytosine nucleobases throughout the 3-10-LNA gapmer are 5-methyl cytosines. In some embodiments, all internucleoside linkages are phosphorothioate internucleoside linkages. [0087]In some embodiments, an ASO of the present disclosure is a 3-11-3 LNA gapmer. 3-11-3 LNA gapmers are 17 nucleobases in length, wherein the central gap segment comprises 112’- deoxynucleosides and each of the 5’ and 3’ wing segments comprises three LNA nucleosides. In some embodiments, all cytosine nucleobases throughout the 3-11-LNA gapmer are 5-methyl cytosines. In some embodiments, all internucleoside linkages are phosphorothioate internucleoside linkages. [0088]In some embodiments, an ASO of the present disclosure is a 4-10-4 MOE gapmer. 4-10-4 gapmers are 18 nucleobases in length, wherein the central gap segment comprises ten 2’- deoxynucleosides and each of the 5’ and 3’ wing segments comprises four 2’-MOE nucleosides. In some embodiments, all cytosine nucleobases throughout the 4-10-4 MOE gapmer are 5-methyl cytosines. In some embodiments, all internucleoside linkages are phosphorothioate internucleoside linkages. [0089]In some embodiments, an ASO of the present disclosure is a 5-10-5 MOE gapmer. 5-10-5 gapmers are 20 nucleobases in length, wherein the central gap segment comprises ten 2’-deoxynucleosides and is flanked by wing segments on both 5’ and 3’ end comprising five 2’-MOE nucleosides. In some embodiments, all cytosine nucleobases throughout the 5-10- WO 2022/189363 PCT/EP2022/055770 MOE gapmer are 5-methyl cytosines. In some embodiments, all internucleoside linkages are phosphorothioate internucleoside linkages. [0090]In certain embodiments, an ASO of the present disclosure is a 3LNA-2MOE- 10DNA-2MOE-3LNA gapmer, wherein each of the nucleosides at positions 1, 2, 3, 18, 19, and 20 of the oligonucleotide comprise an LNA modification, each of nucleosides at positions 4, 5, 16, and 17 of the oligonucleotide comprise a 2’-MOE modification, and each of the nucleosides at positions 6-15 are 2’-deoxynucleosides. In some embodiments, all internucleoside linkages are phosphodiester internucleoside linkages. In some embodiments, the internucleoside linkages between the nucleosides at positions 2 and 3, 4 and 5, 16 and and 18 and 19 are phosphodiester internucleoside linkages. In some embodiments, the internucleoside linkages between the nucleosides at positions 2 and 3, 4 and 5, and 16 and are phosphodiester internucleoside linkages. In some embodiments, the internucleoside linkages between the nucleosides at positions 2 and 3, 3 and 4, 4 and 5, 16 and 17 and 17 and are phosphodiester internucleoside linkages. In some embodiments, the internucleoside linkages between the nucleosides at positions 3 and 4, 4 and 5, 16 and 17, and 17 and 18 are phosphodiester internucleoside linkages. In some embodiments, the remainder of the internucleoside linkages are phosphorothioate internucleoside linkages. In some embodiments, each cytosine nucleobase is a 5-methyl cytosine. [0091]In certain embodiments, an ASO of the present disclosure is a 2BNA-3MOE- 10DNA-3MOE-2BNA gapmer, wherein each of nucleosides at positions 1,2, 19, and comprise a BNA modification, each of the nucleosides at positions 3, 4, 5, 16, 17, and comprise a 2’-M0E modification, and each of the nucleosides at positions 6-15 are 2’- deoxynucleosides. In some embodiments, the internucleoside linkages between the nucleosides at positions 3 and 4, 4 and 5, 16 and 17, and 17 and 18 are phosphodiester internucleoside linkages. In some embodiments, the internucleoside linkages between the nucleosides at positions 2 and 3, 4 and 5, and 16 and 17 are phosphodiester internucleoside linkages. In some embodiments, the internucleoside linkages between the nucleosides at positions 2 and 3, 3 and 4, 4 and 5, 16 and 17 and 17 and 18 are phosphodiester internucleoside linkages. In some embodiments, the internucleoside linkages between the nucleosides at positions 3 and 4, 4 and 5, 16 and 17, and 17 and 18 are phosphodiester internucleoside linkages. In some embodiments, the remainder of the interncueloside linkages are phosphorothioate internucleoside linkages. In some embodiments, each cytosine nucleobase is a 5-methyl cytosine.

WO 2022/189363 PCT/EP2022/055770 id="p-92" id="p-92" id="p-92" id="p-92" id="p-92" id="p-92" id="p-92" id="p-92"

[0092]In certain embodiments, an ASO of the present disclosure is a 3BNA-2MOE- 10DNA-2MOE-3BNA gapmer, wherein each of the nucleosides at positions 1, 2, 3, 18, 19, and 20 of the oligonucleotide comprise a BNA modification, each of nucleosides at positions 4, 5, 16, and 17 of the oligonucleotide comprise a 2’-MOE modification, and each of the nucleosides at positions 6-15 are 2’-deoxynucleosides. In some embodiments, the all internucleoside linkages are phosphodiester internucleoside linkages. In some embodiments, the internucleoside linkages between the nucleosides at positions 2 and 3, 4 and 5, 16 and and 18 and 19 are phosphodiester internucleoside linkages. In some embodiments, the internucleoside linkages between the nucleosides at positions 2 and 3, 4 and 5, and 16 and are phosphodiester internucleoside linkages. In some embodiments, the internucleoside linkages between the nucleosides at positions 2 and 3, 3 and 4, 4 and 5, 16 and 17 and 17 and are phosphodiester internucleoside linkages. In some embodiments, the internucleoside linkages between the nucleosides at positions 3 and 4, 4 and 5, 16 and 17, and 17 and 18 are phosphodiester internucleoside linkages. In some embodiments, the remainder of the internucleoside linkages are phosphorothioate internucleoside linkages. In some embodiments, each cytosine nucleobase is a 5-methyl cytosine. [0093]In certain embodiments, an ASO of the present disclosure is a 2LNA-3MOE- 10DNA-3MOE-2LNA gapmer, wherein each of nucleosides at positions 1,2, 19, and comprise an ENA modification, each of the nucleosides at positions 3, 4, 5, 16, 17, and comprise a 2’-M0E modification, and each of the nucleosides at positions 6-15 are 2’- deoxynucleosides. In some embodiments, the internucleoside linkages between the nucleosides at positions 3 and 4, 4 and 5, 16 and 17, and 17 and 18 are phosphodiester internucleoside linkages. In some embodiments, the internucleoside linkages between the nucleosides at positions 2 and 3, 4 and 5, and 16 and 17 are phosphodiester internucleoside linkages. In some embodiments, the internucleoside linkages between the nucleosides at positions 2 and 3, 3 and 4, 4 and 5, 16 and 17 and 17 and 18 are phosphodiester internucleoside linkages. In some embodiments, the internucleoside linkages between the nucleosides at positions 3 and 4, 4 and 5, 16 and 17, and 17 and 18 are phosphodiester internucleoside linkages. In some embodiments, the remainder of the interncueloside linkages are phosphorothioate internucleoside linkages. In some embodiments, each cytosine nucleobase is a 5-methyl cytosine. [0094]In a particular embodiment, the present disclosure provides the ASOs listed in the following table and described in more detail below.

WO 2022/189363 PCT/EP2022/055770 Table B. Representative ASOs Unmodified ASO Sequence 2BNA-3MOE-10DNA- 3MOE-2BNA gapmer compound number 3LNA-2MOE-10DNA- 2MOE-3LNA gapmer compound number GCAGTTCTATCCCACTCATC (SEQ ID NO: 4)01608 (SEQ ID NO: 18) 01618 (SEQ ID NO: 32) AATAGCATCCTTCCACACCA (SEQ ID NO: 5)01613 (SEQ ID NO: 19) 01623 (SEQ ID NO: 33) ATCACCTTCAAACCCCTTTC (SEQ ID NO: 6)01615 (SEQ ID NO: 20) 01625 (SEQ ID NO: 34) CCGGTGCCATTACTCCCTTT (SEQ ID NO: 7)01609 (SEQ ID NO: 21) 01619 (SEQ ID NO: 35) TTGCAGATAAACCATCCCAC (SEQ ID NO: 8)01611 (SEQ ID NO: 22) 01621 (SEQ ID NO: 36) AGTGCCAGACCCTTTCATTA(SEQ ID NO: 9)01614 (SEQ ID NO: 23) 01624 (SEQ ID NO: 37) CCAAGTGCCAGACCCTTTCA (SEQ ID NO: 10)01610 (SEQ ID NO: 24) 01620 (SEQ ID NO: 38) GCAGATAAACCATCCCACTT (SEQ ID NO: 11)01612 (SEQ ID NO: 25) 01622 (SEQ ID NO: 39) GAACTGATGCCTCTACCTCC (SEQ ID NO: 12)01790 (SEQ ID NO: 27) 01823 (SEQ ID NO: 41) ACTGAACTGATGCCTCTACC (SEQ ID NO: 13)01791 (SEQ ID NO: 28) 01824 (SEQ ID NO: 42) TACATGGCCAGAAACCACTT(SEQ ID NO: 14)01792 (SEQ ID NO: 29) 01825 (SEQ ID NO: 43) AAGCCAAGCCCAAACACTAA(SEQ ID NO: 15)01793 (SEQ ID NO: 30) 01826 (SEQ ID NO: 44) TCCAAAGGAGCACCAACCAA (SEQ ID NO: 16)01789 (SEQ ID NO: 31) 01822 (SEQ ID NO: 45) CGGTGCCATTACTCCCTTTC (SEQ ID NO: 17)01616 (SEQ ID NO: 26) 01626 (SEQ ID NO: 40) D.I. Representative BNA/MOE Gapmer Compounds [0095]In some embodiments, an ASO of the present disclosure is a BNA/MOE gapmer compound, e.g., a compound described below.

WO 2022/189363 PCT/EP2022/055770 id="p-96" id="p-96" id="p-96" id="p-96" id="p-96" id="p-96" id="p-96" id="p-96"

[0096]Compound SNCA_ASO_01608 is characterized as a 2BNA-3MOE-10DNA- 3MOE-2BNA gapmer having a sequence, from 5’ to 3’, of GCAGTTCTATCCCACTCATC (unmodified oligonucleotide SEQ ID NO: 4), wherein each of nucleosides 1-2 and 19-comprise a BNA modification, each of nucleosides 3-5 and 16-18 comprise a 2’-M0Emodification, each of nucleosides 6-15 are 2’-deoxynucleosides, the internucleoside linkages between nucleosides 3-4, 4-5, 16-17 and 17-18 are phosphodiester internucleoside linkages, the other internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine. [0097]Compound SNCA ASO 01608 is characterized by the following chemicalnotation: Gbs mCbs Aeo Geo Tes Tds mCds Tds Ads Tds mCds mCds mCds Ads mCds Teo mCeo Aes Tbs mCb (modified oligonucleotide SEQ ID NO: 18), wherein A is an adenine nucleobase, mC is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a thymine nucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, b is a bridged nucleic acid, o is a phosphodiester internucleoside linkage, and s is a phosphorothioateinternucleoside linkage. [0098]Compound SNCA ASO 01608 is characterized by the following chemical structure (VI): WO 2022/189363 PCT/EP2022/055770 id="p-99" id="p-99" id="p-99" id="p-99" id="p-99" id="p-99" id="p-99" id="p-99"

[0099]Compound SNCA_ASO_01613 is characterized as a 2BNA-3MOE-10DNA- 3MOE-2BNA gapmer having a sequence, from 5’ to 3’, of AATAGCATCCTTCCACACCA (unmodified oligonucleotide SEQ ID NO: 5), wherein each of nucleosides 1-2 and 19-20comprise a BNA modification, each of nucleosides 3-5 and 16-18 comprise a 2’-M0E modification, each of nucleosides 6-15 are 2’-deoxynucleosides, the internucleoside linkages between nucleosides 3-4, 4-5, 16-17 and 17-18 are phosphodiester internucleoside linkages, the other internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine. [0100]Compound SNCA ASO01613 is characterized by the following chemicalnotation: Abs Abs Teo Aeo Ges mCds Ads Tds mCds mCds Tds Tds mCds mCds Ads mCeo Aeo mCes mCbs Ab (modified oligonucleotide SEQ ID NO: 19), wherein A is an adenine nucleobase, mC is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a thymine nucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, b is a bridged nucleic WO 2022/189363 PCT/EP2022/055770 acid, o is a phosphodiester internucleoside linkage, and s is a phosphorothioate internucleoside linkage. [0101]Compound SNCA ASO01613 is characterized by the following chemical structure (VII): — (VII) id="p-102" id="p-102" id="p-102" id="p-102" id="p-102" id="p-102" id="p-102" id="p-102"

[0102]Compound SNCA_ASO_01615 is characterized as a 2BNA-3MOE-10DNA- 3MOE-2BNA gapmer having a sequence, from 5’ to 3’, of ATCACCTTCAAACCCCTTTC (unmodified oligonucleotide SEQ ID NO: 6), wherein each of nucleosides 1-2 and 19-comprise a BNA modification, each of nucleosides 3-5 and 16-18 comprise a 2’-M0Emodification, each of nucleosides 6-15 are 2’-deoxynucleosides, the internucleoside linkagesbetween nucleosides 3-4, 4-5, 16-17 and 17-18 are phosphodiester internucleoside linkages, the other internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine. [0103]Compound SNCA ASO01615 is characterized by the following chemicalnotation: Abs Tbs mCeo Aeo mCes mCds Tds Tds mCds Ads Ads Ads mCds mCds mCds mCeo Teo Tes Tbs mCb (modified oligonucleotide SEQ ID NO: 20), wherein A is an adenine nucleobase, mC is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a WO 2022/189363 PCT/EP2022/055770 thymine nucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, b is a bridged nucleic acid, o is a phosphodiester internucleoside linkage, and s is a phosphorothioate internucleoside linkage. [0104]Compound SNCA_ASO_01615 is characterized by the following chemicalstructure (VIII): id="p-105" id="p-105" id="p-105" id="p-105" id="p-105" id="p-105" id="p-105" id="p-105"

[0105]Compound SNCA_ASO_01609 is characterized as a 2BNA-3MOE-10DNA- 3MOE-2BNA gapmer having a sequence, from 5’ to 3’, of CCGGTGCCATTACTCCCTTT (unmodified oligonucleotide SEQ ID NO: 7), wherein each of nucleosides 1-2 and 19-20comprise a BNA modification, each of nucleosides 3-5 and 16-18 comprise a 2’-MOE modification, each of nucleosides 6-15 are 2’-deoxynucleosides, the internucleoside linkages between nucleosides 3-4, 4-5, 16-17 and 17-18 are phosphodiester internucleoside linkages, the other internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine. [0106]Compound SNCA ASO 01609 is characterized by the following chemicalnotation: mCbs mCbs Geo Geo Tes Gds mCds mCds Ads Tds Tds Ads mCds Tds mCds WO 2022/189363 PCT/EP2022/055770 mCeo mCeo Tes Tbs Tb (modified oligonucleotide SEQ ID NO: 21), wherein A is an adenine nucleobase, mC is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a thymine nucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, b is a bridged nucleic acid, o is a phosphodiester internucleoside linkage, and s is aphosphorothioate internucleoside linkage. [0107]Compound SNCA ASO 01609 is characterized by the following chemical 3MOE-2BNA gapmer having a sequence, from 5’ to 3’, of TTGCAGATAAACCATCCCAC (unmodified oligonucleotide SEQ ID NO: 8), wherein each of nucleosides 1-2 and 19-comprise a BNA modification, each of nucleosides 3-5 and 16-18 comprise a 2’-MOE modification, each of nucleosides 6-15 are 2’-deoxynucleosides, the internucleoside linkages between nucleosides 3-4, 4-5, 16-17 and 17-18 are phosphodiester internucleoside linkages,the other internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine.

WO 2022/189363 PCT/EP2022/055770 id="p-109" id="p-109" id="p-109" id="p-109" id="p-109" id="p-109" id="p-109" id="p-109"

[0109]Compound SNCA_ASO_01611 is characterized by the following chemicalnotation: Tbs Tbs Geo mCeo Aes Gds Ads Tds Ads Ads Ads mCds mCds Ads Tds mCeomCeo mCes Abs mCb (modified oligonucleotide SEQ ID NO: 22), wherein A is an adeninenucleobase, mC is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a thyminenucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, b is a bridged nucleic acid, o is a phosphodiester internucleoside linkage, and s is a phosphorothioate internucleoside linkage. [0110]Compound SNCA_ASO_01611 is characterized by the following chemical id="p-111" id="p-111" id="p-111" id="p-111" id="p-111" id="p-111" id="p-111" id="p-111"

[0111]Compound SNCA_ASO_01614 is characterized as a 2BNA-3MOE-10DNA- 3MOE-2BNA gapmer having a sequence, from 5’ to 3’, of AGTGCCAGACCCTTTCATTA (unmodified oligonucleotide SEQ ID NO: 9), wherein each of nucleosides 1-2 and 19-comprise a BNA modification, each of nucleosides 3-5 and 16-18 comprise a 2’-MOEmodification, each of nucleosides 6-15 are 2’-deoxynucleosides, the internucleoside linkages between nucleosides 3-4, 4-5, 16-17 and 17-18 are phosphodiester internucleoside linkages, WO 2022/189363 PCT/EP2022/055770 the other internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine. [0112]Compound SNCA ASO 01614 is characterized by the following chemical notation: Abs Gbs Teo Geo mCes mCds Ads Gds Ads mCds mCds mCds Tds Tds Tds mCeoAeo Tes Tbs Ab (modified oligonucleotide SEQ ID NO: 23), wherein A is an adenine nucleobase, mC is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a thymine nucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, b is a bridged nucleic acid, o is a phosphodiester internucleoside linkage, and s is a phosphorothioate internucleoside linkage. [0113]Compound SNCA ASO 01614 is characterized by the following chemical 3MOE-2BNA gapmer having a sequence, from 5’ to 3’, of CCAAGTGCCAGACCCTTTCA (unmodified oligonucleotide SEQ ID NO: 10), wherein each of nucleosides 1-2 and 19-20comprise a BNA modification, each of nucleosides 3-5 and 16-18 comprise a 2’-MOE WO 2022/189363 PCT/EP2022/055770 modification, each of nucleosides 6-15 are 2’-deoxynucleosides, the internucleoside linkages between nucleosides 3-4, 4-5, 16-17 and 17-18 are phosphodiester internucleoside linkages, the other internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine. [0115]Compound SNCA ASO01610 is characterized by the following chemicalnotation: mCbs mCbs Aeo Aeo Ges Tds Gds mCds mCds Ads Gds Ads mCds mCds mCds Teo Teo Tes mCbs Ab (modified oligonucleotide SEQ ID NO: 24), wherein A is an adenine nucleobase, mC is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a thymine nucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, b is a bridged nucleicacid, o is a phosphodiester internucleoside linkage, and s is a phosphorothioate internucleoside linkage. [0116]Compound SNCA ASO01610 is characterized by the following chemical structure (XII): id="p-117" id="p-117" id="p-117" id="p-117" id="p-117" id="p-117" id="p-117" id="p-117"

[0117]Compound SNCA_ASO_01612 is characterized as a 2BNA-3MOE-10DNA-3MOE-2BNA gapmer having a sequence, from 5’ to 3’, of GCAGATAAACCATCCCACTT (unmodified oligonucleotide SEQ ID NO: 11), wherein each of nucleosides 1-2 and 19- WO 2022/189363 PCT/EP2022/055770 comprise a BNA modification, each of nucleosides 3-5 and 16-18 comprise a 2’-M0E modification, each of nucleosides 6-15 are 2’-deoxynucleosides, the internucleoside linkages between nucleosides 3-4, 4-5, 16-17 and 17-18 are phosphodiester internucleoside linkages, the other internucleoside linkages are phosphorothioate internucleoside linkages, and eachcytosine is a 5-methyl cytosine. [0118]Compound SNCA ASO 01612 is characterized by the following chemical notation: Gbs mCbs Aeo Geo Aes Tds Ads Ads Ads mCds mCds Ads Tds mCds mCds mCeo Aeo mCes Tbs Tb (modified oligonucleotide SEQ ID NO: 25), wherein A is an adeninenucleobase, mC is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a thyminenucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, b is a bridged nucleic acid, o is a phosphodiester internucleoside linkage, and s is a phosphorothioate internucleoside linkage. [0119]Compound SNCA ASO 01612 is characterized by the following chemical structure (XIII): id="p-120" id="p-120" id="p-120" id="p-120" id="p-120" id="p-120" id="p-120" id="p-120"

[0120]Compound SNCA_ASO_01616 is characterized as a 2BNA-3MOE-10DNA-3MOE-2BNA gapmer having a sequence, from 5’ to 3’, of CGGTGCCATTACTCCCTTTC WO 2022/189363 PCT/EP2022/055770 (unmodified oligonucleotide SEQ ID NO: 17), wherein each of nucleosides 1-2 and 19-comprise a BNA modification, each of nucleosides 3-5 and 16-18 comprise a 2’-M0E modification, each of nucleosides 6-15 are 2’-deoxynucleosides, the internucleoside linkages between nucleosides 3-4, 4-5, 16-17 and 17-18 are phosphodiester internucleoside linkages, the other internucleoside linkages are phosphorothioate internucleoside linkages, and eachcytosine is a 5-methyl cytosine. [0121]Compound SNCA ASO01616 is characterized by the following chemical notation: mCbs Gbs Geo Teo Ges mCds mCds Ads Tds Tds Ads mCds Tds mCds mCds mCeo Teo Tes Tbs mCb (modified oligonucleotide SEQ ID NO:26), wherein A is anadenine nucleobase, mC is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a thymine nucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, b is a bridged nucleic acid, o is a phosphodiester internucleoside linkage, and s is a phosphorothioate internucleoside linkage. [0122]Compound SNCA ASO01616 is characterized by the following chemicalstructure (XIV): (XIV) WO 2022/189363 PCT/EP2022/055770 id="p-123" id="p-123" id="p-123" id="p-123" id="p-123" id="p-123" id="p-123" id="p-123"

[0123]Compound SNCA_ASO_01790 is characterized as a 2BNA-3MOE-10DNA- 3MOE-2BNA gapmer having a sequence, from 5’ to 3’, of GAACTGATGCCTCTACCTCC (unmodified oligonucleotide SEQ ID NO: 12), wherein each of nucleosides 1-2 and 19-comprise a BNA modification, each of nucleosides 3-5 and 16-18 comprise a 2’-M0Emodification, each of nucleosides 6-15 are 2’-deoxynucleosides, the internucleoside linkages between nucleosides 3-4, 4-5, 16-17 and 17-18 are phosphodiester internucleoside linkages, the other internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine. [0124]Compound SNCA_ASO_01790 is characterized by the following chemicalnotation: Gbs Abs Aeo mCeo Tes Gds Ads Tds Gds mCds mCds Tds mCds Tds Ads mCeo mCeo Tes mCbs mCb (modified oligonucleotide SEQ ID NO: 27), wherein A is an adenine nucleobase, mC is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a thymine nucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, b is a bridged nucleic acid, o is a phosphodiester internucleoside linkage, and s is a phosphorothioateinternucleoside linkage. [0125]Compound SNCA ASO01790 is characterized by the following chemical structure (XV): WO 2022/189363 PCT/EP2022/055770 id="p-126" id="p-126" id="p-126" id="p-126" id="p-126" id="p-126" id="p-126" id="p-126"

[0126]Compound SNCA_ASO_01791 is characterized as a 2BNA-3MOE-10DNA- 3MOE-2BNA gapmer having a sequence, from 5’ to 3’, of ACTGAACTGATGCCTCTACC (unmodified oligonucleotide SEQ ID NO: 23), wherein each of nucleosides 1-2 and 19-comprise a BNA modification, each of nucleosides 3-5 and 16-18 comprise a 2’-M0Emodification, each of nucleosides 6-15 are 2’-deoxynucleosides, the internucleoside linkages between nucleosides 3-4, 4-5, 16-17 and 17-18 are phosphodiester internucleoside linkages, the other internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine.[0127] Compound SNCA ASO 01791 is characterized by the following chemicalnotation: Abs mCbs Teo Geo Aes Ads mCds Tds Gds Ads Tds Gds mCds mCds Tds mCeo Teo Aes mCbs mCb (modified oligonucleotide SEQ ID NO: 28), wherein A is an adenine nucleobase, mC is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a thymine nucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, b is a bridged nucleic acid, o is a phosphodiester internucleoside linkage, and s is a phosphorothioateinternucleoside linkage. [0128]Compound SNCA ASO 01791 is characterized by the following chemical structure (XVI): WO 2022/189363 PCT/EP2022/055770 id="p-129" id="p-129" id="p-129" id="p-129" id="p-129" id="p-129" id="p-129" id="p-129"

[0129]Compound SNCA_ASO_01792 is characterized as a 2BNA-3MOE-10DNA- 3MOE-2BNA gapmer having a sequence, from 5’ to 3’, ofTACATGGCCAGAAACCACTT (unmodified oligonucleotide SEQ ID NO: 14), wherein each of nucleosides 1-2 and 19-20 comprise a BNA modification, each of nucleosides 3-5and 16-18 comprise a 2’-M0E modification, each of nucleosides 6-15 are 2’- deoxynucleosides, the internucleoside linkages between nucleosides 3-4, 4-5, 16-17 and 17- are phosphodiester internucleoside linkages, the other internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine. [0130]Compound SNCA ASO 01792 is characterized by the following chemicalnotation: Tbs Abs mCeo Aeo Tes Gds Gds mCds mCds Ads Gds Ads Ads Ads mCds mCeo Aeo mCes Tbs Tb (modified oligonucleotide SEQ ID NO: 29), wherein A is an adenine nucleobase, mC is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a thymine nucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, b is a bridged nucleic acid, o is a phosphodiester internucleoside linkage, and s is a phosphorothioateinternucleoside linkage. [0131]Compound SNCA ASO 01792 is characterized by the following chemical structure (XVII): WO 2022/189363 PCT/EP2022/055770 id="p-132" id="p-132" id="p-132" id="p-132" id="p-132" id="p-132" id="p-132" id="p-132"

[0132]Compound SNCA_ASO_01793 is characterized as a 2BNA-3MOE-10DNA- 3MOE-2BNA gapmer having a sequence, from 5’ to 3’, ofAAGCCAAGCCCAAACACTAA (unmodified oligonucleotide SEQ ID NO: 15), wherein each of nucleosides 1-2 and 19-20 comprise a BNA modification, each of nucleosides 3-5and 16-18 comprise a 2’-M0E modification, each of nucleosides 6-15 are 2’- deoxynucleosides, the internucleoside linkages between nucleosides 3-4, 4-5, 16-17 and 17- are phosphodiester internucleoside linkages, the other internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine. [0133]Compound SNCA ASO 01793 is characterized by the following chemicalnotation: Abs Abs Geo mCeo mCes Ads Ads Gds mCds mCds mCds Ads Ads Ads mCds Aeo mCeo Tes Abs Ab (modified oligonucleotide SEQ ID NO: 30), wherein A is an adenine nucleobase, mC is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a thymine nucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, b is a bridged nucleic acid, o is a phosphodiester internucleoside linkage, and s is a phosphorothioateinternucleoside linkage. [0134]Compound SNCA ASO 01793 is characterized by the following chemical structure (XVIII): (XVIII) WO 2022/189363 PCT/EP2022/055770 id="p-135" id="p-135" id="p-135" id="p-135" id="p-135" id="p-135" id="p-135" id="p-135"

[0135]Compound SNCA_ASO_01789 is characterized as a 2BNA-3MOE-10DNA- 3MOE-2BNA gapmer having a sequence, from 5’ to 3’, ofTCCAAAGGAGCACCAACCAA (unmodified oligonucleotide SEQ ID NO: 16), wherein each of nucleosides 1-2 and 19-20 comprise aBNA modification, each of nucleosides 3-5and 16-18 comprise a 2’-M0E modification, each of nucleosides 6-15 are 2’- deoxynucleosides, the internucleoside linkages between nucleosides 3-4, 4-5, 16-17 and 17- are phosphodiester internucleoside linkages, the other internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine. [0136]Compound SNCA ASO 01789 is characterized by the following chemicalnotation: Tbs mCbs mCeo Aeo Aes Ads Gds Gds Ads Gds mCds Ads mCds mCds Ads Aeo mCeo mCes Abs Ab (modified oligonucleotide SEQ ID NO: 31), wherein A is an adenine nucleobase, mC is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a thymine nucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, b is a bridged nucleic acid, o is a phosphodiester internucleoside linkage, and s is a phosphorothioateinternucleoside linkage. [0137]Compound SNCA ASO 01789 is characterized by the following chemical structure (XIX): WO 2022/189363 PCT/EP2022/055770 D.2. Representative LNA/MOE Gapmer Compounds [0138]In some embodiments, an ASO of the present disclosure is an LNA/MOE gapmer compound, e.g., a compound described below. [0139]Compound SNCA_ASO_01618 is characterized as a 3LNA-2MOE-10DNA- 2MOE-3LNA gapmer having a sequence, from 5’ to 3’, of GCAGTTCTATCCCACTCATC (unmodified oligonucleotide SEQ ID NO: 4), wherein each of nucleosides 1-3 and 18-comprise a LNA modification, each of nucleosides 4-5 and 16-17 comprise a 2’-MOE modification, each of nucleosides 6-15 are 2’-deoxynucleosides, the internucleoside linkages between nucleosides 2-3, 4-5, 16-17 and 18-19 are phosphodiester internucleoside linkages, the other internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine. [0140]Compound SNCA ASO01618 is characterized by the following chemical notation: Gls mClo Ais Geo Tes Tds mCds Tds Ads Tds mCds mCds mCds Ads mCds Teo mCes Alo TIs mCl (modified oligonucleotide SEQ ID NO: 32), wherein A is an adenine nucleobase, mC is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a thymine nucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, 1 is a locked nucleic acid, o is a phosphodiester internucleoside linkage, and s is a phosphorothioate internucleoside linkage. [0141]Compound SNCA ASO 01618 is characterized by the following chemical structure (XX): WO 2022/189363 PCT/EP2022/055770 id="p-142" id="p-142" id="p-142" id="p-142" id="p-142" id="p-142" id="p-142" id="p-142"

[0142]Compound SNCA_ASO_01623 is characterized as a 3LNA-2MOE-10DNA-2MOE-3LNA gapmer having a sequence, from 5’ to 3’, of AATAGCATCCTTCCACACCA (unmodified oligonucleotide SEQ ID NO: 5), wherein each of nucleosides 1-3 and 18-20comprise a LNA modification, each of nucleosides 4-5 and 16-17 comprise a 2’-M0E modification, each of nucleosides 6-15 are 2’-deoxynucleosides, the internucleoside linkages between nucleosides 2-3, 4-5, 16-17 and 18-19 are phosphodiester internucleoside linkages, the other internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine. [0143]Compound SNCA ASO 01623 is characterized by the following chemical notation: Ais Alo TIs Aeo Ges mCds Ads Tds mCds mCds Tds Tds mCds mCds Ads mCeo Aes mClo mCls Al (modified oligonucleotide SEQ ID NO: 33), wherein A is an adenine nucleobase, mC is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a thymine nucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, 1 is a locked nucleicacid, o is a phosphodiester internucleoside linkage, and s is a phosphorothioate internucleoside linkage.

WO 2022/189363 PCT/EP2022/055770 id="p-144" id="p-144" id="p-144" id="p-144" id="p-144" id="p-144" id="p-144" id="p-144"

[0144]Compound SNCA ASO 01623 is characterized by the following chemical structure (XXI):NH, id="p-145" id="p-145" id="p-145" id="p-145" id="p-145" id="p-145" id="p-145" id="p-145"

[0145]Compound SNCA_ASO_01625 is characterized as a 3LNA-2MOE-10DNA-2MOE-3LNA gapmer having a sequence, from 5’ to 3’, of ATCACCTTCAAACCCCTTTC (unmodified oligonucleotide SEQ ID NO: 6), wherein each of nucleosides 1-3 and 18-comprise a LNA modification, each of nucleosides 4-5 and 16-17 comprise a 2’-M0E modification, each of nucleosides 6-15 are 2’-deoxynucleosides, the internucleoside linkages between nucleosides 2-3, 4-5, 16-17 and 18-19 are phosphodiester internucleoside linkages, the other internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine. [0146]Compound SNCA ASO 01625 is characterized by the following chemical notation: Ais T10 mCls Aeo mCes mCds Tds Tds mCds Ads Ads Ads mCds mCds mCds mCeo Tes Tlo TIs mCl (modified oligonucleotide SEQ ID NO: 34), wherein A is an adenine nucleobase, mC is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a thymine nucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, 1 is a locked nucleic WO 2022/189363 PCT/EP2022/055770 acid, o is a phosphodiester internucleoside linkage, and s is a phosphorothioate internucleoside linkage. [0147]Compound SNCA_ASO_01625 is characterized by the following chemical structure (XXII): (XXII) [0148]Compound SNCA_ASO_01619 is characterized as a 3LNA-2MOE-10DNA- 2MOE-3LNA gapmer having a sequence, from 5’ to 3’, of CCGGTGCCATTACTCCCTTT (unmodified oligonucleotide SEQ ID NO: 7), wherein each of nucleosides 1-3 and 18-20comprise a LNA modification, each of nucleosides 4-5 and 16-17 comprise a 2’-M0E modification, each of nucleosides 6-15 are 2’-deoxynucleosides, the internucleoside linkages between nucleosides 2-3, 4-5, 16-17 and 18-19 are phosphodiester internucleoside linkages, the other internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine.

WO 2022/189363 PCT/EP2022/055770 id="p-149" id="p-149" id="p-149" id="p-149" id="p-149" id="p-149" id="p-149" id="p-149"

[0149]Compound SNCA ASO 01619 is characterized by the following chemical notation: mCls mClo GIs Geo Tes Gds mCds mCds Ads Tds Tds Ads mCds Tds mCds mCeo mCes T10 TIs TI (modified oligonucleotide SEQ ID NO: 35), wherein A is an adenine nucleobase, mC is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a thyminenucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, 1 is a locked nucleic acid, o is a phosphodiester internucleoside linkage, and s is a phosphorothioate internucleoside linkage. [0150]Compound SNCA ASO01619 is characterized by the following chemical structure (XXIII): id="p-151" id="p-151" id="p-151" id="p-151" id="p-151" id="p-151" id="p-151" id="p-151"

[0151]Compound SNCA_ASO_01621 is characterized as a 3LNA-2MOE-10DNA- 2MOE-3LNA gapmer having a sequence, from 5’ to 3’, of TTGCAGATAAACCATCCCAC (unmodified oligonucleotide SEQ ID NO: 8), wherein each of nucleosides 1-3 and 18-20comprise a LNA modification, each of nucleosides 4-5 and 16-17 comprise a 2’-M0E modification, each of nucleosides 6-15 are 2’-deoxynucleosides, the internucleoside linkages between nucleosides 2-3, 4-5, 16-17 and 18-19 are phosphodiester internucleoside linkages, WO 2022/189363 PCT/EP2022/055770 the other internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine. [0152]Compound SNCA_ASO_01621 is characterized by the following chemical notation: TIs T10 GIs mCeo Aes Gds Ads Tds Ads Ads Ads mCds mCds Ads Tds mCeomCes mClo Ais mCl (modified oligonucleotide SEQ ID NO: 36), wherein A is an adenine nucleobase, mC is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a thymine nucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, 1 is a locked nucleic acid, o is a phosphodiester internucleoside linkage, and s is a phosphorothioate internucleoside linkage. [0153]Compound SNCA ASO 01621 is characterized by the following chemicalstructure (XXIV): id="p-154" id="p-154" id="p-154" id="p-154" id="p-154" id="p-154" id="p-154" id="p-154"

[0154]Compound SNCA_ASO_01624 is characterized as a 3LNA-2MOE-10DNA-2MOE-3LNA gapmer having a sequence, from 5’ to 3’ of AGTGCCAGACCCTTTCATTA (unmodified oligonucleotide SEQ ID NO: 9), wherein each of nucleosides 1-3 and 18-20comprise a LNA modification, each of nucleosides 4-5 and 16-17 comprise a 2’-M0E WO 2022/189363 PCT/EP2022/055770 modification, each of nucleosides 6-15 are 2’-deoxynucleosides, the internucleoside linkages between nucleosides 2-3, 4-5, 16-17 and 18-19 are phosphodiester internucleoside linkages, the other internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine.[0155] Compound SNCA ASO 01624 is characterized by the following chemicalnotation: Ais Glo TIs Geo mCes mCds Ads Gds Ads mCds mCds mCds Tds Tds Tds mCeo Aes T10 TIs Al (modified oligonucleotide SEQ ID NO: 37), wherein A is an adenine nucleobase, mC is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a thymine nucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, 1 is a locked nucleicacid, o is a phosphodiester internucleoside linkage, and s is a phosphorothioate internucleoside linkage. [0156]Compound SNCA ASO 01624 is characterized by the following chemical structure (XXV): id="p-157" id="p-157" id="p-157" id="p-157" id="p-157" id="p-157" id="p-157" id="p-157"

[0157]Compound SNCA_ASO_01620 is characterized as a 3LNA-2MOE-10DNA-2MOE-3LNA gapmer having a sequence, from 5’ to 3’, of CCAAGTGCCAGACCCTTTCA WO 2022/189363 PCT/EP2022/055770 (unmodified oligonucleotide SEQ ID NO: 10), wherein each of nucleosides 1-3 and 18-comprise a LNA modification, each of nucleosides 4-5 and 16-17 comprise a 2’-M0E modification, each of nucleosides 6-15 are 2’-deoxynucleosides, the internucleoside linkages between nucleosides 2-3, 4-5, 16-17 and 18-19 are phosphodiester internucleoside linkages, the other internucleoside linkages are phosphorothioate internucleoside linkages, and eachcytosine is a 5-methyl cytosine. [0158]Compound SNCA ASO 01620 is characterized by the following chemical notation: mCls mClo Ais Aeo Ges Tds Gds mCds mCds Ads Gds Ads mCds mCds mCds Teo Tes Tlo mCls Al (modified oligonucleotide SEQ ID NO: 38), wherein A is an adeninenucleobase, mC is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a thymine nucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, 1 is a locked nucleic acid, o is a phosphodiester internucleoside linkage, and s is a phosphorothioate internucleoside linkage. [0159]Compound SNCA ASO 01620 is characterized by the following chemicalstructure (XXVI): id="p-160" id="p-160" id="p-160" id="p-160" id="p-160" id="p-160" id="p-160" id="p-160"

[0160]Compound SNCA_ASO_01622 is characterized as a 3LNA-2MOE-10DNA-2MOE-3LNA gapmer having a sequence, from 5’ to 3’, of GCAGATAAACCATCCCACTT WO 2022/189363 PCT/EP2022/055770 (unmodified oligonucleotide SEQ ID NO: 11), wherein each of nucleosides 1-3 and 18-comprise a LNA modification, each of nucleosides 4-5 and 16-17 comprise a 2’-M0E modification, each of nucleosides 6-15 are 2’-deoxynucleosides, the internucleoside linkages between nucleosides 2-3, 4-5, 16-17 and 18-19 are phosphodiester internucleoside linkages, the other internucleoside linkages are phosphorothioate internucleoside linkages, and eachcytosine is a 5-methyl cytosine. [0161]Compound SNCA ASO 01622 is characterized by the following chemical notation: GIs mClo Ais Geo Aes Tds Ads Ads Ads mCds mCds Ads Tds mCds mCds mCeo Aes mClo TIs TI (modified oligonucleotide SEQ ID NO: 39), wherein A is an adeninenucleobase, mC is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a thymine nucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, 1 is a locked nucleic acid, o is a phosphodiester internucleoside linkage, and s is a phosphorothioate internucleoside linkage. [0162]Compound SNCA ASO 01622 is characterized by the following chemicalstructure (XXVII): (XXVII) WO 2022/189363 PCT/EP2022/055770 id="p-163" id="p-163" id="p-163" id="p-163" id="p-163" id="p-163" id="p-163" id="p-163"

[0163]Compound SNCA_ASO_01626 is characterized as a 3LNA-2MOE-10DNA- 2MOE-3LNA gapmer having a sequence, from 5’ to 3’, of CGGTGCCATTACTCCCTTTC (unmodified oligonucleotide SEQ ID NO: 17), wherein each of nucleosides 1-3 and 18-comprise a LNA modification, each of nucleosides 4-5 and 16-17 comprise a 2’-M0Emodification, each of nucleosides 6-15 are 2’-deoxynucleosides, the internucleoside linkages between nucleosides 2-3, 4-5, 16-17 and 18-19 are phosphodiester internucleoside linkages, the other internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine. [0164]Compound SNCA ASO 01626 is characterized by the following chemicalnotation: mCls Glo Gls Teo Ges mCds mCds Ads Tds Tds Ads mCds Tds mCds mCds mCeo Tes Tlo TIs mCl (modified oligonucleotide SEQ ID NO: 40), wherein A is an adenine nucleobase, mC is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a thymine nucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, 1 is a locked nucleic acid, o is a phosphodiester internucleoside linkage, and s is a phosphorothioateinternucleoside linkage. [0165]Compound SNCA ASO 01626 is characterized by the following chemical structure (XXVIII): WO 2022/189363 PCT/EP2022/055770 id="p-166" id="p-166" id="p-166" id="p-166" id="p-166" id="p-166" id="p-166" id="p-166"

[0166]Compound SNCA_ASO_01823 is characterized as a 3LNA-2MOE-10DNA-2MOE-3LNA gapmer having a sequence, from 5’ to 3’, of GAACTGATGCCTCTACCTCC (unmodified oligonucleotide SEQ ID NO: 12), wherein each of nucleosides 1-3 and 18-20comprise a LNA modification, each of nucleosides 4-5 and 16-17 comprise a 2’-M0E modification, each of nucleosides 6-15 are 2’-deoxynucleosides, the internucleoside linkages between nucleosides 2-3, 4-5, 16-17 and 18-19 are phosphodiester internucleoside linkages, the other internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine. [0167]Compound SNCA ASO 01823 is characterized by the following chemical notation: GIs Alo Ais mCeo Tes Gds Ads Tds Gds mCds mCds Tds mCds Tds Ads mCeo mCes Tlo mCls mCl (modified oligonucleotide SEQ ID NO: 41), wherein A is an adenine nucleobase, mC is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a thymine nucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, 1 is a locked nucleicacid, o is a phosphodiester internucleoside linkage, and s is a phosphorothioate internucleoside linkage.

WO 2022/189363 PCT/EP2022/055770 id="p-168" id="p-168" id="p-168" id="p-168" id="p-168" id="p-168" id="p-168" id="p-168"

[0168]Compound SNCA ASO 01823 is characterized by the following chemical structure (XXIX): id="p-169" id="p-169" id="p-169" id="p-169" id="p-169" id="p-169" id="p-169" id="p-169"

[0169]Compound SNCA_ASO_01824 is characterized as a 3LNA-2MOE-10DNA-2MOE-3LNA gapmer having a sequence, from 5’ to 3’, of ACTGAACTGATGCCTCTACC (unmodified oligonucleotide SEQ ID NO: 13), wherein each of nucleosides 1-3 and 18-comprise a LNA modification, each of nucleosides 4-5 and 16-17 comprise a 2’-M0E modification, each of nucleosides 6-15 are 2’-deoxynucleosides, the internucleoside linkages between nucleosides 2-3, 4-5, 16-17 and 18-19 are phosphodiester internucleoside linkages, the other internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine. [0170]Compound SNCA ASO 01824 is characterized by the following chemical notation: Ais mClo TIs Geo Aes Ads mCds Tds Gds Ads Tds Gds mCds mCds Tds mCeo Tes Alo mCls mCl (modified oligonucleotide SEQ ID NO: 42), wherein A is an adenine nucleobase, mC is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a thymine nucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, 1 is a locked nucleic WO 2022/189363 PCT/EP2022/055770 acid, o is a phosphodiester internucleoside linkage, and s is a phosphorothioate internucleoside linkage. [0171]Compound SNCA ASO 01824 is characterized by the following chemical id="p-172" id="p-172" id="p-172" id="p-172" id="p-172" id="p-172" id="p-172" id="p-172"

[0172]Compound SNCA_ASO_01825 is characterized as a 3LNA-2MOE-10DNA- 2MOE-3LNA gapmer having a sequence, from 5’ to 3’, of TACATGGCCAGAAACCACTT (unmodified oligonucleotide SEQ ID NO: 14), wherein each of nucleosides 1-3 and 18-comprise a LNA modification, each of nucleosides 4-5 and 16-17 comprise a 2’-M0Emodification, each of nucleosides 6-15 are 2’-deoxynucleosides, the internucleoside linkages between nucleosides 2-3, 4-5, 16-17 and 18-19 are phosphodiester internucleoside linkages, the other internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine. [0173]Compound SNCA ASO 01825 is characterized by the following chemicalnotation: TIs Alo mCls Aeo Tes Gds Gds mCds mCds Ads Gds Ads Ads Ads mCds mCeo Aes mClo TIs TI (modified oligonucleotide SEQ ID NO: 43), wherein A is an adenine nucleobase, mC is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a thymine WO 2022/189363 PCT/EP2022/055770 nucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, 1 is a locked nucleic acid, o is a phosphodiester internucleoside linkage, and s is a phosphorothioate internucleoside linkage. [0174]Compound SNCA ASO 01825 is characterized by the following chemicalstructure (XXXI): id="p-175" id="p-175" id="p-175" id="p-175" id="p-175" id="p-175" id="p-175" id="p-175"

[0175]Compound SNCA_ASO_01826 is characterized as a 3LNA-2MOE-10DNA- 2MOE-3LNA gapmer having a sequence, from 5’ to 3’, of AAGCCAAGCCCAAACACTAA (unmodified oligonucleotide SEQ ID NO: 15), whereineach of nucleosides 1-3 and 18-20 comprise a ENA modification, each of nucleosides 4-and 16-17 comprise a 2’-M0E modification, each of nucleosides 6-15 are 2’- deoxynucleosides, the internucleoside linkages between nucleosides 2-3, 4-5, 16-17 and 18- are phosphodiester internucleoside linkages, the other internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine. [0176]Compound SNCA ASO 01826 is characterized by the following chemicalnotation: Ais Alo Gls mCeo mCes Ads Ads Gds mCds mCds mCds Ads Ads Ads mCds Aeo mCes Tlo Ais Al (modified oligonucleotide SEQ ID NO: 44), wherein A is an adenine WO 2022/189363 PCT/EP2022/055770 nucleobase, mC is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a thymine nucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, 1 is a locked nucleic acid, o is a phosphodiester internucleoside linkage, and s is a phosphorothioateinternucleoside linkage.[0177] Compound SNCA ASO 01826 is characterized by the following chemical id="p-178" id="p-178" id="p-178" id="p-178" id="p-178" id="p-178" id="p-178" id="p-178"

[0178]Compound SNCA_ASO_01822 is characterized as a 3LNA-2MOE-10DNA- 2MOE-3LNA gapmer having a sequence, from 5’ to 3’, ofTCCAAAGGAGCACCAACCAA (unmodified oligonucleotide SEQ ID NO: 16), wherein each of nucleosides 1-3 and 18-20 comprise a LNA modification, each of nucleosides 4-and 16-17 comprise a 2’-M0E modification, each of nucleosides 6-15 are 2’- deoxynucleosides, the internucleoside linkages between nucleosides 2-3, 4-5, 16-17 and 18- are phosphodiester internucleoside linkages, the other internucleoside linkages arephosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine. [0179]Compound SNCA ASO 01822 is characterized by the chemical notation TIs mClo mCls Aeo Aes Ads Gds Gds Ads Gds mCds Ads mCds mCds Ads Aeo mCes mClo Ais Al (modified oligonucleotide SEQ ID NO: 45), wherein A is an adenine nucleobase, mC WO 2022/189363 PCT/EP2022/055770 is a 5-methyl cytosine nucleobase, G is a guanine nucleobase, T is a thymine nucleobase, e is a 2’-MOE modified sugar, d is a 2’-deoxyribose sugar, 1 is a locked nucleic acid, o is a phosphodiester internucleoside linkage, and s is a phosphorothioate internucleoside linkage. [0180]Compound SNCA ASO 01822 is characterized by the following chemicalstructure (XXXIII): (XXXIII) III. Methods of Making Antisense Oligonucleotides [0181]An antisense oligonucleotide of the present disclosure may be synthesized by any method known in the art. For example, an ASO may be synthesized by in vitro transcription and purification (e.g., using commercially available in vitro RNA synthesis kits), by transcription and purification from cells (e.g., cells comprising an expression cassette/vector encoding the ASO), by use of an automated solid-phase synthesizer, and the like. In solid- phase oligonucleotide synthesis, monomeric nucleoside units are added iteratively to agrowing oligonucleotide chain covalently bound to a solid support. In the case of phosphodiester linkages, electrophilic 3’ phosphoramidite monomeric units may be used. However, any suitable electrophilic group can be used to covalently link two nucleosides.

WO 2022/189363 PCT/EP2022/055770 id="p-182" id="p-182" id="p-182" id="p-182" id="p-182" id="p-182" id="p-182" id="p-182"

[0182]The present ASOs may be purified following solid-phase synthesis through any method known in the art. For example, oligonucleotides may be precipitated from solution through treatment of the solution with ethanol and divalent cations. The present ASOs may also be purified using, e.g., sizing columns, reverse-phase chromatography, high-performance liquid chromatography, and polyacrylamide gel electrophoresis. [0183]Exemplary methods of synthesizing antisense oligonucleotides using solid-phase supports and purifying said oligonucleotides are described in, for example, Ellington et al., Introduction to the synthesis and purification of oligonucleotides. Curr. Protoc. Nucleic Acid Chem. (2001) Appendix 3C.

IV. Compositions of Antisense Oligonucleotides [0184]In some embodiments, the present disclosure relates to compositions (e.g., pharmaceutical compositions) comprising an ASO described herein. In some embodiments, the composition is useful for treating a disease or disorder associated with expression or overexpression of alpha-synuclein, e.g., a synucleinopathy. Compositions of the present disclosure may be formulated based upon the mode of delivery. [0185]A pharmaceutical composition described herein may comprise a pharmaceutically acceptable excipient. A pharmaceutically acceptable excipient can be liquid or solid, and may be selected with the planned manner of administration in mind so as to provide for the desired bulk, consistency, and other pertinent transport and chemical properties. Any known pharmaceutically acceptable carrier or diluent may be used, including, for example, water, saline solution, buffering agents, preservatives, and the like. For example, the ASOs of the present disclosure may be administered to a patient as a formulation in phosphate buffered saline (PBS). Example of pharmaceutically acceptable excipients include water, saline, buffer solution, or artificial cerebrospinal fluid. The pharmaceutically acceptable excipient is preferably sterile. [0186]The ASOs of the present disclosure may be administered as pharmaceutically acceptable salts. A pharmaceutically acceptable salt is a salt of the ASOs of the present disclosure that is physiologically acceptable, and retains the desired biological activity of the ASO without having undesired toxicological effects. As used herein, the term ASO encompasses both the free acid form and salt forms (e.g., sodium salt form) of the oligonucleotides.

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[0187]The ASOs of the present disclosure may be admixed, encapsulated (e.g., in a lipid nanoparticles), conjugated, or otherwise associated with other molecules, molecular structures, or mixtures of nucleic acids. [0188]U.S. Patent Publication Number 2020/0385723 provides suitable pharmaceutical compositions for use with the ASOs of the present disclosure.

V. Methods of Using Antisense Oligonucleotides [0189]The ASOs of the present disclosure typically inhibit the activity of transcripts encoded by the SNCA gene in a mammalian cell, such as a human cell. In some embodiments, the cell is a neuronal cell. In certain embodiments, the cell is a cell of the central nervous system (CNS), including cells of the motor cortex, frontal cortex, caudate, amygdala, pons, substantia nigra, putamen, cerebellar peduncle, corpus collosum, dorsal cochlear nucleus (DCN), entorhinal cortex (Ent Cortex), hippocampus, insular cortex, medulla oblongata, central gray matter, pulvinar, occipital cortex, cerebral cortex, temporal cortex, globus pallidus, superior colliculi, and basal forebrain nuclei. [0190]The present disclosure provides methods of down-regulating the abundance or activity of SNCA gene transcripts in cells or in tissues comprising contacting the cells or tissues with an effective amount of one or more of the ASOs or compositions of the disclosure. The methods may be carried out in vitro or in vivo. [0191]In some embodiments, the ASOs of the present disclosure can be utilized for treatment or prophylaxis. The ASOs of the present disclosure can be used as therapeutics in animals suspected of having a disease or disorder that can be treated by modulating the expression of the SNCA gene transcript and/or alpha-synuclein protein. The animal may also be prone to having the disease or disorder associated with the expression of the SNCA gene, and is not necessarily suspected of having the disease or disorder. The animal is treated by administering a therapeutically or prophylactically effective amount of one or more of the ASO compounds or pharmaceutical compositions of the present disclosure. In some embodiments, the animal is a mammal. In some embodiments, the animal is a human. [0192]In some embodiments, the ASOs described herein may be used to treat a neurodegenerative disease, such as Parkinson’s disease, Lewy body dementia, diffuse Lewy body disease, pure autonomic failure, multiple system atrophy, neuronopathic Gaucher’s disease, and Alzheimer’s disease. In general, a neurodegenerative disease results in the death of neurons.

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[0193] In some embodiments, the ASOs of the present disclosure ameliorate the symptoms of a disease or disorder associated with the expression of the SNCA gene. Amelioration may refer to a reduction in the severity or the frequency of occurrence of a symptom. Amelioration may also refer to a delay in the onset or progression of a symptom. In some embodiments, a symptom alleviated by treatment with the ASO is motor dysfunction, aggregation of alpha-synuclein, neurodegeneration, cognitive decline, or dementia. Amelioration of these symptoms may result in improved motor function, reduction of alpha-synuclein aggregations, reduced neurodegeneration, reduced or reversed cognitive decline, and/or reduced or reversed dementia.[0194] A "therapeutically effective amount" of an ASO as disclosed herein is an amount sufficient to carry out a specifically stated purpose. Such an amount can be determined empirically and in a routine manner, in relation to the stated purpose. Certain factors may influence the dosage and timing required to effectively treat a subject, including, but not limited to, severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and one or more other diseases being present. Moreover, treatment of a subject with a therapeutically effective amount of a pharmaceutical composition can include a single treatment or a series of treatments. Estimates of effective dosages and in vivo half-lives for the ASOs of the present disclosure may be made using conventional methodologies or on the basis of in vivo testing using appropriate animal models. A therapeutically effective amount may alleviate the symptoms of a disease.[0195] In certain embodiments, the ASOs or pharmaceutical compositions of the present disclosure are prepared for injection (e.g., intravenous, subcutaneous, intramuscular, intrathecal (IT), intracerebroventricular (ICV), intracranial, and the like). In preferred embodiments, the pharmaceutical composition is injected intrathecally or intracranially to the subject.[0196] In some embodiments, the ASOs of the present disclosure can be used for research purposes. For example, an ASO may be used to specifically inhibit the synthesis of the alpha-synuclein protein in cells and experimental animals. ASO-mediated inhibition of alpha-synuclein synthesis can be used to perform functional analyses of alpha-synuclein protein.

VI. Kits and Articles of Manufacture [0197] The present disclosure also provides kits and articles of manufacture comprising an ASO described herein. Kits or articles of manufacture comprising an ASO of the present WO 2022/189363 PCT/EP2022/055770 disclosure can be used to perform the methods described herein. A kit or article of manufacture comprises at least one ASO in one or more containers. [0198]In some embodiments, a kit or an article of manufacture described herein may be used for the treatment and/or prevention of a disease associated with the expression of the SNCA gene (e.g., a synucleinopathy). The kit or article of manufacture may further comprise a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc. The containers may be formed from a variety of materials such as glass or plastic, and may hold a composition which is by itself or combined with another composition effective for treating or preventing the disease and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The kit or article of manufacture may further comprise a package insert indicating that the compositions can be used to treat a particular disease. Alternatively, or additionally, the article of manufacture or kit may further comprise a second (or third) container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer’s solution and dextrose solution. It may further include other materials desirable from a commercial and/or user standpoint, including other buffers, diluents, filters, needles, and syringes. [0199]In some embodiments, the kits contain all of the components necessary and/or sufficient to perform a detection assay, including all controls, directions for performing assays, and any necessary software for analysis and presentation of results. One skilled in the art will readily recognize that the disclosed ASO can be readily incorporated into one of the established kit formats which are well known in the art. [0200]Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. Exemplary methods and materials are described below, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure. In case of conflict, the present specification, including definitions, will control. Generally, nomenclature used in connection with, and techniques of neurology, medicine, medicinal and pharmaceutical chemistry, and cell biology described herein are those well-known and commonly used in the art. Enzymatic reactions and purification techniques are performed according to manufacturer’s specifications, as commonly accomplished in the art or as described herein. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

WO 2022/189363 PCT/EP2022/055770 Throughout this specification and embodiments, the words "have" and "comprise," or variations such as "has," "having," "comprises," or "comprising," will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. As used herein, the term "approximately" or "about" as applied to one or more values of interest refers to a value that is similar to a stated reference value. In certain embodiments, the term refers to a range of values that fall within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context. [0201]All publications and other references mentioned herein are incorporated by reference in their entirety. Although a number of documents are cited herein, this citation does not constitute an admission that any of these documents forms part of the common general knowledge in the art. [0202]In order that this invention may be better understood, the following examples are set forth. These examples are for purposes of illustration only and are not to be construed as limiting the scope of the invention in any manner.

EXAMPLES [0203]The materials and methods used in the experiments described below are as follows. Construction of ASOs [0204]The ASOs were constructed to be complementary to the sense strand of the genomic SNCA sequence (SEQ ID NO: 1) as well as the sequence of the mRNA transcribed from the SNCA gene (NC_000004.12::89724099..89838324, SEQ ID NO: 2). Sk-Mel-2 Cell Culture [0205]Sk-Mel-2 cells were cultured in Eagle’s minimum essential medium (EMEM) supplemented with 10% Fetal Bovine Serum (FBS). Transgenic Human SNCA Mice and Collection of Neurons [0206]C57BL/6Tac mice (Taconic) were genetically engineered to introduce the entire wildtype human SNCA gene starting from its 5’UTR (SEQ ID NO: 1) into the mouse genome in place of the mouse SNCA gene and under the control of the mouse SNCA promoter.C57BL/6Tac mice (Taconic) were genetically engineered to introduce the entire human SNCA gene starting from its 5’UTR (SEQ ID NO: 1) mutated in position A53T into the mouse genome in place of the mouse SNCA gene and under the control of the mouse SNCA promoter. Primary cortical neurons were collected from embryos removed from pregnant WO 2022/189363 PCT/EP2022/055770 homozygous human SNCA knock-in mice at embryonic day 17.5. Cortical tissue of each embryo was dissected on ice-cold Hank’s Balanced Salt Solution. Pooled tissue was minced and digested with papain at 37 °C for 12 minutes. Digestion then was halted by the addition of 10% FBS/DMEM. The cells were triturated and resuspended in NeurobasalT Plus media supplemented with GlutaMAXTM, 2% penicillin/streptomycin, and B-27™ Plus supplement. Cells were seeded at a density of 15000 cells/well onto 384-well poly-E-lysine + boric acid coated plates in 40 pL supplemented NeurobasalT media (containing B-27™ supplement and GlutaMAX). The neurons were then incubated for four days at 37°C under a 5% COatmosphere. Male Winstar Rats [0207]Male Wistar Rats weighed 200-225g at their arrival and were housed in groups of two animals per cage at room temperature with food and water available ad libitum. All procedures were approved by the Institut de Recherches SERVIER ethical committee in accordance with the principles of the Guide to the Care and Use of Experimental Animals. ASO Screenings in Neurons in vitro [0208]For single dose screenings, neurons were treated with 300 nM of the given ASO. For multiple dose screenings, neurons were treated with serial dilutions of the given ASO starting at 3 pM (%2 log dilutions, 11 concentrations total). Seven days after treatment with the ASO, the culture media was replaced with new Neurobasal™ media. 15 days after the treatment, RNA was extracted from the cells using the TaqMan™ Fast Advanced Cells-to- CT Kit (ThermoFisher). Cells were then washed in PBS and lysed in solution for five minutes at room temperature, with simultaneous DNase treatment. Lysis was terminated by treatment of the mixture with Stop Solution, followed by a two-minute incubation at room temperature. Reverse transcription was conducted immediately after cell lysis using Fast Advanced RT Enzyme Mix (ThermoFisher). The cDNA samples were then used for quantitative real-time PCR measurement using TaqMan™ genotyping assays. Specific probes and primers were used for SNCA mRNA quantification (Hs00240906_ml SNCA; ThermoFisher). SNCA mRNA levels were adjusted to the measured levels of the housekeeping gene PPM (probe/primer PPIA_Mm02342430_gl; ThermoFisher). [0209]In a qPCR reaction, the quantification cycle value (Ct) is defined as the number of cycles required for the fluorescent signal to exceed the background fluorescence. The QuantStudio™ Real-Time PCR software program (Applied Biosystems, Foster City, CA) sets this threshold at ten standard deviations above the mean baseline fluorescence. The comparative Ct method normalized the Ct value of a target gene to housekeeping genes WO 2022/189363 PCT/EP2022/055770 before comparisons were made between samples. First, the difference between Ct values (ACt) of the target gene and the housekeeping gene was calculated for each sample, and then the difference in the ACt (AACt) was calculated between two samples (e.g., control and treatment). The fold-change in expression of the two samples was calculated as 2־AACt. The percentage of reduction was calculated by subtracting the value 1 to the 2־AACt of the ASO group mean of interest and by multiplying by 100, % reduction (1- 2-AACtASO group mean) x 100. Mouse Model [0210]The entire wildtype (WT) human SNCA gene (SEQ ID NO: 1) was introduced into the mouse genome in place of the mouse SNCA gene locus in C57BL/6Tac mice (Taconic) as shown in FIG. 1.The expression of human and murine SNCA proteins in different brain areas and peripherical organs was analyzed by mass spectrometry analysis (FIG. 2A-2C). Three- to four-month-old homozygous male mice expressing the WT human SNCA gene (referred to as "hSNCA+,+KI mice" or "hSNCA mice") were housed in groups of three animals maximum per cage at room temperature with food and water available ad libitum. All procedures were approved by the Institut de Recherches SERVIER ethical committee in accordance with the principles of the Guide to the Care and Use of Experimental Animals hSNCA A53T neurons [0211]The entire human A53T SNCA gene was introduced into the mouse genome in place of the mouse SNCA gene locus of C57BL/6Tac mice (Taconic) as described in FIG.I. Homozygous female mice expressing human A53TSAG4 gene (referred to as hA53TSNCA+/+KI) were housed isolated with one animal per cage at room temperature with food and water available ad libitum. All procedures were approved by the Institut de Recherches SERVIER ethical committee in accordance with the principles of the Guide to the Care and Use of Experimental Animals. Intracerebroventricular (ICV) Injection [0212]Sterile saline syringes and nuclease-free centrifuge tubes were used to prepare dosing solutions. The tubes containing ASO powder were briefly centrifuged before adding saline solution, then re-centrifuged for 10 minutes to fully dissolve the ASO powder. The solution was vortexed for approximately one minute and stored at 4°C until use. [0213]hSNCA mice received a single unilateral bolus injection of oligonucleotide at a dose of 30 nmol. Mice were anesthetized with isoflurane at a concentration of 4.5-5% and maintained during surgery with a concentration of 1.5-2% isoflurane. For pain management, buprenorphine at a dosage of 0.04 mg/kg was administered subcutaneously at least WO 2022/189363 PCT/EP2022/055770 minutes before injection. The scalps of the mice were shaved and, following loss of the pedal reflex, mice were placed in a stereotaxic frame (David Kopf Instruments, CA). The scalp was sterilized using three alternating wipes of Betadine and 70% ethanol. An incision was made in the scalp and the skull surface exposed and bregma positively identified. A hole was drilled in the skull at 0.5 mm AP, 1.1 mm ML, relative to bregma. The ASO was injected through a canula (31g) connected to a microsyringe pump controller. The dorsoventral DV coordinate was measured at 1 mm below the skull surface. Once the canula was positioned, the ASO solution was administered in 5 pL of saline vehicle over 30 seconds. The canula was left in place for an additional three minutes after injection to allow diffusion of the solution in the brain. After a slow withdrawing of the canula, the scalp was sutured and mice were subcutaneously injected with 1 mL of warm sterile saline solution to aid rehydration and placed in their warm home cage. A control group of mice was similarly dosed with saline vehicle control. Mice were observed until they regained consciousness and mobility to prevent potential adverse behavioral effects. Drug tolerability was scored one hour following dosing. Animals dosed with non-tolerated compounds (tolerability score >8) were euthanized immediately following the one-hour evaluation. [0214]The antisense oligonucleotides described above were tested in hSNCA+!+ KI (Knock In) mice as described above to assess their tolerability profile. ASO SNCA 00033 as previously described in PCT Patent Publication WO 2012/068405 was also tested as a comparator. In all instances, ASO SNCA 00033 has a 5-10-5 MOE gapmer pattern in which all of the internucleoside linkages are phosphorothioate internucleoside linkages and all cytosine residues are 5-methyl cytosines. Intrathecal (IT) Injection [0215]Male Wistar rats received a single intrathecal bolus injection of oligonucleotide at a dose of 2.5mg. Rat were anesthetized with isoflurane at a concentration of 4 % and maintained during surgery with a concentration of 2-2.5 % isoflurane. For pain management, Carprofene 5mg/kg and Buprenorphine 0.05 mg/kg was administered subcutaneously at least minutes before injection. Rat were shaved and, following loss of the pedal reflex, an incision was made between the Sth and the 6th lumbar vertebra. Muscle around this area was dissected allowing to access of the spinal canal to insert the catheter used for ASO injection. Once the catheter was positioned, ASO solution was administered in 30pl of artificial CSF over -30 seconds. The catheter was left in place and sealed to avoid diffusion of the CSF fluid. Muscle and skin were sutured, and the rats were subcutaneously injected with 1 mL warm sterile saline to aid rehydration and placed in their warm home cage. A control group WO 2022/189363 PCT/EP2022/055770 of rats were similarly dosed with artificial CSF. Rats were observed until they regained consciousness and mobility to prevent potential adverse behavioral effects. Drug tolerability was scored at one, three, and 24 hours post dosing. Animals dosed with non-tolerated compounds (tolerability score >8) were euthanized immediately following the one-hour evaluation. ASO Acute Tolerability Assessment [0216]At one and three hours post injection, adverse effects were monitored and scored in dosed mice according to the criteria shown in FIG. 3.At one, three, and twenty-four hours post injection, adverse effects were monitored and scored in dosed rats according to the criteria shown in FIG. 10.A normal tolerability score is 0 and a highly toxic score corresponds to 16. The final tolerability score was calculated based on the sum of all criteria. For some oligonucleotides, an intolerable acute toxicity was observed without reaching the first observational time point. In these cases, the ASO was scored with an acute toxicity score of 14, and the mice were immediately euthanized. If a score of higher than 6 was measured at the one-hour time point, mice were more closely monitored over the course of the experiment. ASO Long Term Tolerability Assessment [0217]Mice were weighed on the injection day and three times per week until completion of the experiment. Any mice displaying intolerable health, behavioral observations, or weight loss of more than 20% of their initial body weight were immediately euthanized. Tissue Sampling [0218]All mice were euthanized by anesthetic overdose. Animals were transcardially perfused in the left ventricle with 0.9 % saline. The thoracic aorta between the lungs and the liver was clamped with hemostatic forceps to block blood flow from the heart to the abdomen, but to allow blood to flow to the brain. The right ventricle was opened with scissors. A constant pressure of 100 to 120 mm Hg was maintained on the perfusion solution by connecting the solution bottle to a manometer-controlled air compressor. Perfusion was continued until the skull surface turned pale and perfusion solution exited the right ventricle. Following perfusion, brain tissues (cortex) and peripherical tissues (kidney and liver) were collected. Samples were cut into small pieces, mixed and aliquoted into three equal parts. All samples were frozen with liquid nitrogen and stored at -80°C until use for RNA, protein, and ASO measurements. For some studies, blood and cerebrospinal fluid (CSF) were also collected.

WO 2022/189363 PCT/EP2022/055770 mRNA Measurements by qRT-PCR [0219]RNA extraction and mRNA quantification by qPCR were performed. From right cortex biopsies, RNA was extracted using RNeasy Mini Kit (Qiagen) with DNase treatment. Total RNA samples were quantified using a Nanodrop™ spectrophotometer and analyzed using TapeStation to determine the quality of the RNA (RIN). In qPCR quantification experiments, the RNA was first reverse transcribed using the High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems™). The reaction was performed in a 100 pL final reaction volume, starting from 1000 ng of total RNA (to a final RNA concentration of ng/pL). Quantification of the human SNCA gene and the mouse PPIA housekeeping gene were performed from 40ng of total cDNA using QuantStudio 7 Flex (Applied Biosystems™), TaqMan™ Universal PCR Master Mix (Applied Biosystems™, Ref. 4324020), and TaqMan™ Gene Expression Assays in duplex (Hs00240906_ml in FAM fluorochrome and Mm02342430_gl in VIC fluorochrome). qPCR analysis was performed in triplicate using the fast run mode. The Ct values of each qPCR plate were analyzed using Excel software. Technical replicates (n = 3) were combined and averaged to the geometric mean. Relative expression was generated for each ASO group using the mouse control PBS condition. hSNCA Protein Expression by Mass Spectrometry Analysis [0220]Mouse brain tissues were homogenized with Pecellys® (2x20s, 5000tr) in lysis buffer (PBS, Sigma Protease and Phosphatase Inhibitor Cocktail, 1% deoxycholate) at 1mg/mL. Brain homogenates were then centrifuged (27000g, 4°C, 20 minutes) and supernatants collected. Brain samples were diluted in a denaturing buffer (ammonium bicarbonate 50mM, deoxycholate 1%) and then heated at 95°C for five minutes. Next, trypsin (lOpg) was added into each sample. The tryptic digestion was performed in an ultrasonic bath (Branson 1200) for one minute followed by an incubation at 52 °C for minutes. The reaction was stopped by the addition of IpL of TCEP (0.5 M) and 1 pL of 100% formic acid followed by incubation at 95°C for five minutes. The samples were then centrifuged at 30,000 g for 15 minutes. Peptide digests were analyzed by a reversed-phase liquid chromatography tandem mass spectrometry (LC-MS/MS) using a Shimadzu LC system (Shimadzu) coupled online to a triple quadrupole mass spectrometer (Shimadzu 8060) operated in the MRM mode. The specific peptides used to measure alpha-synuclein protein abundance were TVEGAGSIAAATGFVK (SEQ ID NO: 46) and TVEGAGNIAAATGFVK (SEQ ID NO: 47). The specific peptide used to measure GAPDH protein abundance was VGVNGFGR (SEQ ID NO: 48). A single 10 pL injection of each brain sample digest was injected on a Waters™ XBridge Peptide BEH C18 column (130 A; 3.5 pm; 150 mm x 2.

WO 2022/189363 PCT/EP2022/055770 mm). Peptides were eluted using a linear gradient of acetonitrile (2-40%) in 0.1% formic acid over 30 min. Chromatograms were analyzed using the Shimadzu Lab Solutions software. The signal intensity obtained for each peptide was normalized by GAPDH signal obtained in each sample and is expressed in arbitrary units (AU). hSNCA Protein or alpha-synuclein Protein Expression by ELISA [0221]Mouse brain tissues were homogenized with Pecellys® (2x20s, 5000tr) in lysis buffer (PBS, Sigma Protease and Phosphatase Inhibitor Cocktail, 1% deoxycholate) at 1mg/mL. Brain homogenates were then centrifuged (27000g, 4°C, 20 minutes) and supernatants collected. The quantification of a-synuclein in brain lysates were performed by using the U-PLEX Human a-Synuclein Kit (K151WKK) following manufacturer instruction. The quantification of total a-synuclein in brain lysates were performed using the ELISA commercial kit from MSD®, U-PLEX Human a-Synuclein Kit (K151WKK). The provided plate was pre-coated with capture antibody for a-synuclein. The sample (brain lysates) was added to a solution containing the detection antibody (anti-a-synuclein) conjugated to an electroluminescent compound label (MSD SULFO-TAG). Analytes in the sample bound to the capture antibodies immobilized on the working electrode surface. Recruitment of the conjugated detection antibody by bound analytes completed the sandwich. An MSD® read buffer was added providing the appropriate chemical environment for electroluminescence and the plate was loaded into an MSD SECTOR® Imager for analysis. Inside the SECTOR Imager, a voltage applied to the plate electrodes caused the probes bound to the electrode surface to emit light. The instrument measured the intensity of emitted light to provide a quantitative measurement of a-synuclein present in the sample. High Performance Liquid Chromatography (HPLC) Fluorescence [0222]Samples were analyzed against a set of calibration standards prepared in water. As no matrix effect was noticed, quantification of all samples (plasma, CSF and tissues) were performed using a water set of standards. Frozen tissues were weighed and grinded into Masterpure™/Proteinase K 97/3 (V/V) buffer for 2x30 seconds at 6500rpm using a Precellys device. Plasma samples (5pL) were diluted into Masterpure™/ptoteinase K 97/3 (70pL).Plasma and tissue homogenates were incubated during 30 minutes at 55°C under soft agitation. Then, lOpL of KC1 3M solution was added into 50pL of tissue homogenates or plasma dilution, rapidly vortexed and sonicated for five minutes. The tubes were centrifuged for ten minutes (20000 g) at +4 °C. CSF samples (lOpL) were diluted into hybridation buffer (Tris HC1 50 mM pH 8.5 / ACN 90/10) (45pL) and proteinase K (1uL) and were incubated during 15 minutes at 55°C. Prior to analysis, a hybridization step was undertaken with a WO 2022/189363 PCT/EP2022/055770 fluorescently labelled peptide nucleic acid oligomer complementary to the quantified oligonucleotide. For calibration standards and tissue homogenates, 40pL hybridation buffer was mixed with lOpL of fluorescent complementary probe and lOpL of calibration standards, quality control sample and study sample supernatants. For plasma samples, 30pL hybridation buffer were mixed with lOpL of fluorescent complementary probe and 60pL of quality control sample and study sample supernatants. For CSF analysis, lOpl of fluorescent complementary probe was directly added into the previous dilution. The mixtures were first incubated 15 minutes at 95°C then 15 minutes at 55°C. Finally, samples were centrifuged for minutes (20000 g) at 4°C. The samples were analyzed under an RP-HPLC system with fluorescence detection. The injected volume was 50pL excepted for plasma (90pL). The amount of fluorescence due to hybridized oligonucleotide to fluorescent probe was measured and compared to the calibration curve. The oligonucleotide concentration in the sample was calculated considering the different dilutions used during sample preparation.

Example 1: mRNA Reduction in vitro Following a Single Dose of ASO [0223]Modified oligonucleotides complementary to the human SNCA nucleotide sequence were designed and tested in cultured Sk-Mel-2 cells for their selective efficacy in reducing SNCA mRNA levels. Cultured Sk-Mel-2 cells at a density of 15000 cells per well were transfected using Lipofectamine 2000 (Invitrogen) with 20 nM or 2 nM concentrations of modified antisense oligonucleotides (ASOs). After 24 hours, RNA was isolated from the cells and SNCA mRNA levels were measured by a branched DNA assay (QuantiGene Singleplex Assay Kit, ThermoFisher). This method relies on the signal amplification of a branched DNA (bDNA) probe that binds to a specific nucleotide sequence. The probe-sets used were XM_005555421 (reactive to dog and human SNCA) and NM_002046 (reactive to human GapDH), which were designed by Affymetrix Inc./ThermoScientific and synthesized by Metabion International. kM N-RLUs were normalized to GapDH relative light units (RLUs) of respective wells. Values were normalized against wells treated with unspecific (Ahsal) ASOs. [0224]The modified oligonucleotides tested in the above experiment are shown in Table Cbelow. Each modified oligonucleotide listed in Table Cis complementary to the human SNCA nucleic acid sequence (SEQ ID NO: 1) and is a 5-10-5 MOE gapmer. The gapmers are nucleobases in length, wherein the central gap segment comprises ten 2’-deoxynucleosides and each of the wing segments comprises five 2’MOE nucleosides. All cytosines throughout WO 2022/189363 PCT/EP2022/055770 each gapmer are 5-methyl cytosines, and all internucleoside linkages are phosphorothioate internucleoside linkages. [0225]The identified position in Table Ccorresponds to the "Start Site," i.e., the 5’ nucleoside to which the gapmer is complementary in the human nucleic acid sequence (SEQ ID NO: 1).

Table C. 5-10-5 MOE Gapmers Compound Name % reduction (20 nM ASO) % reduction (2 nM ASO) Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA_AS 0027285.11 62.97CGTAGTCTTGATACCCTTCC109019SNCA_AS O 0027584.16 60.66GTTCGTAGTCTTGATACCCT109022SNCA_AS O 0027677.48 47.04GGTTCGTAGT CTTGATACCC109023SNCA_AS O 0027773.6 32.35AGGTTCGTAG TCTTGATACC109024SNCA_AS O 0027877.14 40.19CAGGTTCGTA GTCTTGATAC109025SNCA_AS O 0028067.22 30.48TTCAGGTTCG TAGTCTTGAT109027SNCA_AS O 0061481.71 69.07GCTATGACCCTCAAGCCATC28601SNCA_AS O 0062382.74 38.79CAACTAACCA CGGCACAATT30828SNCA_AS O 0067581.9 80.45TAGCCGACATACATCTCCAA49733SNCA_AS O 0083883.79 82.2CGGTGCCATT ACTCCCTTTC16400SNCA_AS O 0083982.04 72.12GTAAATATGT CAGTCTCCCG18540SNCA_AS O 0084077.2 72.64GGGTTCTCTA ACGACAGTAG25550SNCA_AS O 0084184.07 76.25GGGGTTCTCTAACGACAGTA25551SNCA_AS O 0084282.59 66.98GGATGGGGTT CTCTAACGAC25555SNCA_AS O 0084376.65 71.55GAGCGATCGG AAGCTCCCTG27763SNCA_AS O 0084478.82 65.01AGAGCGATCG GAAGCTCCCT27764SNCA_AS O 0084687.75 83.14GTTGCTATCTAGGGATCACC29769SNCA_AS O 0084785.38 68.17GCGAAGGACT ATATAATAGG33628SNCA_AS O 0084874.92 79.56GGTAACTTAGGACAAGGTCC38957 WO 2022/189363 PCT/EP2022/055770 Compound Name % reduction (20 nM ASO) % reduction (2 nM ASO) Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA_AS 0084982.08 75.02TTCACATAAA GTAGCCGCTA40930SNCA_AS 0085081.94 77.39ACTTCACATA AAGTAGCCGC40932SNCA_AS 0085284.48 79.71ATAGCCGACA TACATCTCCA49734SNCA_AS 0085368.5 72.58GACGGATCAG ACACTCTTAC52858SNCA_AS 0085479.16 66.41TGCCTCACGG ATGTCCGTGT59974SNCA_AS 0085570.93 77.42GCTCGAGATT AGTTCTTCCC69469SNCA_AS 0085680.22 66.67GCCACTAGTAGATGACAGTT71531SNCA_AS 0085774.41 64.94GATGGAATTTACCCCCTAGT74726SNCA_AS 0085876.66 65.96AGCAGAAGCA TGCGGCTACC76062SNCA_AS 0085975.83 66.3GGTATCGTCATGGAATTTGGN/ASNCA_AS 0086036.95 0GATCTAAGGA CCCTCAACAAN/ASNCA_AS 0086138.54 3.53GGATCTAAGG ACCCTCAACAN/ASNCA_AS 0086244.27 11.32ACTCTATCTT GAGGCACACCN/ASNCA_AS 0086351.23 20.83CTGTTAATGT AGTAGGAGCAN/ASNCA_AS 0086447.89 13.36ACTGTTAATG TAGTAGGAGCN/ASNCA_AS 0157358.1 12.31TTTGGGGTTT ACCTACCTAC118SNCA_AS 0157479.88 45.93TACTGACTGT CCAAGGGTGT7961SNCA_AS 0157561.12 33.36TCAGGGCAAG GGTATGCTTG14181SNCA_AS 0157656.77 45.29TCCAGTCAGG TGGTGTATGA15923SNCA_AS 0157779.77 57.72ATGGGGTTCTCTAACGACAG25553SNCA_AS 0157877.99 52.47TGGATGGGGT TCTCTAACGA25556SNCA_AS 0157966.87 55.72AAGAGCGATC GGAAGCTCCC27765SNCA_AS 0158067.08 47.85TTTTCAAGAG CGATCGGAAG27770SNCA_AS 0158174.45 61.9CTAGCGAAGG ACTATATAAT33631SNCA_AS 0158280.41 29.7CTATCTTACGTGGCTATATC35367 WO 2022/189363 PCT/EP2022/055770 Compound Name % reduction (20 nM ASO) % reduction (2 nM ASO) Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA_AS 0158378.91 46.37AAGTAGCCGC TACTGCTTAA40922SNCA_AS 0158475.21 63.17TCTGGACAGG CGCTTATCTA41589SNCA_AS 0158574.66 54.27GATGGAGTAC CTACCAACTT43655SNCA_AS 0158669.99 40.76ACACGTGGCC AGATCAATCC48683SNCA_AS 0158768.06 41.86CTACACACGT GGCCAGATCA48687SNCA_AS 0158869.37 42.92ACTACACACG TGGCCAGATC48688SNCA_AS 0158967.29 51.66TTTGGGCATG ACTACACACG48698SNCA_AS 0159077.21 63.81ATGGGCCATT GGCAATCAAG52775SNCA_AS 0159160.33 45.55CCTGCCTCAC GGATGTCCGT100 59976SNCA_AS 0159267.92 44.6TCCTGCCTCA CGGATGTCCG101 59977SNCA_AS 0159358.46 32.41CATAAGATCGATTAAGTGGA102 60755SNCA_AS 0159461.41 42.21ACATAAGATCGATTAAGTGG103 60756SNCA_AS 0159564.63 24.95TACATAAGAT CGATTAAGTG104 60757SNCA_AS 0159674.37 47.48ATTAGGCCTGATTAGCTAAA105 61840SNCA_AS 0159770.46 61.73TATCTGTAAC CACGCCCTTA106 72245SNCA_AS 0159860.72 31.9GAAGCATGCG GCTACCATGC107 76058SNCA_AS 0159968.09 45.51AAGCAGAAGC ATGCGGCTAC108 76063SNCA_AS 0160078.89 53.15TATAAATCTTCAGGGACTCG109 78150SNCA_AS 0160170.13 49.38TGGTTCGATA ATAGCTAAGC110 78175SNCA_AS 016021131 59.33CGTCATGGAA TTTGGTCTGTill N/ASNCA_AS 0160335.25 24.55GGGATTCATC TGGCATTAGG112 N/ASNCA_AS 0160467.81 30.82ATGCTAAGCC AAACCTAGCA113 98646SNCA_AS 0160569.62 44.58CAGTAGACCA CTGATGATCT114 98760SNCA_AS 0160674.43 56.16TAGAGTGACA GGTCTGGTAC115 99041SNCA_AS 0160751.55 23.37GGGAGTGTGT ACATAGTGTA116 100146 WO 2022/189363 PCT/EP2022/055770 id="p-226" id="p-226" id="p-226" id="p-226" id="p-226" id="p-226" id="p-226" id="p-226"

[0226]Each modified oligonucleotide listed in Table Dis complementary to the human SNCA nucleic acid sequence (SEQ ID NO: 1) and is a 4-10-4 MOE gapmer. The gapmers are nucleobases in length, wherein the central gap segment comprises ten 2’- deoxynucleosides, and the wing segments on both the 5’ and 3’ ends comprise four 2’-MOEnucleosides. All cytosines throughout each gapmer are 5-methyl cytosines, and all internucleoside linkages are phosphorothioate linkages. [0227]The identified position in Table Dcorresponds to the "Start Site," i.e., the 5’ nucleoside to which the gapmer is complementary in the human SNCA nucleic acid sequence (SEQ ID NO: 1).

Table D. 4-10-4 MOE Gapmers Compound Name % reduction (20 nM ASO) % reduction (2 nM ASO) Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 0152883.87 37.6GCCATACTAGTTATGACA117 9579SNCA ASO 0152985.7 66.86AACCGGTGC CATTACTCC118 16405SNCA ASO0153089.66 69.2CTTCATATAC GAGTTGAC119 19976SNCA ASO 0153172.22 30.17GGATGGGGT TCTCTAACG120 25557SNCA ASO 015320.97GTAGTTAGA GTGTAGTTG121 27133SNCA ASO 0153385.58 75.16AGCGATCGG AAGCTCCCT122 27764SNCA ASO 0153486.63 56.47TTTTCAAGA GCGATCGGA123 27772SNCA ASO 0153589.02 74.3GTTTTCAAG AGCGATCGG124 27773SNCA ASO0153684.19 42.89TGTTTTCAAG AGCGATCG125 27774SNCA ASO 0153785.67 62.46GACCCTCAA GCCATCTAG126 28598SNCA ASO 0153884.55 62.09GCTATGACC CTCAAGCCA127 28603SNCA ASO 0153979.43 43.53ATGGTTGCC CAGAAGTTA128 30182SNCA ASO 0154085.01 19.2AACTAACCA CGGCACAAT129 30829SNCA ASO 0154188.05 53.48GACTATATA ATAGGCTCA130 33624SNCA ASO 0154284.27 65.84CTAGCGAAG GACTATATA131 33633SNCA ASO 0154386.84 64.53GCTAGCGAA GGACTATAT132 33634 WO 2022/189363 PCT/EP2022/055770 Compound Name % reduction (20 nM ASO) % reduction (2 nM ASO) Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 0154485.63 53.47TGCTAGCGA AGGACTATA133 33635SNCA ASO 0154583.15 28.94TGAATAGCC TTTGTAGGT134 38993SNCA ASO 0154681.44 19.91TAACCCCTTT ACAGATCC135 39060SNCA ASO 0154777.53 22.56ACTGTGGATGAAGGTTAC136 40883SNCA ASO 0154884.42 47.1TGGACAGGC GCTTATCTA137 41589SNCA ASO 0154982.65 60.99CTGGACAGG CGCTTATCT138 41590SNCA ASO 0155072.95 30.2CTAGGGGTA CAACAGGGT139 43719SNCA ASO 0155178.75 42.33GTTGGCTGCCCAACTTAC140 46937SNCA ASO0155281.93 33.39TAATAGCCG ACATACATC141 49738SNCA ASO 0155384.56 30.26TTTTAATAGC CGACATAC142 49741SNCA ASO 0155468.89 22.27TATACCCCT GGCATCATA143 50660SNCA ASO 0155585.37 54.9ATCTACAGA CACGGCTTT144 52719SNCA ASO0155681.68 41.97ATTTTTGACG GATCAGAC145 52866SNCA ASO 0155778.28 33.62TAGTTTGGGTCCATGCCA146 60075SNCA ASO 0155874.77 45.27GAGGGGTGC TTTTAAGCC147 60194SNCA ASO0155985.21 53.15ATGCTCGAG ATTAGTTCT148 69473SNCA ASO 0156068.51 24.05GAAGCATGC GGCTACCAT149 76060SNCA ASO 0156163.79 49.76GTTCGATAATAGCTAAGC150 78175SNCA ASO0156277.35 22.75AACATCGCC TCAGTCAAT151 N/ASNCA ASO 0156381.73 58.54GGTATCGTC ATGGAATTT152 N/ASNCA ASO 0156452.15 0.9CTTAAGAGG CTTATATAG153 N/ASNCA ASO 0156574.32 3.9AATTAAACG AGAGTCTCA154 N/ASNCA ASO0156659.05 7.62TAATTGCAT CCTAGTAAG155 99558SNCA ASO 0156769.39 13.29ACCTGTAGG GTTGAATAG156 101644SNCA ASO 0156849.87 6.72AATCCACAG CTATAGTCC157 106131 WO 2022/189363 PCT/EP2022/055770 Compound Name % reduction (20 nM ASO) % reduction (2 nM ASO) Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO0156940.82 3.27GGGGAAACA TTGCGGCAA158 106212SNCA ASO 0157082.57 42.67CGTAGTCTT GATACCCTT159 109021SNCA ASO 0157161.43 16.56TTCGTAGTCT TGATACCC160 109023SNCA ASO 0157259.6 23.23GTTCGTAGT CTTGATACC161 109024 id="p-228" id="p-228" id="p-228" id="p-228" id="p-228" id="p-228" id="p-228" id="p-228"

[0228]Each modified oligonucleotide listed in Table Eis complementary to the human SNCA nucleic acid sequence (SEQ ID NO: 1) and is a 3-10-3 LNA gapmer. The gapmers are nucleobases in length, wherein the central gap segment comprises ten 2’-deoxynucleosides and each wing segments on the 5’ and 3’ ends comprise three LNA nucleosides. All cytosines throughout each gapmer are 5-methyl cytosines, and all internucleoside linkages are phosphorothioate linkages. [0229]The identified position in Table Ecorresponds to the "Start Site," i.e., the 5’ nucleoside to which the gapmer is complementary in the modified human nucleic acid sequence (SEQ ID NO: 1).

Table E. 3-10-3 LNA Gapmers Compound name % reduction (20 nM ASO) % reduction (2 nM ASO) Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 0144291.84 91.36TCATATACG AGTTGAC162 19976SNCA ASO 0144388.65 70.25GGGGTTCTC TAACGAC163 25555SNCA ASO 0144489.05 76.38TGGGGTTCT CTAACGA164 25556SNCA ASO 0144586.64 80.33ATGGGGTTC TCTAACG165 25557SNCA ASO 0144688.45 88.73CGATCGGA AGCTCCCT166 27764SNCA ASO 0144789.46 85.02GCGATCGG AAGCTCCC167 27765SNCA ASO 0144888.12 60.51GAGCGATCGGAAGCTC168 27767SNCA ASO 0144993.85 89.48TTCAAGAGC GATCGGA169 27772SNCA ASO 0145091.9 88.36TTTCAAGAG CGATCGG170 27773SNCA ASO 0145192.54 90.88CTTTAGAGT ATACGGA171 30794 WO 2022/189363 PCT/EP2022/055770 Compound name % reduction (20 nM ASO) % reduction (2 nM ASO) Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 0145292.19 92.64CCTTTAGAG TATACGG172 30795SNCA ASO 0145391.27 89.18CCACGGCA CAATTTGA173 30825SNCA ASO 0145488.09 90.9TACAACTAA CCACGGC174 30834SNCA ASO 0145590.25 84.95CTAGCGAA GGACTATA175 33635SNCA ASO 0145688.63 78.7GCTAGCGA AGGACTAT176 33636SNCA ASO 0145790.24 87.29TGCTAGCGA AGGACTA177 33637SNCA ASO 0145891.83 83.36CGTGGCTAT ATCACTA178 35363SNCA ASO 0145991.07 86.2TACTATCTT ACGTGGC179 35373SNCA ASO 0146088.38 79.63AGCCGCTAC TGCTTAA180 40922SNCA ASO 0146175.61 36.09TAGCCGCTA CTGCTTA181 40923SNCA ASO 0146289.37 85.29CACATAAA GTAGCCGC182 40932SNCA ASO 0146382.9 78.1TGGACAGG CGCTTATC183 41591SNCA ASO 0146490.13 76.21TTAATAGCC GACATAC184 49741SNCA ASO 0146591.74 90.68CGATTAATC AACTGGC185 54363SNCA ASO 0146688.11 82.36CGGATGTCC GTGTGTG186 59971SNCA ASO 0146789.87 84.88GATCGATTA AGTGGAG187 60754SNCA ASO 0146890.06 81.92AAGATCGA TTAAGTGG188 60756SNCA ASO 0146989.82 89.77GCTCGAGAT TAGTTCT189 69473SNCA ASO 0147089.87 84.21TGCTCGAGA TTAGTTC190 69474SNCA ASO 0147188.72 67.05ATATGCTCG AGATTAG191 69477SNCA ASO 0147279.21 76.19TGTAACCAC GCCCTTA192 72245SNCA ASO 0147384.27 68.53GAAGCATG CGGCTACC193 76062SNCA ASO 0147489.88 85.07TCGATAATA GCTAAGC194 78175SNCA ASO 0147586.87GGTTCGATA ATAGCTA195 78178SNCA ASO 0147647.73 26.67GCGGCAAC ATGGGTTA196 106203 WO 2022/189363 PCT/EP2022/055770 Compound name % reduction (20 nM ASO) % reduction (2 nM ASO) Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 0147756.39 28.27ACATTGCGG CAACATG197 106208SNCA ASO 0147875.75 34.02GAAACATT GCGGCAAC198 106211SNCA ASO 0147989.75 70.77CGTAGTCTT GATACCC199 109023SNCA ASO 0148088.96 50.96TCGTAGTCT TGATACC200 109024SNCA ASO 0148174.88 36.38GCTTCAGGT TCGTAGT201 109033 id="p-230" id="p-230" id="p-230" id="p-230" id="p-230" id="p-230" id="p-230" id="p-230"

[0230]Each modified oligonucleotide listed in Table Fis complementary to the human SNCA nucleic acid sequence (SEQ ID NO: 1) and is a 3-11-3 LNA gapmer. The gapmers are nucleobases in length, wherein the central gap segment comprises eleven 2’-deoxynucleosides and is flanked by wing segments on both 5’ and 3’ end comprising three LNA nucleosides. All cytosines residues throughout each gapmer are 5-methyl cytosines, and all internucleoside linkages are phosphorothioate linkages. [0231]The identified position in Table Fcorresponds to the "Start Site" i.e. the 5’ nucleoside to which the gapmer is complementary in the human nucleic acid sequence (SEQ IDNO:1).

Table F. 3-11-3 LNA Gapmers Compound name % reduction (20 nM ASO) % reduction (2 nM ASO) Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 0148273.1 58.15GATACGGTC ATTCAGTA202 12279SNCA ASO 0148391.73 90.53CTTCATATA CGAGTTGA203 19977SNCA ASO 0148489.5 83.82GGGTTCTCT AACGACAG204 25553SNCA ASO 0148586.15 60.66TGGGGTTCT CTAACGAC205 25555SNCA ASO 0148685.97 86.26ATGGGGTTC TCTAACGA206 25556SNCA ASO 0148785.29 83.66GCGATCGGA AGCTCCCT207 27764SNCA ASO 0148886.31 86.29AGCGATCGG AAGCTCCC208 27765SNCA ASO 0148982.5 38.59GAGCGATCG GAAGCTCC209 27766SNCA ASO 0149085.82 61.64TTCAAGAGC GATCGGAA210 27771 WO 2022/189363 PCT/EP2022/055770 Compound name % reduction (20 nM ASO) % reduction (2 nM ASO) Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 0149185.42 86.32TTTTCAAGA GCGATCGG211 27773SNCA ASO0149288.42 88.97GTTTTCAAG AGCGATCG212 27774SNCA ASO 0149390.44 89.31GTTGCTATC TAGGGATC213 29772SNCA ASO 0149490.09 84.27ACCACGGCA CAATTTGA214 30825SNCA ASO 0149589.74 75.35CTAGCGAAG GACTATAT215 33634SNCA ASO 0149682.13 56.81GCTAGCGAA GGACTATA216 33635SNCA ASO 0149789.66 74.3TGCTAGCGA AGGACTAT217 33636SNCA ASO 0149891.93 85ACGTGGCTA TATCACTA218 35363SNCA ASO0149987.56 82.24GCCAGGCGA GAATTTGC219 40023SNCA ASO 0150080.04 77.83CTGGACAGG CGCTTATC220 41591SNCA ASO 0150185.11 71.53TCTGGACAG GCGCTTAT221 41592SNCA ASO0150281.75 39.67ACGTGGCCA GATCAATC222 48684SNCA ASO 0150392.39 82.02ATCTACAGA CACGGCTT223 52720SNCA ASO 0150484.65 71.57GCCTCACGG ATGTCCGT224 59976SNCA ASO 0150589.07 78.71AGATCGATT AAGTGGAG225 60754SNCA ASO 0150687.82 68.11ATAAGATCG ATTAAGTG226 60757SNCA ASO 0150788.38 83.61GCGTATGGG CATCTCCA227 64115SNCA ASO 0150889.95 81.02TGCGTATGG GCATCTCC228 64116SNCA ASO0150984.51 85.54CTTTCTGCG TATGGGCA229 64121SNCA ASO 0151086.8 85GCTTTCTGC GTATGGGC230 64122SNCA ASO 0151186.12 76.59GACCTCCAT CAGTAGTA231 65615SNCA ASO 0151287.88 85.32TCGAGATTA GTTCTTCC232 69470SNCA ASO 0151388.06 85.21CTCGAGATT AGTTCTTC233 69471SNCA ASO 0151487.53 84.41GCTCGAGAT TAGTTCTT234 69472SNCA ASO 0151587.05 84.6TGCTCGAGA TTAGTTCT235 69473 WO 2022/189363 PCT/EP2022/055770 Compound name % reduction (20 nM ASO) % reduction (2 nM ASO) Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 0151678.8 80.93TATCTGTAA CCACGCCC236 72248SNCA ASO 0151743.2 14.63TGCGGCTAC CATGCTAC237 76055SNCA ASO 0151827.72 4.5GCATGCGGC TACCATGC238 76058SNCA ASO 0151986.73 80.28GTTCGATAA TAGCTAAG239 78176SNCA ASO0152082.4 83.76GGTTCGATA ATAGCTAA240 78177SNCA ASO 0152187.9 84.41GAAGAGAT GGTTCGATA241 78185SNCA ASO 0152285.18 77.71AATCGTGTT TATCCTCG242 N/ASNCA ASO 0152378.22 46.69GGAAACATT GCGGCAAC243 106211SNCA ASO 0152488.01 76.7CGTAGTCTT GATACCCT244 109022SNCA ASO 0152590.64 72.76TCGTAGTCT TGATACCC245 109023SNCA ASO0152669.2 54.44GCTTCAGGT TCGTAGTC246 109032SNCA ASO 0152777.67 52.98TAGGCTTCA GGTTCGTA247 N/A Example 2: mRNA Reduction in vitro Following a Single Dose of MOE-Modified ASO [0232]Modified oligonucleotides complementary to the human SNCA nucleic acid sequence were designed and tested in vitro in primary cortical neurons for their selectiveefficacy in reducing SNCA mRNA levels. Neurons were treated with 300 nM of each antisense oligonucleotide. mRNA levels were quantified using qRT-PCR (TaqMan™) with the following probes: TGGCAACAGTGGCTGAGAAGACCAA (SEQ ID NO: 248) with the primers Hs00240906_ml SNCA (ThermoFisher), andCCAAGACTGAATGGCTGGATGGCAA (SEQ ID NO: 249) with the primersPPIA_MmO234243 0_g 1 (Therm0Fi sher) (control). id="p-233" id="p-233" id="p-233" id="p-233" id="p-233" id="p-233" id="p-233" id="p-233"

[0233]Each modified oligonucleotide listed in Table Gand Table His complementary to the human SNCA DNA (SEQ ID NO: 1) or mRNA (SEQ ID NO: 3) sequence. The sequences in Table Gare complementary to exons of the mRNA sequence, whereas thesequences in Table Hare complementary to the introns of the mRNA sequence. Each ASO WO 2022/189363 PCT/EP2022/055770 is a 5-10-5 MOE gapmer that is 20 nucleobases in length, wherein the central gap segment comprises ten 2’-deoxynucleosides and the wing segments on both 5’ and 3’ ends comprise five 2’-MOE nucleosides. All cytosines residues throughout each gapmer are 5-methyl cytosines, and all internucleoside linkages are phosphorothioate linkages. [0234]The identified position in Table Gand Table Hcorresponds to the "start site,"i .e., the 5’ nucleoside to which the gapmer is complementary in the modified human nucleic acid sequences SEQ ID NO: 1 and SEQ ID NO: 3. "#N/A" signifies that the sequence does not align to SEQ ID NO: 1 (e.g., where the sequence bridges an exon-exon junction only present in the mature mRNA).

Table G. MOE-Modified ASOs Complementary to SNCA RNA Exons Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 3 Position in SEQ ID NO: 1 SNCA ASO 00031TCCTTGGCCT TTGAAAGTCC250 19 19SNCA ASO00033CCAACATTTG TCACTTGCTC251 181 13307SNCA ASO00037CCTTTCATGA ATACATCCAT252 1 1SNCA ASO 00038TCCTTTCATG AATACATCCA253 2 2SNCA ASO00039GTCCTTTCAT GAATACATCC254 3 3SNCA ASO00040AGTCCTTTCA TGAATACATC255 4 4SNCA ASO 00041AAGTCCTTTC ATGAATACAT256 5 5SNCA ASO 00042CTTGGCCTTT GAAAGTCCTT257 17 17SNCA ASO 00043CCTTGGCCTT TGAAAGTCCT258 18 18SNCA ASO00044CTCCTTGGCC TTTGAAAGTC259 20 20SNCA ASO 00045CCTCCTTGGC CTTTGAAAGT260 21 21SNCA ASO 00046CCCTCCTTGG CCTTTGAAAG261 22 22SNCA ASO 00047TCCCTCCTTG GCCTTTGAAA262 23 23SNCA ASO 00048CTCCCTCCTTGGCCTTTGAA263 24 24SNCA ASO 00049ACTCCCTCCT TGGCCTTTGA264 25 25SNCA ASO 00050AACTCCCTCC TTGGCCTTTG265 26 26 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 3 Position in SEQ ID NO: 1 SNCA ASO 00051CAACTCCCTC CTTGGCCTTT266 27 27SNCA ASO 00052ACAACTCCCT CCTTGGCCTT267 28 28SNCA ASO 00053CACAACTCCC TCCTTGGCCT268 29 29SNCA ASO 00054CCACAACTCC CTCCTTGGCC269 30 30SNCA ASO 00055GCCACAACTC CCTCCTTGGC270 31 31SNCA ASO 00056AGCCACAACT CCCTCCTTGG271 32 32SNCA ASO00057CAGCCACAAC TCCCTCCTTG272 33 33SNCA ASO 00058GCAGCCACAA CTCCCTCCTT273 34 34SNCA ASO 00059TCAGCAGCAG CCACAACTCC274 40 40SNCA ASO 00060CTCAGCAGCA GCCACAACTC275 41 41SNCA ASO 00061TCTCAGCAGC AGCCACAACT276 42 42SNCA ASO 00062TTCTCAGCAG CAGCCACAAC277 43 43SNCA ASO 00063TTTCTCAGCA GCAGCCACAA278 44 44SNCA ASO 00064TTTTCTCAGC AGCAGCCACA279 45 45SNCA ASO 00065GTTTTCTCAG CAGCAGCCAC280 46 46SNCA ASO 00066GGTTTTCTCA GCAGCAGCCA281 47 47SNCA ASO00067TGGTTTTCTC AGCAGCAGCC282 48 48SNCA ASO 00068TTGGTTTTCTC AGCAGCAGC283 49 49SNCA ASO 00069TTTGGTTTTCT CAGCAGCAG284 50 50SNCA ASO 00070GTTTGGTTTTC TCAGCAGCA285 51 51SNCA ASO 00071TGTTTGGTTTT CTCAGCAGC286 52 52SNCA ASO00072CTGTTTGGTTT TCTCAGCAG287 53 53SNCA ASO 00073CCTGTTTGGT TTTCTCAGCA288 54 54SNCA ASO 00074CCCTGTTTGG TTTTCTCAGC289 55 55SNCA ASO 00075ACCCTGTTTG GTTTTCTCAG290 56 56 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 3 Position in SEQ ID NO: 1 SNCA ASO00076CACCCTGTTTGGTTTTCTCA291 57 57SNCA ASO 00077ACACCCTGTT TGGTTTTCTC292 58 58SNCA ASO 00078CACACCCTGT TTGGTTTTCT293 59 59SNCA ASO00079CCACACCCTG TTTGGTTTTC294 60 60SNCA ASO00080GCCACACCCT GTTTGGTTTT295 61 61SNCA ASO 00081TGCCACACCC TGTTTGGTTT296 62 62SNCA ASO 00082CTGCCACACC CTGTTTGGTT297 63 63SNCA ASO 00083TCTGCCACAC CCTGTTTGGT298 64 64SNCA ASO00084TTCTGCCACA CCCTGTTTGG299 65 65SNCA ASO 00085CTTCTGCCAC ACCCTGTTTG300 66 66SNCA ASO 00086GCTTCTGCCA CACCCTGTTT301 67 67SNCA ASO 00087TGCTTCTGCC ACACCCTGTT302 68 68SNCA ASO 00088CTGCTTCTGC CACACCCTGT303 69 69SNCA ASO 00089GCTGCTTCTG CCACACCCTG304 70 70SNCA ASO 00090TGCTGCTTCT GCCACACCCT305 71 71SNCA ASO 00091CTGCTGCTTC TGCCACACCC306 72 72SNCA ASO00092CCTGCTGCTT CTGCCACACC307 73 73SNCA ASO00093TCCTGCTGCT TCTGCCACAC308 74 74SNCA ASO 00094TTCCTGCTGC TTCTGCCACA309 75 75SNCA ASO 00095TTTCCTGCTG CTTCTGCCAC310 76 76SNCA ASO 00096CTTTCCTGCT GCTTCTGCCA311 77 77SNCA ASO00097TCTTTCCTGCT GCTTCTGCC312 78 78SNCA ASO 00098GTCTTTCCTGCTGCTTCTGC313 79 79SNCA ASO00099TGTCTTTCCTG CTGCTTCTG314 80 80SNCA ASO 00100TTGTCTTTCCT GCTGCTTCT315 81 81 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 3 Position in SEQ ID NO: 1 SNCA ASO 00101TTTGTCTTTCC TGCTGCTTC316 82 82SNCA ASO 00102TTTTGTCTTTC CTGCTGCTT317 83 83SNCA ASO 00103CTTTTGTCTTT CCTGCTGCT318 84 84SNCA ASO 00104TCTTTTGTCTT TCCTGCTGC319 85 85SNCA ASO 00105CTCTTTTGTCT TTCCTGCTG320 86 86SNCA ASO 00106CCTCTTTTGTC TTTCCTGCT321 87 87SNCA ASO 00107CCCTCTTTTGT CTTTCCTGC322 88 88SNCA ASO 00108ACCCTCTTTT GTCTTTCCTG323 89 89SNCA ASO 00109CACCCTCTTTT GTCTTTCCT324 90 90SNCA ASO 00110ACACCCTCTT TTGTCTTTCC325 91 91SNCA ASO 00111AACACCCTCT TTTGTCTTTC326 92 92SNCA ASO 00112GAACACCCTC TTTTGTCTTT327 93 93SNCA ASO 00113AGAACACCCT CTTTTGTCTT328 94 94SNCA ASO 00114GAGAACACCC TCTTTTGTCT329 95 95SNCA ASO 00115CCTACATAGAGAACACCCTC330 103 103SNCA ASO 00116GCCTACATAG AGAACACCCT331 104 #N/ASNCA ASO 00117AGCCTACATA GAGAACACCC332 105 #N/ASNCA ASO 00118GAGCCTACAT AGAGAACACC333 106 #N/ASNCA ASO 00119GGAGCCTACATAGAGAACAC334 107 #N/ASNCA ASO 00120TGGAGCCTAC ATAGAGAACA335 108 #N/ASNCA ASO 00121TTGGAGCCTA CATAGAGAAC336 109 #N/ASNCA ASO00122TTTGGAGCCTACATAGAGAA337 110 #N/ASNCA ASO 00123TTTTGGAGCCTACATAGAGA338 ill #N/ASNCA ASO 00124GTTTTGGAGCCTACATAGAG339 112 #N/ASNCA ASO 00125GGTTTTGGAG CCTACATAGA340 113 #N/A WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 3 Position in SEQ ID NO: 1 SNCA ASO00126TGGTTTTGGA GCCTACATAG341 114 #N/ASNCA ASO 00127TTGGTTTTGGAGCCTACATA342 115 #N/ASNCA ASO 00128CTTGGTTTTG GAGCCTACAT343 116 #N/ASNCA ASO00129CCTTGGTTTT GGAGCCTACA344 117 7488SNCA ASO 00130TCCTTGGTTTT GGAGCCTAC345 118 7489SNCA ASO 00131ACTCCCTCCT TGGTTTTGGA346 124 7495SNCA ASO00132CACTCCCTCCTTGGTTTTGG347 125 7496SNCA ASO 00133CCACTCCCTC CTTGGTTTTG348 126 7497SNCA ASO 00134TCAGCCACTG TTGCCACACC349 151 #N/ASNCA ASO 00135CTCAGCCACTGTTGCCACAC350 152 #N/ASNCA ASO00136TCTCAGCCACTGTTGCCACA351 153 #N/ASNCA ASO 00137TTCTCAGCCA CTGTTGCCAC352 154 #N/ASNCA ASO 00138CTTCTCAGCC ACTGTTGCCA353 155 #N/ASNCA ASO00139TCTTCTCAGC CACTGTTGCC354 156 #N/ASNCA ASO 00140GTCTTCTCAGCCACTGTTGC355 157 #N/ASNCA ASO 00141GGTCTTCTCA GCCACTGTTG356 158 #N/ASNCA ASO 00142TGGTCTTCTC AGCCACTGTT357 159 #N/ASNCA ASO 00143TTGGTCTTCTC AGCCACTGT358 160 #N/ASNCA ASO 00144TTTGGTCTTCT CAGCCACTG359 161 13287SNCA ASO 00145CTTGCTCTTTG GTCTTCTCA360 168 13294SNCA ASO 00146ACTTGCTCTTT GGTCTTCTC361 169 13295SNCA ASO 00147TGTCACTTGC TCTTTGGTCT362 173 13299SNCA ASO 00148TTGTCACTTG CTCTTTGGTC363 174 13300SNCA ASO 00149TTTGTCACTT GCTCTTTGGT364 175 13301SNCA ASO 00150ATTTGTCACT TGCTCTTTGG365 176 13302 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 3 Position in SEQ ID NO: 1 SNCA ASO 00151CATTTGTCAC TTGCTCTTTG366 177 13303SNCA ASO00152ACATTTGTCA CTTGCTCTTT367 178 13304SNCA ASO 00153AACATTTGTC ACTTGCTCTT368 179 13305SNCA ASO 00154CAACATTTGT CACTTGCTCT369 180 13306SNCA ASO 00155TCCAACATTTGTCACTTGCT370 182 13308SNCA ASO 00156CTCCAACATT TGTCACTTGC371 183 13309SNCA ASO 00157CTCCTCCAAC ATTTGTCACT372 186 13312SNCA ASO 00158GCTCCTCCAA CATTTGTCAC373 187 13313SNCA ASO00159GCTGTCACAC CCGTCACCAC374 208 13334SNCA ASO 00160TGCTGTCACA CCCGTCACCA375 209 13335SNCA ASO 00161CTGCTGTCAC ACCCGTCACC376 210 13336SNCA ASO00162ACTGCTGTCACACCCGTCAC377 211 13337SNCA ASO 00163TACTGCTGTC ACACCCGTCA378 212 13338SNCA ASO 00164CTACTGCTGT CACACCCGTC379 213 13339SNCA ASO 00165GCTACTGCTGTCACACCCGT380 214 13340SNCA ASO 00166GGCTACTGCT GTCACACCCG381 215 13341SNCA ASO 00167GGGCTACTGC TGTCACACCC382 216 13342SNCA ASO 00168TGGGCTACTG CTGTCACACC383 217 13343SNCA ASO00169CTGGGCTACTGCTGTCACAC384 218 13344SNCA ASO 00170TCTGGGCTACTGCTGTCACA385 219 13345SNCA ASO 00171TTCTGGGCTACTGCTGTCAC386 220 13346SNCA ASO 00172CTTCTGGGCTACTGCTGTCA387 221 13347SNCA ASO 00173TCTTCTGGGCTACTGCTGTC388 222 13348SNCA ASO 00174GTCTTCTGGG CTACTGCTGT389 223 13349SNCA ASO 00175TGTCTTCTGG GCTACTGCTG390 224 13350 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 3 Position in SEQ ID NO: 1 SNCA ASO 00176CTGTCTTCTG GGCTACTGCT391 225 13351SNCA ASO 00177ACTGTCTTCT GGGCTACTGC392 226 13352SNCA ASO 00178CACTGTCTTC TGGGCTACTG393 227 13353SNCA ASO 00179CCACTGTCTT CTGGGCTACT394 228 13354SNCA ASO 00180TCCACTGTCT TCTGGGCTAC395 229 13355SNCA ASO 00181CTCCACTGTC TTCTGGGCTA396 230 13356SNCA ASO 00182CCTCCACTGTCTTCTGGGCT397 231 13357SNCA ASO 00183CCCTCCACTG TCTTCTGGGC398 232 13358SNCA ASO 00184TCCCTCCACT GTCTTCTGGG399 233 13359SNCA ASO 00185CTCCCTCCACTGTCTTCTGG400 234 13360SNCA ASO 00186GCTCCCTCCA CTGTCTTCTG401 235 13361SNCA ASO 00187TGCTCCCTCCACTGTCTTCT402 236 13362SNCA ASO 00188CTGCTCCCTCCACTGTCTTC403 237 13363SNCA ASO 00189CCCTGCTCCCTCCACTGTCT404 239 13365SNCA ASO 00190TCCCTGCTCC CTCCACTGTC405 240 13366SNCA ASO 00191CTCCCTGCTC CCTCCACTGT406 241 13367SNCA ASO00192GCTCCCTGCTCCCTCCACTG407 242 13368SNCA ASO 00193TGCTCCCTCC TCCCTCCACT408 243 13369SNCA ASO 00194ATGCTCCCTG CTCCCTCCAC409 244 13370SNCA ASO 00195AATGCTCCCT GCTCCCTCCA410 245 13371SNCA ASO00196CAATGCTCCC TGCTCCCTCC411 246 13372SNCA ASO 00197GCAATGCTCC CTGCTCCCTC412 247 13373SNCA ASO 00198TGCAATGCTC CCTGCTCCCT413 248 13374SNCA ASO00199CTGCAATGCT CCCTGCTCCC414 249 13375SNCA ASO 00200GCTGCAATGC TCCCTGCTCC415 250 13376 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 3 Position in SEQ ID NO: 1 SNCA ASO 00201TGCTGCAATG CTCCCTGCTC416 251 13377SNCA ASO00202CTGCTGCAAT GCTCCCTGCT417 252 13378SNCA ASO00203GCTGCTGCAA TGCTCCCTGC418 253 13379SNCA ASO 00204GGCTGCTGCA ATGCTCCCTG419 254 13380SNCA ASO 00205TGGCTGCTGCAATGCTCCCT420 255 13381SNCA ASO 00206GTGGCTGCTG CAATGCTCCC421 256 13382SNCA ASO00207AGTGGCTGCT GCAATGCTCC422 257 13383SNCA ASO 00208CAGTGGCTGC TGCAATGCTC423 258 13384SNCA ASO00209CCAGTGGCTG CTGCAATGCT424 259 13385SNCA ASO 00210GCCAGTGGCTGCTGCAATGC425 260 13386SNCA ASO 00211GCCCAACTGG TCCTTTTTGA426 284 13410SNCA ASO00212TGCCCAACTG GTCCTTTTTG427 285 13411SNCA ASO 00213TTGCCCAACT GGTCCTTTTT428 286 13412SNCA ASO 00214CTTGCCCAAC TGGTCCTTTT429 287 13413SNCA ASO 00215TCTTGCCCAA CTGGTCCTTT430 288 #N/ASNCA ASO00216TTCTTGCCCA ACTGGTCCTT431 289 #N/ASNCA ASO 00217ATTCTTGCCC AACTGGTCCT432 290 #N/ASNCA ASO 00218CATTCTTGCC CAACTGGTCC433 291 #N/ASNCA ASO00219TCATTCTTGC CCAACTGGTC434 292 #N/ASNCA ASO00220TTCATTCTTGC CCAACTGGT435 293 #N/ASNCA ASO 00221CTTCATTCTTG CCCAACTGG436 294 #N/ASNCA ASO00222TCTTCATTCTT GCCCAACTG437 295 #N/ASNCA ASO00223TTCTTCATTCT TGCCCAACT438 296 #N/ASNCA ASO 00224CTTCTTCATTC TTGCCCAAC439 297 #N/ASNCA ASO00225CCTTCTTCATT CTTGCCCAA440 298 #N/A WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 3 Position in SEQ ID NO: 1 SNCA ASO00226TCCTTCTTCAT TCTTGCCCA441 299 #N/ASNCA ASO 00227CTCCTTCTTCA TTCTTGCCC442 300 #N/ASNCA ASO 00228GCTCCTTCTTC ATTCTTGCC443 301 #N/ASNCA ASO00229GGCTCCTTCT TCATTCTTGC444 302 #N/ASNCA ASO00230GGGCTCCTTC TTCATTCTTG445 303 #N/ASNCA ASO 00231GGGGCTCCTT CTTCATTCTT446 304 #N/ASNCA ASO00232TGGGGCTCCT TCTTCATTCT447 305 106399SNCA ASO00233GTGGGGCTCC TTCTTCATTC448 306 106400SNCA ASO 00234TGTGGGGCTC CTTCTTCATT449 307 106401SNCA ASO00235CTGTGGGGCT CCTTCTTCAT450 308 106402SNCA ASO00236CCTGTGGGGC TCCTTCTTCA451 309 106403SNCA ASO 00237TCCTGTGGGG CTCCTTCTTC452 310 106404SNCA ASO 00238TTCCTGTGGG GCTCCTTCTT453 311 106405SNCA ASO00239CTTCCTGTGGGGCTCCTTCT454 312 106406SNCA ASO 00240CCTTCCTGTG GGGCTCCTTC455 313 106407SNCA ASO 00241TCCTTCCTGT GGGGCTCCTT456 314 106408SNCA ASO 00242TTCCTTCCTGT GGGGCTCCT457 315 106409SNCA ASO 00243ATTCCTTCCT GTGGGGCTCC458 316 106410SNCA ASO 00244AATTCCTTCC TGTGGGGCTC459 317 106411SNCA ASO 00245GAATTCCTTC CTGTGGGGCT460 318 106412SNCA ASO 00246AGAATTCCTT CCTGTGGGGC461 319 106413SNCA ASO00247AGGATCCACA GGCATATCTT462 341 106435SNCA ASO 00248CAGGATCCAC AGGCATATCT463 342 106436SNCA ASO 00249TCAGGATCCA CAGGCATATC464 343 106437SNCA ASO 00250GTCAGGATCC ACAGGCATAT465 344 106438 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 3 Position in SEQ ID NO: 1 SNCA ASO 00251TGTCAGGATC CACAGGCATA466 345 106439SNCA ASO00252TTGTCAGGAT CCACAGGCAT467 346 106440SNCA ASO00253AGCCTCATTG TCAGGATCCA468 353 106447SNCA ASO 00254AAGCCTCATT GTCAGGATCC469 354 106448SNCA ASO00255TAAGCCTCATTGTCAGGATC470 355 106449SNCA ASO00256ATAAGCCTCA TTGTCAGGAT471 356 106450SNCA ASO 00257CATAAGCCTC ATTGTCAGGA472 357 106451SNCA ASO 00258GCATTTCATA AGCCTCATTG473 363 106457SNCA ASO00259GGCATTTCAT AAGCCTCATT474 364 106458SNCA ASO 00260CAGAAGGCAT TTCATAAGCC475 369 106463SNCA ASO 00261TCAGAAGGCA TTTCATAAGC476 370 106464SNCA ASO00262CTCAGAAGGC ATTTCATAAG477 371 106465SNCA ASO00263CCTCAGAAGG CATTTCATAA478 372 106466SNCA ASO 00264TCCTCAGAAG GCATTTCATA479 373 #N/ASNCA ASO00265TTCCTCAGAA GGCATTTCAT480 374 #N/ASNCA ASO00266CTTGATACCC TTCCTCAGAA481 384 #N/ASNCA ASO 00267TCTTGATACC CTTCCTCAGA482 385 #N/ASNCA ASO 00268GTCTTGATAC CCTTCCTCAG483 386 #N/ASNCA ASO00269AGTCTTGATA CCCTTCCTCA484 387 #N/ASNCA ASO00270TAGTCTTGATACCCTTCCTC485 388 #N/ASNCA ASO 00271GTAGTCTTGA TACCCTTCCT486 389 109018SNCA ASO 00272CGTAGTCTTGATACCCTTCC390 109019SNCA ASO 00273TCGTAGTCTT GATACCCTTC487 391 109020SNCA ASO00274TTCGTAGTCT TGATACCCTT488 392 109021SNCA ASO 00275GTTCGTAGTCTTGATACCCT393 109022 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 3 Position in SEQ ID NO: 1 SNCA ASO 00276GGTTCGTAGT CTTGATACCC394 109023SNCA ASO 00277AGGTTCGTAG TCTTGATACC395 109024SNCA ASO 00278CAGGTTCGTA GTCTTGATAC396 109025SNCA ASO 00279TCAGGTTCGTAGTCTTGATA489 397 109026SNCA ASO 00280TTCAGGTTCG TAGTCTTGAT398 109027SNCA ASO 00281CTTCAGGTTC GTAGTCTTGA490 399 109028SNCA ASO 00282GCTTCAGGTT CGTAGTCTTG491 400 109029SNCA ASO 00283GGCTTCAGGT TCGTAGTCTT492 401 109030SNCA ASO 00284AGGCTTCAGG TTCGTAGTCT493 402 109031SNCA ASO 00285TAGGCTTCAG GTTCGTAGTC494 403 #N/ASNCA ASO 00286TTAGGCTTCA GGTTCGTAGT495 404 #N/A Table H. MOE-Modified ASOs Complementary to SNCA RNA Introns Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO00446TACCTCTGACTCAGTCCACC 496 243SNCA ASO 00447ATACCTCTGACTCAGTCCAC 497 244SNCA ASO 00448ACAGGGGCATATCAAAGTCA 498 547SNCA ASO 00449CCCTCAAGCACTTTTCTCTG 499 671SNCA ASO 00450CAGCCCTCAAGCACTTTTCT 500 674SNCA ASO 00451TCAGCTAGGCAACTCAATGT 501 1058SNCA ASO 00452TGTTTCAGCTAGGCAACTCA 502 1062SNCA ASO 00453ACAAGACAATTCCAGCCCAC 503 2298SNCA ASO00454TGGTTTGTGTGATTAGTGCA 504 2358SNCA ASO 00455GGGAAGTGATGCTCAGAGAT 505 2438SNCA ASO 00456GAGTGGAGAAGAAGGTCAGA 506 3188 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 00457AAAAGAGCACAGAGTGGAGA 507 3199SNCA ASO 00458CCCAACCTCAAAAGAGCACA 508 3208SNCA ASO 00459TCCCAACCTCAAAAGAGCAC 509 3209SNCA ASO 00460TTCCCAACCTCAAAAGAGCA 510 3210SNCA ASO 00461CTTCCCAACCTCAAAAGAGC 511 3211SNCA ASO 00462CTTGTCTTCCCAACCTCAAA 512 3216SNCA ASO 00463ATCTTGTCTTCCCAACCTCA 513 3218SNCA ASO00464CCCTTGCCACAAAAACAACA 514 4049SNCA ASO 00465GCCCTTGCCACAAAAACAAC 515 4050SNCA ASO 00466TGCCCTTGCCACAAAAACAA 516 4051SNCA ASO 00467GCTGCCCTTGCCACAAAAAC 517 4053SNCA ASO 00468TGGATTTTAGCTGCCCTTGC 518 4062SNCA ASO 00469TGCTTGGAATCCCAGTGCTT 519 4965SNCA ASO 00470TTGCTTGGAATCCCAGTGCT 520 4966SNCA ASO 00471CTTGCTTGGAATCCCAGTGC 521 4967SNCA ASO00472AGAGGCTGACAAGGGTAAGA 522 5403SNCA ASO 00473GGGCATTGCTGTCTGTATGA 523 5909SNCA ASO 00474GCAGTGACAACATCCTCAGG 524 6106SNCA ASO 00475CAGCAGTGACAACATCCTCA 525 6108SNCA ASO 00476AATTGCAGCAGTGACAACAT 526 6113SNCA ASO 00477TGAATTGCAGCAGTGACAAC 527 6115SNCA ASO 00478CTGGGACACCTTCACTCTTT 528 6209SNCA ASO00479CCCTTTGTTCCCACATCACA 529 7210SNCA ASO00480CCCCTTTGTTCCCACATCAC 530 7211SNCA ASO 00481TCCCCTTTGTTCCCACATCA 531 7212 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 00482ATCCCCTTTGTTCCCACATC 532 7213SNCA ASO 00483TATCCCCTTTGTTCCCACAT 533 7214SNCA ASO 00484TTATCCCCTTTGTTCCCACA 534 7215SNCA ASO 00485AGCTTACCTGTTGCCACACC 535 7522SNCA ASO00486GAGCTTACCTGTTGCCACAC 536 7523SNCA ASO 00487GGAGCTTACCTGTTGCCACA 537 7524SNCA ASO 00488TGGAGCTTACCTGTTGCCAC 538 7525SNCA ASO 00489TGGGCCACACTAATCACTAG 539 7579SNCA ASO 00490ACTGGGCCACACTAATCACT 540 7581SNCA ASO 00491ATACTGGGCCACACTAATCA 541 7583SNCA ASO 00492TTTCTGGCACTCTCATCCTC 542 8181SNCA ASO 00493CAGAGCCCATTAAAGGTGCA 543 8791SNCA ASO 00494ACAGAGCCCATTAAAGGTGC 544 8792SNCA ASO 00495AACAGAGCCCATTAAAGGTG 545 8793SNCA ASO 00496CAACAGAGCCCATTAAAGGT 546 8794SNCA ASO00497GCAACAGAGCCCATTAAAGG 547 8795SNCA ASO 00498TGCAACAGAGCCCATTAAAG 548 8796SNCA ASO 00499TTGCAACAGAGCCCATTAAA 549 8797SNCA ASO 00500ATTGCAACAGAGCCCATTAA 550 8798SNCA ASO 00501GATTGCAACAGAGCCCATTA 551 8799SNCA ASO 00502GGATTGCAACAGAGCCCATT 552 8800SNCA ASO 00503TGGATTGCAACAGAGCCCAT 553 8801SNCA ASO 00504TTGGATTGCAACAGAGCCCA 554 8802SNCA ASO 00505CTCATGGGTTCTTCCTCAAC 555 8980SNCA ASO 00506ACCTCATGGGTTCTTCCTCA 556 8982 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO00507TTCACTACTGCCAGGGTGGT 557 9545SNCA ASO 00508ACTCCCCAGATAAGCCTCAG 558 11985SNCA ASO 00509TGGGGACACTCATCTAAGGA 559 12036SNCA ASO 00510GAGAGTGGAGGATGGGGACA 560 12048SNCA ASO 00511GAACAGTGGAGGAGAGTGGA 561 12059SNCA ASO00512GAGAACAGTGGAGGAGAGTG 562 12061SNCA ASO 00513TCTCAGCCACTGGTACAAAT 563 13279SNCA ASO 00514TTCTCAGCCACTGGTACAAA 564 13280SNCA ASO 00515CAAGGGGAGGGTCAGGTAGC 565 13537SNCA ASO 00516ACAAGGGGAGGGTCAGGTAG 566 13538SNCA ASO 00517CACAAGGGGAGGGTCAGGTA 567 13539SNCA ASO 00518GTCAGGGCAAGGGTATGCTT 568 14182SNCA ASO00519TGTCAGGGCAAGGGTATGCT 569 14183SNCA ASO 00520CACTCTCATGGTGCCTACAT 570 14572SNCA ASO 00521TTCACTCTCATGGTGCCTAC 571 14574SNCA ASO00522TTTCACTCTCATGGTGCCTA 572 14575SNCA ASO00523ATTTCACTCTCATGGTGCCT 573 14576SNCA ASO 00524GGAAACTCTCCCAGACACTT 574 14624SNCA ASO00525TGGAAACTCTCCCAGACACT 575 14625SNCA ASO00526TCTTGGACTACCCACTTCCT 576 15415SNCA ASO 00527GGGGAAGTGATATAGTGGCT 577 15480SNCA ASO 00528TGGGGAAGTGATATAGTGGC 578 15481SNCA ASO00529AGACCCAAAGGAAGGTAAGT 579 15515SNCA ASO 00530GTACATGTTTCCCTGTTGCT 580 15596SNCA ASO 00531AGGTGGTGTATGAGCAGAGA 581 15916 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO00532CAGGTGGTGTATGAGCAGAG 582 15917SNCA ASO00533GTCAGGTGGTGTATGAGCAG 583 15919SNCA ASO 00534AGTCAGGTGGTGTATGAGCA 584 15920SNCA ASO00535CAGTCAGGTGGTGTATGAGC 585 15921SNCA ASO00536CCAGTCAGGTGGTGTATGAG 586 15922SNCA ASO 00537CCGGTGCCATTACTCCCTTT 7 16401SNCA ASO 00538TGGGATAGACCAAGTGTTCT 587 17009SNCA ASO00539GCAAGACACTGTTGAGGAGC 588 17029SNCA ASO 00540ACAACTGGCTAGCTATCCTT 589 17504SNCA ASO 00541CACAACTGGCTAGCTATCCT 590 17505SNCA ASO 00542ACACAACTGGCTAGCTATCC 591 17506SNCA ASO 00543CACACAACTGGCTAGCTATC 592 17507SNCA ASO00544CAGAGGGTCCATAACACTCA 593 17667SNCA ASO 00545TCAGAGGGTCCATAACACTC 594 17668SNCA ASO 00546TGTGACCTGTGCTTGTTTGT 595 17747SNCA ASO 00547TTGCCTGTGACCTGTGCTTG 596 17752SNCA ASO 00548GTCAAGCACAAGGACAAGAA 597 17954SNCA ASO 00549AGTCAAGCACAAGGACAAGA 598 17955SNCA ASO 00550AAGTCAAGCACAAGGACAAG 599 17956SNCA ASO 00551GAAGTCAAGCACAAGGACAA 600 17957SNCA ASO00552TGAAGTCAAGCACAAGGACA 601 17958SNCA ASO00553TCTGAAGTCAAGCACAAGGA 602 17960SNCA ASO 00554GCAGTTCTATCCCACTCATC 4 18926SNCA ASO 00555ATGCAGTTCTATCCCACTCA 603 18928SNCA ASO 00556AAGGAACAAGGGAAGTGCAC 604 18983 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO00557GAAGGAACAAGGGAAGTGCA 605 18984SNCA ASO 00558TGAAGGAACAAGGGAAGTGC 606 18985SNCA ASO00559TCTGGCTCAGTATTCTTTGC 607 20158SNCA ASO 00560CCCACATCTAAGCAGGAAGA 608 20258SNCA ASO 00561CCATCATGCTGGATCAAACA 609 20946SNCA ASO00562GCCATCATGCTGGATCAAAC 610 20947SNCA ASO00563CTGGCCATCATGCTGGATCA 611 20950SNCA ASO 00564TCACACTCCAACCCTGGGCA 612 21314SNCA ASO 00565TTCACACTCCAACCCTGGGC 613 21315SNCA ASO 00566CATTCACACTCCAACCCTGG 614 21317SNCA ASO00567TCATTCACACTCCAACCCTG 615 21318SNCA ASO 00568GCAGATAAACCATCCCACTT 11 22295SNCA ASO00569TGCAGATAAACCATCCCACT 616 22296SNCA ASO00570TTGCAGATAAACCATCCCAC 8 22297SNCA ASO 00571AGGCAGTTGTGGTAGGGGTT 617 22602SNCA ASO 00572GGTGTTGTCTGAAAGCAGGA 618 22782SNCA ASO 00573TGGTGTTGTCTGAAAGCAGG 619 22783SNCA ASO 00574TTGGTGTTGTCTGAAAGCAG 620 22784SNCA ASO 00575GGGAGAAGGGATTTTCAAGG 621 22882SNCA ASO00576AGTGCCAGACCCTTTCATTA 9 22932SNCA ASO 00577CCAAGTGCCAGACCCTTTCA 10 22935SNCA ASO 00578TAGCATCCTTCCACACCATT 622 23408SNCA ASO 00579AATAGCATCCTTCCACACCA 5 23410SNCA ASO 00580CAATAGCATCCTTCCACACC 623 23411SNCA ASO 00581CAATAGCATCCTTCCACACC 623 23412 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 00582AAATGCAAAATGGGCTTCAC 624 23563SNCA ASO 00583TGCTTGTTGCCATGCTGGGG 625 23674SNCA ASO00584TGTGCTTGTTGCCATGCTGG 626 23676SNCA ASO 00585TTGTGCTTGTTGCCATGCTG 627 23677SNCA ASO 00586TTTGTGCTTGTTGCCATGCT 628 23678SNCA ASO 00587TTTTGTGCTTGTTGCCATGC 629 23679SNCA ASO 00588ATTTTGTGCTTGTTGCCATG 630 23680SNCA ASO 00589ATGGATGGGTGGACAAATGG 631 24058SNCA ASO 00590TGGATCAGATGGATGGGTGG 632 24066SNCA ASO 00591ATGGATCAGATGGATGGGTG 633 24067SNCA ASO00592AATGGATCAGATGGATGGGT 634 24068SNCA ASO00593CTTGGGCTGGACTTTTTTGC 635 26606SNCA ASO 00594GTCACTGGATGGTTGGGAGC 636 26998SNCA ASO00595GGTCACTGGATGGTTGGGAG 637 26999SNCA ASO00596AGGTCACTGGATGGTTGGGA 638 27000SNCA ASO 00597GAGGTCACTGGATGGTTGGG 639 27001SNCA ASO 00598AGAGGTCACTGGATGGTTGG 640 27002SNCA ASO00599TAAGAGGTCACTGGATGGTT 641 27004SNCA ASO 00600GCAATGGAACACTGCTACAT 642 28023SNCA ASO 00601TGCAATGGAACACTGCTACA 643 28024SNCA ASO 00602TTGCAATGGAACACTGCTAC 644 28025SNCA ASO 00603CTTGCAATGGAACACTGCTA 645 28026SNCA ASO 00604TCTTGCAATGGAACACTGCT 646 28027SNCA ASO 00605TTCTTGCAATGGAACACTGC 647 28028SNCA ASO 00606CTTCTTGCAATGGAACACTG 648 28029 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO00607CCTCAAGCCATCTAGCTCAA 649 28593SNCA ASO 00608CCCTCAAGCCATCTAGCTCA 650 28594SNCA ASO 00609ACCCTCAAGCCATCTAGCTC 651 28595SNCA ASO 00610GACCCTCAAGCCATCTAGCT 652 28596SNCA ASO 00611TGACCCTCAAGCCATCTAGC 653 28597SNCA ASO00612ATGACCCTCAAGCCATCTAG 654 28598SNCA ASO 00613CTATGACCCTCAAGCCATCT 655 28600SNCA ASO 00614GCTATGACCCTCAAGCCATC 55 28601SNCA ASO 00615CACCTTCAAACCCCTTTCAA 656 29753SNCA ASO 00616TCACCTTCAAACCCCTTTCA 657 29754SNCA ASO 00617ATCACCTTCAAACCCCTTTC 6 29755SNCA ASO 00618AGGGATCACCTTCAAACCCC 658 29759SNCA ASO00619TGTTTTGCTGCTCGAATCAT 659 29794SNCA ASO 00620TGAAGAACGAAGCAAGTTGT 660 30645SNCA ASO 00621CTGAAGAACGAAGCAAGTTG 661 30646SNCA ASO00622AACTGAAGAACGAAGCAAGT 662 30648SNCA ASO00623CAACTAACCACGGCACAATT 56 30828SNCA ASO 00624ACAACTAACCACGGCACAAT 663 30829SNCA ASO00625TACAACTAACCACGGCACAA 664 30830SNCA ASO00626GAGTTTTACCCAAGTGGCAC 665 33340SNCA ASO 00627GGAGGAAAGTAAGGTCAGGT 666 34639SNCA ASO 00628GGGAGGAAAGTAAGGTCAGG 667 34640SNCA ASO00629AGGGAGGAAAGTAAGGTCAG 668 34641SNCA ASO 00630GAGGGAGGAAAGTAAGGTCA 669 34642SNCA ASO 00631GGAGGGAGGAAAGTAAGGTC 670 34643 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO00632GAGTATTGTGTGTGCCCTTT 671 35204SNCA ASO00633TGAGTATTGTGTGTGCCCTT 672 35205SNCA ASO 00634GGGAAGAGGAAAAGCTTGGA 673 35562SNCA ASO00635AGCAGAGATTATGGCAGAGA 674 36416SNCA ASO00636CACAAGTAGGCAGCACAGGT 675 37759SNCA ASO 00637GCACAAGTAGGCAGCACAGG 676 37760SNCA ASO 00638TGCACAAGTAGGCAGCACAG 677 37761SNCA ASO00639AGCAAGGAAACTACAGCCCA 678 38425SNCA ASO 00640GCAATGGGATCCACCACAGC 679 38484SNCA ASO 00641AGCAATGGGATCCACCACAG 680 38485SNCA ASO 00642CAGCAATGGGATCCACCACA 681 38486SNCA ASO 00643GCAGCAATGGGATCCACCAC 682 38487SNCA ASO00644AAGTTTTGGAGTGGAGGAGT 683 38845SNCA ASO 00645GGAAAATATGGGGGCAACAG 684 39851SNCA ASO 00646GGGAAAATATGGGGGCAACA 685 39852SNCA ASO 00647GGGGAAAATATGGGGGCAAC 686 39853SNCA ASO 00648AGGGGAAAATATGGGGGCAA 687 39854SNCA ASO 00649GAGGGGAAAATATGGGGGCA 688 39855SNCA ASO 00650CACCAACCAACCAGAGGGGA 689 39868SNCA ASO 00651GCACCAACCAACCAGAGGGG 690 39869SNCA ASO00652AGCACCAACCAACCAGAGGG 691 39870SNCA ASO00653GAGCACCAACCAACCAGAGG 692 39871SNCA ASO 00654CAAAAGAGAAGCAACCCACT 693 40413SNCA ASO 00655GGGTCTCACTAGCCTAAAGT 694 42636SNCA ASO 00656GGGGTCTCACTAGCCTAAAG 695 42637 100 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO00657AGTGTGAGAGGAGCAAGCTG 696 45030SNCA ASO 00658GAGTCTCCATGAGCAATGCT 697 45715SNCA ASO00659CATTCCCAAGAGACCCAGAT 698 45873SNCA ASO 00660CCATTCCCAAGAGACCCAGA 699 45874SNCA ASO 00661ACCACCTGAGAACACTGAAT 700 46764SNCA ASO00662GACCACCTGAGAACACTGAA 701 46765SNCA ASO00663AGACCACCTGAGAACACTGA 702 46766SNCA ASO 00664GAGACCACCTGAGAACACTG 703 46767SNCA ASO 00665AGAGACCACCTGAGAACACT 704 46768SNCA ASO 00666TAGAGACCACCTGAGAACAC 705 46769SNCA ASO00667CTAGAGACCACCTGAGAACA 706 46770SNCA ASO 00668TGCCCAACTTACAATTCTCC 707 46929SNCA ASO00669ACTGCCATTGACCTCTGCTT 708 47247SNCA ASO00670CACTGCCATTGACCTCTGCT 709 47248SNCA ASO 00671ACACTGCCATTGACCTCTGC 710 47249SNCA ASO 00672CCACTTCACCCAGAATTCCT 711 47665SNCA ASO 00673AAACACACTTCAGACCACAC 712 49443SNCA ASO 00674AGCCGACATACATCTCCAAA 713 49732SNCA ASO 00675TAGCCGACATACATCTCCAA 57 49733SNCA ASO00676GTCAATCAACTGCATCCAGA 714 50632SNCA ASO 00677CTGTCAATCAACTGCATCCA 715 50634SNCA ASO 00678GGCACTAGGAGACCCTGGGA 716 51765SNCA ASO 00679CATGCATAAGCAGCCTGAGT 717 51841SNCA ASO 00680GTCATCATGCATAAGCAGCC 718 51846SNCA ASO 00681AACCCTTCTGTCATCATGCA 719 51855 101 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 00682TGGGAACCCTTCTGTCATCA 720 51859SNCA ASO 00683AGGCAGGGCTAGACAAAATG 721 52064SNCA ASO00684GAGGCAGGGCTAGACAAAAT 722 52065SNCA ASO 00685AGAGGCAGGGCTAGACAAAA 723 52066SNCA ASO 00686CAGAGGCAGGGCTAGACAAA 724 52067SNCA ASO 00687GGCAATCAAGCCAAACAAAT 725 52765SNCA ASO 00688ACCCTGCTAGCCAGAAGAGA 726 59374SNCA ASO 00689AACCCTGCTAGCCAGAAGAG 727 59375SNCA ASO 00690AAACCCTGCTAGCCAGAAGA 728 59376SNCA ASO 00691AGACCTAGTTCCCCTGCCCC 729 60164SNCA ASO00692GAGACCTAGTTCCCCTGCCC 730 60165SNCA ASO00693CTGAGAGGGGTGCTTTTAAG 731 60196SNCA ASO 00694TTCCTGAGAGGGGTGCTTTT 732 60199SNCA ASO00695TTTCCTGAGAGGGGTGCTTT 733 60200SNCA ASO00696CCATGAAGCTTAACCCTCTC 734 60572SNCA ASO 00697CCCATGAAGCTTAACCCTCT 735 60573SNCA ASO 00698TCCCATGAAGCTTAACCCTC 736 60574SNCA ASO00699TTCCCATGAAGCTTAACCCT 737 60575SNCA ASO 00700ACCCTGCTGATTTCCCATGA 738 60586SNCA ASO 00701CTACCCTGCTGATTTCCCAT 739 60588SNCA ASO00702ACTACCCTGCTGATTTCCCA 740 60589SNCA ASO 00703AACTACCCTGCTGATTTCCC 741 60590SNCA ASO 00704CCTTTTGACCCTCTGTTTGC 742 62701SNCA ASO 00705GCACAATGCTTGAGAAGGTG 743 63958SNCA ASO00706CAATGGGAGACAGGAGCTAA 744 64029 102 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 00707ACAATGGGAGACAGGAGCTA 745 64030SNCA ASO 00708GACAATGGGAGACAGGAGCT 746 64031SNCA ASO00709AGACAATGGGAGACAGGAGC 747 64032SNCA ASO 00710CAGACAATGGGAGACAGGAG 748 64033SNCA ASO 00711TCAGACAATGGGAGACAGGA 749 64034SNCA ASO 00712CTCAGACAATGGGAGACAGG 750 64035SNCA ASO 00713CAGCTCTCAGACAATGGGAG 751 64040SNCA ASO 00714GCAGCTCTCAGACAATGGGA 752 64041SNCA ASO 00715GGCAGCTCTCAGACAATGGG 753 64042SNCA ASO 00716ATATCCTAGTGGCAGCTCTC 754 64052SNCA ASO 00717CCCACCTAGCCTTCTTATCT 755 64443SNCA ASO 00718ACCCACCTAGCCTTCTTATC 756 64444SNCA ASO 00719CACCCACCTAGCCTTCTTAT 757 64445SNCA ASO00720GCACCCACCTAGCCTTCTTA 758 64446SNCA ASO 00721AGCACCCACCTAGCCTTCTT 759 64447SNCA ASO 00722GAGCACCCACCTAGCCTTCT 760 64448SNCA ASO 00723AGAGCACCCACCTAGCCTTC 761 64449SNCA ASO00724GAGAGCACCCACCTAGCCTT 762 64450SNCA ASO 00725CACAAAGCAGATTGCCAGCA 763 64943SNCA ASO 00726TCATAGATTTCCAAGGCTGC 764 65064SNCA ASO 00727CCAAAACTGCAACAGACCCT 765 65429SNCA ASO 00728TCCAAAACTGCAACAGACCC 766 65430SNCA ASO 00729TTCCAAAACTGCAACAGACC 767 65431SNCA ASO00730TTCCCACTGCCTACCAGCCC 768 65642SNCA ASO 00731CTTCCCACTGCCTACCAGCC 769 65643 103 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 00732CACACGAATGCACACACATG 770 65742SNCA ASO 00733ACACACGAATGCACACACAT 771 65743SNCA ASO00734GACACACGAATGCACACACA 772 65744SNCA ASO 00735GGACACACGAATGCACACAC 773 65745SNCA ASO 00736CTCACCATTCCTCTGTACCT 774 66341SNCA ASO 00737AAGGGAGGTCCTGAAACCAA 775 66718SNCA ASO 00738CAAGGGAGGTCCTGAAACCA 776 66719SNCA ASO 00739TAACCAACTCTCAGAGCCCA 777 69419SNCA ASO 00740TTAACCAACTCTCAGAGCCC 778 69420SNCA ASO 00741CTTCCCTCAGCAACAGGCGC 779 69455SNCA ASO00742CCTCTTGCCTCCTGTCATTT 780 69612SNCA ASO 00743GGAAGGACCTGCTGATCTAA 781 71345SNCA ASO 00744GGGAAGGACCTGCTGATCTA 782 71346SNCA ASO 00745AGGGAAGGACCTGCTGATCT 783 71347SNCA ASO 00746GAGGGAAGGACCTGCTGATC 784 71348SNCA ASO 00747GGAGGGAAGGACCTGCTGAT 785 71349SNCA ASO 00748TGGAGGGAAGGACCTGCTGA 786 71350SNCA ASO00749GGAGATGCAGGGAAGAGTAA 787 71734SNCA ASO00750TGGAGATGCAGGGAAGAGTA 788 71735SNCA ASO 00751AAGGGCAACTAACCAACAGA 789 71917SNCA ASO 00752ATATCTGTAACCACGCCCTT 790 72246SNCA ASO 00753CATATCTGTAACCACGCCCT 791 72247SNCA ASO 00754ACATATCTGTAACCACGCCC 792 72248SNCA ASO 00755AACATATCTGTAACCACGCC 793 72249SNCA ASO00756AATGCCCCACTAAGAAACCA 794 72621 104 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 00757AAATGCCCCACTAAGAAACC 795 72622SNCA ASO 00758GTTGTGGCTTTGATCTGGTT 796 73343SNCA ASO 00759AGTTGTGGCTTTGATCTGGT 797 73344SNCA ASO00760CTCAAGGTGCCATATCTGAG 798 73362SNCA ASO 00761TCTCAAGGTGCCATATCTGA 799 73363SNCA ASO 00762CAGGGACTGACACAGAGACC 800 73481SNCA ASO 00763CCAGGGACTGACACAGAGAC 801 73482SNCA ASO 00764GCCAGGGACTGACACAGAGA 802 73483SNCA ASO 00765AGCCAGGGACTGACACAGAG 803 73484SNCA ASO00766GGAAGTCAACTGCTGGAAAA 804 73895SNCA ASO 00767TGGAAGTCAACTGCTGGAAA 805 73896SNCA ASO 00768CTGGAAGTCAACTGCTGGAA 806 73897SNCA ASO 00769ACTGGAAGTCAACTGCTGGA 807 73898SNCA ASO 00770CACTGGAAGTCAACTGCTGG 808 73899SNCA ASO 00771GCACTGGAAGTCAACTGCTG 809 73900SNCA ASO 00772TGCACTGGAAGTCAACTGCT 810 73901SNCA ASO 00773TTGCACTGGAAGTCAACTGC 811 73902SNCA ASO 00774GCTACCATGCTACATTGCTC 812 76048SNCA ASO 00775GGCTACCATGCTACATTGCT 813 76049SNCA ASO 00776TGTGTGCTTTGATATGGCTT 814 76506SNCA ASO 00777CTTTGGTCTGTGCTGGCTGC 815 76797SNCA ASO 00778ACTTTGGTCTGTGCTGGCTG 816 76798SNCA ASO 00779CAAAACTGTCAACTCTGCCA 817 78391SNCA ASO 00780CCAAAACTGTCAACTCTGCC 818 78392SNCA ASO 00781CTCTTCAGCCCTAGTCTCTT 819 78999 105 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO00782TCTCTTCAGCCCTAGTCTCT 820 79000SNCA ASO 00783GCTAATGGGCAAGCAAAAAA 821 79504SNCA ASO 00784AGCTAATGGGCAAGCAAAAA 822 79505SNCA ASO 00785GGGAGGGTAGGCTTTGACAA 823 96843SNCA ASO 00786GGGGAGGGTAGGCTTTGACA 824 96844SNCA ASO 00787TGGGGAGGGTAGGCTTTGAC 825 96845SNCA ASO 00788GTGGGGAGGGTAGGCTTTGA 826 96846SNCA ASO00789AGTGGGGAGGGTAGGCTTTG 827 96847SNCA ASO00790CAGTGGGGAGGGTAGGCTTT 828 96848SNCA ASO 00791TCAGTGGGGAGGGTAGGCTT 829 96849SNCA ASO 00792AATCAGTGGGGAGGGTAGGC 830 96851SNCA ASO 00793AAATCAGTGGGGAGGGTAGG 831 96852SNCA ASO00794GAAATCAGTGGGGAGGGTAG 832 96853SNCA ASO 00795AGAAATCAGTGGGGAGGGTA 833 96854SNCA ASO 00796GAGAAATCAGTGGGGAGGGT 834 96855SNCA ASO 00797TGAGAAATCAGTGGGGAGGG 835 96856SNCA ASO 00798GTGAGAAATCAGTGGGGAGG 836 96857SNCA ASO 00799GGTGAGAAATCAGTGGGGAG 837 96858SNCA ASO00800GGGTGAGAAATCAGTGGGGA 838 96859SNCA ASO 00801AGATGGGTCAAGCTGAGAAA 839 97294SNCA ASO 00802AAGATGGGTCAAGCTGAGAA 840 97295SNCA ASO 00803GAAGATGGGTCAAGCTGAGA 841 97296SNCA ASO00804TGAAGATGGGTCAAGCTGAG 842 97297SNCA ASO 00805GCAACAAGGCTGAGTGAAGA 843 98629SNCA ASO 00806AACCTAGCAACAAGGCTGAG 844 98635 106 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 00807AAACCTAGCAACAAGGCTGA 845 98636SNCA ASO 00808CAAACCTAGCAACAAGGCTG 846 98637SNCA ASO 00809CCAAACCTAGCAACAAGGCT 847 98638SNCA ASO 00810GCCAAACCTAGCAACAAGGC 848 98639SNCA ASO 00811AGCCAAACCTAGCAACAAGG 849 98640SNCA ASO 00812AAGCCAAACCTAGCAACAAG 850 98641SNCA ASO 00813GTTTGGTTGGCCTGACTTTA 851 98950SNCA ASO 00814GGTTTGGTTGGCCTGACTTT 852 98951SNCA ASO 00815AGGTTTGGTTGGCCTGACTT 853 98952SNCA ASO 00816TAGGTTTGGTTGGCCTGACT 854 98953SNCA ASO 00817TTAGGTTTGGTTGGCCTGAC 855 98954SNCA ASO 00818TTTAGGTTTGGTTGGCCTGA 856 98955SNCA ASO 00819TTTTAGGTTTGGTTGGCCTG 857 98956SNCA ASO 00820GGGGAGTGTGTACATAGTGT 858 100147SNCA ASO 00821AGGGGAGTGTGTACATAGTG 859 100148SNCA ASO 00822GGCTGGTTGGTCTTTGGTAT 860 100872SNCA ASO 00823AGGCTGGTTGGTCTTTGGTA 861 100873SNCA ASO 00824CAGGGAAGTGAAAGTGAAGG 862 101514SNCA ASO 00825GGAAACAGAAATGGCTGAGA 863 101709SNCA ASO 00826AGGAAACAGAAATGGCTGAG 864 101710SNCA ASO00827TCTGCCCTTGCCAATGCCCT 865 104952SNCA ASO 00828TTCTGCCCTTGCCAATGCCC 866 104953SNCA ASO 00829ATCATTCTGCCCTTGCCAAT 867 104957SNCA ASO 00830ATGGTAGGTGGGCAGAGAAG 868 104984SNCA ASO 00831TATGGTAGGTGGGCAGAGAA 869 104985 107 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 00832TTATGGTAGGTGGGCAGAGA 870 104986SNCA ASO 00833TTGCTCCTGTGATGCCTGGT 871 108008SNCA ASO 00834TTTGCTCCTGTGATGCCTGG 872 108009SNCA ASO 00835TTCCCACCCAGATCAACATT 873 108107SNCA ASO 00836TTTCCCACCCAGATCAACAT 874 108108SNCA ASO00837TTTTCCCACCCAGATCAACA 875 108109SNCA ASO 00975GTTTCAGCTAGGCAACTCAA 876 1061SNCA ASO 00976CTGGGCCACACTAATCACTA 877 7580SNCA ASO 00977GGGCCACACTAATCACTAGA 878 7578SNCA ASO 00978CAGCTAGGCAACTCAATGTG 879 1057SNCA ASO 00979TTCAGCTAGGCAACTCAATG 880 1059SNCA ASO 00980GGAGAACAGTGGAGGAGAGT 881 12062SNCA ASO 00981GGGGACACTCATCTAAGGAA 882 12035SNCA ASO 00982TACAAGACAATTCCAGCCCA 883 2299SNCA ASO 00983TACTGGGCCACACTAATCAC 884 7582SNCA ASO 00984AGAACAGTGGAGGAGAGTGG 885 12060SNCA ASO 00985AGAGAGGATCAGCCAGGCAC 886 22451SNCA ASO 00986AGAGTGGAGGATGGGGACAC 887 12047SNCA ASO00987TCACTGGATGGTTGGGAGCA 888 26997SNCA ASO 00988CACAGGGGCATATCAAAGTC 889 548SNCA ASO 00989TACTCCCCAGATAAGCCTCA 890 11986SNCA ASO00990GCTTGGGCTGGACTTTTTTG 891 26607SNCA ASO 00991CCCCAGATAAGCCTCAGTCT 892 11982SNCA ASO00992CACTGGATGGTTGGGAGCAG 893 26996SNCA ASO00993CAAGTGCCAGACCCTTTCAT 894 22934 108 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 00994TTGTTTTGCTGCTCGAATCA 895 29795SNCA ASO00995TGTGTCTATGCCTGTGGATG 896 914SNCA ASO00996GTGCATGTTCTTTCCACTCT 897 2343SNCA ASO 00997TCCCCAGATAAGCCTCAGTC 898 11983SNCA ASO 00998GGAGCACCAACCAACCAGAG 899 39872SNCA ASO00999AAGACACAATACCTGCCTTC 900 39991SNCA ASO 01000AGAGGGTTCCAAAGGAGCAC 901 39885SNCA ASO 01001AAGTGCCAGACCCTTTCATT 902 22933SNCA ASO 01002TCCAAGTGCCAGACCCTTTC 903 22936SNCA ASO 01003GATTGTTTTGCTGCTCGAAT 904 29797SNCA ASO 01004GTGTCTATGCCTGTGGATGA 905 913SNCA ASO 01005TAGTTGCCACCAGAGAATGT 906 994SNCA ASO 01006CTTGGTGTTGTCTGAAAGCA 907 22785SNCA ASO 01007GCCAGATAAAACAAGGCCCT 908 26439SNCA ASO 01008CAGCAGCAATGGGATCCACC 909 38489SNCA ASO 01009TGAACTGTGCTTGGGGTTGT 910 22248SNCA ASO 01010TGTACTGATTTGTGCCTGGC 911 38056SNCA ASO 01011GATCACCTTCAAACCCCTTT 912 29756SNCA ASO 01012AAGAGGTCACTGGATGGTTG 913 27003SNCA ASO 01013ATTGTTTTGCTGCTCGAATC 914 29796SNCA ASO 01014TAGGGATCACCTTCAAACCC 915 29760SNCA ASO 01015TTGCACAAGTAGGCAGCACA 916 37762SNCA ASO 01016CAGAGGGTTCCAAAGGAGCA 917 39886SNCA ASO 01017GGCAGTTGTGGTAGGGGTTC 918 22601SNCA ASO 01018TTGAACTGTGCTTGGGGTTG 919 22249 109 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 01019GAGGAAGAATGGGCAATGTG 920 949SNCA ASO 01020TTGGGCTGGACTTTTTTGCA 921 26605SNCA ASO 01021TTCCAAGTGCCAGACCCTTT 922 22937SNCA ASO01022TGGGCTGGACTTTTTTGCAT 923 26604SNCA ASO 01023CCCTTTTAGACCCCTGAAGT 924 22474SNCA ASO 01024AGCAGCAATGGGATCCACCA 925 38488SNCA ASO 01025TCCCTTTTAGACCCCTGAAG 926 22475SNCA ASO01026TCCAAAGGAGCACCAACCAA 16 39878SNCA ASO 01027AGAGGGGAAAATATGGGGGC 927 39856SNCA ASO 01028GCAGAGAGGAGAACAGTGGA 928 12069SNCA ASO01029GAAAATATGGGGGCAACAGA 929 39850SNCA ASO 01030GGGATCACCTTCAAACCCCT 930 29758SNCA ASO 01031TAGAGGCTGACAAGGGTAAG 931 5404SNCA ASO01032ACAAGTAGGCAGCACAGGTT 932 37758SNCA ASO 01033GTCTATGCCTGTGGATGAGA 933 911SNCA ASO 01034GGCTGACAAGGGTAAGAGGG 934 5400SNCA ASO 01035ATGGGGACACTCATCTAAGG 935 12037SNCA ASO01036GGATCACCTTCAAACCCCTT 936 29757SNCA ASO 01037AGGGTTCCAAAGGAGCACCA 937 39883SNCA ASO 01038AGGCACTAGGAGACCCTGGG 938 51766SNCA ASO01039AGTGAACAGATTCCAGCAGA 939 36430SNCA ASO 01040ACTGTGCTTGGGGTTGTTTC 940 22245SNCA ASO 01041GGGTTCCAAAGGAGCACCAA 941 39882SNCA ASO 01042GCAGCAGCAATGGGATCCAC 942 38490SNCA ASO 01043GGGAACCCTTCTGTCATCAT 943 51858 110 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 01044GGAAGAGGAAAAGCTTGGAG 944 35561SNCA ASO 01045CTGGGAACCCTTCTGTCATC 945 51860SNCA ASO 01046GGCAGGGCTAGACAAAATGG 946 52063SNCA ASO 01047ACCCTTCTGTCATCATGCAT 947 51854SNCA ASO 01048CTCCCCAGATAAGCCTCAGT 948 11984SNCA ASO 01049CAGATAAAACAAGGCCCTGA 949 26437SNCA ASO 01050GGGCTGGACTTTTTTGCATG 950 26603SNCA ASO 01051TTTGCACAAGTAGGCAGCAC 951 37763SNCA ASO01052CTTTGAACTGTGCTTGGGGT 952 22251SNCA ASO 01053AAGGACAAGAGGCTTTCTCC 953 11490SNCA ASO 01054GAACTGTGCTTGGGGTTGTT 954 22247SNCA ASO 01055CTTTGCACAAGTAGGCAGCA 955 37764SNCA ASO 01056GTCTGAGAGGAGTTACACCA 956 11966SNCA ASO 01057AGGACAAGAGGCTTTCTCCT 957 11489SNCA ASO 01058AGGAAGAATGGGCAATGTGT 958 948SNCA ASO01059AGTCTGAGAGGAGTTACACC 959 11967SNCA ASO 01060GAGGGTTCCAAAGGAGCACC 960 39884SNCA ASO 01061CCAGATAAAACAAGGCCCTG 961 26438SNCA ASO01062GCTGGGAGAGAAAAGCAGAG 962 39720SNCA ASO 01063GTACTGATTTGTGCCTGGCA 963 38055SNCA ASO 01064GCACTAGGAGACCCTGGGAC 964 51764SNCA ASO 01065GTACTCCCCAGATAAGCCTC 965 11987SNCA ASO 01066CAGAGGGGAAAATATGGGGG 966 39857SNCA ASO 01067TGTGCTGAACACCCATTATG 967 7029SNCA ASO 01068TCAAACGACAAATTCCAGCT 968 36118 ill WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO01069GCTGACAAGGGTAAGAGGGA 969 5399SNCA ASO 01070TCATCATGCATAAGCAGCCT 970 51845SNCA ASO 01071AGCAGAGAGGAGAACAGTGG 971 12070SNCA ASO 01072ATCATGCATAAGCAGCCTGA 972 51843SNCA ASO 01073TTGTAGGTCATGGGAAGTCA 973 35808SNCA ASO 01074TGTCATCATGCATAAGCAGC 974 51847SNCA ASO 01075GAACCCTTCTGTCATCATGC 975 51856SNCA ASO 01076TGTAGGTCATGGGAAGTCAT 976 35807SNCA ASO 01077CATCATGCATAAGCAGCCTG 977 51844SNCA ASO 01078TTTGAACTGTGCTTGGGGTT 978 22250SNCA ASO 01079TACTGATTTGTGCCTGGCAT 979 38054SNCA ASO 01080GTGGAGGATGGGGACACTCA 980 12044SNCA ASO 01081AATTCCAAGTGCCAGACCCT 981 22939SNCA ASO 01082TCATGCATAAGCAGCCTGAG 982 51842SNCA ASO 01083ATGCATAAGCAGCCTGAGTC 983 51840SNCA ASO 01084CTGACAAGGGTAAGAGGGAG 984 5398SNCA ASO 01085AAGCCTGACATAGCCACACA 985 11450SNCA ASO 01086TGCATAAGCAGCCTGAGTCT 986 51839SNCA ASO 01087AAGAGGCTATTGAGCACCCT 987 12324SNCA ASO 01088AAGCAGCCTGAGTCTTAGAT 988 51834SNCA ASO 01089AGGCTTTAACATGTGCTGAA 989 7040SNCA ASO 01090AGAGGAAGAATGGGCAATGT 990 950SNCA ASO 01091GGAAGGACTTGGGTCTTACT 991 22765SNCA ASO01092GAAGAATGGGCAATGTGTCT 992 946SNCA ASO 01093AGACAGGCACTAGGAGACCC 993 51770 112 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 01094ACTGATTTGTGCCTGGCATC 994 38053SNCA ASO 01095CAGCAGAGATTATGGCAGAG 995 36417SNCA ASO01096ATTCCAAGTGCCAGACCCTT 996 22938SNCA ASO 01097AAGTAGGCAGCACAGGTTTT 997 37756SNCA ASO 01098CTCAACTCAGGCTAGCTACT 998 36619SNCA ASO01099GGCTGGACTTTTTTGCATGG 999 26602SNCA ASO 01100AAAATATGGGGGCAACAGAG 1000 39849SNCA ASO 01101GGAAGAATGGGCAATGTGTC 1001 947SNCA ASO 01102TGTGAATCCATTTGTCCAGC 1002 64296SNCA ASO 01103GCATAAGCAGCCTGAGTCTT 1003 51838SNCA ASO 01104GTTCCAAAGGAGCACCAACC 1004 39880SNCA ASO 01105CCAACCAACCAGAGGGGAAA 1005 39866SNCA ASO 01106GGCCTGGAGAATAGGGAGAG 1006 52353SNCA ASO 01107GGAACCCTTCTGTCATCATG 1007 51857SNCA ASO 01108CCTGGTGTGTGCAAACATGT 1008 35411SNCA ASO 01109CCTTTGTTCCCACATCACAT 1009 7209SNCA ASO OHIOCAAGGAAACTACAGCCCAGA 1010 38423SNCA ASO 01111CAGTTGTGGTAGGGGTTCTT 1011 22599SNCA ASO 01112GAGGCTGACAAGGGTAAGAG 1012 5402SNCA ASO 01113AGAGGCTATTGAGCACCCTT 1013 12323SNCA ASO 01114AAGGAAACTACAGCCCAGAC 1014 38422SNCA ASO 01115GGGGCTTTGAACTGTGCTTG 1015 22255SNCA ASO 01116AGCCTGACATAGCCACACAG 1016 11449SNCA ASO 01117TAGATTGTTTTGCTGCTCGA 1017 29799SNCA ASO 01118AGGAAGGACTTGGGTCTTAC 1018 22766 113 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 01119TCTGGCTAGAAATGTAGGCA 1019 35620SNCA ASO 01120CAATGGGATCCACCACAGCA 1020 38483SNCA ASO 01121AGGGCCACAAATAGGTCTCT 1021 578SNCA ASO 01122GCAGTTGTGGTAGGGGTTCT 1022 22600SNCA ASO 01123CCTCTGGTGCCTCTAGTTTT 1023 59845SNCA ASO 01124GGCTTTAACATGTGCTGAAC 1024 7039SNCA ASO 01125AGGAGGGGGCTTTGAACTGT 1025 22260SNCA ASO 01126TAAACCCTGCTAGCCAGAAG 1026 59377SNCA ASO 01127ACCAACCAACCAGAGGGGAA 1027 39867SNCA ASO 01128TCAACTCAGGCTAGCTACTT 1028 36618SNCA ASO 01129GCCAGGCGAGAATTTGCTTT 1029 40020SNCA ASO 01130CCCTGCTAGCCAGAAGAGAT 1030 59373SNCA ASO 01131CAGAGAGGAGAACAGTGGAG 1031 12068SNCA ASO 01132GCAAGGAAACTACAGCCCAG 1032 38424SNCA ASO 01133GTTGCCACCAGAGAATGTGA 1033 992SNCA ASO 01134GAGGCTATTGAGCACCCTTA 1034 12322SNCA ASO 01135GGGGGCTTTGAACTGTGCTT 1035 22256SNCA ASO 01136AACTGATGCCTCTACCTCCA 1036 38134SNCA ASO 01137GGAGGGGGCTTTGAACTGTG 1037 22259SNCA ASO 01138GGCCAGAAACCACTTAGAAC 1038 53762SNCA ASO 01139AGTTGCCACCAGAGAATGTG 1039 993SNCA ASO 01140TTGCCACCAGAGAATGTGAA 1040 991SNCA ASO 01141TAAATTCCAAGTGCCAGACC 1041 22941SNCA ASO 01142ATGTACTGATTTGTGCCTGG 1042 38057SNCA ASO 01143GGTTCCAAAGGAGCACCAAC 1043 39881 114 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 01144ACTAGCATGAGAGCACCCAC 1044 64458SNCA ASO 01145GGACAAGAGGCTTTCTCCTT 1045 11488SNCA ASO 01146CAAGTAGGCAGCACAGGTTT 1046 37757SNCA ASO 01147CTGACATAGCCACACAGCCC 1047 11446SNCA ASO 01148CCTGACATAGCCACACAGCC 1048 11447SNCA ASO 01149GTGTTGTCTGAAAGCAGGAA 1049 22781SNCA ASO 01150AGGAGAGCATGTTATCCCTT 1050 22489SNCA ASO 01151AGATTGTTTTGCTGCTCGAA 1051 29798SNCA ASO 01152AAATTCCAAGTGCCAGACCC 1052 22940SNCA ASO 01153TTCCAAAGGAGCACCAACCA 1053 39879SNCA ASO 01154ACTCCAGTAACCACCACAAT 1054 7301SNCA ASO 01155GCTTTGAACTGTGCTTGGGG 1055 22252SNCA ASO 01156CATAGATTTCCAAGGCTGCA 1056 65063SNCA ASO 01157TAGGGCCACAAATAGGTCTC 1057 579SNCA ASO 01158GGGCCACAAATAGGTCTCTT 1058 577SNCA ASO 01159GCCACCAGAGAATGTGAAAA 1059 989SNCA ASO 01160TCCAAGGCTGCAAAAGCTAA 1060 65055SNCA ASO 01161CAGGCAAGAGATCTGGCTAG 1061 35631SNCA ASO 01162TTAGGGCCACAAATAGGTCT 1062 580SNCA ASO 01163AGCATGAGAGCACCCACCTA 1063 64455SNCA ASO 01164ACATGGCCAGAAACCACTTA 1064 53766SNCA ASO 01165AACATGTGCTGAACACCCAT 1065 7033SNCA ASO 01166AGGCTGACAAGGGTAAGAGG 1066 5401SNCA ASO 01167GATCTGTCCACCTTAGCCTC 1067 40073SNCA ASO 01168TGTACTCCCCAGATAAGCCT 1068 11988 115 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 01169AAGCAGAGAGGAGAACAGTG 1069 12071SNCA ASO 01170AGGAAACTACAGCCCAGACA 1070 38421SNCA ASO 01171CCAGCAGAGATTATGGCAGA 1071 36418SNCA ASO 01172ACAAGCAAAGTGACCAAGAG 1072 52148SNCA ASO 01173AACTCCAGTAACCACCACAA 1073 7302SNCA ASO 01174TTGTACTCCCCAGATAAGCC 1074 11989SNCA ASO 01175CAAGCAAAGTGACCAAGAGA 1075 52147SNCA ASO 01176AGAGGAGTTACACCATGTCA 1076 11961SNCA ASO 01177AACAAGCAAAGTGACCAAGA 1077 52149SNCA ASO 01178ATAAACCCTGCTAGCCAGAA 1078 59378SNCA ASO 01179AACTGTGCTTGGGGTTGTTT 1079 22246SNCA ASO 01180CTTGGGTCTTACTCCCTGGT 1080 22758SNCA ASO 01181TTAGAGGCTGACAAGGGTAA 1081 5405SNCA ASO 01182GGCTTTGAACTGTGCTTGGG 1082 22253SNCA ASO 01183CAGGAAGGACTTGGGTCTTA 1083 22767SNCA ASO 01184GCTGAGGCACTGTGACCCTG 1084 23055SNCA ASO 01185TGCCAGGCGAGAATTTGCTT 1085 40021SNCA ASO 01186TCTATGCCTGTGGATGAGAG 1086 910SNCA ASO 01187GAACTGATGCCTCTACCTCC 12 38135SNCA ASO 01188GCATGAGAGCACCCACCTAG 1087 64454SNCA ASO 01189CCTTGCCCAACTGGTCCTTT 1088 13414SNCA ASO 01190TCCAGCAGAGATTATGGCAG 1089 36419SNCA ASO 01191CCAGGCGAGAATTTGCTTTT 1090 40019SNCA ASO 01192ATGGGAGACAGGAGCTAATG 1091 64027SNCA ASO 01193TTCTGCGTATGGGCATCTCC 1092 64116 116 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 01194ACATGTGCTGAACACCCATT 1093 7032SNCA ASO 01195TGCCTCTACCTCCAGCAAGC 1094 38128SNCA ASO 01196TTTCTGCGTATGGGCATCTC 1095 64117SNCA ASO 01197TGAACAGATTCCAGCAGAGA 1096 36428SNCA ASO 01198TGTGTTTCAACTGTGGGCTT 1097 52452SNCA ASO 01199CATGCCAGGCGAGAATTTGC 1098 40023SNCA ASO 01200GAGAGGAAGAATGGGCAATG 1099 951SNCA ASO 01201AGGACTTGGGTCTTACTCCC 1100 22762SNCA ASO01202GCTACTAGCATGAGAGCACC 1101 64461SNCA ASO 01203ATGCCAGGCGAGAATTTGCT 1102 40022SNCA ASO 01204AAGACAGGCACTAGGAGACC 1103 51771SNCA ASO 01205GACATAGCCACACAGCCCAA 1104 11444SNCA ASO01206TCTCAACTCAGGCTAGCTAC 1105 36620SNCA ASO 01207GGAAACCACAGTGCTATGAA 1106 37467SNCA ASO 01208ACATAGCCACACAGCCCAAG 1107 11443SNCA ASO01209AGGGGGCTTTGAACTGTGCT 1108 22257SNCA ASO 01210AGGAGTTACACCATGTCAGC 1109 11959SNCA ASO 01211ATGGCCAGAAACCACTTAGA 1110 53764SNCA ASO 01212CAGGAGAGCATGTTATCCCT 1111 22490SNCA ASO 01213TGGCAGCTCTCAGACAATGG 1112 64043SNCA ASO 01214GAAGGAACTCCAGTAACCAC 1113 7307SNCA ASO 01215AGGCAAGAGATCTGGCTAGA 1114 35630SNCA ASO 01216GTAGGCAGCACAGGTTTTCT 1115 37754SNCA ASO 01217GGGCTTTGAACTGTGCTTGG 1116 22254SNCA ASO 01218GTGAACAGATTCCAGCAGAG 1117 36429 117 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 01219GCTTCCCAAGAGTATCAGGA 1118 51200SNCA ASO01220GGAGCTTCCCAAGAGTATCA 1119 51203SNCA ASO 01221GGCAAGAGATCTGGCTAGAA 1120 35629SNCA ASO 01222CATGTGCTGAACACCCATTA 1121 7031SNCA ASO 01223CTGGGAGAGAAAAGCAGAGA 1122 39719SNCA ASO01224AGCTTCCCAAGAGTATCAGG 1123 51201SNCA ASO 01225GGACTTGGGTCTTACTCCCT 1124 22761SNCA ASO 01226GTGGCAGCTCTCAGACAATG 1125 64044SNCA ASO 01227TGTCTATGCCTGTGGATGAG 1126 912SNCA ASO 01228GGAGTTACACCATGTCAGCT 1127 11958SNCA ASO 01229GACAGGCACTAGGAGACCCT 1128 51769SNCA ASO01230CCAAGGCTGCAAAAGCTAAA 1129 65054SNCA ASO 01231CATGGCCAGAAACCACTTAG 1130 53765SNCA ASO 01232AGTAGGCAGCACAGGTTTTC 1131 37755SNCA ASO 01233CCTGCTAGCCAGAAGAGATT 1132 59372SNCA ASO01234GCATGCCTTTGCTCACCTGT 1133 64278SNCA ASO 01235TGAGAGGAGTTACACCATGT 1134 11963SNCA ASO 01236ATGAGAGCACCCACCTAGCC 1135 64452SNCA ASO 01237TGGGAGAGAAAAGCAGAGAT 1136 39718SNCA ASO 01238GCCTGACATAGCCACACAGC 1137 11448SNCA ASO 01239TAGCCACACAGCCCAAGACC 1138 11440SNCA ASO 01240AGCACAGGTTTTCTGACTTT 1139 37748SNCA ASO 01241AATGGGAGACAGGAGCTAAT 1140 64028SNCA ASO01242TGCCACCAGAGAATGTGAAA 1141 990SNCA ASO 01243TAGCATGAGAGCACCCACCT 1142 64456 118 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 01244ACTGATGCCTCTACCTCCAG 1143 38133SNCA ASO 01245CATGAGAGCACCCACCTAGC 1144 64453SNCA ASO 01246CTAGCATGAGAGCACCCACC 1145 64457SNCA ASO 01247CCAGAGGGGAAAATATGGGG 1146 39858SNCA ASO 01248GCCAAGCCCAAACACTAAGA 1147 59754SNCA ASO01249GGCTTGGGCTGGACTTTTTT 1148 26608SNCA ASO01250TACTAGCATGAGAGCACCCA 1149 64459SNCA ASO 01251TCCAATTAGCTGCCAGGAGT 1150 38527SNCA ASO 01252AGCCAAGCCCAAACACTAAG 1151 59755SNCA ASO 01253TGAGGCACTGTGACCCTGGG 1152 23053SNCA ASO 01254CTACTAGCATGAGAGCACCC 1153 64460SNCA ASO 01255TGAGAGCACCCACCTAGCCT 1154 64451SNCA ASO01256TGGAAACCACAGTGCTATGA 1155 37468SNCA ASO 01257GTTGTCTGAAAGCAGGAAGG 1156 22779SNCA ASO 01258GTGTTTCAACTGTGGGCTTA 1157 52451SNCA ASO 01259TGACATAGCCACACAGCCCA 1158 11445SNCA ASO01260CTGAACTGATGCCTCTACCT 1159 38137SNCA ASO 01261TGAACTGATGCCTCTACCTC 1160 38136SNCA ASO 01262CAGCACAGGTTTTCTGACTT 1161 37749SNCA ASO 01263CCAGTGCCAAAGTAAGAGGA 1162 64098SNCA ASO 01264CTTTTTGGAGTTCTGGAGGC1163 26625SNCA ASO 01265ATCAGCTGAGGCACTGTGAC 1164 23059SNCA ASO01266TCTGTAGCCAAATGAATGGG 1165 52790SNCA ASO 01267TAACATGTGCTGAACACCCA 1166 7034SNCA ASO 01268ACCAGAGGGGAAAATATGGG 1167 39859 119 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 01269CTGATGCCTCTACCTCCAGC 1168 38132SNCA ASO 01270ACTGAACTGATGCCTCTACC 13 38138SNCA ASO 01271AACGACAAATTCCAGCTTCT 1169 36115SNCA ASO 01272CATAGCCACACAGCCCAAGA 1170 11442SNCA ASO 01273TTCCTGGAAACCACAGTGCT 1171 37472SNCA ASO 01274TGGAGGATGGGGACACTCAT 1172 12043SNCA ASO 01275AAGCCAAGCCCAAACACTAA 15 59756SNCA ASO 01276TAGCTAATGGGCAAGCAAAA 1173 79506SNCA ASO 01277CCTAGTGGCAGCTCTCAGAC 1174 64048SNCA ASO 01278TGGCCTGGAGAATAGGGAGA 1175 52354SNCA ASO 01279TCAGCTGAGGCACTGTGACC 1176 23058SNCA ASO 01280AACCAACCAGAGGGGAAAAT 1177 39864SNCA ASO 01281ACAGGAGAGCATGTTATCCC 1178 22491SNCA ASO01282CATTATCATGGTTGCCCAGA 1179 30187SNCA ASO 01283CTTTCTGCGTATGGGCATCT 1180 64118SNCA ASO 01284TTGACGGATCAGACACTCTT 1181 52860SNCA ASO 01285TTTGACGGATCAGACACTCT 1182 52861SNCA ASO 01286AACTACAGCCCAGACATGTC 1183 38417SNCA ASO 01287TGGTGTGTGCAAACATGTAT 1184 35409SNCA ASO 01288AGTGCCAAAGTAAGAGGAGA 1185 64096SNCA ASO01289ACCAACCAGAGGGGAAAATA 1186 39863SNCA ASO01290CTCCAATTAGCTGCCAGGAG 1187 38528SNCA ASO 01291GCTGGACTTTTTTGCATGGA 1188 26601SNCA ASO 01292TGGAGCTTCCCAAGAGTATC 1189 51204SNCA ASO 01293TACCTTGCCCAACTGGTCCT 1190 13416 120 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO01294TGGCCAGAAACCACTTAGAA 1191 53763SNCA ASO 01295TTTGCTTTCTGCGTATGGGC 1192 64122SNCA ASO 01296TTTTGACGGATCAGACACTC 1193 52862SNCA ASO 01297TATCCTAGTGGCAGCTCTCA 1194 64051SNCA ASO 01298TCCTGGAAACCACAGTGCTA 1195 37471SNCA ASO 01299ATAGCCACACAGCCCAAGAC 1196 11441SNCA ASO 01300TGTTGTCTGAAAGCAGGAAG 1197 22780SNCA ASO 01301TTCCAGCAGAGATTATGGCA 1198 36420SNCA ASO01302TTAACATGTGCTGAACACCC 1199 7035SNCA ASO 01303TGACAAGGGTAAGAGGGAGG 1200 5397SNCA ASO 01304CCTGGAAACCACAGTGCTAT 1201 37470SNCA ASO 01305GGAAACTACAGCCCAGACAT 1202 38420SNCA ASO01306TACATGGCCAGAAACCACTT 14 53767SNCA ASO 01307CCTTCCTGCCTCACGGATGT 1203 59980SNCA ASO 01308CCAATTAGCTGCCAGGAGTG 1204 38526SNCA ASO01309AAAAGGAACATCAAAGGCGC 1205 64232SNCA ASO 01310CTGCTAGCCAGAAGAGATTG 1206 59371SNCA ASO 01311TGATCTTGGGCAAAAGTGTG 1207 36390SNCA ASO 01312GTTAGTGAGCCAAGGCCCAG 1208 96733SNCA ASO 01313GACTTGGGTCTTACTCCCTG 1209 22760SNCA ASO 01314AAGGACTTGGGTCTTACTCC 1210 22763SNCA ASO 01315GAGGGGGCTTTGAACTGTGC 1211 22258SNCA ASO 01316GAAACTACAGCCCAGACATG 1212 38419SNCA ASO 01317GCCTCTACCTCCAGCAAGCA 1213 38127SNCA ASO 01318AGACATTCACTCTGTGCTCA 1214 30347 121 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 01319AGCTGAGGCACTGTGACCCT 1215 23056SNCA ASO01320CTTCCTGCCTCACGGATGTC 1216 59979SNCA ASO 01321GTGAAGATGGGTCAAGCTGA 1217 97298SNCA ASO 01322ACTTGTGACCTTCAGTACCA 1218 30266SNCA ASO 01323AACAAGGCCCTGAGTAACAA 1219 26430SNCA ASO01324AAACAAGGCCCTGAGTAACA 1220 26431SNCA ASO 01325CTGGCCTGGAGAATAGGGAG 1221 52355SNCA ASO 01326CAAAAGGAACATCAAAGGCG 1222 64233SNCA ASO 01327GCAGCACAGGTTTTCTGACT 1223 37750SNCA ASO 01328CTGGAAACCACAGTGCTATG 1224 37469SNCA ASO 01329AAAATGCAGGTTTGTAGGGC 1225 101226SNCA ASO01330ACCTTGCCCAACTGGTCCTT 1226 13415SNCA ASO 01331TCTGCGTATGGGCATCTCCA 1227 64115SNCA ASO 01332TTCCTGCCTCACGGATGTCC 1228 59978SNCA ASO 01333TTATCATGGTTGCCCAGAAG 1229 30185SNCA ASO01334GCCTGGAGAATAGGGAGAGA 1230 52352SNCA ASO 01335CTAGTGGCAGCTCTCAGACA 1231 64047SNCA ASO 01336GATCTTGGGCAAAAGTGTGT 1232 36389SNCA ASO 01337AAACTACAGCCCAGACATGT 1233 38418SNCA ASO 01338ATGTACATGGCCAGAAACCA 1234 53770SNCA ASO 01339TTTTGCTTTCTGCGTATGGG 1235 64123SNCA ASO 01340CTGGTGTGTGCAAACATGTA 1236 35410SNCA ASO 01341GGCAGCACAGGTTTTCTGAC 1237 37751SNCA ASO01342ATCCTAGTGGCAGCTCTCAG 1238 64050SNCA ASO 01343TGTACATGGCCAGAAACCAC 1239 53769 122 WO 2022/189363 PCT/EP2022/055770 Compound Name % Reduction in SNCA mRNA Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 01344TATGCTGTGCCTTTTTGCTT 1240 64135SNCA ASO 01345TAAGCCAGAAACAGAAAGGC 1241 12151SNCA ASO 01346TGATGCCTCTACCTCCAGCA 1242 38131SNCA ASO 01347GGAGGGTAGGCTTTGACAAA 1243 96842SNCA ASO 01348GGATGGATGAATGCATGGAT 1244 51892SNCA ASO01349AAAGACAGGCACTAGGAGAC 1245 51772SNCA ASO01350CAATTAGCTGCCAGGAGTGC 1246 38525SNCA ASO 01351CAGCTGAGGCACTGTGACCC 1247 23057SNCA ASO 01352ACTGGCCTGGAGAATAGGGA 1248 52356SNCA ASO 01353GCTTTCTGCGTATGGGCATC 1249 64119SNCA ASO 01354TCCTAGTGGCAGCTCTCAGA 1250 64049SNCA ASO 01355GATGCCTCTACCTCCAGCAA 1251 38130SNCA ASO01356ACAAGGCCCTGAGTAACAAG 1252 26429SNCA ASO 01357ATGCCTCTACCTCCAGCAAG 1253 38129SNCA ASO 01358CTGTAGCCAAATGAATGGGC 1254 52789SNCA ASO 01359TGGGTGAGAAATCAGTGGGG 1255 96860SNCA ASO01360CTGAGGCACTGTGACCCTGG 1256 23054SNCA ASO 01361CAAGTCCTGCCCTGCCACTC 1257 64423SNCA ASO 01362CAGTGCCAAAGTAAGAGGAG 1258 64097SNCA ASO 01363AAAACAAGGCCCTGAGTAAC 1259 26432SNCA ASO 01364AAGTCCTGCCCTGCCACTCT 1260 64422SNCA ASO 01365AAGATTACCACCTGGGCACA 1261 59513SNCA ASO01366GCAGGTTTGTAGGGCCTTGT 1262 101221 123 WO 2022/189363 PCT/EP2022/055770 Example 3: mRNA Reduction in vitro Following Multiple Doses of MOE-modified ASOs [0235]Modified oligonucleotides complementary to the human SNCA nucleic acid sequence were tested in vitro in primary cortical neurons for their selective efficacy in reducing SNCA mRNA levels. Neurons were treated with multiple doses (3 pM; 1/2 log dilution; 11 concentrations) of the given antisense oligonucleotide. This assay provided the in vitro cellular potency (pIC50= -Log(IC50)) and efficacy (Delta Inhib Obs (%)) of the given ASO in neurons. In addition, the Hill coefficient, which is the slope of the line in a Hill plot, was measured in order to observe the shape of the dose response curve for each ASO. [0236]Each modified oligonucleotide listed in Table I, Table J, and Table Kis complementary to human SNCA nucleic acid sequence SEQ ID NO: 1 and/or SEQ ID NO: 3. The ASOs in Table Jare designed to be complementary to introns in the SNCA mRNA sequence, whereas the ASOs in Tables Iand Kare designed to be complementary to exons in the SNCA mRNA sequence. [0237]Each of the ASOs in Tables I, J, and Kis a 5-10-5 MOE gapmer. The gapmers are 20 nucleobases in length, wherein the central gap segment comprises ten 2’- deoxynucleosides and each of the flanking wing segments comprises five 2’-MOE nucleosides. All cytosines throughout each gapmer are 5-methyl cytosines, and all internucleoside linkages are phosphorothioate linkages. [0238]The SNCA_ASO_01617 in Table Jis a 5-10-5 MOE gapmer. The gapmer is nucleobases in length, wherein the central gap segment comprises ten 2’deoxynucleosides and is flanked by wing segments on both 5’ and 3’ end comprising five 2’-MOE nucleosides. All cytosines residues throughout each gapmer are 5-methyl cytosines. All internucleoside linkages are phosphorothioates linkages except between nucleosides 2 and 3, 3 and 4, 4 and 5, 16 and 17, and 17 and 18, which are phosphodiester linkages. [0239]Each of the ASOs in Table Lis a 3-2-10-2-3 LNA/MOE mixed gapmer. The gapmers are 20 nucleobases in length, wherein the central gap segment comprises ten 2’- deoxynucleosides and each wing segment comprises three LNA nucleosides and two 2’-MOE nucleosides. The ASO therefore comprises, from 5’ to 3’, 3 LNA nucleosides, two 2’-MOE nucleosides, 10 2’-deoxynucleosides, two 2’-MOE nucleosides, and 3 LNA nucleosides. All cytosines residues throughout each gapmer are 5-methyl cytosines and all internucleoside linkages are phosphorothioate (PS) linkages except for the linkages between nucleosides and 3, 4 and 5, 16 and 17, and 18 and 19, which are phosphodiester (PO) linkages. [0240]Each ASO listed in Table Mis a 2-3-10-3-2 BNA/MOE gapmer. The gapmers are 20 nucleobases in length, wherein the central gap segment comprises ten 2’- 124 WO 2022/189363 PCT/EP2022/055770 deoxynucleosides and each wing segment comprises two BNA nucleosides and three 2’- MOE nucleosides. Each ASO therefore comprises, from 5’ to 3’, two BNA nucleosides, three 2’-MOE nucleosides, 10 2’-deoxynucleosides, three 2’-MOE nucleosides, and two BNA nucleosides. All cytosines throughout each gapmer are 5-methyl cytosines, and all internucleoside linkages are phosphorothioate linkages except the linkages betweennucleosides 3 and 4, 4 and 5, 16 and 17, and 17 and 18, which are phosphodiester (PO) linkages. [0241]The identified positions in Tables I, J, K, L, and Mcorrespond to the "StartSite," i.e., the 5’ nucleoside to which the gapmer is complementary in the human SNCA nucleic acid sequence SEQ ID NO: 1 and/or SEQ ID NO: 3.

Table 1. 5-10-5 MOE Gapmers Complementary to SNCA RNA Exons Compound Name DELTA Inhib Obs (%) IC50 (M) nH )־(pICso)־( Unmodified Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 3 Position in SEQ ID NO: 1 SNCA ASO 00038115 1.89E-08 0.9 7.72TCCTTTCATGA ATACATCCA253 2 2SNCA ASO000392.66E-09 0.5 8.58GTCCTTTCATG AATACATCC254 3 3SNCA ASO00040102 2.68E-08 0.9 7.57AGTCCTTTCAT GAATACATC255 4 4SNCA ASO00044106 2.63E-09 0.4 8.58CTCCTTGGCCT TTGAAAGTC259 20 20SNCA ASO 00049108 1.53E-08 0.8 7.81ACTCCCTCCTT GGCCTTTGA264 25 25SNCA ASO 00050110 2.01E-08 0.8 7.7AACTCCCTCCT TGGCCTTTG265 26 26SNCA ASO 000542.58E-09 0.6 8.59CCACAACTCCC TCCTTGGCC269 30 30SNCA ASO 00056121 6.74E-08 0.7 7.17AGCCACAACT CCCTCCTTGG271 32 32SNCA ASO00057108 3.08E-08 0.9 7.51CAGCCACAAC TCCCTCCTTG272 33 33SNCA ASO 00058117 3.22E-08 0.6 7.49GCAGCCACAA CTCCCTCCTT273 34 34SNCA ASO000801.08E-08 0.6 7.97GCCACACCCTG TTTGGTTTT295 61 61SNCA ASO 00087110 5.49E-08 0.8 7.26TGCTTCTGCCA CACCCTGTT302 68 68SNCA ASO 00089105 5.03E-08 0.9 7.3GCTGCTTCTGC CACACCCTG304 70 70SNCA ASO 00090101 7.72E-08 0.9 7.11TGCTGCTTCTG CCACACCCT305 71 71SNCA ASO 00091103 2.04E-09 0.5 8.69CTGCTGCTTCT GCCACACCC306 72 72 125 WO 2022/189363 PCT/EP2022/055770 Compound Name DELTA Inhib Obs (%) IC50 (M) nH )־(pICso)־( Unmodified Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 3 Position in SEQ ID NO: 1 SNCA ASO 00106106 6.75E-08 0.8 7.17CCTCTTTTGTC TTTCCTGCT321 87 87SNCA ASO 00116113 4.62E-08 0.7 7.34GCCTACATAG AGAACACCCT331 104 NASNCA ASO 00117114 5.00E-08 0.9 7.3AGCCTACATA GAGAACACCC332 105 NASNCA ASO 00133117 1.53E-08 0.6 7.81CCACTCCCTCC TTGGTTTTG348 126 7497SNCA ASO 001499.22E-08 0.5 7.04TTTGTCACTTG CTCTTTGGT364 175 13301SNCA ASO 001506.16E-08 0.6 7.21ATTTGTCACTT GCTCTTTGG365 176 13302SNCA ASO 00151102 8.42E-08 0.4 7.07CATTTGTCACT TGCTCTTTG366 177 13303SNCA ASO001522.81E-08 0.4 7.55ACATTTGTCAC TTGCTCTTT367 178 13304SNCA ASO 00153101 2.05E-08 0.4 7.69AACATTTGTCA CTTGCTCTT368 179 13305SNCA ASO 00154101 1.27E-08 0.6 7.89CAACATTTGTC ACTTGCTCT369 180 13306SNCA ASO 00155101 3.82E-09 0.4 8.42TCCAACATTTG TCACTTGCT370 182 13308SNCA ASO 001835.95E-08 0.6 7.23CCCTCCACTGT CTTCTGGGC398 232 13358SNCA ASO 001842.78E-08 0.8 7.56TCCCTCCACTG TCTTCTGGG399 233 13359SNCA ASO 001852.44E-09 0.6 8.61CTCCCTCCACT GTCTTCTGG400 234 13360SNCA ASO 001863.25E-09 0.7 8.49GCTCCCTCCAC TGTCTTCTG401 235 13361SNCA ASO 001875.99E-09 0.8 8.22TGCTCCCTCCA CTGTCTTCT402 236 13362SNCA ASO 00188112 1.85E-09 0.7 8.73CTGCTCCCTCC ACTGTCTTC403 237 13363SNCA ASO 00189108 2.57E-09 0.9 8.59CCCTGCTCCCT CCACTGTCT404 239 13365SNCA ASO 00190109 3.51E-09 0.7 8.45TCCCTGCTCCC TCCACTGTC405 240 13366SNCA ASO 001916.85E-08 0.7 7.16CTCCCTGCTCC CTCCACTGT406 241 13367SNCA ASO00192108 1.10E-09 0.9 8.96GCTCCCTGCTC CCTCCACTG407 242 13368SNCA ASO 00193109 2.80E-09 0.9 8.55TGCTCCCTGCT CCCTCCACT408 243 13369SNCA ASO 00194105 5.25E-09 0.6 8.28ATGCTCCCTGC TCCCTCCAC409 244 13370SNCA ASO 00195110 1.79E-09 0.5 8.75AATGCTCCCTG CTCCCTCCA410 245 13371SNCA ASO00196100 7.87E-08 0.7 7.1CAATGCTCCCT GCTCCCTCC411 246 13372 126 WO 2022/189363 PCT/EP2022/055770 Compound Name DELTA Inhib Obs (%) IC50 (M) nH )־(pICso)־( Unmodified Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 3 Position in SEQ ID NO: 1 SNCA ASO 001974.62E-09 0.7 8.34GCAATGCTCCC TGCTCCCTC412 247 13373SNCA ASO 00198102 6.66E-09 0.6 8.18TGCAATGCTCC CTGCTCCCT413 248 13374SNCA ASO00199107 4.65E-09 0.5 8.33CTGCAATGCTC CCTGCTCCC414 249 13375SNCA ASO 002001.61E-08 0.6 7.79GCTGCAATGCT CCCTGCTCC415 250 13376SNCA ASO 002016.40E-08 0.6 7.19TGCTGCAATGC TCCCTGCTC416 251 13377SNCA ASO002025.32E-08 0.8 7.28CTGCTGCAATG CTCCCTGCT417 252 13378SNCA ASO002031.66E-08 1 7.78GCTGCTGCAAT GCTCCCTGC418 253 13379SNCA ASO 002044.91E-08 1.2 7.31GGCTGCTGCA ATGCTCCCTG419 254 13380 Table J. 5-10-5 MOE Gapmers Complementary to SNCA RNA Introns Compound Name DELTA Inhib Obs (%) IC50 (M) nH )־(pICso)־( Unmodified Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO00523114 1.36E-09 0.4 8.86ATTTCACTCTC ATGGTGCCT573 14576SNCA ASO 00530104 6.55E-09 0.6 8.19GTACATGTTTC CCTGTTGCT580 15596SNCA ASO 00537132 8.6E-09 0.9 8.06CCGGTGCCAT TACTCCCTTT16401SNCA ASO 00554101 7.86E-10 0.6 9.1GCAGTTCTATCCCACTCATC18926SNCA ASO 00555114 3.07E-09 0.7 8.51ATGCAGTTCTATCCCACTCA603 18928SNCA ASO00559104 4.31E-10 0.6 9.36TCTGGCTCAG TATTCTTTGC607 20158SNCA ASO 00560105 2.81E-09 0.6 8.55CCCACATCTAAGCAGGAAGA608 20258SNCA ASO 005684.16E-09 0.7 8.38GCAGATAAAC CATCCCACTT22295SNCA ASO00569ill 1.34E-08 0.7 7.88TGCAGATAAA CCATCCCACT616 22296SNCA ASO00570112 5.77E-09 0.7 8.24TTGCAGATAAACCATCCCAC22297SNCA ASO00576103 8.28E-09 0.6 8.08AGTGCCAGAC CCTTTCATTA22932SNCA ASO 00577116 4.24E-09 0.7 8.37CCAAGTGCCA GACCCTTTCA22935SNCA ASO 00579124 9.8E-10 0.5 9.01AATAGCATCC TTCCACACCA23410SNCA ASO 00580102 3.12E-09 0.6 8.5CAATAGCATC CTTCCACACC623 23411 127 WO 2022/189363 PCT/EP2022/055770 Compound Name DELTA Inhib Obs (%) IC50 (M) nH )־(pICso)־( Unmodified Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO00593104 1.12E-08 0.5 7.95CTTGGGCTGG ACTTTTTTGC635 26606SNCA ASO 006149.38E-10 0.5 9.03GCTATGACCCTCAAGCCATC28601SNCA ASO 00617115 6.22E-09 0.8 8.21ATCACCTTCA AACCCCTTTC29755SNCA ASO00619119 3.18E-09 0.7 8.5TGTTTTGCTGC TCGAATCAT659 29794SNCA ASO006351.54E-09 0.7 8.81AGCAGAGATT ATGGCAGAGA674 36416SNCA ASO00636104 2.96E-09 1 8.53CACAAGTAGG CAGCACAGGT675 37759SNCA ASO 006371.84E-09 0.8 8.74GCACAAGTAG GCAGCACAGG676 37760SNCA ASO 00646102 3.75E-07 0.9 6.42GGGAAAATAT GGGGGCAACA685 39852SNCA ASO 006482.63E-07 1.6 6.58AGGGGAAAAT ATGGGGGCAA687 39854SNCA ASO 006509.8E-08 0.5 7.01CACCAACCAA CCAGAGGGGA689 39868SNCA ASO 006755.91E-10 0.8 9.23TAGCCGACATACATCTCCAA49733SNCA ASO 006821.44E-08 0.7 7.84TGGGAACCCT TCTGTCATCA720 51859SNCA ASO 00683103 8.48E-08 0.7 7.07AGGCAGGGCTAGACAAAATG721 52064SNCA ASO00684106 2.41E-08 0.9 7.61GAGGCAGGGC TAGACAAAAT722 52065SNCA ASO 006858.21E-09 0.7 8.09AGAGGCAGGG CTAGACAAAA723 52066SNCA ASO 00688115 5.53E-08 0.5 7.26ACCCTGCTAG CCAGAAGAGA726 59374SNCA ASO 006891.88E-07 0.7 6.73AACCCTGCTA GCCAGAAGAG727 59375SNCA ASO 00710113 3.98E-08 0.7 7.4CAGACAATGG GAGACAGGAG748 64033SNCA ASO 007335.05E-08 1 7.3ACACACGAAT GCACACACAT771 65743SNCA ASO 00744ill 9.7E-08 1 7.01GGGAAGGACC TGCTGATCTA782 71346SNCA ASO 007639.43E-08 0.9 7.02CCAGGGACTGACACAGAGAC801 73482SNCA ASO007893.16E-07 6.5AGTGGGGAGG GTAGGCTTTG827 96847SNCA ASO 009813.62E-07 8.3 6.44GGGGACACTCATCTAAGGAA882 12035SNCA ASO 009837.18E-08 0.6 7.14TACTGGGCCA CACTAATCAC884 7582SNCA ASO 009841.47E-07 1.5 6.83AGAACAGTGGAGGAGAGTGG885 12060 128 WO 2022/189363 PCT/EP2022/055770 Compound Name DELTA Inhib Obs (%) IC50 (M) nH )־(pICso)־( Unmodified Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 00994ill 7.75E-09 0.8 8.11TTGTTTTGCTG CTCGAATCA895 29795SNCA ASO 01000102 3.99E-08 0.7 7.4AGAGGGTTCC AAAGGAGCAC901 39885SNCA ASO 010055.01E-08 0.8 7.3TAGTTGCCAC CAGAGAATGT906 994SNCA ASO 01013115 1.28E-08 0.9 7.89ATTGTTTTGCT GCTCGAATC914 29796SNCA ASO 01014103 3.47E-08 0.9 7.46TAGGGATCAC CTTCAAACCC915 29760SNCA ASO01026116 1.73E-08 0.8 7.76TCCAAAGGAG CACCAACCAA39878SNCA ASO 010271.02E-06 16.6 5.99AGAGGGGAAA ATATGGGGGC927 39856SNCA ASO 01037105 2.75E-08 0.8 7.56AGGGTTCCAA AGGAGCACCA937 39883SNCA ASO 01042117 3.47E-08 0.4 7.46GCAGCAGCAA TGGGATCCAC942 38490SNCA ASO 010462.89E-08 1.1 7.54GGCAGGGCTA GACAAAATGG946 52063SNCA ASO 010511.64E-08 1 7.79TTTGCACAAG TAGGCAGCAC951 37763SNCA ASO010525.59E-08 1.4 7.25CTTTGAACTGT GCTTGGGGT952 22251SNCA ASO 010602.49E-08 0.9 7.6GAGGGTTCCA AAGGAGCACC960 39884SNCA ASO 010611.82E-07 0.7 6.74CCAGATAAAA CAAGGCCCTG961 26438SNCA ASO 01063ill 1.51E-07 0.5 6.82GTACTGATTT GTGCCTGGCA963 38055SNCA ASO 01070108 7.36E-09 0.6 8.13TCATCATGCA TAAGCAGCCT970 51845SNCA ASO 01074106 3.63E-08 0.4 7.44TGTCATCATG CATAAGCAGC974 51847SNCA ASO 010812.46E-07 0.4 6.61AATTCCAAGT GCCAGACCCT981 22939SNCA ASO 01086106 1.66E-07 0.4 6.78TGCATAAGCA GCCTGAGTCT986 51839SNCA ASO 010875.45E-08 0.7 7.26AAGAGGCTAT TGAGCACCCT987 12324SNCA ASO 01091112 5.30E-08 0.6 7.28GGAAGGACTT GGGTCTTACT991 22765SNCA ASO 01098106 4.10E-08 0.6 7.39CTCAACTCAGGCTAGCTACT998 36619SNCA ASO 011126.80E-08 0.6 7.17GAGGCTGACA AGGGTAAGAG1012 5402SNCA ASO 01115102 9.77E-08 0.7 7.01GGGGCTTTGA ACTGTGCTTG1015 22255SNCA ASO 01119102 1.44E-08 0.9 7.84TCTGGCTAGA AATGTAGGCA1019 35620 129 WO 2022/189363 PCT/EP2022/055770 Compound Name DELTA Inhib Obs (%) IC50 (M) nH )־(pICso)־( Unmodified Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 011312.55E-07 0.6 6.59CAGAGAGGAG AACAGTGGAG1031 12068SNCA ASO 01141107 3.48E-08 0.6 7.46TAAATTCCAA GTGCCAGACC1041 22941SNCA ASO 011481.02E-07 0.8 6.99CCTGACATAGCCACACAGCC1048 11447SNCA ASO 011571.87E-07 0.5 6.73TAGGGCCACA AATAGGTCTC1057 579SNCA ASO 011589.36E-08 0.6 7.03GGGCCACAAA TAGGTCTCTT1058 577SNCA ASO 011645.83E-08 0.5 7.23ACATGGCCAG AAACCACTTA1064 53766SNCA ASO 01181107 7.65E-08 1.2 7.12TTAGAGGCTG ACAAGGGTAA1081 5405SNCA ASO 01185148 4.42E-08 0.7 7.35TGCCAGGCGA GAATTTGCTT1085 40021SNCA ASO 01187136 5.41E-09 0.9 8.27GAACTGATGC CTCTACCTCC38135SNCA ASO 01188133 6.10E-09 0.9 8.21GCATGAGAGC ACCCACCTAG1087 64454SNCA ASO 011891.06E-08 0.9 7.98CCTTGCCCAA CTGGTCCTTT1088 13414SNCA ASO01206117 6.23E-09 0.8 8.21TCTCAACTCA GGCTAGCTAC1105 36620SNCA ASO01209113 3.25E-08 0.6 7.49AGGGGGCTTT GAACTGTGCT1108 22257SNCA ASO 01214107 3.70E-08 0.8 7.43GAAGGAACTC CAGTAACCAC1113 7307SNCA ASO 01218115 2.07E-09 0.9 8.68GTGAACAGATTCCAGCAGAG1117 36429SNCA ASO01230100 7.91E-09 0.8 8.1CCAAGGCTGC AAAAGCTAAA1129 65054SNCA ASO 012311.01E-08 1.1 8CATGGCCAGA AACCACTTAG1130 53765SNCA ASO 01232119 3.01E-09 1.2 8.52AGTAGGCAGC ACAGGTTTTC1131 37755SNCA ASO 01236121 2.54E-08 1.1 7.6ATGAGAGCAC CCACCTAGCC1135 64452SNCA ASO 01237110 1.70E-08 0.7 7.77TGGGAGAGAAAAGCAGAGAT1136 39718SNCA ASO 01264116 5.53E-09 0.7 8.26CTTTTTGGAGT TCTGGAGGC1163 26625SNCA ASO 01270104 5.70E-09 0.7 8.24ACTGAACTGA TGCCTCTACC38138SNCA ASO 01275123 1.68E-08 0.7 7.78AAGCCAAGCC CAAACACTAA59756SNCA ASO012893.75E-08 0.6 7.43ACCAACCAGAGGGGAAAATA1186 39863SNCA ASO 013014.98E-08 0.6 7.3TTCCAGCAGAGATTATGGCA1198 36420 130 WO 2022/189363 PCT/EP2022/055770 Compound Name DELTA Inhib Obs (%) IC50 (M) nH )־(pICso)־( Unmodified Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO013022.29E-08 0.2 7.64TTAACATGTG CTGAACACCC1199 7035SNCA ASO013068.57E-09 0.6 8.07TACATGGCCAGAAACCACTT53767SNCA ASO013093.54E-08 0.6 7.45AAAAGGAACA TCAAAGGCGC1205 64232SNCA ASO 013225.10E-09 0.6 8.29ACTTGTGACC TTCAGTACCA1218 30266SNCA ASO 013353.33E-08 0.6 7.48CTAGTGGCAG CTCTCAGACA1231 64047SNCA ASO 013369.10E-08 1.1 7.04GATCTTGGGC AAAAGTGTGT1232 36389SNCA ASO 01341114 1.97E-08 0.9 7.71GGCAGCACAG GTTTTCTGAC1237 37751SNCA ASO 01343121 8.78E-08 0.6 7.06TGTACATGGC CAGAAACCAC1239 53769SNCA ASO 01347112 8.52E-08 1 7.07GGAGGGTAGG CTTTGACAAA1243 96842SNCA ASO 01353117 1.03E-08 1 7.99GCTTTCTGCGT ATGGGCATC1249 64119SNCA ASO 01617103 1.77E-9 0.8 8.75GTTTTCATCAATATCTGCAA1264 46216 Table K. 5-10-5 MOE Gapmers Complementary to SNCA RNA Exons Compound Name DELTA Inhib Obs (%) IC50 (M) nH )־(pICso)־( Unmodified Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 008383.74E-1110.43CGGTGCCATT ACTCCCTTTC16400SNCA ASO 008391.81E -100.5 9.74GTAAATATGT CAGTCTCCCG18540SNCA ASO008401121.03E-090.6 8.99GGGTTCTCTA ACGACAGTAG25550SNCA ASO 008411164.46E-090.4 8.35GGGGTTCTCTAACGACAGTA25551SNCA ASO 008421091.72E-080.5 7.77GGATGGGGTT CTCTAACGAC25555SNCA ASO 008431074.88E-090.7 8.31GAGCGATCGG AAGCTCCCTG27763SNCA ASO 008441086.86E-090.6 8.16AGAGCGATCG GAAGCTCCCT27764SNCA ASO008467.09E-100.6 9.15GTTGCTATCTAGGGATCACC29769SNCA ASO 008471.95E-090.7 8.71GCGAAGGACT ATATAATAGG33628SNCA ASO 00848ill2.12E-090.9 8.67GGTAACTTAGGACAAGGTCC38957SNCA ASO 008491022.42E-090.7 8.62TTCACATAAA GTAGCCGCTA40930 131 WO 2022/189363 PCT/EP2022/055770 SNCA ASO 008501.02E-090.9 8.99ACTTCACATA AAGTAGCCGC40932SNCA ASO 008523.67E-100.9 9.44ATAGCCGACA TACATCTCCA49734SNCA ASO 008536.94E-100.8 9.15GACGGATCAG ACACTCTTAC52858SNCA ASO008541053.67E-080.9 7.44TGCCTCACGG ATGTCCGTGT59974SNCA ASO 008556.28E-100.7 9.2GCTCGAGATT AGTTCTTCCC69469SNCA ASO 008563.14E-090.5 8.5GCCACTAGTAGATGACAGTT71531SNCA ASO 008573.05E-090.5 8.52GATGGAATTTACCCCCTAGT74726SNCA ASO 008582.53E-080.5 7.6AGCAGAAGCA TGCGGCTACC76062SNCA ASO 008591.25E-090.6 8.9GGTATCGTCATGGAATTTGGN/ASNCA ASO 008602.15E-070.6 6.67GATCTAAGGA CCCTCAACAAN/ASNCA ASO 008611072.55E-080.8 7.59GGATCTAAGG ACCCTCAACAN/ASNCA ASO 008623.76E-100.5 9.42ACTCTATCTT GAGGCACACCN/ASNCA ASO 008638.79E-090.5 8.06CTGTTAATGT AGTAGGAGCAN/ASNCA ASO008642.15E-080.7 7.67ACTGTTAATG TAGTAGGAGCN/A Table L. 3-2-10-2-3 LNA/MOE mixed gapmer Compound Name DELTA Inhib Obs (%) IC50 (M) nH )־(pICso (-) Unmodified Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCAASO 016181001.74E-090.8 8.76GCAGTTCTATCCCACTCATC18926SNCAASO 016191261.21E-080.8 7.92CCGGTGCCAT TACTCCCTTT16401SNCAASO 016203.16E-0912.8.5CCAAGTGCCA GACCCTTTCA22935SNCAASO 016211181.18E -090.9 8.93TTGCAGATAAACCATCCCAC22297SNCAASO 016236.79E-101.2 9.17AATAGCATCC TTCCACACCA23410SNCAASO 016261133.94E-091.1 8.4CGGTGCCATT ACTCCCTTTC16400 132 WO 2022/189363 PCT/EP2022/055770 Table M. 2-3-10-3-2 BNA/MOE mixed gapmer Compound Name DELTA Inhib Obs (%) IC50 (M) nH )־(pICso)־( Unmodified Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 SNCA ASO 016081.11E-091.1 8.96GCAGTTCTATCCCACTCATC18926SNCA ASO016091054.09E-080.7 7.39CCGGTGCCAT TACTCCCTTT16401SNCA ASO 016102.74E-091.2 8.56CCAAGTGCCA GACCCTTTCA22935SNCA ASO 016111154.63E-098.33TTGCAGATAAACCATCCCAC22297SNCA ASO 016122.24E-090.8 8.65GCAGATAAAC CATCCCACTT22295SNCA ASO 016138.49E-100.7 9.07AATAGCATCC TTCCACACCA23410SNCA ASO 016141002.85E-090.8 8.54AGTGCCAGAC CCTTTCATTA22932SNCA ASO 016152.52E-091.1 8.6ATCACCTTCA AACCCCTTTC29755SNCA ASO 016161.16E-080.9 7.93CGGTGCCATT ACTCCCTTTC16400 Example 4: Tolerability and Efficacy of Modified Oligonucleotides Complementary to Human SNCA in hSNCA Mice [0242]Three-month-old hSNCA mice received a single bolus ICV injection of a modifiedoligonucleotide listed in the indicated table at a dose of 30 nmol. Each modified oligonucleotide is complementary to the human SNCA genomic nucleic acid sequence (SEQ ID NO: 1). The positions in the tables indicate the 5’ nucleoside to which the oligonucleotide is complementary in the human nucleic acid sequence (SEQ ID NO: 1). [0243]For tolerability studies, the tolerability score is represented as the FunctionalObservational Battery (FOB) score at one hour post-injection. [0244]For efficacy studies, most treatment groups consisted of three animals. Mice were sacrificed two weeks or six weeks post-injection, as indicated. Brain tissue was collected and the level of hSNCA mRNA was measured as described above. Results are presented in thetables as percent reduction of the amount of SNCA mRNA relative to vehicle control groups. A value of 0% reduction indicates that the compound had no effect. 1. Tolerability of 5-10-5 MOE Gapmers (PS) [0245]Each ASO in Table Nis a 5-10-5 MOE gapmer as described above, in which all cytosines residues throughout each gapmer are 5-methyl cytosines and all internucleoside 133 WO 2022/189363 PCT/EP2022/055770 linkages are phosphorothioate (PS) linkages. FIG. 4is a bar graph that compares the tolerability of select 5-10-5 MOE gapmers. Compounds having an FOB of greater than ten were excluded from further assays. The structure of SNCA ASO 01617 is as described above.

Table N. Tolerability of 5-10-5 MOE Gapmers in hSNCA Mice Compound Name Unmodified Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 FOB (lh) SNCA ASO_ 00033CCAACATTTGTCACTTGCTC 251 13307 6.25SNCA ASO_00033CCAACATTTGTCACTTGCTC 251 13307 3.3SNCA ASO_ 00038TCCTTTCATGAATACATCCA 253 2 0SNCA ASO_00040AGTCCTTTCATGAATACATC 255 4 3SNCA ASO_ 00056AGCCACAACTCCCTCCTTGG 271 32 14SNCA ASO_ 00057CAGCCACAACTCCCTCCTTG 272 33 11SNCA ASO_ 00058GCAGCCACAACTCCCTCCTT 273 34 4SNCA ASO_00080GCCACACCCTGTTTGGTTTT 295 61 3SNCA ASO_ 00091CTGCTGCTTCTGCCACACCC 306 72 8SNCA ASO_ 00116GCCTACATAGAGAACACCCT 331 N/A 3SNCA ASO_ 00162ACTGCTGTCACACCCGTCAC 377 13337 5SNCA ASO_ 00165GCTACTGCTGTCACACCCGT 380 13340 11SNCA ASO_ 00166GGCTACTGCTGTCACACCCG 381 13341 8SNCA ASO_ 00186GCTCCCTCCACTGTCTTCTG 401 13361 12SNCA ASO_ 00187TGCTCCCTCCACTGTCTTCT 402 13362 8SNCA ASO_ 00189CCCTGCTCCCTCCACTGTCT 404 13365 3SNCA ASO_ 00190TCCCTGCTCCCTCCACTGTC 405 13366 9SNCA ASO_ 00194ATGCTCCCTGCTCCCTCCAC 409 13370 0SNCA ASO_ 00198TGCAATGCTCCCTGCTCCCT 413 13374 7SNCA ASO_00199CTGCAATGCTCCCTGCTCCC 414 13375 4 134 WO 2022/189363 PCT/EP2022/055770 Compound Name Unmodified Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 FOB (ih) SNCA ASO_ 00215TCTTGCCCAACTGGTCCTTT 430 N/A 11SNCA ASO_00523ATTTCACTCTCATGGTGCCT 573 14576 9SNCA ASO_00530GTACATGTTTCCCTGTTGCT 580 15596 9SNCA ASO_00537CCGGTGCCATTACTCCCTTT 7 16401 1SNCA ASO_00554GCAGTTCTATCCCACTCATC 4 18926 0SNCA ASO_ 00555ATGCAGTTCTATCCCACTCA 603 18928 2.33SNCA ASO_00559TCTGGCTCAGTATTCTTTGC 607 20158 10SNCA ASO_00560CCCACATCTAAGCAGGAAGA 608 20258 10.33SNCA ASO_ 00568GCAGATAAACCATCCCACTT 11 22295 4.33SNCA ASO_00569TGCAGATAAACCATCCCACT 616 22296 0.66SNCA ASO_ 00570TTGCAGATAAACCATCCCAC 8 22297 1.66SNCA ASO_00576AGTGCCAGACCCTTTCATTA 9 22932 3.66SNCA ASO_ 00577CCAAGTGCCAGACCCTTTCA 10 22935 4SNCA ASO_00579AATAGCATCCTTCCACACCA 5 23410 0.33SNCA ASO_00580CAATAGCATCCTTCCACACC 623 23411 1SNCA ASO_00593CTTGGGCTGGACTTTTTTGC 635 26606 11SNCA ASO_ 00617ATCACCTTCAAACCCCTTTC 6 29755 0.66SNCA ASO_ 00619TGTTTTGCTGCTCGAATCAT 659 29794 10PBS N/A N/A 0.3SNCA ASO_00635AGCAGAGATTATGGCAGAGA 674 36416 10SNCA ASO_00033CCAACATTTGTCACTTGCTC 251 13307 3.3SNCA ASO_00636CACAAGTAGGCAGCACAGGT 675 37759 12SNCA ASO_00637GCACAAGTAGGCAGCACAGG 676 37760 14SNCA ASO_00646GGGAAAATATGGGGGCAACA 685 39852 1SNCA ASO_ 00648AGGGGAAAATATGGGGGCAA 687 39854 0.33 135 WO 2022/189363 PCT/EP2022/055770 Compound Name Unmodified Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 FOB (ih) SNCA ASO_00650CACCAACCAACCAGAGGGGA 689 39868 0.33SNCA ASO_00682TGGGAACCCTTCTGTCATCA 720 51859 8SNCA ASO_ 00683AGGCAGGGCTAGACAAAATG 721 52064 0SNCA ASO_00684GAGGCAGGGCTAGACAAAAT 722 52065 11SNCA ASO_ 00685AGAGGCAGGGCTAGACAAAA 723 52066 9SNCA ASO_ 00688ACCCTGCTAGCCAGAAGAGA 726 59374 10SNCA ASO_00689AACCCTGCTAGCCAGAAGAG 727 59375 9SNCA ASO_ 00710CAGACAATGGGAGACAGGAG 748 64033 11SNCA ASO_ 00733ACACACGAATGCACACACAT 771 65743 4.66SNCA ASO_ 00744GGGAAGGACCTGCTGATCTA 782 71346 10SNCA ASO_ 00763CCAGGGACTGACACAGAGAC 801 73482 9SNCA ASO_ 00789AGTGGGGAGGGTAGGCTTTG 827 96847 11SNCA ASO_ 00838CGGTGCCATTACTCCCTTTC 17 16400 1.33SNCA ASO_00839GTAAATATGTCAGTCTCCCG 58 18540 12SNCA ASO_ 00840GGGTTCTCTAACGACAGTAG 59 25550 10SNCA ASO_ 00841GGGGTTCTCTAACGACAGTA 60 25551 11SNCA ASO_00842GGATGGGGTTCTCTAACGAC 61 25555 14SNCA ASO_00849TTCACATAAAGTAGCCGCTA 67 40930 9SNCA ASO_00850ACTTCACATAAAGTAGCCGC 68 40932 11SNCA ASO_ 00851TAGCCGACATACATCTCCAA 57 49733 1SNCA ASO_00852ATAGCCGACATACATCTCCA 69 49734 3SNCA ASO_00854TGCCTCACGGATGTCCGTGT 71 59974 6SNCA ASO_ 00855GCTCGAGATTAGTTCTTCCC 72 69469 4SNCA ASO_00856GCCACTAGTAGATGACAGTT 73 71531 10SNCA ASO_ 00858AGCAGAAGCATGCGGCTACC 75 76062 10 136 WO 2022/189363 PCT/EP2022/055770 Compound Name Unmodified Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 FOB (lh) SNCA ASO_00859GGTATCGTCATGGAATTTGG 76 N/A 14SNCA ASO_00860GATCTAAGGACCCTCAACAA 77 N/A 6SNCA ASO_ 00861GGATCTAAGGACCCTCAACA 78 N/A 4.33SNCA ASO_00862ACTCTATCTTGAGGCACACC 79 N/A 5SNCA ASO_ 01897ATTCCTTTACACCACACT 1263 N/A 0.33SNCA ASO_00033CCAACATTTGTCACTTGCTC 251 13307 1.67PBS N/A N/A 0.33SNCA ASO_00033CCAACATTTGTCACTTGCTC 251 13307 6.33SNCA ASO_ 00033CCAACATTTGTCACTTGCTC 251 13307 3.67SNCA ASO_00033CCAACATTTGTCACTTGCTC 251 13307 5.67SNCAASOO1617GTTTTCATCAATATCTGCAA 1264 46216 0.67 II. Efficacy of 5-10-5 MOE Gapmers (PS) [0246]Each ASO listed in Table Ois a 5-10-5 MOE gapmer as described above, in which all cytosine residues throughout each gapmer are 5-methyl cytosines and allinternucleoside linkages are phosphorothioate linkages. FIG. 4is a bar graph that compares the efficacy of select 5-10-5 MOE gapmers. The structure of SNCA_ASO_01617 is as described above. [0247]As shown below, several of the ASOs reduced the amount of human SNCA mRNA in mice two weeks post-injection.

Table O. Effect of 5-10-5 MOE Gapmers in hSNCA Mice Compound Name Unmodified ASO Sequence (SEQ ID NO) SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 Time post injection % mRNA Reduction SNCA ASO00033CCAACATTTGTCACTTGCTC 251 13307 2 weeks 67SNCA ASO 00537CCGGTGCCATTACTCCCTTT 7 16401 2 weeks 45SNCA ASO 00554GCAGTTCTATCCCACTCATC 4 18926 2 weeks 70SNCA ASO 00555ATGCAGTTCTATCCCACTCA 603 18928 2 weeks 55 137 WO 2022/189363 PCT/EP2022/055770 Compound Name Unmodified ASO Sequence (SEQ ID NO) SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 Time post injection % mRNA Reduction SNCA ASO 00568GCAGATAAACCATCCCACTT 11 22295 2 weeks 30SNCA ASO00569TGCAGATAAACCATCCCACT 616 22296 2 weeks 20SNCA ASO00570TTGCAGATAAACCATCCCAC 8 22297 2 weeks 22SNCA ASO00576AGTGCCAGACCCTTTCATTA 9 22932 2 weeks 19SNCA ASO 00577CCAAGTGCCAGACCCTTTCA 10 22935 2 weeks 42SNCA ASO 00579AATAGCATCCTTCCACACCA 5 23410 2 weeks 43SNCA ASO 00580CAATAGCATCCTTCCACACC 623 23411 2 weeks 39SNCA ASO 00617ATCACCTTCAAACCCCTTTC 6 29755 2 weeks 30PBS N/A 2 weeks 0SNCA ASO00033CCAACATTTGTCACTTGCTC 251 13307 2 weeks 67SNCA ASO 00646GGGAAAATATGGGGGCAACA 685 39852 2 weeks 11SNCA ASO 00648AGGGGAAAATATGGGGGCAA 687 39854 2 weeks 6SNCA ASO 00650CACCAACCAACCAGAGGGGA 689 39868 2 weeks 0SNCA ASO 00733ACACACGAATGCACACACAT 771 65743 2 weeks 11SNCA ASO 00838CGGTGCCATTACTCCCTTTC 17 16400 2 weeks 42SNCA ASO 00851TAGCCGACATACATCTCCAA 57 49733 2 weeks 54SNCA ASO 00852ATAGCCGACATACATCTCCA 69 49734 2 weeks 58SNCA ASO 00855GCTCGAGATTAGTTCTTCCC 72 69469 2 weeks 40SNCA ASO 00860GATCTAAGGACCCTCAACAA 77 N/A 2 weeks 0SNCA ASO 00861GGATCTAAGGACCCTCAACA 78 N/A 2 weeks 0SNCA ASO 00862ACTCTATCTTGAGGCACACC 79 N/A 2 weeks 28SNCA ASO 01897ATTCCTTTACACCACACT 1263 N/A 2 weeks 0SNCA ASO00033CCAACATTTGTCACTTGCTC 251 13307 2 weeks 66SNCA ASO00033CCAACATTTGTCACTTGCTC 251 13307 2 weeks 70SNCA ASO 01617GTTTTCATCAATATCTGCAA 1264 46216 2 weeks 58.4 138 WO 2022/189363 PCT/EP2022/055770 III. Tolerability of 3-2-10-2-3 LNA/MOE Mixed Gapmers (PS) [0248]Each ASO listed in Table Pis a 3-2-10-2-3 LNA/MOE mixed gapmer, except for SNCA_ASO_00033, which is a 5-10-5 MOE gapmer as described above, used as a comparator. The LNA/MOE mixed gapmers are 20 nucleobases in length, wherein the central gap segment comprises ten 2’-deoxynucleosides and each wing segment comprises three LNA nucleosides and two 2’-MOE nucleosides. The ASO therefore comprises, from 5’ to 3’, 3 LNA nucleosides, two 2’-MOE nucleosides, 10 2’-deoxynucleosides, two 2’-MOE nucleosides, and 3 LNA nucleosides. All cytosines residues throughout each gapmer are 5- methyl cytosines, and all internucleoside linkages are phosphorothioate linkages. [0249]Further experimentation to determine the level of mRNA reduction was not performed for compounds 00937, 00938, 00941 and 00942 because they did not exhibit promising FOB results. The mice treated with these compounds were sacrificed.

Table P. Tolerability of 3-2-10-2-3 LNA/MOE Mixed Gapmers in hSNCA Mice Compound Name Unmodified ASO Sequence (SEQ ID NO) SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 FOB (lh) SNCA ASO 00937CCACGGCACAATTTGA 173 N/A 14SNCA ASO 00938TACAACTAACCACGGC 174 N/A 11SNCA ASO 00941TACTATCTTACGTGGC 179 N/A 12SNCA ASO 00942CACATAAAGTAGCCGC 182 N/A 12SNCA ASO00033CCAACATTTGTCACTTGCTC 251 13307 1.67PBS N/A 0.33 IV. Tolerability of 3-2-10-2-3 LNA/MOE Gapmers (PS/PO) [0250]Each ASO listed in Table Q(aside from comparator SNCA ASO 00033) is a 3- 2-10-2-3 LNA/MOE mixed gapmer. FIG. 5is a bar graph that compares the tolerability of select 3-2-10-2-3 LNA/MOE mixed gapmers. All cytosines throughout each gapmer are 5- methyl cytosines, and all internucleoside linkages are phosphorothioate (PS) linkages except for the linkages between nucleosides 2 and 3, 4 and 5, 16 and 17, and 18 and 19, which are phosphodiester (PO) linkages. 139 WO 2022/189363 PCT/EP2022/055770 Table Q. Tolerability of 3-2-10-2-3 LNA/MOE Mixed Gapmers in hSNCA Mice Compound Name Unmodified ASO Sequence (SEQ ID NO) SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 FOB (lh) SNCA ASO 01618GCAGTTCTATCCCACTCATC 4 18926 0.67SNCA ASO 01619CCGGTGCCATTACTCCCTTT 7 16401 3.33SNCA ASO01620CCAAGTGCCAGACCCTTTCA 10 22935 2.33SNCA ASO 01621TTGCAGATAAACCATCCCAC 8 22297 0.33SNCA ASO 01622GCAGATAAACCATCCCACTT 11 22295 1SNCA ASO 01623AATAGCATCCTTCCACACCA 5 23410 0.83SNCA ASO 01624AGTGCCAGACCCTTTCATTA 9 22932 1SNCA ASO 01625ATCACCTTCAAACCCCTTTC 6 29755 1.33SNCA ASO01626CGGTGCCATTACTCCCTTTC 17 16400 1.33SNCA ASO00033CCAACATTTGTCACTTGCTC 251 13307 6.33PBS N/A 0SNCA ASO00033CCAACATTTGTCACTTGCTC 251 13307 3.67SNCA ASO 01823GAACTGATGCCTCTACCTCC 12 38135 7.33SNCA ASO 01824ACTGAACTGATGCCTCTACC 13 38138 5.67SNCA ASO 01825TACATGGCCAGAAACCACTT 14 53767 2.67SNCA ASO 01826AAGCCAAGCCCAAACACTAA 15 59756 3.67SNCA ASO01822TCCAAAGGAGCACCAACCAA 16 39878 2PBS N/A 0.67SNCA ASO00033CCAACATTTGTCACTTGCTC 251 13307 5.67PBS N/A N/A 0.67 V. Tolerability of 3-2-10-2-3 LNA/MOE Gapmers (PS/PO) [0251]Each ASO listed in Table Ris a 3-2-10-2-3 LNA/MOE gapmer. All cytosinesresidues throughout each gapmer are 5-methyl cytosines. All internucleoside linkages are phosphorothioate linkages except for the linkages between nucleosides 2 and 3, 4 and 5, and and 17, which are phosphodiester linkages. 140 WO 2022/189363 PCT/EP2022/055770 Table R. Tolerability of 3-2-10-2-3- LNA/MOE Mixed Gapmers in hSNCA Mice Compound Name Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 FOB (lh) SNCA ASO 01818GCAGTTCTATCCCACTCATC 4 18926 2.33SNCA ASO 01819TTGCAGATAAACCATCCCAC 8 22297 0SNCA ASO 01820ATCACCTTCAAACCCCTTTC 6 29755 0.67SNCA ASO 01821CCGGTGCCATTACTCCCTTT 7 16401 0.33 VI. Tolerability of 3-2-10-2-3 LNA/MOE Gapmers (PS/PO) [0252]Each ASO listed in Table Sis a 3-2-10-2-3 LNA/MOE gapmer. All cytosinesresidues throughout each gapmer are 5-methyl cytosines, and all internucleoside linkages are phosphorothioate linkages except the linkages between nucleosides 2 and 3, 3 and 4, 4 and 5, and 17, and 17 and 18, which are phosphodiester linkages.

Table S. Tolerability of 3-2-10-2-3 LNA/MOE Mixed Gapmers in hSNCA Mice Compound Name Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 FOB (lh) SNCA ASO 01811GCAGTTCTATCCCACTCATC 4 18926 0.67SNCA ASO 01814TTGCAGATAAACCATCCCAC 8 22297 0.33SNCA ASO 01815ATCACCTTCAAACCCCTTTC 6 29755 0.67SNCA ASO 01817CCGGTGCCATTACTCCCTTT 7 16401 1 VII. Efficacy of 3-2-10-2-3 LNA/MOE Gapmers (PS/PO) [0253]Each ASO listed in Table T(aside from comparator SNCA ASO 00033) is a 3- 2-10-2-3 LNA/MOE mixed gapmer. FIG. 5is a bar graph that compares the efficacy of select 3-2-10-2-3 LNA/MOE mixed gapmers. All cytosines throughout each gapmer are 5- methyl cytosines, and all internucleoside linkages are phosphorothioate linkages except the linkages between nucleosides 2 and 3, 4 and 5, 16 and 17, and 18 and 19, which are phosphodiester linkages. [0254]As shown below, several of the ASOs reduced the amount of human SNCA mRNA in mice two weeks post injection. 141 WO 2022/189363 PCT/EP2022/055770 Table T. Effect of 3-2-10-2-3 LNA/MOE Mixed Gapmers in hSNCA Mice Compound Name Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 Time Post- Injection % mRNA Reduction SNCA ASO_00033CCAACATTTGTCACTTGCTC 251 13307 2 weeks 66PBS N/A N/A 2 weeks 0SNCA_ASO_ 01618GCAGTTCTATCCCACTCATC 4 18926 2 weeks 56SNCA_ASO_ 01619CCGGTGCCATTACTCCCTTT 7 16401 2 weeks 20SNCA_ASO_ 01620CCAAGTGCCAGACCCTTTCA 10 22935 2 weeks 49SNCA_ASO_ 01621TTGCAGATAAACCATCCCAC 8 22297 2 weeks 46SNCA_ASO_ 01622GCAGATAAACCATCCCACTT 11 22295 2 weeks 30SNCA_ASO_ 01623AATAGCATCCTTCCACACCA 5 23410 2 weeks 52SNCA_ASO_ 01624AGTGCCAGACCCTTTCATTA 9 22932 2 weeks 26SNCA_ASO_ 01625ATCACCTTCAAACCCCTTTC 6 29755 2 weeks 54SNCA_ASO_ 01626CGGTGCCATTACTCCCTTTC 17 16400 2 weeks 26SNCA_ASO_ 00033CCAACATTTGTCACTTGCTC 251 13307 2 weeks 70SNCA_ASO_ 01824ACTGAACTGATGCCTCTACC 13 38138 6 weeks 37SNCA_ASO_ 01825TACATGGCCAGAAACCACTT 14 53767 6 weeks 0SNCA_ASO_ 01826AAGCCAAGCCCAAACACTAA 15 59756 6 weeks 6SNCA_ASO_ 01822TCCAAAGGAGCACCAACCAA 16 39878 6 weeks 48SNCA_ASO_ 00033CCAACATTTGTCACTTGCTC 251 13307 6 weeks 66SNCA_ASO_ 01623AATAGCATCCTTCCACACCA 5 23410 6 weeks 72.6SNCA_ASO_ 01625ATCACCTTCAAACCCCTTTC 6 29755 6 weeks 71.9SNCA_ASO_ 01621TTGCAGATAAACCATCCCAC 8 22297 6 weeks 63.4 VIII. Efficacy of 3-2-10-2-3 LNA/MOE Gapmers (PS/PO) [0255]Each ASO in Table Uis a 3-2-10-2-3 LNA/MOE gapmer. All cytosinesthroughout each gapmer are 5-methyl cytosines, and all internucleoside linkages are phosphorothioate linkages, except the linkages between nucleosides 2 and 3, 4 and 5, and and 17, which are phosphodiester linkages. 142 WO 2022/189363 PCT/EP2022/055770 id="p-256" id="p-256" id="p-256" id="p-256" id="p-256" id="p-256" id="p-256" id="p-256"

[0256]As shown below, the ASOs reduced the amount of human SNCA mRNA in micetwo weeks post injection.

Table U. Effect of 3-2-10-2-3 LNA/MOE Mixed Gapmers in hSNCA Mice Compound Name Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 % mRNA Reduction SNCA_ASO_01818GCAGTTCTATCCCACTCATC 4 18926 67.5SNCA_ASO_01819TTGCAGATAAACCATCCCAC 8 22297 57.4SNCA_ASO_01820ATCACCTTCAAACCCCTTTC 6 29755 62.2SNCA_ASO_01821CCGGTGCCATTACTCCCTTT 7 18602 50.8 IX. Efficacy of 3-2-10-2-3 LNA/MOE Gapmers (PS/PO) [0257]Each ASO in Table Vis a 3-2-10-2-3 LNA/MOE gapmer. All cytosine residues throughout each gapmer are 5-methyl cytosines, and all internucleoside linkages are phosphorothioate linkages except the linkages between nucleosides 2 and 3, 3 and 4, 4 and 5, 16 and 17, and 17 and 18, which are phosphodiester linkages. [0258]As shown below, the ASOs reduced the amount of human SNCA mRNA in mice two weeks post injection.

Table V. Effect of 3-2-10-2-3 LNA/MOE Mixed Gapmers in hSNCA Mice Compound Name Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 % mRNA Reduction SNCAASO 01811GCAGTTCTATCCCACTCATC 4 18926 24.2SNCAASO 01814TTGCAGATAAACCATCCCAC 8 22297 47SNCAASO 01815ATCACCTTCAAACCCCTTTC 6 29755 42.6SNCAASO 01817CCGGTGCCATTACTCCCTTT 7 18602 57.9 X. Tolerability of 2-3-10-3-2 BNA/MOE Gapmers (PS/PO) [0259]Each ASO listed in Table W(aside from comparator SNCA_ASO_00033) is a 2- 3-10-3-2 BNA/MOE gapmer. FIG. 6is a bar graph that compares the tolerability of select 2- 3-10-3-2 BNA/MOE gapmers. The gapmers are 20 nucleobases in length, wherein the 143 WO 2022/189363 PCT/EP2022/055770 central gap segment comprises ten 2’-deoxynucleosides and each wing segment comprises two BNA nucleosides and three 2’-MOE nucleosides. Each ASO therefore comprises, from 5’ to 3’, two BNA nucleosides, three 2’-M0E nucleosides, 10 2’-deoxynucleosides, three 2’- MOE nucleosides, and two BNA nucleosides. All cytosines throughout each gapmer are 5- methyl cytosines, and all internucleoside linkages are phosphorothioate linkages except thelinkages between nucleosides 3 and 4, 4 and 5, 16 and 17, and 17 and 18, which are phosphodiester linkages.

Table W. Tolerability of 2-3-10-3-2 BNA/MOE Mixed Gapmer s in hSNCA Mice Compound Name Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 FOB (lh) SNCA ASO00033CCAACATTTGTCACTTGCTC 251 13307 1.67PBS N/A N/A 0.33SNCA ASO 01608GCAGTTCTATCCCACTCATC 4 18926 0.5SNCA ASO01609CCGGTGCCATTACTCCCTTT 7 16401 2SNCA ASO 01610CCAAGTGCCAGACCCTTTCA 10 22935 3SNCA ASO 01611TTGCAGATAAACCATCCCAC 8 22297 0.81SNCA ASO 01612GCAGATAAACCATCCCACTT 11 22295 1SNCA ASO 01613AATAGCATCCTTCCACACCA 5 23410 0.33SNCA ASO 01614AGTGCCAGACCCTTTCATTA 9 22932 1SNCA ASO 01615ATCACCTTCAAACCCCTTTC 6 29755 1.33SNCA ASO 01616CGGTGCCATTACTCCCTTTC 17 16400 2.67SNCA ASO00033CCAACATTTGTCACTTGCTC 251 13307 6.33PBS N/A N/A 0SNCA ASO 01790GAACTGATGCCTCTACCTCC 12 38135 9SNCA ASO 01791ACTGAACTGATGCCTCTACC 13 38138 6.33SNCA ASO 01792TACATGGCCAGAAACCACTT 14 53767 2.67SNCA ASO 01793AAGCCAAGCCCAAACACTAA 15 59756 1SNCA ASO 01789TCCAAAGGAGCACCAACCAA 16 39878 2SNCA ASO00033CCAACATTTGTCACTTGCTC 251 13307 3.67 144 WO 2022/189363 PCT/EP2022/055770 Compound Name Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 FOB (lh) PBS N/A N/A 0.67 XI. Efficacy of 3-2-10-2-3 BNA/MOE Gapmers (PS/PO) [0260]Each ASO listed in Table X(aside from comparator SNCA ASO 00033) is a 3- 2-10-2-3 BNA/MOE gapmer. FIG. 6is a bar graph that compares the efficacy of select 2-3- 10-3-2 BNA/MOE gapmers. The gapmers are 20 nucleobases in length, wherein the centralgap segment comprises ten 2’-deoxynucleosides and each wing segment comprises three BNA nucleosides and two 2’-MOE nucleosides. Each ASO therefore comprises, from 5’ to 3’, three BNA nucleosides, two 2’-MOE nucleosides, 10 2’-deoxynucleosides, two 2’-MOE nucleosides, and three BNA nucleosides. All cytosines throughout each gapmer are 5-methyl cytosines, and all internucleoside linkages are phosphorothioate linkages except for thelinkages between nucleosides 3 and 4, 4 and 5, 16 and 17, and 17 and 18, which are phosphodiester linkages. [0261]As shown below, the ASOs significantly reduced the amount of human SNCA mRNA in mice as quickly as two weeks post injection.

Table X. Effect of 2-3-10-3-2 BNA/MOE Mixed Gapmers in hSNCA Mice Compound Name Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 Time Post- Injection % mRNA Reduction SNCA ASO00033CCAACATTTGTCACTTGCTC 251 13307 2 weeks 66PBS N/A N/A 2 weeks 0SNCA ASO 01608GCAGTTCTATCCCACTCATC 4 18926 2 weeks 67SNCA ASO01609CCGGTGCCATTACTCCCTTT 7 16401 2 weeks 27SNCA ASO 01610CCAAGTGCCAGACCCTTTCA 10 22935 2 weeks 50SNCA ASO 01611TTGCAGATAAACCATCCCAC 8 22297 2 weeks 58SNCA ASO 01612GCAGATAAACCATCCCACTT 11 22295 2 weeks 55SNCA ASO 01613AATAGCATCCTTCCACACCA 5 23410 2 weeks 78SNCA ASO 01614AGTGCCAGACCCTTTCATTA 9 22932 2 weeks 49SNCA ASO 01615ATCACCTTCAAACCCCTTTC 6 29755 2 weeks 44 145 WO 2022/189363 PCT/EP2022/055770 Compound Name Unmodified ASO Sequence SEQ ID NO of Unmodified Oligonucleotide Position in SEQ ID NO: 1 Time Post- Injection % mRNA Reduction SNCA ASO 01616CGGTGCCATTACTCCCTTTC 17 16400 2 weeks 50SNCA ASO00033CCAACATTTGTCACTTGCTC 251 13307 2 weeks 70SNCA ASO 01791ACTGAACTGATGCCTCTACC 13 38138 6 weeks 44,5SNCA ASO 01792TACATGGCCAGAAACCACTT 14 53767 6 weeks 19.7SNCA ASO 01793AAGCCAAGCCCAAACACTAA 15 59756 6 weeks 6.7SNCA ASO 01789TCCAAAGGAGCACCAACCAA 16 39878 6 weeks 37.7SNCA ASO00033CCAACATTTGTCACTTGCTC 251 13307 6 weeks 69,7SNCA ASO 01613AATAGCATCCTTCCACACCA 5 23410 6 weeks 82,2SNCA ASO 01608GCAGTTCTATCCCACTCATC 4 18926 6 weeks 76,8SNCA ASO 01611TTGCAGATAAACCATCCCAC 8 22297 6 weeks 43,5SNCA ASO 01612GCAGATAAACCATCCCACTT 11 22295 6 weeks 46,5SNCA ASO00033CCAACATTTGTCACTTGCTC 251 13307 6 weeks 65,9 Example 5: Tolerability, Efficacy and Biodistribution of Multiple Doses of Modified Oligonucleotides Complementary to Human SNCA in hSNCA Mice [0262]Three-month-old hSNCA mice received a single bolus ICV injection of a modifiedoligonucleotide listed at doses described in the indicated tables. hSNCA mice were divided into groups of six mice. A group of six mice received PBS as negative control for each experiment. For tolerability studies, the tolerability score is represented as the Functional Observational Battery (FOB) score at one-hour post-injection. [0263]For efficacy studies, mice were sacrificed four weeks post-injection, exceptfigures followed by an asterisk wherein analyzes were two weeks post-injection. Cortical brain tissue was collected and the level of hSNCA mRNA was measured as described above and the level of alpha-synuclein protein was measured by ELISA kit as described above. Results are presented in the tables as percent reduction of the amount of SNCA mRNA andalpha-synuclein protein relative to vehicle (PBS) control groups. A value of 0% reduction indicates that the compound had no effect. 146 WO 2022/189363 PCT/EP2022/055770 id="p-264" id="p-264" id="p-264" id="p-264" id="p-264" id="p-264" id="p-264" id="p-264"

[0264]For biodistribution studies, the concentration of SNCAASO in the cortex of hSNCA mice is quantified by High Performance Liquid Chromatography (HPLC) Fluorescence. 1. Tolerability and Efficacy of multiple dose of 2-3-10-3-2 BNA/MOE, 3-2-10- 2-3 LNA/MOE, and 5-10-5 MOE Gapmers (PS/PO) [0265]SNCA_ASO_01613 in Table Yis a 2-3-10-3-2 BNA/MOE gapmer as described above, in which the internucleoside linkages between nucleosides 3 and 4, 4 and 5, 16 and 17, and 17-18 are phosphodiester internucleoside linkages, the other internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine.SNCA_ASO_01625 in Table Zis a 3-2-10-2-3 LNA/MOE gapmer as described above, in which the internucleoside linkages between nucleosides 2 and 3, 4 and 5, 16 and 17, and and 19 are phosphodiester internucleoside linkages, the remaining internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine. SNCA_ASO_01617 (SEQ ID NO: 1264) in Table AAis a 5-10-5 MOE gapmer wherein the central gap segment comprises ten 2’ deoxynucleosides and is flanked by wing segments on both 5’ and 3’ end comprising five 2’MOE nucleosides. In SNCA_ASO_01617, all cytosines residues throughout each gapmer are 5-methyl cytosines, and all internucleoside linkages are phosphorothioates linkages except between 2 and 3, 3 and 4, 4 and 5, 16 and 17, and 17 and positions which are phosphodiester linkages. [0266] FIG. 7isa bar graph that compares the efficacy of SNCA ASO1613, SNCA_ASO_1617 and SNCA_ASO_1625 based on the expression of SNCA mRNA at different doses of 1, 5, 10, 30 or 100 nmol. FIG. 8is a bar graph that compares the efficacy of SNCA_ASO_1613, SNCA_ASO_1617 and SNCA_ASO_1625 based on the expression of alpha synuclein protein at different doses of 1, 5, 10, 30 or 100 nmol. Reductions in mRNA and protein levels were analyzed two weeks post injection.

Table Y. Tolerability and Efficacy of multiple dose of 2-3-10-3-2 BNA/MOE Mixed Gapmers in hSNCA Mice Compound Name Unmodified ASO Sequence Dose (nmol) FOB (lb) % mRNA Reduction % Protein Reduction ED50 (nmol) SNCA_ASO_01613AATAGCATCC TTCCACACCA 1 0 0 17 8.750.83 30 270.2 56 550 80 55100 0.33 92 58 147 WO 2022/189363 PCT/EP2022/055770 Table Z. Tolerability and Efficacy of multiple dose of 3-2-10-2-3 LNA/MOE Mixed Gapmers in hSNCA Mice Compound Name Unmodified ASO Sequence Dose (nmol) FOB (lb) % mRNA Reduction % Prot Reduction ED50 (nmol) SNCA_ASO_01625ATCACCTTCA AACCCCTTTC 1 0.67 5 15 19.281.17 17 320.33 31 330.17 61 48100 1 74* 42* Table AA. Tolerability and Efficacy of multiple dose of 5-10-5 MOE Gapmers in hSNCA Mice Compound Name Unmodified ASO Sequence Dose (nmol) FOB (lb) % mRNA Reduction % Protein Reduction ED50 (nmol) SNCA_ASO_01617GTTTTCATCA ATATCTGCAA 1 0.67 6 0 34.970.17 8 30.5 21 210.33 45 44100 1.83 69 52 II. Dose effect of ASO Concentration in the Cortex by ELISA analysis [0267]In Table AB,SNCA_ASO_01613 is a 2-3-10-3-2 BNA/MOE gapmer as described above, in which the internucleoside linkages between nucleosides 3 and 4, 4 and 5, and 17, and 17 and 18 are phosphodiester internucleoside linkages, the other internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine; SNCA_ASO_01625 is a 3-2-10-2-3 LNA/MOE gapmer as described above, in which the internucleoside linkages between nucleosides 2 and 3, 4 and 5, 16 and 17, and 18 and 19 are phosphodiester internucleoside linkages, the other internucleoside linkages are phosphorothioate internucleoside linkages, and each cytosine is a 5-methyl cytosine; and SNCA ASO 01617 is a 5-10-5 MOE gapmer in which all cytosine nucleobases throughout the 5-10-5 MOE gapmer are 5-methyl cytosines as described above. [0268] FIG. 9is a dot graph that represents the amount of ASO quantified per mg of cortex by HPLC fluorescence after a single ICV injection of multiple doses. 148 WO 2022/189363 PCT/EP2022/055770 Table AB. Dose effect of ASO Concentration in the Cortex of hSNCA mice Compound Name Unmodified ASO Sequence Dose (nmol) Cortex Median ASO concentration (fmol/mg) SNCA_ASO_01613AATAGCATCC TTCCACACCA 1 62.98158.73271.14866.00100 2244.38 SNCA_ASO_01625ATCACCTTCA AACCCCTTTC 1 34113.9151.6464.6100 1935.9 SNCA_ASO_01617GTTTTCATCA ATATCTGCAA 1 12.7542.3072.35193.32100 590.57 Example 6 : Tolerability of of Modified Oligonucleotides in Rat [0269]Male Winstar rats received a single intrathecal bolus injection of oligonucleotideat a dose of 2.5 mg. Sterile saline syringes and nuclease free centrifuge tubes were used to prepare dosing solutions. The tubes containing ASO powder were briefly centrifuged before adding aCSF solution, then re-centrifuged for 10 minutes to fully dissolve the ASO powder. The solution was vortexed for -1 min, stored at 4°C and filtered with a 0.22pm filter untiluse. [0270]For tolerability studies, the tolerability score is represented as the Functional Observational Battery (FOB) score at one-hour, three-hour and twenty-four hours post- injection. [0271]In Table AC,the tolerability profile of SNCA_ASO_01617 andSNCA ASO 01613 is compared in rat at a dosage of 2.5 mg as a function of time. 149 WO 2022/189363 PCT/EP2022/055770 Table AC. Tolerability Scoring Analysis in Rats Compound Name Unmodified ASO Sequence Dose (mg) FOB (Ih) FOB (3h) FOB (24h) SNCA_ASO_01617 GTTTTCATCAATATCTGCAA 2.5 4 0 0SNCA_ASO_01613 AATAGCATCCTTCCACACCA 2.5 0.75 0 0Artificial CSF - 1.67 0 0 Example 7 : Duration of Action on Multiple Doses of Modified Oligonucleotides in hSNCA Mice [0272]Three-month-old hSNCA mice, divided into groups of five to six mice each, received a single unilateral bolus injection of oligonucleotide SNCA ASO1613 or SNCA_ASO_1617 at two doses of 10 and 50 nmol described in Table ADbelow. A group of three mice received PBS as a negative control for each experiment. [0273]For efficacy studies, mice were sacrificed at different timepoint (2-6-12-20 weeks) post-injection. Cortical, cerebellum and striatum brain tissue were collected and the level of hSNCA mRNA was measured by qRT-PCR as described above and the level of alpha synuclein protein was measured by ELISA kit as described above. Results are presented in the tables as percent reduction of the amount of SNCA mRNA and alpha synuclein protein relative to vehicle (PBS) control groups. A value of 0% reduction indicates that the compound had no effect. [0274] FIG. 11is a dot graph that compares the SNCA-ASO-01617 and SNCA_ASO_01613 at the dose of lOnmol and 50 nmol in the cortex based on SNCA mRNA expression quantified by qRT-PCR as described above. [0275] FIG. 12is a dot graph a dots graph that compares the SNCA-ASO-01617 and SNCA ASO 01613 at the dose of lOnmol and 50 nmol in the cerebellum based on SNCA mRNA expression quantified by qRT-PCR as described above. [0276] FIG. 13is a dot graph a dots graph that compares the SNCA-ASO-01617 and SNCA ASO 01613 at the dose of lOnmol and 50 nmol in the striatum based on SNCA mRNA expression quantified by qRT-PCR as described above. 150 WO 2022/189363 PCT/EP2022/055770 Table AD. PK/PD analysis at different timepoint in hSNCA mice ASO Name Unmodified ASO Sequence Dose (nmol) Timepoint (weeks) Cortex Striatum Cerebellum % mRNA Red. % hSNCA PROT Red. % mRNA Red. % hSNCA PROT Red. % mRNA Red. % hSNCA PROT Red.

SNCA ASO 01613AATAGCATCC TTCCACACCA 1043 48 76 1 0 055 23 72 78 22 2939 51 51 41 15 3025 12 0 2 20 0 5086 64 94 42 29 1688 59 87 85 48 4781 84 89 77 52 6969 59 63 51 50 34 SNCA ASO 01617GTTTTCATCA ATATCTGCAA 1026 33 47 10 0 220 7 30 48 15 014 2 0 0 0 30 32 17 15 0 0 5063 51 65 25 4 049 15 55 66 33 3930 40 21 20 12 1611 23 0 0 20 0 Example 8: In vitro Alpha-synuclein Pathology Reduction [0277]At DIVO, primary neuronal culture (35000 cells per well) from hSNCA A53Tmice as described above were cultured and then were transfected with 200 nM of human alpha-synuclein preformed fibrils (PFFs, from StressMarq Bioscience SPR-316) at seven days post primary neuronal culture (DIV7) and were treated with 6, 20, 60, 200 or 170 nM of SNCA_ASO_01613 or SNCA_ASO_01617 at four (DIV4), seven (DIV7) or ten (DIVIO) days post primary neuronal culture as illustrated in the diagram FIG.14.A control with anunspecific (Malatl) ASOs was used. After 19 days post primary neuronal culture (DIV19), cells were lysed and the alpha-synuclein pathology was analyzed by measuring the level of the phosphorylated form (pS129) of alpha-synuclein with a commercial immunoassay kit (Cisbio, #6FSYNPEG) according to the manufacturer’s instructions. This assay is based on a sandwich assay with two different specific antibodies, one binding the pS129 motif of alpha-synuclein and the other recognizing the alpha-synuclein protein, labelled with a donor or an acceptor dye. Their specific binding and close proximity on the phosphorylated alpha- synuclein produces a FRET (Fluorescence Resonance Energy Transfer) signal proportional to the protein level. 151 WO 2022/189363 PCT/EP2022/055770 id="p-278" id="p-278" id="p-278" id="p-278" id="p-278" id="p-278" id="p-278" id="p-278"

[0278] FIG. 15is a bar graph that represents the level of alpha-synuclein pathology (phosphorylated form) in primary neuronal culture measuring by a TR-FRET based immunoassay. The level of phosphorylated alpha-synuclein was normalized by the level of alpha-tubulin and values were related to wells treated with vehicle (PBS). Seeded neuronswere treated at DIV7 with a high dose (330nM) of specific ASOs (SNCA) or an unspecific ASO (Malatl) as described in Table AEbelow.

Table AE. Levels of Phosphorylated Alpha-Synuclein in Primary Neurons Compound name Unmodified ASO Sequence Treatment time (DIV) Dose (nM) Phosphorylated aSyn FRET ratio (relative to PBS, %) SNCAASO01613AATAGCATCC TTCCACACCADIV7 330 1.18 SNCAASO01617GTTTTCATCA ATATCTGCAADIV7 330 0.70 MalatlASOTGCCTTTAGG ATTCTAGACADIV7 330 101.15 id="p-279" id="p-279" id="p-279" id="p-279" id="p-279" id="p-279" id="p-279" id="p-279"

[0279] FIG. 16is a bar graph that represents the level of alpha-synuclein pathology(phosphorylated form) in primary neuronal culture measuring by a TR-FRET based immunoassay, the mean±SEM. The level of phosphorylated alpha-synuclein was normalized by the level of alpha-tubulin and values were related to wells treated with vehicle (PBS). Dose-response effect were evaluated in seeded neurons treated with specific ASO at four,seven or ten days as described in Table AF.

Table AF. Levels of Phosphorylated Alpha-Synuclein in Primary Neurons

Claims

WO 2022/189363 PCT/EP2022/055770 CLAIMS

1. An oligonucleotide comprising a nucleotide sequence of 15 to 30 contiguous nucleotides, wherein the nucleotide sequence is complementary to a region of the same length found in nucleotidesa) 16350-16450,b) 18926-19030,c) 22250-22471,d) 22933-23079,e) 23408-23700,f) 29753-29819,g) 38128-38158,h) 39852-39906,i) 53762-53799, orj) 59754-59865of SEQ ID NO: 1, optionally wherein the nucleotide sequence comprises no more than mismatches to said region.

2. The oligonucleotide of claim 1, wherein the nucleotide sequence is 16 to contiguous nucleotides in length.

3. The oligonucleotide of claim 1 or 2, wherein the nucleotide sequence comprises 0, 1, or 2 mismatches to said region.

4. The oligonucleotide of any one of the preceding claims, wherein the oligonucleotide is single-stranded.

5. The oligonucleotide of any one of the preceding claims, wherein the nucleotide sequence is selected from SEQ ID NOs: 18-40.

6. The oligonucleotide of any one of the preceding claims, comprising one or more ribonucleotides, one or more deoxyribonucleotides, or a combination of both. 153 WO 2022/189363 PCT/EP2022/055770

7. The oligonucleotide of any one of the preceding claims, wherein the oligonucleotide comprises one or more modified nucleotides.

8. The oligonucleotide of any one of the preceding claims, wherein the one or more modified nucleotides comprise a 2’-O-m ethoxy ethyl (2’-MOE) nucleotide, a locked nucleic acid (LNA) nucleotide, a bridged nucleic acid (BNA) nucleotide, or any combination thereof.

9. The oligonucleotide of any one of the preceding claims, wherein all cytosines in the oligonucleotide are 5-methyl cytosines.

10. The oligonucleotide of any one of the preceding claims, comprising at least 1, 2, 3, 4, or 5 phosphodiester internucleoside linkages.

11. The oligonucleotide of any one of the preceding claims, wherein at least 1, 2, 3, 4, or 5, or all internucleoside linkages are phosphorothioate internucleoside linkages.

12. The oligonucleotide of any one of claims 7-11, wherein the oligonucleotide comprises:i) a 5-10-5 MOE gapmer;ii) a 4-10-4 MOE gapmer;iii) a 3-10-3 LNA gapmer;iv) a 3 -11 -3 LNA gapmer;v) a 3-2-10-2-3 LNA/MOE gapmer;vi) a 2-3-10-3-2 BNA/MOE gapmer;vii) a 3-2-10-2-3 BNA/MOE gapmer; orviii) a 2-3-10-3-2 LNA/MOE gapmer.

13. The oligonucleotide of claim 12, wherein the oligonucleotide comprises:i) a 3-2-10-2-3 LNA/MOE gapmer;ii) a 2-3-10-3-2 BNA/MOE gapmer;iii) a 3-2-10-2-3 BNA/MOE gapmer; oriv) a 2-3-10-3-2 LNA/MOE gapmer;and wherein the internucleoside linkages between nucleosidesv) 2 and 3, 4 and 5, 16 and 17, and 18 and 19; 154 WO 2022/189363 PCT/EP2022/055770 vi) 2 and 3, 4 and 5, and 16 and 17;vii) 2 and 3, 3 and 4, 4 and 5, 16 and 17 and 17 and 18; orviii) 3 and 4, 4 and 5, 16 and 17, and 17 and 18are phosphodiester internucleoside linkages; and the remainder of the internucleoside linkages are phosphorothioate internucleoside linkages.

14. An oligonucleotide comprising the following formula:i) Ais Tlo mCls Aeo mCes mCds Tds Tds mCds Ads Ads Ads mCds mCds mCds mCeo Tes Tlo TIs mCl (SEQ ID NO: 34),ii) Abs Tbs mCeo Aeo mCes mCds Tds Tds mCds Ads Ads Ads mCds mCds mCds mCeo Teo Tes Tbs mCb (SEQ ID NO: 20),iii) Ais Alo TIs Aeo Ges mCds Ads Tds mCds mCds Tds Tds mCds mCds Ads mCeo Aes mClo mCls Al (SEQ ID NO: 33),iv) Abs Abs Teo Aeo Ges mCds Ads Tds mCds mCds Tds Tds mCds mCds Ads mCeo Aeo mCes mCbs Ab (SEQ ID NO: 19),v) Gbs mCbs Aeo Geo Tes Tds mCds Tds Ads Tds mCds mCds mCds Ads mCds Teo mCeo Aes Tbs mCb (SEQ ID NO: 18),vi) mCbs mCbs Geo Geo Tes Gds mCds mCds Ads Tds Tds Ads mCds Tds mCds mCeo mCeo Tes Tbs Tb (SEQ ID NO: 21),vii) Tbs Tbs Geo mCeo Aes Gds Ads Tds Ads Ads Ads mCds mCds Ads Tds mCeo mCeo mCes Abs mCb (SEQ ID NO: 22),viii) Abs Gbs Teo Geo mCes mCds Ads Gds Ads mCds mCds mCds Tds Tds Tds mCeo Aeo Tes Tbs Ab (SEQ ID NO: 23),ix) mCbs mCbs Aeo Aeo Ges Tds Gds mCds mCds Ads Gds Ads mCds mCds mCds Teo Teo Tes mCbs Ab (SEQ ID NO: 24),x) Gbs mCbs Aeo Geo Aes Tds Ads Ads Ads mCds mCds Ads Tds mCds mCds mCeo Aeo mCes Tbs Tb (SEQ ID NO: 25),xi) mCbs Gbs Geo Teo Ges mCds mCds Ads Tds Tds Ads mCds Tds mCds mCds mCeo Teo Tes Tbs mCb (SEQ ID NO: 26),xii) Gbs Abs Aeo mCeo Tes Gds Ads Tds Gds mCds mCds Tds mCds Tds Ads mCeo mCeo Tes mCbs mCb (SEQ ID NO: 27),xiii) Abs mCbs Teo Geo Aes Ads mCds Tds Gds Ads Tds Gds mCds mCds Tds mCeo Teo Aes mCbs mCb (SEQ ID NO: 28), 155 WO 2022/189363 PCT/EP2022/055770 xiv) Tbs Abs mCeo Aeo Tes Gds Gds mCds mCds Ads Gds Ads Ads Ads mCds mCeo Aeo mCes Tbs Tb (SEQ ID NO: 29),xv) Abs Abs Geo mCeo mCes Ads Ads Gds mCds mCds mCds Ads Ads Ads mCds Aeo mCeo Tes Abs Ab (SEQ ID NO: 30),xvi) Tbs mCbs mCeo Aeo Aes Ads Gds Gds Ads Gds mCds Ads mCds mCds Ads Aeo mCeo mCes Abs Ab (SEQ ID NO: 31),xvii) GIs mClo Ais Geo Tes Tds mCds Tds Ads Tds mCds mCds mCds Ads mCds Teo mCes Alo TIs mCl (SEQ ID NO: 32),xviii) mCls mClo GIs Geo Tes Gds mCds mCds Ads Tds Tds Ads mCds Tds mCds mCeo mCes Tlo TIs TI (SEQ ID NO: 35),xix) TIs Tlo GIs mCeo Aes Gds Ads Tds Ads Ads Ads mCds mCds Ads Tds mCeo mCes mClo Ais mCl (SEQ ID NO: 36),xx) Ais Glo TIs Geo mCes mCds Ads Gds Ads mCds mCds mCds Tds Tds Tds mCeo Aes Tlo TIs Al (SEQ ID NO: 37),xxi) mCls mClo Ais Aeo Ges Tds Gds mCds mCds Ads Gds Ads mCds mCds mCds Teo Tes Tlo mCls Al (SEQ ID NO: 38),xxii) GIs mClo Ais Geo Aes Tds Ads Ads Ads mCds mCds Ads Tds mCds mCds mCeo Aes mClo TIs TI (SEQ ID NO: 39),xxiii) mCls Glo GIs Teo Ges mCds mCds Ads Tds Tds Ads mCds Tds mCds mCds mCeo Tes Tlo TIs mCl (SEQ ID NO: 40),xxiv) GIs Alo Ais mCeo Tes Gds Ads Tds Gds mCds mCds Tds mCds Tds Ads mCeo mCes Tlo mCls mCl (SEQ ID NO: 41),xxv) Ais mClo TIs Geo Aes Ads mCds Tds Gds Ads Tds Gds mCds mCds Tds mCeo Tes Alo mCls mCl (SEQ ID NO: 42),xxvi) TIs Alo mCls Aeo Tes Gds Gds mCds mCds Ads Gds Ads Ads Ads mCds mCeo Aes mClo TIs TI (SEQ ID NO: 43),xxvii) Ais Alo GIs mCeo mCes Ads Ads Gds mCds mCds mCds Ads Ads Ads mCds Aeo mCes Tlo Ais Al (SEQ ID NO: 44),xxviii) TIs mClo mCls Aeo Aes Ads Gds Gds Ads Gds mCds Ads mCds mCds Ads Aeo mCes mClo Ais Al (SEQ ID NO: 45), whereinA is adenine, mC is a 5-methyl cytosine, G is guanine, 156 WO 2022/189363 PCT/EP2022/055770 T is thymine,e is a 2’-MOE modified ribose,d is a 2’-deoxyribose,b is a BNA,is an LNA,o is a phosphodiester internucleoside linkage, and s is a phosphorothioate internucleoside linkage.

15. An oligonucleotide comprising the structural formula: 157

16.Wo2"22'«»363

17.WO 2022/189363 PCT/EP2022/055770

18. An oligonucleotide comprising the structural formula:

19. An oligonucleotide conjugate comprising the oligonucleotide of any one of the preceding claims.

20. A pharmaceutical composition comprising the oligonucleotide of any one of claims 1- or the oligonucleotide conjugate of claim 19, and a pharmaceutically acceptable excipient.

21. A method of reducing alpha-synuclein expression in a mammalian cell, comprising contacting the cell with the oligonucleotide of any one of claims 1-18, the oligonucleotide conjugate of claim 19, or the pharmaceutical composition of claim 20, thereby reducing alpha-synuclein expression in the cell.

22. The method of claim 21, wherein the cell is a cell in the central nervous system, optionally a cell in the human brain. 159 WO 2022/189363 PCT/EP2022/055770

23. A method for treating a synucleinopathy in a subject in need thereof, comprising administering a therapeutically effective amount of the oligonucleotide of any one of claims 1-18, the oligonucleotide conjugate of claim 19, or the pharmaceutical composition of claim to the subject.

24. The method of any one of claims 21-23, wherein the oligonucleotide reduces SNCA mRNA levels by at least 25, 50, 75, or 80% in murine primary cortical neurons engineered to express human alpha-synuclein.

25. The method of claim 23 or 24, wherein the oligonucleotide is injected intrathecally or intracranially to the subject.

26. Use of the oligonucleotide of any one of claims 1-18 or the oligonucleotide conjugate of claim 19 for the manufacture of a medicament in treating a synucleinopathy in a subject in need thereof in the method of any one of claims 23-25.

27. The oligonucleotide of any one of claims 1-18, the oligonucleotide conjugate of claim 19, or the pharmaceutical composition of claim 20 for use in treating a synucleinopathy in a subject in need thereof in the method of any one of claims 23-25.

28. The method, use, oligonucleotide for use, oligonucleotide conjugate for use, or pharmaceutical composition for use of any one of claims 23-27, wherein the synucleinopathy is Parkinson’s disease, Lewy body dementia, Alzheimer’s disease, or multiple system atrophy. 160