Oligonucleotide-based delivery vehicle for oligonucleotides agents and methods of use thereof

Abstract

Provided are nucleic acids, specifically as it relates to an oligonucleotide agent comprising a double-stranded RNA (dsRNA, duplex) and a non-targeting accessory oligonucleotide (ACO) that is covalently tethered to the dsRNA and pharmaceutical use thereof.

Description

FIELD OF THE INVENTION The present application relates to the technical field of nucleic acids, specifically as it relates to an oligonucleotide agent comprising a double-stranded RNA (dsRNA, duplex) and a nontargeting accessory oligonucleotide (ACO) that is covalently tethered to the dsRNA and pharmaceutical use thereof. Cross-Reference to Related Applications This application claims priority to the filing date of Provisional Patent Application Serial No. PCT / CN2021 / 105081 filed July 07, 2021 and to the filing date of Provisional Patent Application Serial No. PCT / CN2022 / 091076 filed May 06, 2022, the disclosure of which application is herein incorporated by reference. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in computer readable format and is hereby incorporated by reference in its entirety. BACKGROUND OF THE IN VENTION Oligonucleotides are an emerging class of therapeutics currently under active development for the treatment of a wide variety of diseases via a myriad of mechanisms of action (MOA). Major categories of oligonucleotide therapeutics include single-stranded antisense oligonucleotides (ASOs) and duplex (double-stranded) RNAs (dsRNAs). Single-stranded ASOs in the form of “gapmer” can be used to suppress gene expression by degrading target mRNA via an RNase H mechanism. Gapmer ASOs have a central DNA region required to support the RNase H activity and two ribonucleotide wings to increase target binding affinity of the ASOs. Another category of ASOs is steric blockers, which are typically composed uniformly of ribonucleotides and bind to pre-mRNA in the nucleus to alter mRNA splicing by blocking the binding of certain splicing factors to the mRNA. dsRNAs can be further classified into two categories: small interfering RNA (siRN A) and small activating RNA (saRNA), both of which require Argonaute (AGO) proteins as their protein partner for function. siRNA binds to target mRNA mainly in the cytoplasm to down-regulate gene expression post-transcriptionany via the RNA interference (RNAi) mechanism. saRNA targets regulatory sequences in the nucleus such as gene promoters to upregulate gene expression at the transcriptional level via the RNAa (RNA activation) mechanism. Almost all single gene diseases and most multi-gene diseases are caused by loss, instead of gain, of a gene’s function. Loss of function could arise from epigenetic aberrations and genetic mutations, leading to transcriptional silencing and erroneous forms of the transcribed mRNA respectively. One of such errors is erroneous splicing of pre-mRNA due to undesired skipping or inclusion of exons, resulting in unfunctional protein when the mRNA is translated. In such instance, ASOs have been used to correct the erroneous splicing events and ultimately to increase the gene’s protein output by sterically blocking the protein-RNA binding interactions between splicing machinery components and the pre-mRNA. Several such ASO drugs have been approved by U.S. Food and Drug Administration (FDA), including an exon inclusion ASO SPINRAZA® for the treatment of spinal muscular atrophy (SMA) and 3 exon skipping ASOs for the treatment of Duchenne muscular dystrophy (DMD). However, the therapeutic potential of such oligonucleotide modalities is limited by delivery technologies that provide access to target tissues, organs, or cell types. Thus, there is a need for improved oligonucleotide-based delivery mechanisms to address these challenges. SUMMARY The present application provides a novel oligonucleotide agent comprising a double-stranded RNA (dsRNA, duplex) and a non-targeting accessory oligonucleotide (ACO or singlestranded oligonucleotide) that is covalently tethered to the dsRNA. The agent, by itself constitutes a system termed oligonucleotide-based delivery vehicle (ODV) with “selfdelivering'” properties. The present inventors found, surprisingly, when ODV is applied to dsRNA (i.e., siRNA or saRNA), favorable biodistribution and activity are obtained for local administration to selected tissues and systemic delivery across several organs / tissues including liver, muscle, lung, kidney, bladder, brain, spinal cord, heart, eye, spleen, etc. The agent possesses certain benefits associated with single-stranded oligonucleotide therapeutics, for instance, unconventional nucleic acid chemistries and modification patterns conducive to delivery, biodistribution, bioavailability, stability, cellular uptake, and other pharmacological properties without concerns of compromising duplex activity. ODV design includes an RNA duplex, such as an siRNA or saRNA, comprised of two complementary' or partial complementary strands with one of the strands covalently linked to an ACO having at least 6 nucleotides with or without one or more linker moieties. The RNA duplex targets at least one nucleic acid sequence (e.g., mRNA) and optionally is chemically modified using oligonucleotide chemistry' technologies (e.g., 2’fluoro, 2’-O-methyl, phosphorothioate, mesyl phosphoramidate or boranophosphate backbone, LNA, etc.) conducive to in vivo activity, stability, and safety. The ACO component is not designed to specifically target any complementary nucleic acid sequence in the subject to be administrated to. The ACO component can be chemically-modified on its backbone, nucleoside or other positions, e.g., a phosphorothioate, mesyl phosphoramidate or boranophosphate backbone, a 2'-fluoro-2'-deoxynucleoside (2'-F), a 2'-O-methyl (T-O- Me). a 2’-O-(2-methoxyethyl) (2-O-MOE), locked nucleic acid (LNA), bridged nucleic acid (BNA), peptide nucleic acid (PNA), 5’-(E)-vinylphosphonate moiety, S'-methyl cytosine moiety, etc., to impart physiochemical properties conducive to improve the agent’s bioavailability7 and delivery. Covalent linker moieties can be natural or unnatural nucleotides, ethlyglycol, carbohydrates, alkyl chains, or any other linker used to covalently connect any two oligonucleotides positioned on the 3’- or 5’- terminus of one or both of the strands within the RNA duplex. Embodiments of the present application are based in part on the surprising discovery7 that an oligonucleotide agent comprising: (a) a double-stranded oligonucleotide composing a sense strand and an antisense strand, wherein the antisense strand has complementarity to a target nucleic acid, and (b) a non-targeting single-stranded oligonucleotide, wherein the singlestranded oligonucleotide is 6-22 nucleotides in length, wherein the double-stranded oligonucleotide and the single-stranded oligonucleotide are covalently linked, with or without one or more linking components, to form the oligonucleotide agent. In certain embodiments of the present application, the double-stranded oligonucleotide is a small interfering RNA (siRNA) or a small activating RN A (saRN A). In certain embodiments, the single-stranded oligonucleotide comprises at least one phosphorothioate (PS) backbone substitution. In certain embodiments, the single-stranded oligonucleotide has at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% of the phosphodiester bonds substituted with phosphorothioate (PS) bond on the backbone of the nucleotide sequence. In certain embodiments, the single-stranded oligonucleotide has 85-95% or 95-100% PS bond. In certain embodiments, the chemical modification in the double-stranded oligonucleotide or the si ng Ie-stranded oligonucleotide is an addition of a 5'-phosophate moiety at the 5’ end of die nucleotide sequence. In certain embodiments, the chemical modification is an addition of a 5’-(E)-vinylphosphonate moiety. In certain embodiments, the chemical modification is an addition of a 5'-methyl cytosine moiety at. the 5’ end of the nucleotide sequence. In certain embodiments, the single-stranded oligonucleotide is RNA, DNA, BNA, ENA or PNA. In certain embodiments, the single-stranded oligonucleotide is 8-16 nucleotides in length. In certain embodiments, the single-stranded oligonucleotide is 10-14 nucleotides in length. In certain embodiments of the present application, the sense strand of the double-stranded oligonucleotide in the oligonucleotide agent is at least 10 nucleotides in length. In certain embodiments of the present application, the sense strand has a nucleotide length ranging from 10-60 nucleotides. In certain embodiments, the sense strand has a nucleotide length ranging from 27-41 nucleotides. In certain embodiments of the present application, the antisense strand has a nucleotide length ranging from 10-60 nucleotides. In certain embodiments, the antisense strand has a nucleotide length ranging from 19-25 nucleotides. In certain embodiments, the single-stranded oligonucleotide comprises a nucleotide sequence that is at least 90% identical to the nucleotide sequence selected from SEQ II) NOs: 1-22. The ACO may also has a specific composition of nucleotides. In some embodiments, the ACO may have a certain percentage of adenines within the nucleotide sequence of the ACO. In some embodiment, the percent composition of adenines is from about 35% to about 65%. In some embodiments, the percent composition of cytosines is from about 35%) to about 72%. In some embodiments, the percent composition of guanosines is from about 35% to about 65%. In some embodiments, the percent composition of uracil is from about 35% to about 72%. In some embodiments, the percent composition of purines is from about 64% to about 78%. In some embodiments, the percent composition of pyrimidines is from about 64% to about 86%. In some embodiment, the specific combination of purines and pyrimidines is about 42-58% purines and about 42-58% pyrimidines. In some embodiments, the nucleotide sequence of the single-stranded oligonucleotide comprises at least about 14%, at least about 28%, at. least about 42%, at. least about 57%, at least about 71%, at least about 85%, at least about 92%, or about 70-100% of the nucleotides having 2’0me modification. In some embodiments, the nucleotide sequence of the single-stranded oligonucleotide is a palindrome sequence. In some embodiments, the single-stranded oligonucleotide comprises a chemically modified nucleotide sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at. least. 99% homology, or 100% identical to a nucleotide sequence selected from the group of SEQ ID NOs: 1299-1379. In some embodiments, the single-stranded oligonucleotide comprises a chemically modified nucleotide sequence that is having 0, 1, 2 or 3 different chemical modifications than a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1299-1379. In some embodiments, the single-stranded oligonucleotide comprises a chemically modified nucleotide sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% homology, or 100% identical to a nucleotide sequence selected from the group of SEQ ID NOs: 1299-1379. In some embodiments, the single-stranded oligonucleotide comprises a chemically modified nucleotide sequence that is having 0, 1, 2 or 3 different chemical modifications than a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1299-1379. In some embodiments, the single-stranded oligonucleotide and the double-stranded oligonucleotide is conjugated without a linking component. In some embodiments, the singlestranded oligonucleotide and the double-stranded oligonucleotide is conjugated with one or more linking components. In some embodiments, the double-stranded oligonucleotide and the single-stranded oligonucleotide are covalently conjugated by a linking component. In some embodiments, the single-stranded oligonucleotide is conjugated to a linking component. In some embodiments, the 5’ end, the 3’ end, or an internal nucleotide of the single-stranded oligonucleotide is conjugated to a linking component. In some embodiments, the doublestranded oligonucleotide comprises a sense strand and an antisense strand, and the singlestranded oligonucleotide is covalently conjugated to the sense strand, the antisense strand, or both the sense and the antisense strands of the double-stranded oligonucleotide by a linking component. In some embodiments, the single-stranded oligonucleotide is covalently conjugated to the 3' end, the 5’ end, both the 3’ and the 5’ ends, or an internal nucleotide of the sense strand of the double-stranded oligonucleotide. In some embodiments, the singlestranded oligonucleotide is covalently conjugated to the 3’ end, the 5’ end, both the 3’ and the 5’ ends, or an internal nucleotide of the antisense strand of the double-stranded oligonucleotide. In some embodiments, the internal nucleotide in the sense or antisense strand of the double-stranded oligonucleotide is substituted by a linking component, wherein the single-stranded oligonucleotide is covalently conjugated with the linking component. In some embodiments, more than one single-stranded oligonucleotides are covalently conjugated to the double-stranded oligonucleotide. In some embodiments, about 2-10 singlestranded oligonucleotides are covalently conjugated to the double-stranded oligonucleotide. In some embodiments, more than one double-stranded oligonucleotides are covalently conjugated to the single-stranded oligonucleotides. In some embodiments, about 2-10 doublestranded oligonucleotides are covalently conjugated to the single-stranded oligonucleotides. In some embodiments, the linking component conjugated with the nucleotide in the singlestranded oligonucleotide or the double-stranded oligonucleotide, or both the single-stranded oligonucleotide and the double-stranded oligonucleotide through phosphorothioate (PS) bond. In some embodiments, the substituted linking component conjugates with each or both adjacent nucleotides on the double-stranded oligonucleotide through phosphorothioate (PS) bond. In some embodiments, the linking component comprises a direct bond, or an oxygen or sulfur atom, or a unit selected from the following group: NR.1, C(O), C(O)O, C(O)NR.l, SO, SO2, and SO2NH; where RI is hydrogen, acyl, aliphatic or substituted aliphatic. In some embodiments, the linking component is selected from the group consisting of: substituted or un substituted alkyl, substituted or an substituted alkenyl, substituted or unsubstituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl alkyl, heteroarylalkenyl, heteroaryl alkynyl, heterocyclylalkyl, heterocyciy I alkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkyland alkenyl, alkylarylalkynyl, alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl, al ky nylary 1 alkenyl, al ky nyl aryl alkynyl, alkyl heteroarylal ky 1, alkylheteroaryl alkenyl, alkylheteroaryl alkynyl, alkenyl heteroarylalkyl, alkenylheteroaiylalkenyl, alkenylheteroarylalkynyl, alkynylheteroarylalkyl, alkynyl heteroarylalkenyl, alkynylheteroarylalkynyl, alkylheterocyclylalkyl, alkylheterocyclylalkenyl, alky 1 hererocyclylalkynyI, alkenylheterocyclylalky I, alkenylheterocyclylalkenyl, alkenylheterocyclyl alkynyl, alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl, alkynyiheterocyclylalkynyl, alkylaryl, alkenylaryl, alkynylaiyd, alkylheteroaryl, alkenylheteroaiyl, alkynylhereroaryl, wherein one or more methylenes are interrupted or terminated by O, S, S(O), SO2, N(R')2, C(O), cleavable linking group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclic. In some embodiments, the linking component is selected from one or more of an ethylene glycol chain, an alkyl chain, an alkenyl chain, an alkynyl chain, a peptide, carbohydrates, thiol linkage, a phosphodi ester, a phosphorothioate, a phosphoramidate, an amide, a carbamate, a tetrazole linkage, and a benzimidazole linkage. In some embodiments, the linking component is selected from the group consisting of: a) LI or SIS (spacer-18 linker) (1,1 -bis(4-methoxyphenyi )-1-phenyl-2,5,8,11,14,17-hexaoxanonadecan- 19-yl (2-cyanoethyl) diisopropylphosphoramidite), b) L4 or C6 (spacer-C6 linker) (6-(bis(4-methoxyphenyl)(phenyl)methoxy)hexyl (2-cy anoethy I) dii sopropy I phosp horam idite); c) L6 (l,l-bis(4-methoxyphenyl)-l-phenyl-2,5,8,l1,14-pentaoxahexadecan-16-yl (2-cy an oe thy 1) di isopropyl ph osphorami di te); d) L9 or S9 (spacer-9 linker) (2-(2-(2-(bis(4-methoxyphenyl)(phenyl)methoxy)ethoxy)ethoxy)ethyl (2-cyanoethyl) diisopropylphosphoramidite); e) L10 or C3 (spacer-C3 linker) (3-(bis(4-methoxyphenyl)(phenyl)methoxy)propyl (2-cyanoethyl) diisopropylphosphoramidite); f) L12(d spacer) ((2R,3 S)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyT)tetrahydroluranpar-3-yl (2-cyanoethyl) di i sopropylphosphorami di te); g) LI3 or C12 (spacer-C1.2 linker) (12-(bis(4-methoxyphenyl)(phenyl)methoxy)dodecyl (2-cyanoethyl) diisopropylphosphoramidite); h) L. 14 (spacer-L 14 linker) (((I r,4r)-4~((bis(4-methoxyphenyl)(phenyr)methoxy)methyl)cyclohexyl (methyl (2-cyanoethyl) di i sopropyl ph osphorami di te); i) L I 5 (spacer-L15 linker) (4-(2-(bis(4-methoxyphenyl)(phenyl)methoxy)ethyl)phenethyl (2-cyanoethy 1) diisopropyIphosphoramidite), j ) L16 (spacer-L16 linker) (2-(l-(2-(bis(4-methoxyphenyr)(phenyl)methoxy)ethyl)cyclohexyl)ethyl (2-cyanoethyl) di i sopropylphosphorami di te); k) C6xl ((2S,3S,4S,5S)-2-((bis(4-methoxyphenyl)(phenyr)methoxy)methyl)-5-methoxy-4-(pent-4-yn-1 -y 1 oxy)tetrahydrofuran-3-yl (2-cyanoethyl) diisopropylphosphoramidite); I) C6x2 ((2S,3S,4S,5S)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-2-methoxy-4-(pent-4-yn-l -yloxy)tetrahydrofuran-3-yl (2-cyanoethyl) diisopropylphosphoramidite), m) C6x5 (2-((2-(bis(4-methoxyph.enyl)(phen.y1)methoxy)ethyl)(pent-4-yn-l-y1)amino)ethyl (2-cyanoethyI) dii sopropyIphosphoramidite); and n) C6x7 ((9H-tluoren-9-yl)rnethyl (4-((28,4R)-2-((bis(4- methoxyphenyl)(phenyl)methoxy)methyi)-4~ ((bi s( di i sopropylamm o )phosp hany I )oxy )pyrrolidin-1 -yl)-4-oxobuty I )carb amate). In some embodiments, the oligonucleotide agent comprises a nucleotide sequence that is at least 90% identical to the nucleotide sequences selected from the group consisting of: a) siSODlM2-AC2(N22)-SlV3v-Qu5 (SEQ ID NO: 58) and an antisense strand having a nucleotide sequence of SEQ ID NO: 57 that has partial complementarity with the sense strand of siSODlM2-AC2(N22)-SlV3v-Qu5 (SEQ ID NO: 58);     ’ b) siSODlM2-AC2(N15)-SlV3v-Qu5 (SEQ ID NO: 60) and an antisense strand having a nucleotide sequence of SEQ ID NO: 57 that has partial complementarity with the sense strand of siSODlM2-AC2(N15)-SlV3v-Qu5 (SEQ ID NO: 60); c) siSOD!M2-AC2(N12)-Sl V3v-Qu5 (SEQ ID NO: 62) and an antisense strand having a nucleotide sequence of SEQ ID NO: 57 that has partial complementarity with the sense strand of siSOD1M2-AC2(N1.2)-S1 V3v-Qu5 (SEQ ID NO: 62); and ' d) siSODlM2-AC2(N6)-SlV3v~Qu5 (SEQ ID NO: 64) and an antisense strand having a nucleotide sequence of SEQ ID NO: 57 that has partial complementarity with the sense strand of siSODlM2-AC2(N6)-Sl V3v-Qu5 (SEQ ID NO: 64).      ' e) The oligonucleotide agent of any one of claims I -27, wherein the oligonucleotide agent comprises a nucleotide sequence that is at least 90% identical to the following nucleotide sequences: 1) siHTT~AC2~SlLI (SEQ ID NO: 28) and an antisense strand having a nucleotide sequence of SEQ ID NO: 27 that has partial complementarity wdth the sense strand of NlTT-AC2-SIIA. (SEQ ID NO: 28). In some embodiments, the oligonucleotide agent comprises a nucleotide sequence that is at least 90% identical to the nucleotide sequences selected from the group of: a) siApp-8-AC2(N18)-SlLlV3v (SEQ ID NO: 32) and an antisense strand having a nucleotide sequence of SEQ ID NO: 31 that has partial complementarity with the sense strand of siApp-8-AC2(Nl 8)-81 El V3v (SEQ ID NO: 32);           ' b) siApp-8-AC2(N15)-SlLl V3v (SEQ ID NO: 34) and an antisense strand having a nucleotide sequence of SEQ ID NO: 3.1 that has partial complementarity with die sense strand of siApp-8-AC2(N15)-SlLlV3v (SEQ ID NO: 34); and c) siApp-8-AC2(N1.2)-S1.Ll V3v (SEQ ID NO: 36) and an antisense strand having a nucleotide sequence of SEQ ID NO: 31 that has partial complementarity with the sense strand of siApp-8-AC2(N12)-SlLl V3y (SEQ ID NO: 36). In some embodiments, the sense or antisense strand of the double-stranded oligonucleotide has a nucleotide sequence that is at least 90% identical to the nucleotide sequence selected from the group of: R6-04(20)~Sl Vlv(CM-4) (SEQ ID NO: 66) or R6-04(20)-SIVlv(CM-4) (SEQ ID NO: 67). In some embodiments, the oligonucleotide agent comprises a nucleotide sequence that is at least 90% identical to the nucleotide sequences selected from the group of: a) R6-O4M1-AC2(18)-S1L1 V3v (SEQ ID NO: 68) and an antisense strand having a nucleotide sequence of SEQ ID NO: 67 that has partial complementarity with the sense strand of R6-04MtyAC2(18)-SlLlV3v (SEQ ID NO: 68),          ' b) R6-04Ml-AC2(16)~SlLlV3v (SEQ ID NO: 70) and an antisense strand having a nucleotide sequence of SEQ ID NO: 67 that has partial complementarity with the sense strand of R6-04M1-AC2Q 6)-S 1L1 V3v (SEQ ID NO: 70):           ' c) R6-O4M1-AC2(15)-S1L1 V3v (SEQ ID NO: 72) and an antisense strand having a. nucleotide sequence of SEQ ID NO: 67 that has partial complementarity with the sense strand of R6-04M1 -AC2( I5>S I LI V3v (SEQ ID NO: 72); d) R6-04M1-AC2(14)-S1L1V3v (SEQ ID NO: 74) and an antisense strand having a nucleotide sequence of SEQ ID NO: 67 that has partial complementarity7 with the sense strand of R6-04Ml-AC2(14)-SlLlV3v (SEQ ID NO: 74),          ' e) R6-04Ml-AC2(13)~SlLlV3v (SEQ ID NO: 76) and an antisense strand having a nucleotide sequence of SEQ ID NO: 67 that has partial complementarity with the sense strand of R6-04MI -AC2(13)-S 1L1 V3v (SEQ ID NO: 76);           ' f) R6-O4M1-AC2(I2)-S1L1 V3v (SEQ ID NO: 78) and an antisense strand having a. nucleotide sequence of SEQ ID NO: 67 that has partial complementarity with the sense strand of R6-O4MDAC2(12)-S1L1 V3v (SEQ ID NO: 78); g) R6-O4M1-AC2(1 l)-S1.L1.V3v (SEQ ID NO: 80) and an antisense strand having a nucleotide sequence of SEQ ID NO: 67 that has partial complementarity'7 with the sense strand of R6-O4M1-AC2(11 )-S HA V3v (SEQ ID NO: 80),           ' h) R6-04Ml-AC2(10)~SlLlV3v (SEQ ID NO: 82) and an antisense strand having a nucleotide sequence of SEQ ID NO: 67 that has partial complementarity with the sense strand of R6-04MI -AC2(10)-S 1 LI V3v (SEQ ID NO: 82);           ' i) R6-04Ml-AC2(9)-SlLlV3v (SEQ ID NO:84) and an antisense strand having a nucleotide sequence of SEQ ID NO: 67 that has partial complementarity with the sense strand of R6-O4MDAC2(9)-S1L1 V3v (SEQ ID NO: 84); and j) R6-O4MI-AC2(8ES1L1 V3v (SEQ ID NO: 86) and an antisense strand having a nucleotide sequence of SEQ ID NO: 67 that has partial complementarity'7 with the sense strand of R6-O4M1-AC2(8)-S11J V3v (SEQ ID NO: 86).            ' In some embodiments, the single-stranded oligonucleotide is conjugated to one or more conjugation groups. In some embodiments, the double-stranded oligonucleotide is conjugated to one or more conjugation groups. In some embodiments, the sense strand or the antisense strand of the double-stranded oligonucleotide is conjugated to one or more conjugation groups. In some embodiments, the conjugation groups are selected from one or more of: a lipid, a fatty acid, a fluorophore, a ligand, a saccharide, a peptide, and an antibody. In some embodiments, the one or more conjugation groups is selected from: a cell-penetrating peptide, polyethylene glycol, an alkaloid, a tryptamine, a benzimidazole, a quinolone, an amino acid, a cholesterol, glucose and N-acetylgalactosamine. In some embodiments, each of the sense strand and the antisense strand independently has a nucleotide length ranging from 15-35 nucleotides. In some embodiments, the sense or anti sense strand of the double-stranded oligonucleotide has a nucleotide sequence that is at least 90% identical to the nucleotide sequence is siApp-8-S1V1 (SEQ ID NO: 28) or siApp-8-SlVl (SEQ ID NO: 27). In some embodiments, the oligonucleotide agent comprises a small interfering RNA (siRNA), wherein the siRNA comprises a sense strand and an antisense strand to form a duplex structure, wherein the antisense strand comprises a nucleotide sequence comprising at least 10 contiguous nucleotides, with 0, 1,2 or 3 mismatches, and having at least 85% nucleotide sequence complementarity or homology to a. portion of the nucleotide sequence of SEQ ID NO: 895, wherein the oligonucleotide agent is capable of inhibiting expression of superoxide dismutase 1 (SOD I) in a ceil. In some embodiments, the sense strand of the double-stranded oligonucleotide has a nucleotide sequence that is at least 90% identical to the nucleotide sequence selected from the group consisting of: siSODl-5 (SEQ ID NO: 357), siSODl-8 (SEQ ID NO: 358), siSODMO (SEQ ID NO: 359), siSODl-11 (SEQ ID NO: 360), siSOD-17 (SEQ ID NO: 357), siSODl-35 (SEQ ID NO: 362), and si SOD 1-3 7 through si SOD 1-447 (SEQ ID NOs: 363-624). In some embodiments, the antisense strand of the double-stranded oligonucleotide has a nucleotide sequence that is at least 90% identical to the nucleotide sequence selected from the group consisting of si SOD 1-5 (SEQ ID NO: 626), si SOD 1-8 (SEQ ID NO: 627), siSODMO (SEQ ID NO: 628), siSODl-11 (SEQ ID NO: 629), siSOD-17 (SEQ ID NO: 630), siSODl-35 (SEQ ID NO: 631), and siSOD 1-37-through slSODl-447 (SEQ ID NOs: 632-893). In some embodiments, the sense strand of the double-stranded oligonucleotide has a nucleotide sequence that is at least 90% identical to the nucleotide sequence selected from the group of: si SOD 1 -231 -E (SEQ ID NO: 3 8); si SOD 1 -231 -TT (SEQ ID NO: 40); si SOD 1 -23I -Ml (SEQ ID NO: 42); siSODl-231-S2 (SEQ ID NO: 44); siSOD 1 -388-E (SEQ ID NO: 46); siSODl-388-TT (SEQ ID NO: 48), siSODl-388-M1. (SEQ ID NO: 50), siSOD!-388-S2 (SEQ ID NO: 52); siSOD J.M2-E1 (SEQ ID NO: 54); and siSOD!M2-Sl V5 (SEQ ID NO: 56). In some embodiments, the antisense strand of the double-stranded oligonucleotide has a nucleotide sequence that is at least 90% identical to the nucleotide sequence selected from the group of siSODl-231-E (SEQ ID NO: 39), siSODl-231-TT (SEQ ID NO: 41), siSOD 1-231-Ml (SEQ ID NO: 43); siSODl-231-S2 (SEQ ID NO: 45); siSODI-388-E (SEQ ID NO: 47), siSODl-388-TT (SEQ ID NO: 49); siSODI-388-Ml (SEQ ID NO: 51); siSODl-388-S2 (SEQ ID NO: 53), siSODIM2-Ll (SEQ ID NO: 47); and siSOD1M2-SlV1v-Qu5 (SEQ ID NO: 57). In some embodiments, the sense strand of the siRNA has a nucleotide sequence that has at least 85% homology to the nucleotide sequence selected from the group consisting of: DS 170001 (SEQ ID NO: 384), DS 17-0002 (SEQ ID NO: 372), DS 17-0003 (SEQ ID NO: 409), DS 17-0004 (SEQ ID NO: 357), DS 17-0005 (SEQ ID NO: 486), DS17-0029 (SEQ ID NO: 588), DS 17-01N3 (SEQ ID NO: 912), DS 17-02N3 (SEQ ID NO: 914), DS17-03N3 (SEQ ID NO: 916), DS17-04N3 (SEQ ID NO: 918), DS17-05N3 (SEQ ID NO: 920) and any of SEQ ID NOs: 976-1021.                                                         ' In some embodiments, the antisense strand of the siRNA has a nucleotide sequence that has at least 85% homology to the nucleotide sequence selected from the group consisting of: DS17-0001 (SEQ ID NO: 653), DS17-0002 (SEQ ID NO: 641), DS17-0003 (SEQ ID NO: 678), DS 17-0004 (SEQ ID NO: 626), DS17-0005 (SEQ ID NO: 755), DS 17-0029 (SEQ ID NO: 857), DS17-01N3 (SEQ ID NO: 913), DS17-02N3 (SEQ ID NO: 915), DS.17-03N3 (SEQ ID NO: 9171 DSl7-04N3 (SEQ ID NO: 919), DS17-05N3 (SEQ ID NO: 921), and SEQ ID NOs: 1022-1067. In some embodiments, the sense strand and the antisense strand of the siRNA have nucleotide sequences that are independently at least 85% homologous to the nucleotide sequence pairs selected from the following groups: a) DS17-0001 (SEQ ID NO: 384 and SEQ ID NO: 653), b) DS 17-0002 (SEQ ID NO: 372 and SEQ ID NO: 641), c) DS 17-0003 (SEQ ID NO: 409 and SEQ ID NO: 678), d) DS17-0004 (SEQ ID NO: 357 and SEQ ID NO: 626), e) DS 17-0005 (SEQ ID NO: 486 and SEQ ID NO: 755), f) DS 17-0029 (SEQ ID NO: 588 and SEQ ID NO: 857), g) DS17-01N3 (SEQ ID NO: 912 and SEQ ID NO: 913), h) DS17-02N3 (SEQ ID NO: 914 and SEQ ID NO: 915), i) DSI7-03N3 (SEQ ID NO: 916 and SEQ ID NO: 917), j) DS 17-04N3 (SEQ ID NO: 918 and SEQ ID NO: 919), and k) DS17-05N3 (SEQ ID NO: 920 and SEQ ID NO: 921). In some embodiments, the sense strand and the antisense strand of the siRNA have nucleotide sequences that is independently at least 85% homologous to the nucleotide sequence pairs selected from the following groups: a) DS17-01M3 (SEQ ID NO: 922 and SEQ ID NO: 923), b) DS17-02M3 (SEQ ID NO: 924 and SEQ ID NO: 925), c) DS N-O3M3 (SEQ ID NO: 926 and SEQ ID NO: 927), d) DS17-04M3 (SEQ ID NO: 928 and SEQ ID NO: 929), and e) DS 17-05M3 (SEQ ID NO: 930 and SEQ ID NO: 931). In some embodiments, the oligonucleotide agent comprising a siRNA and a non-targeting ACO, wherein the ACO comprises a nucleotide sequence that, is at least 90%, at least 95%, or 100% identical to SEQ ID NO: 954, and the oligonucleotide agent is capable of inhibiting the expression of superoxide dismutase 1 (SOD1) in a cell. In some embodiments, the sense strand and the antisense strand of the siRNA have nucleotide sequences that independently share at least 85% homologous to the nucleotide sequence pairs selected from the following groups: a) DS17-01M3 (SEQ ID NO: 922 and SEQ ID NO: 923), b) DS17-02M3 (SEQ ID NO: 924 and SEQ ID NO: 925), c)  DS l 7-03M3 (SEQ ID NO: 926 and SEQ ID NO: 927), d) DS17-04M3 (SEQ ID NO: 928 and SEQ ID NO: 929), e) DS 17-05M3 (SEQ ID NO: 930 and SEQ ID NO: 931), f) DS17-01M3-AC1 (mel4)-L9V3 (SEQ ID NO: 932 and SEQ ID NO: 933 ), g) DS17-02M3-AC1 (mel4)-L9V3 (SEQ ID NO: 934 and SEQ ID NO: 935), h) DS17-03M3-AC1 (mel4)-L9V3 (SEQ ID NO: 936 and SEQ ID NO: 937), i) DS 17-04M3-AC1 (mel 4EL9V3 (SEQ ID NO: 938 and SEQ ID NO: 939), j) DSI7-05M3-ACI (me!4)-L9V3 (SEQ ID NO: 940 and SEQ ID NO: 941), k) DS17-29M2-AC1 (mel4)-L9V3 (SEQ ID NO: 942 and SEQ ID NO: 47), () DSl7-01M3v-ACl (mel4)-L9V3 (SEQ ID NO: 932 and SEQ ID NO: 47), m) DS17-02M3v-ACl cmeUH.0\3 (SEQ ID NO: 934 and SEQ ID NO : 943), n) DS17-03M3v-ACl (me 14)-L9V3 (SEQ ID NO: 936 and SEQ ID NO: 944), o) DS17-04M3v-ACl (meI4)-L9V3 (SEQ ID NO: 938 and SEQ ID NO: 950), p) DS 17-05M3v-AC I c me U H .9X3 (SEQ ID NO: 940 and SEQ ID NO: 951), and q) DS17-04M3-asSODl-l-L9V3 (SEQ ID NO: 952 and SEQ ID NO: 939). In some embodiments, the oligonucleotide agent comprises a non-targeting ACO conjugated sense strand of a siRN A and an antisense strand of the siRNA, wherein the non-targeting ACO conjugated sense strand comprises a linking component covalently conjugating the ACO and the sense strand, wherein the antisense strand comprises a nucleotide sequence that is at least 90%, at least 95% homology, or 100% identical to SEQ ID NO: 57. In some embodiments, the non-targeting ACO conjugated sense strand comprises a nucleotide sequence that is at least 90%, at least 95%, or 100% identical to a nucleotide sequences selected from the group consisting of SEQ IDNOs: 1197-1288 and SEQ ID NOs: 1291-1298. In some embodiments, the linking component is selected from the linking component group listed in SEQ ID NOs: 1197-1288 in Table 28 and SEQ ID NOs: 1291-1298 in Table 30. In some embodiments, the single-stranded oligonucleotide of the oligonucleotide agent improves the stability, bioavailability, biodistribution, and / or cellular uptake of the doublestranded oligonucleotide as compared to an oligonucleotide agent without the single-stranded oligonucleotide. In some embodiments, the single-stranded oligonucleotide of the oligonucleotide agent increases the biodistribution of double-stranded oligonucleotide within one or more target tissues as compared to an oligonucleotide agent without the single-stranded oligonucleotide. In some embodiments, the one or more target tissues is selected from tissues of brain, spinal cord, muscle, spleen, lung, heart, liver, bladder, and kidney. In some embodiments, the one or more target tissues is selected from the group consisting of: prefrontal cortex, cerebellum, and rest, of brain, cervical, thoracic and lumbar in spinal cord; heart, forelimb, hindlimb, nape, and gluteus. At least part of the present, disclosure provides a siRNA comprising an oligonucleotide sequence having a length ranging from 16 to 35 consecutive nucleotides, wherein the oligonucleotide sequence comprises a nucleotide sequence having at least 75%), at least 80%, at. least. 85%, at least 90%, at least 95% or 100% homology or complementarity to an equal length portion of SEQ ID NO:59, wherein the siRNA inhibits the mRNA transcript of SOD1 gene by at least 80%) as compared to the baseline of SOD] mRNA level. In certain embodiments, the nucleotide sequence has at least 75%, at least 80%, at least 85%, at least 90%, at least 95%) or 100% homology or complementarity to an equal length portion of SEQ ID NO: 61 or 63, wherein, the oligonucleotide agent inhibits the mRNA transcript of SOD1 gene by at least 80% as compared to the baseline of SOD1 mRNA level. Certain embodiments of the present application relate to a hotspot in the 3' UTR of the SODI gene, wherein the hotspot has a nucleic acid sequence selected from SEQ ID NO: 61 (HI) and SEQ ID NO: 63 (H2). Certain embodiments of the present application relate to a siRNA target sequence in the mRNA transcript from the 3’-UTR of the SODI gene, wherein the target sequence in the mRNA transcript has at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% homology to a sequence selected from SEQ ID NOs:1068-1113. Certain embodiments of the present application also relate to a siRNA target sequence in the mRNA transcript from the SODI gene, wherein the target sequence in the mRNA transcript has at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% homology to a sequence selected from SEQ ID NOs:88-355. Certain embodiments of the present application also relate to a siRNA comprising a sense strand and an antisense strand, wherein the sense strand of the siRNA has a nucleotide sequence that is at least 85%, at least 90%, at least 95% or 100% homology to the nucleotide sequence selected from the group of SEQ ID NOs: 976-1021, wherein the siRNA inhibits the mRNA transcript of SODI gene by at least 80% as compared to the baseline of SODI mRNA I evel. The present disclosure further provides a siRNA comprising a sense strand and an antisense strand, wherein the antisense strand of the siRNA has a nucleotide sequence that is at least 85%, at least 90%, at least 95% or 100% homology to the nucleotide sequence selected from the group of SEQ ID NOs: 1022-1067, wherein the siRNA inhibits the mRNA transcript of SOD I gene by at least 80%) as compared to the baseline of SODI mRNA level. In some embodiments, the sense strand and the antisense strand of the siRNA have nucleotide sequences that is independently at least 85%), at least 90%, at least 95% or 100%) homology to die nucleotide sequence pairs selected from the group of si SOD 1-547 through si SOD 1-694 (sense strand of SEQ ID NOs: 976-1021, and antisense strand of SEQ ID NOs: 1022-1067, respectively, in Table 22). At least part of the present disclosure also relates an antisense oligonucleotide (ASO) comprising an oligonucleotide sequence having a length ranging from 12 to 30 consecutive nucleotides, wherein the oligonucleotide sequence comprises a nucleotide sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% homology or complementarity to an equal length portion of SEQ ID NO:59, wherein the ASO inhibits the mRNA transcript O' SODI gene by at least 60% as compared to the baseline of SODI mRNA level. In some embodiments, the ASO has at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% complementarity to an equal length portion of SEQ ID NO: 65, wherein the ASO inhibits the mRNA transcript of SODI gene by at least 60% as compared to the baseline of SODI mRNA level. Certain embodiments of the present application relate to a hotspot in the 3’ UTR of the SODI gene, wherein the hotspot has a nucleic acid sequence of SEQ ID NO: 65 (H3). Certain embodiments of the present application relate to an A SO target sequence in the mRNA transcript from the 3’-UTR of the SODI gene, wherein the target sequence in the mRNA transcript has at least 75%), at least 80%, at least 85%, at least 90%), at least 95%, at least 97%, at least 99% or 100% homology to the nucleotide sequence selected from group consisting of SEQ ID NOs: 1114-1154. Certain embodiments of the present application also relate to an ASO comprising a singlestranded oligonucleotide sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% homology or 100% identical to the nucleotide sequence selected from group consisting of chemically modified SEQ IDNOs: 1155-1195 and their unmodified naked sequences SEQ ID NOs: 1114-1154, wherein the ASO inhibits the mRNA transcript of SODI gene by at least 60% as compared to the baseline of SODI mRNA level. Also provided here are vectors and cells comprising the oligonucleotide agents of the present disclosure. In some embodiments, the cell is a mammalian cell and is optionally a human cell. In some embodiments, the cell is a host cell. In some embodiments, the cell is in vitro. In some embodiments, the cell exists in a mammalian body. Certain embodiments of the present application relate to a pharmaceutical composition comprising the oligonucleotide agent comprising: (a) a double-stranded oligonucleotide comprising a sense strand and an antisense strand, wherein the antisense strand has complementarity to a target nucleic acid; and (b) a non-targeting single-stranded oligonucleotide, wherein the single-stranded oligonucleotide is 6-22 nucleotides in length, wherein the double-stranded oligonucleotide and the single-stranded oligonucleotide are covalently linked, with or without one or more Linking components, to form the oligonucleotide agent. The target nucleic acids can be any target nucleic acid. The target nucleic acid includes, without limitation, a SOD I gene, a HIT gene, an App gene, a SMN2 gene, etc. In certain embodiments of the present application, the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier selected from an aqueous carrier, Liposome or LNP, polymer, micelle, colloid, metal nanoparticle, non-metallic nanoparticle, bioconjugates, and polypeptide. In certain embodiments, the pharmaceutical composition decreases or silences the transcription of the SODI gene or SOD I protein. In certain embodiments, the pharmaceutical composition increases or activates the expression of the HTT, App or SMN2 gene or HTT, App or SMN2 protein. Also provided herein are kits comprising the oligonucleotide agents or the pharmaceutical compositions of the present disclosure. Certain embodiments relate to kits comprising a pharmaceutical composition of the present disclosure. Certain embodiments rel ate to a method of decreasing or silencing the transcription of a SODI gene or protein, comprising administering to a subject a pharmaceutical composition of the present disclosure. Certain embodiments relate to a method for treating or delaying the onset or progression of Amyotrophic lateral sclerosis (ALS) in a subject, the method comprising: administering to a subject a pharmaceutical composition of the present disclosure. In certain embodiments, the subject has sporadic ALS (sALS). In certain embodiments, the subject has familial ALS (%l.S). Certain embodiments of the present application relate to a method for increasing or activating expression of an HIT gene or huntington protein, comprising administering to a subject the pharmaceutical composition. Certain embodiments of the present application relate to a method for treating or delaying the onset or progression of Huntington’s disease in a subject, the method comprising: administering to the subject the pharmaceutical composition. Certain embodiments of the present application relate to a method for treating or delaying the onset or progression spinal muscular atrophy (SMA) in a. subject, the method comprising: administering to the subject the pharmaceutical composition. Certain embodiments of the present appli cati on relate to a method for increasing or acti vating expression of an App gene or amyloid precursor protein (APP), comprising administering to a subject the pharmaceutical composition. Certain embodiments of the present application relate to a method for treating or delaying the onset or progression of APP associated diseases including Cerebral Amyloid Angiopathy App-related (CA.A-APP) and .Alzheimer Disease (AD) in a subject, the method comprising, administering to the subject the pharmaceutical composition. Certain embodiments of the present application relate to a method for increasing or activating expression of SMN2 gene, comprising administering to a subject the pharmaceutical composition. Certain embodiments of the present application relate to a method for treating or delaying the onset or progression of spinal muscular atrophy (SMA) in a subject, the method comprising: administering to a subject a pharmaceutical composition of the present disclosure. In certain embodiments, the pharmaceutical composition decreases or silences the expression of the SOD1 gene or protein. In certain embodiments, the single-stranded oligonucleotide of the oligonucleotide agent improves the stability, bioavai lability, biodistribution, and / or cellular uptake of the doublestranded oligonucleotide as compared to an oligonucleotide agent without the single-stranded oligonucleotide. In certain embodiments, the single-stranded oligonucleotide of the oligonucleotide agent increases the biodistribution of double-stranded oligonucleotide within one or more target tissues as compared to an oligonucleotide agent without the single-stranded oligonucleotide. In certain embodiments, the single-stranded, oligonucleotide of the oligonucleotide agent increases the biodistribution of double-stranded oligonucleotide within two or more target cell types in a tissue as compared to an oligonucleotide agent without the single-stranded oligonucleotide. In certain embodiments, the one or more target tissues is selected from the tissues from brain, spinal cord, muscle, spleen, lung, heart, liver, bladder, and kidney. In certain embodiments, the one or more target tissues is selected from the group of: prefrontal cortex, cerebellum, and rest of brain; cervical, thoracic and lumbar in spinal cord; heart, forelimb, hindlimb, nape, and gluteus. Certain embodiments of the present application relate to a use of the oligonucleotide agent of the present disclosure, in manufacturing a. medicament, for treating or delaying the onset or progression of Amyotrophic lateral sclerosis GALS). Certain embodiments of the present application relate to a use of the pharmaceutical composition of the present disclosure in manufacturing a medicament for treating or delaying the onset or progression of Amyotrophic lateral sclerosis (ALS). In certain embodiments, the ALS comprises sporadic ALS DA I .S) and / or familial AL.S (fALS). Certain embodiments of the present application relate to the oligonucleotide agent of the present disclosure for use in treating or delaying the onset or progression of Amyotrophic lateral sclerosis (ALS), optionally, the ALS comprises sporadic ALS (sALS) and / or familial ALS(EALS).                ’ Certain embodiments of the present application also relate to the pharmaceutical composition of the present disclosure for use in treating or delaying the onset or progression of Amyotrophic lateral sclerosis (ALS), optionally, the ALS comprises sporadic ALS (sALS) and / or familial ALS (fALS). BRIEF DESCRIPTION OF THE DRAWINGS The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are employed, and the accompanying drawings (also ‘‘figure’" and “FIG.” herein), of which: FIG. LA-IC is a visual illustration of example ODV structures. Double-stranded RNA (dsRNA) duplex (siRNA or saRNA) is linked to single-stranded accessory oligonucleotides (ACOs) at the 3’- (FIGI A), 5’-terminus (FIG. IB) or an internal position (FIG. IC) of their passenger (P) strand. Also labeled are the guide (G) strand and linker (L) bridging the ACO to each dsRNA FIG. 2 shows the ESI mass spectrograms and RP-HPLC profiles of purified ODV compounds siSOD!M2-AC2(N22)-SlV3v and siSODlM2-AC2(N6)-SlV3v in comparison to siRNA duplexes with (siSOD!M2-L1) or without (siSODl-388-E) linker. All duplexes were conjugated to Quasar 570 (Qu5) dye at the 5’-terminus of passenger strand. RP-HPLC analytics via reverse phase chromatography was performed using an acetonitrile gradient at a flow'- rate of 1.0 mL / min and detection wavelength set to 260 nm. FIG. 3A-3B shows the in vivo knockdown activity of ODV-optimized siRNA (siHTT-AC2-S1 LI) on Hit mRNA expression in the brain and spinal cord of C57BL / 6 pup mice (PND4). siRNAs were injected via ICV administration at the indicated doses. Saline was injected as a negative control. siHTT-S1.Vl lacked ODV composition and served as comparison for si.HTT-AC2-SlLl activity. Mice were sacrificed 3 days after treatment. Brain (FIG. 3 A) and spinal cord (FTG.3B) tissue samples were collected for analysis by RT-qPCR. Hit mRNA levels are mean values of two animals / group (n:::2) relative to saline treatment after normalizing to Tbp reference levels. FIG. 4 shows in vitro knockdown activity of App mRNA. by ODV-siRNAs with ACOs at different lengths. NSC-34 ceils were treated with 1 or 10 nM of the indicated siRNAs for 24 hours. Mock treatments were transfected in absence oligonucleotide. dsCon2 served as a nonspecific control duplex. App mRNA levels were quantified by RT-qPCR using gene specific primer sets. Tbp was amplified as an internal reference. Showm are the mean expression values of App mRNA relative to Mock treatment after normalizing to Tbp reference levels. FIG. 5 shows ACO impact on in vivo knockdown activity of ODV-siRNAs in the CNS. All siRNAs w'ere administered via ICV injection into C57BL / 6 pup mice (PND4) at a 40 mg / kg dose. Saline was injected as a negative control. Mice were sacrificed 3 days after treatment. Brain and spinal cord tissue samples were collected for analysis by RT-qPCR. App mRNA levels are mean values of three animals / group (n=3) relative to saline treatment after normalizing to Tbp reference levels. FIG. 6A-6B shows the upregulation of SMN2 mRNA transcripts via ODV-optimized saRNAs in human primary cells. An example saRNA duplex, termed R6-04(20)-S1 Vlv(CM-4), is an activator of human SMN2 gene expression. Several ODV variants of R6-04(20)-Sl Vlv(CM-4) were synthesized with ACOs at lengths ranging from 8 to 18 nucleotides. Primary human fibroblasts derived from SMA Type-2 (GM03813 cells) and SMA Type-1 (GM09677 cells) patients were transfected with each ODV-saRNA variant at 25 nM for 3 days. Mock treatments were transfected in absence oligonucleotide. dsCon2 sewed as a non-specific control duplex. Both full length (SMN2FL) and A 7 (5MV2J7) splicing variants of SMN2 were quantified by RT-qPCR using isoform specific primer sets. TBP was amplified as an. internal reference. Shown are the mean expression values of SMN2FL and SMN2A 7 transcripts relative to Mock treatment after normalizing to TBP reference levels in GM03813 (FIG.6A) and GM09677 (FIG.6B) cells. FIG. 7A-7B shows the associated upregulation of SMN2 protein by ODV-saRN / k in human primary cells. R6-04(20)-SlVlv(CM-4) and its ODV-saRNA variants were transfected, at 25 nM for 3 days into GM03813 and GM09677 patient-derived cells. Mock treatments were transfected in absence oligonucleotide. dsCon2 served as a non-specific control duplex. Whole cell protein extracts were harvested for immunoblot analysis. Total SMN protein levels were detected using an indiscriminate monoclonal antibody that recognized both SMN1 and SMN2 gene product. Immunodetection of a / p-Tubulin served as a protein loading control. Scanning optical densitometry' was used to quantify protein band intensity from example immunoblot images (not shown). Shown are relative changes in total SMN protein levels relative to Mock treatment after normalizing to a / p-Tubulin band intensity in GM03813 (HG.7A) and GM09677 (FIG. 7B) cells. FIG. 8 shows the upregulation of SMN2 mRNA transcripts via ODV-saRNAs in primary mouse hepatocytes (PMH) carrying human SMN2 transgene. R6-04(20)-S1.Vlv(CM-4) and its ODV-saRNA. variants wzere transfected at 25 nM for 3 days in PMH cells derived from a liver harvested from the SMA-like mouse model. Mock treatments were transfected in absence oligonucleotide. dsCon2 served as a non-specific control duplex. Full length (SMN2FL) and A7 {SMN2A7} splicing variants of the human SMN2 transgene were quantified by RT-qPCR using isoform specific primer sets. Mouse Tbp (mTbp) was amplified as an internal reference. Shown are the mean expression values of SMN2FL and SMN2A7 transcripts relative to Mock treatment after normalizing to mTbp reference levels FIG. 9 shows high throughput screening data comparing knockdown activity of 268 siRNAs on human SOD1 mRNA. HEK293A cells were transfected with each siRNA duplex at 0.1 and 10 nM for 24 hours. Mock treatments were transfected in absence oligonucleotide. SOD I expression levels were quantified, by RT-qPCR using gene specific primer sets. TBP was amplified as an internal reference. Shown are the mean expression values of SOD I mRNA relative to Mock treatment after normalizing to TBP reference levels at both treatment concentrations. FIG. 10 shows a general absence of cytotoxicity for the top 30 SOD1 siRNAs in HEK293A cells. Dose escalating concentrations representing approximate multiples of ICso (half maximal inhibitory concentration) values were transfected into HEK293A cells. Mock treatments were transfected in absence oligonucleotide. Both mRNA expression levels and cytotoxicity' were quantified for each siRNA at every dose by RT-qPCR and PI staining, respectively. Plotted is optical density (OD) of PI staining in comparison to SOD1 knockdown relative to Mock treatments. FIG. 11 shows SODI knockdown by 6 lead siRNAs in a human neuroblastoma cell line. SH-SY5Y cells were treated with SODI siRNAs (he., si SOD 1-63, si SOD 1-47, siSODl-104, siSODl-5, siSOD 1-231 and si SOD 1-388) at 1 and 10 bM for 24 hours. Mock, treatments were transfected in absence oligonucleotide. dsCon2 served as a non-specific control duplex. SODI mRNA levels w7ere quantified by RT-qPCR using gene specific primer sets. TBP was amplified as an internal reference. Shown are the mean expression values of SODI relative to Mock treatment after normalizing to TBP. FIG. 12A-12B shows Sadi knockdown of 4 lead siRNAs targeting conserved sequence in mouse motor neuron-like cell lines. NSC-34 and N-2a ceils were treated with SODI siRNAs (i.e., siSOD 1-231, si SOD 1-229, siSODl-388, and siSODl-387) at 1 and 10 nM for 24 hours. Mock treatments were transfected in absence oligonucleotide. dsCon2 served as a nonspecific control duplex. Mouse Sodl levels were quantified by RT-qPCR using gene specific primer sets. Mouse Tbp was amplified as an internal reference. Shown are the mean expression values of Sodl transcript relative to Mock treatment after normalizing to mTbp reference levels in NSC-34 (FIG. 12A) and N-2a (IRG. 12B) ceils. FIG. 13A-13C shows impact of medicinal chemistry on si SOD 1-231 and siSODl-388 knockdown activity. Chemical modification patterns and duplex structures used to test knockdown activity are depicted in FIG. 13A using siSODl-388 as model sequence. Modification symbols: Upper case in bold, 2’0me; lower case, 2’F; chevron (A), PS; T, deoxythymidine. Human 239A and mouse NE-4C (neuroepithelial) ceils were treated with chemically modified versions of si SOD 1-231 (i.e., siSODl-231-E, si SOD 1-231-TT, siSODl-231-Ml, or siSODl-231-S2) and siSODl-388 (i.e., siSODl-388-E, siSODl-388-TT, si.SODl-388-Ml, or siSODl-388-S2) at. 1 and 10 nM for 24 hours. Mock treatments were transfected in absence oligonucleotide. dsCon2 served as anon-specific control duplex. Expression levels of SODl / Sodl was quantified by RT-qPCR using species-specific gene primer sets. TBP / Tbp was amplified as an internal reference. Shown are the mean, expression values of SODI / Sod] transcript relative to Mock treatments after normalizing to internal reference levels in EIEK293A (FIG. 13A) and NE-2C (FIG. 13B) cells. FIG. 14 shows in vitro knockdown activity of Sod] mRN A by ODV-optimized si SOD I -388-E [siSOD 1M2-AC2(N15)-S1V3v-Qu5], NSC-34 cells were treated with 0.1 or 1 nM of the indicated siRNAs for 3 days. Mock treatments were transfected in absence oligonucleotide. dsCon2 served as a non-specific control duplex. Sodl mRNA levels were quantified by RT-qPCR using gene specific primer sets. Tbp was amplified as an internal reference. Shown are the mean expression values of Sodl mRNA relative to Mock treatment after normalizing to Tbp reference levels. FIG. 15A-15C shows biodistribution and in vivo knockdown activity of siSODlM2-AC2(N15)-Sl V3v-Qu5 via ICV injection in the organs of pup mice (PND4). Qu5-labeled ODV-siRNA (siSOD!M2-AC2(N15)-SlV3v-Qu5) was administered via ICV injection into C57BL / 6 pup mice (PND4) at a 40 mg / kg dose. Injection of a. Qu5-labeled siRNA variant siSOD1M2-S1.V1v-Qu5, which lacked any accessory oligonucleotide, served as a comparative control. Mice were sacrificed 3 days following treatment and whole organ fluorescence w'as quantified on an IVIS Imaging System using 520 nm excitation and 570 nm emission filters. FIG. 15A is an example IVIS image depicting siSOD 1M2-AC2(N15)-SI V3v-Qu5 biodistribution via Qu5 signal in all major organs comparative to siSOD!M2-S.lVlv-Qu5 following ICV injection. FIG.15B quantifies fluorescence intensity of siSOD 1M2-AC2(N15)-S1V3v-Qu5 emitted by each organ. Sodl mRNA knockdown was quantified in organ tissue via RT-qPCR using gene specific primer sets. Tbp was amplified as an internal reference. FIG.15C shows Sodl knockdown in each organ relative to mRNA levels from a non-treated animal after normalizing to Tbp. FIG. 16A-16B shows the biodistribution and in vivo knockdown activity ofsiSOD!M2-AC2(N12)-S1 V3v-Qu5 via ICV injection in the organs of adult mice. Qu54abeled ODV-siRNA. (siSODlM2-AC2(N12)~Sl V3v-Qu5) was administered via bilateral ICV injection into adult C57BL / 6 mice at a 10 mg / kg total dose. Injection of a Qu54abeled siRNA variant siSOD!M2-Sl Vlv-Qu5, which lacked any accessory' oligonucleotide, served as a comparative control. Mice were sacrificed 5 days after the injection and whole organ fluorescence was quantified on an IVIS Imaging System using 520 nm excitation and 570 nm emission filters. FIG.16A quantifies Qu5 signal intensity of siSOD1M2-A.C2(Nl2)-S1.V3v-Qu5 emitted from each major organ comparative to siSODlM2-SlVlv-Qu5 following ICV injection. Sodl mRNA knockdown w7as quantified within tissues of the CNS and select peripheral tissues (i.e., muscle and kidney) via RT-qPCR using gene specific primer sets. Tbp was amplified as an internal reference. FIG.16B shows mean knockdown levels of Sodl in each of the indicated adult tissues relative to mRNA levels in saline treated animals after normalizing to Tbp. FIG. 17 demonstrates ACO length impacts distribution of ODV-siRNA knockdown activity in CNS tissues in vivo. Sodl ODV-siRNA variants with ACOs at lengths of either 22 nucleotides (siSOD1M2-AC2(N22)-Sl¥3v-Qu5) or 6 nucleotides (siSODl.M2-AC2(N6)-S1 V3v-Qu5) were administered to adult C57BL / O mice via bilateral ICV injection at a 10 mg / kg total dose. Mice wzere sacrificed 10 days following treatment and Sodl mRNA knockdown was quantified within different tissues of the CNS and liver via RT-qPCR using gene specific primer sets. Tbp was amplified as an internal reference. Mean expression levels from 2 animals (n=2) are shown in each of the indicated adult tissues relative to mRNA levels in non-treated animals after normalizing to Tbp. FIG. 18 shows the inhibiting potency of 6 lead siRNAs on SOD1 mRNA level in SH-SY5Y human neuroblastoma cells. SH-SY5Y cells were treated with SOD1 siRNAs (be., DS 170001, DS17-0002, DS17-0003, DS17-0004, DS17-0005 and DS 17-0029) at 0.1 and 1 nM for 24 hours. Mock treatments were transfected in absence of oligonucleotide. dsCon2 served as a non-specific duplex control. SODl mRNA levels were quantified by RT-qPCR using gene specific primer sets. TBP was amplified as an internal reference. Shown are the mean values of SOD1 mRNA relative to Mock treatment after normalizing to TBP. FIG. 19 shows the inhibiting potency of 7 siRNAs on the SOD1 mRNA level in HEK293A cells. HEK293A. cells were treated with DS17-04N3 siRNA and 6 prior art siRN As (DS 1.7-Vol49, DS 17-VoI49(c), DS17-Vol53, and DS17-Vol53(c) from US10570395B2; DS17-A1289 and DS17-A1102 from WO2006066203A2) at 0.004, 0.016, 0.063, 0.250, 1.000 and 4.000 nM for 24 hours, respectively. Mock treatments were transfected in absence of oligonucleotide. dsCon2 served as a non-specific duplex control. Mock and dsCon2 data are not shown. SOD1 mRNA levels were quantified by RT-qPCR using gene specific primer sets. TBP wzas amplified as an internal reference. Shown are the mean values of SOD1 mRNA relative to Mock treatment after normalizing to TBP. FIG. 20A-20B show the inhibiting potency of 9 siRNAs on the SOD1 mRNA levels in HeLa and HEK293A cells. HeLa and HEK293A cells were treated with DS17-02N3 siRNA and 8 prior art siRNAs (DS17AMI95&60 and DS17-Vol95 (D-2763) from US20170314028A1, and DS17-A1148, DS17-A1194, DS17-A1290, DS17-A1405, DS17-A1447 and DS17-A1600 from WO2006066203A2) at 0.004, 0.016. 0.063, 0.250, 1.000 and 4.000 nM for 24 hours. respectively. FIG.20A shows the SODl mRNA level in HeLa cells. FIG.20B shows the SODl mRNA level in HEK293A cells. Mock treatments were transfected in absence of oligonucleotide. dsCon2 served as a non-specific duplex control. Mock and dsCon2 data are not shown. SODl mRNA. levels were quantified by RT-qPCR using gene specific primer sets. TBP was amplified as an internal reference. Shown are the mean values of SOD] relative to Mock treatment after normalizing to TBP. FIG. 21A-21B show the inhibiting potency of 5 lead siRNAs with chemical modification on the SOD1 mRNA levels in T98G and HEK293A cells. T98G and HEK293A cells were treated with SODl siRNAs (i.e., DSI7-01M3, DS17-02M3, DS17-03M3, DS17-04M3 and DS17-05M3) at 0.002, 0.005, 0.015, 0.046, 0.137, 0.412, 1.235, 3.704, 11.111, 33.333 and 100 nM for 24 hours, respectively. FIG.21A shows the SODl mRNA level in T98G cells. FIG.21B show's the SODl mRNA level in HEK293A ceils. Mock treatments were transfected in absence of oligonucleotide. dsCon2 served as a non-specific duplex control. Mock and dsCon2. data are not shown. SODl mRNA levels were quantified by RT-qPCR using gene specific primer sets. TBP was amplified as an internal reference. Shown are the mean values of SODl relative to Mock treatment after normalizing to TBP. FIG. 22A.-22B show the inhibiting potency of 4 lead ODV-siRNAs with chemical modification on the SODl mRNA level in HEK293A cells. Cells were treated with 4 SODl ODV-siRNAs (Le.. DS 17-02M3-AC1(mel4)-L9V3, DS17-03M3-AC1(mel4)-L9V3, DS17-04M3-ACl(mel4)-L9V3 and DS17-29M2-ACl(mel4)-L9V3) at 0.00002, 0.00009, 0.00037, 0.0015, 0.0059, 0.023, 0.094, 0.375, 1.5 and 6 nM for 24 hours, respectively. FIG.2.2A show's the SODl mRNA level in HEK293A cells. FIG.22B shows the caspase 3 / 7 activity in HEK293A cells. Mock treatments were transfected in absence of oligonucleotide. dsCon2 served as a non-specific duplex control. Mock and dsCon2 data are not shown. SODl mRNA levels were quantified by RT-qPCR using gene specific primer sets. TBP was amplified as an internal reference. Shown are the mean values of SODl relative to Mock treatment after normalizing to TBP. Caspase 3 / 7 activity w7as detected using caspase 3 / 7 activity kit. FIG. 23A-23B show the in vivo inhibiting potency of ODV-siRNA leads on the SODl mRNA level via ICV injection in CNS of adult SODR9'4 mice. 3 ODV-siRNA s (i.e., DS17-01 M3 - AC I (me 14)-L9 V3, DS .17-04M3 - AC I (me 14)-L9 V3 and D S17-05M3 -AC 1 (me 14)-L9V3) were administered via unilateral ICV injection into adult SOD1G93A mice on postnatal day (PND) 46 at a 0.4 mg total dose. An ODV-duplex dsCon2M3-A.Cl(mel4)-L9V3 served as a non-specific duplex control. asSODl-1 (Tofersen) was also injected at die same dose as a positive control. Mice w'ere sacrificed 7 days after the treatment and SODl mRNA knockdown was quantified in different tissues of the CNS via RT-qPCR using gene specific primer sets. FIG.23 A show's the SODl mRNA level in different brain tissues. FIG.23B shows the SODl mRNA level in different spinal cord tissues. Tbp w'as amplified as an internal reference. Mean mRNA levels of 4 animals (n:::4) each treatment group are shown by indicated tissues relative to non-treated group after normalizing to Tbp. FIG. 24A-24B show the latency and body weight change of adult SOD1&3A mice after ICV injection with siRNA. ODV-siRNA (DS17-04M3-ACl(mel4)-L9V3) was administered via unilateral ICV injection into adult          mice on PND 46 at a 20 nmole total dose. FIG.24 A shows the efficacy by rotarod behavior test after PND 68. FIG.2.4B show's the body weight fluctuation after the injection at PND 46 (normalized as day 0). Tofersen w'as injected at a 20 nmole dose as a positive control. Artificial CSF (aCSF) was injected as a non-treated negative control. Mean SODl mRNA levels of 4 animals (n=4) are shown in each treatment. FIG. 25 shows the siRNA concentration in adult          mouse brain after ICV injection. z\n ODV-siRNA (DS17-04M3-ACl(mel4)-L9V3) was administered via unilateral ICV injection into adult SOb)l&yA mice on PND 46 at a 0.4 mg total dose. The mice were sacrificed at 1-, 7-, 28- and 56-days following treatment and the concentration ofDS17-04M3-AC1(mel4)-L9V3 was quantified in different brain tissues via stem-loop RT-qPCR using gene specific primer sets. Mean values of siRNA concentrations from 3 animals (n::::3 ) are shown in each treatment. FIG. 26 shows the in vivo inhibiting potency of an ODV-siRNA lead on the SOD] mRNA levels in different CNS tissues via ICV injection in adult SODl&}iA mice. An ODV-siRNA (DSl7-04M3-ACl(me14)-L9V3) was administered on PND 46 days via unilateral ICV injection at 0.1-, 0.4-, 1- and 1.6-mg total dose. aCSF was injected as a non-treated negative control. Mice were sacrificed at 14 days following treatment and SOD I mRNA knockdown was quantified in different. CNS and liver tissues via RT-qPCR using gene specific primer sets. Tbp was amplified as an internal reference. Mean SOD1 mRNA levels of 1-3 animals in V3) are shown in each of the indicated tissues relative to mRNA levels in non-treated group after normalizing to Tbp. FIG. 27 shows the in vitro inhibiting potency of ODV-siRNA leads on the SOD1 mRNA. level in T98G cells. T98G cells were treated with 5 SOD1 ODV-siRNAs (i.e., DS17-01M3v-AC1 (me 14)-L9 V3. DS 17-02M3 v-AC 1 (me 14)-L9V3, DS I7-03M3 v-AC 1 (me 14)-L9V3, DS17-04M3v-ACl(mel4)-L9V3 and DS17-05M3v-ACl(mel4)-L9V3) at 0.0003, 0.0011, 0.0044, 0.0176, 0.0703, 0.2813, 1.1250, 4.5 and 18 nM for 24 hours, respectively. Mock treatments were transfected in absence of oligonucleotide. dsCon2 served as a non-specific duplex control. Mock, and dsCon2 data are not. shown. SOD1 mRNA levels were quantified by RT-qPCR using gene specific primer sets. TBP was amplified as an internal reference. Shown are the mean SOD1 mRNA values relative to Mock treatment after normalizing to TBP                                                              ~ FIG. 28 shows the in vivo inhibiting potency of ODV-siRNA leads on the SOD] mRNA level via ICV injection in adult SOD7G93A mice. 5 ODV-siRNA s (i.e.„ DS17-01M3v-ACl(mel4)-L9V3, DS17-02M3v-AC1(me14)-L9V3, DS17-03M3v-AC1(me14)-L9V3, DS17-04M3v-ACl(me,14)-L9V3 and DSI 7~05M3v~ACl(meI4)~L9V3) were administered via unilateral ICV injection into adult SODP19jAmice on PND 46 at a 0.2 mg total dose. aCSF was injected as a non-treated negative control. DS17-04M3(Scr)-ACl(mel4)-L9V3 was served as a nonspecific duplex control. Mice were sacrificed 14 days following treatment and SOD] mRNA knockdown wzas quantified in different CNS and fiver tissues via RT-qPCR using gene specific primer sets. Tbp was amplified as an internal reference. Mean SOD1 mRNA levels from 2-4 animals (n=2-4) are shown in each of the indicated tissues relative to mRNA levels in non-treated group after normalizing to Tbp. FIG. 29A-29C show the in vivo inhibiting potency of different ODV-siRNA leads on the SOD] mRNA level via ICV injection in adult SODl^^ mice. Tw'O ODV-siRNAs (DS17-04M3-ACI(mel4)-L.9V3 and DS 17-04M3v-ACl(me14)-L9V3) were administered on PND 46 via unilateral ICV injection. aCSF was injected as a non-treated negative control. FIG.29A shows the SOD] mRNA transcript level in different tissues at. a low dose (0.2 mg) after treatment for 14 days. FIG.29B shows the SOD1 mRNA transcript level in different tissues at a high dose (0.4 mg) after treatment for 14 days. FIG.29C show's the SOD1 mRNA transcript level in different tissues at a high dose (0.4 mg) after treatment for 56 days. Mice were sacrificed at 14- and 56-days following treatment and SOD1 mRNA knockdown was quantified in different CNS and liver tissues via RT-qPCR using gene specific primer sets. Tbp was amplified as an internal reference. Mean SOD] mRNA levels from 2-4 animals (n=2-4) are shown in each of the indicated tissues relative to mRNA levels in nonAreated group after normalizing to Tbp. FIG. 30A-30G show the in vivo inhibiting potency of ODV-siRNA leads on the SODI mRNA transcript level via ICV injection in adult SOD1&3A mice. ODV-siRNAs (DS17-04M3-ACl(mel4)-L9V3 and DS17-04M3v-ACl(mel4)-L9V3) were administered onPND 46 via unilateral ICV injection at a at 20 nmole total dose. Tofersen was injected at same dose as a positive control. aCSF was injected as a non-treated negative control. FIG.30A, FIG.30B, FIG.30C, FIG30D, FIG.30E, FIG.30F and FIG. 30G show the SODI mRNA levels in Brain-frontal cortex, Brain-cerebellum, Rest of brain, Spinal cord-cervical, Spinal cord-thoracic, Spinal cord-lumbar and liver tissues, respectively. Mice were sacrificed at 2-and 8-weeks following treatment and SODI mRNA knockdown was quantified in different CNS and liver tissues via RT-qPCR using gene specific primer sets. Tbp was amplified as an internal reference. Mean SODI mRNA levels of 4 animals (n=4) are shewn in each of the indicated tissues relative to mRNA levels in non-treated group after normalizing to Tbp. FIG. 31A-31C show the immunostimulatory' activity of SODI ODV-siRNA in ICR mice. ICR mice were treated with DS17-04M3. ?\C1-L9V3 and DSl7-04M3-ACl(me14)-L9V3 at 10.18 nmole (low dose) and 40.71 nmole (high dose) by SC injection, respectively. Treatment with saline alone served as a vehicle control to establish baseline levels. Mice were sacrificed 8 hours after treatment in serum were harvested to detect the JL-ip (FIG.31 A), IFN-y (FIG.3 IB) and TNF-a (FIG.3IC) protein levels by ELISA assay as described in ELISA assay of Materials and Methods. FIG. 32A-32C show levels of ALT (32A), AST (32B) and CREA (32C) in ICR mouse after SC injection of DS17-04M3, AC1-L9V3 and DS17-04M3-ACl(mel4)-L9v3. The indicated test compounds were administered via SC injection into ICR mice at 10.18 nmole and 40.71 nmole, respectively. Serum levels of ALT (FIG.32A), AST (FIG.32B) and CREA (FIG.32C) was detected by using their specific detection kits as described in Materials and Methods. FIG. 33A-33B show screening data comparing knockdown activity of 46 siRNAs targeting human SODI 3’UTR. HEK293A cells were transfected with each siRNA duplex at 0.1 and 1 nM for 24 hours. FIG.33A shows SODI mRNA expression levels of 46 siRNAs sorted by location in HEK293A cells. FIG.33B shows SOD I. mRNA levels of 46 siRNAs sorted by activity on 3’UTR in HEK293A cells. Mock treatments were transfected in absence of oligonucleotide. dsCon2 sewed as a non-specific duplex control. Mock and dsCon2 data are not shown. SOD] mRNA levels were quantified by RT-qPCR using gene specific primer sets. TBP and HPRT1 were amplified as internal reference. Shown are the mean expression values of SODI mRNA relative to Mock treatment after normalizing to TBP and HPRTl reference levels at both treatment concentrations. The value (y-axis) shows the fold changes in SOD] mRNA expression levels by each of the siRNAs relative to Mock treatment after normalized to TBP and HPRTl. siRNAs are sorted on x-axis by their location on the 3’UTR from 540 bp and 700 bp downstream of SODI transcription start site (TSS). Locations of the 2 siRNA hotspot regions were marked as Hl to H2 in rectangular dotted boxes. FIG. 34. shows the dose dependent characterization for the candidates of SODI in HEK293A cells. siRNAs were transfected into EIEK293A cells in dose escalated concentrations representing approximate multiples of IC50 (half maximal inhibitory concentration) values. Mock treatments were transfected in absence of oligonucleotide (not shown). SODI mRNA expression levels were quantified by RT-qPCR using gene specific primer sets. TBP and HPRT1 were amplified as internal reference. Shown are the mean expression values of 500.7 mRNA relative to Mock treatment after normalizing to TBP and HPRT1 reference levels at both treatment concentrations. FIG. 35A-35B show7 screening data comparing knockdown activity of ASOs targeting human SOD1 3’UTR. HEK293A cells were transfected with 16 ASOs at 5 nM and 50 nM, and 33 ASOs at 3.125, 12.5, 50 and 200 nM for 24 hours. FIG.35A show' SOD1 mRNA levels of 16 ASOs in HEK293A cells. FIG.35B show SOD1 mRNA levels of 33 ASOs in HEK293A ceils. Mock treatments were transfected in absence of oligonucleotide. dsCon2 served as a non-specific duplex control. Mock and dsCon2 data are not shown. SOD! mRNA levels were quantified by RT-qPCR using gene specific primer sets. TBP and HPRT.1 were amplified as internal reference. Shown are the mean expression values of SOD1 mRNA relative to Mock treatment after normalizing to TBP and HPRT1 reference levels at both treatment concentrations. The value (y-axis, log2) shows the fold changes in SOD1 mRNA expression levels by each of the ASOs relative to Mock treatment after normalized to TBP and HPRT1. ASOs are sorted on x-axis by their location on the 3’UTR from 544 bp and 576 bp downstream of SOD1 transcription start site (TSS). Locations of the 1 ASO hotspot region was marked as H3 in rectangular dotted boxes. FIG. 36A-36C. show7 the dose-dependent characterization for the candidates of SOD1 ASOs in HEK293A cells. ASOs were transfected into HEK293A ceils in dose escalated concentrations representing approximate multiples of IC50 (half maximal inhibitory concentration) values. Mock treatments were transfected in absence of oligonucleotide (not shown). FIG.36A show7 the mRNA expression levels, FIG.36B show7 the apoptosis and FIG.36C show the cytotoxicity were quantified for each ASO at. every dose by RT-qPCR, Caspase 3 / 7 kit (G8092, Promega) and CCK8 kit (CK04, Dojindo, Japan) in HEK293A cells, respectively. FIG. 37A-37B show screening data for knockdown activity and cytotoxicity of 90 ODV-siRNA designs by free uptake in PMH ceils. The indicated ODV-siRNAs were added to PMH cell culture media at 0.1 pM and 1 pM final concentration. The cells were then incubated for 3 days. RD-12556 and RD-12559 served as duplex control and ODV control, respectively. Mock was treated in absence of oligonucleotide and not shown. FIG.37A shows Sodl mRNA levels by each of the ODV-siRNAs in PMH cells. Sodl mRNA levels were quantified by RT-qPCR using gene specific primer sets. Tbp and Hprtl were amplified as internal reference. The value (y-axis) shows the mean expression values of Sodl mRNA relative to Mock treatment after normalizing to Tbp and Hprll reference levels at both treatment concentrations. FIG.37B shows cytotoxicity levels of 90 ODV-siRNAs in PMH cells by PI staining. A microplate reader system (Infinite M2000 Pro) was used to detect the optical density (OD) of PI staining at 535 nm excitation and 615 nm emission wavelengths. The value (y-axis) shows the mean values of PI staining by each of the ODV-siRNAs at both concentrations relative to Mock. Total 90 ODV-siRNAs are marked as (A) to (L) in 12 different rectangular dotted boxes. The rectangular dotted boxes stand for various design groups with different linkers (A), Palindromic AC1 sequence variants (B), varying numbers of PS modification (C), varying numbers of 2’0me (D), varying ACO sizes (E), adenine-rich sequence composition (F), cytosine-rich sequence composition (G), guanine-rich sequence composition (H), uracil-rich sequence composition (I), purines-rich sequence composition (J), pyrimidines-rich sequence composition (K) and balanced purines / pyrimidine composition CQ.                                                 ' '                               ’ FIG. 38 shows the effect of various ODV linkers used in ODV-siRNAs, as indicated in group (A) of FIG.37, on in vitro knockdown activity in PMH cells. Group A (Linker group) included 10 compounds {be., RD-12941, RD-12942, RD-12943, RD-12944, RD-12945, RD-12947, RD-12948, RD-12949, RD-12950 and RD-12951). RD-12556 and RD-12559 served as duplex control and ODV control, respectively. FIG.38 shows the Sodl mRNA levels in PMH cells after free uptake treatments of ODV-siRNAs at 0.1 pM and 1 pM for 3 days. Mock was treated in absence of oligonucleotide and not shown. Sodl mRNA levels were quantified by RT-qPCR using gene specific primer sets. Tbp and Hprtl were amplified as internal reference. The value (y-axis) shows the mean expression values of Sodl mRNA relative to Mock treatment after normalizing to Tbp and Hprtl reference levels at both treatment concentrations. FIG. 39 shows the effect of different palindromic AC I sequence used in ODV-siRNAs, as indicated in group (B) of FIG.37, on in vitro knockdown activity in PMH cells. Group B (palindromic AC 1 sequence group) included 15 compounds containing sequence derivatives based on the exemplary ACO called AC1 Ge., RD-12952, RD-12953 MID-12954, RD-12955, RD-12956, RD-12957^ RD-12958, RD-12959, RD-12960, RD-12961, RD-12962, RD-12963, RD-12964, RD-12965, and RD-12966). RD-12556 and RD-12559 served as duplex control and ODV control, respectively. FIG.39 shows the Sodl mRNA levels in PMH cells after free uptake treatments of ODV-siRNAs at 0.1 pM and 1 pM for 3 days. Mock was treated in absence of oligonucleotide and not shown. Sodl mPA A levels w^ere quantified by RT-qPCR using gene specific primer sets. Tbp and Hprtl were amplified as internal reference. The value (y-axis) shows the mean expression values of Sodl mRNA relative to Mock treatment after normalizing to Tbp and Hprtl reference levels at both treatment concentrations. FIG. 40 shows the effect of PS modification used in ODV-siRNAs, as indicated in group (C) of FIG.37, on in vitro knockdown activity in PMH cells. Group C (PS modification group) included 6 compounds (£<?., RD-12967, RD-12968, RD-12969, RD-12970, RD-12971 and RD-12972) each with the same 14-nt .ACO containing either 2, 4, 6, 8, 10 or 12 PS modifications, respectively. RD-12556 and RD-12559 served as duplex control and ODV control, respectively. FIG.40 shows the Sodl mRNA levels in PMH cells after free uptake treatments of ODV-siRNAs at 0.1 uM and I uM for 3 days. Mock was treated in absence of oligonucleotide and not shown. Sodl mRNA levels were quantified by RT-qPCR. using gene specific primer sets. Tbp and Hprtl were amplified as internal reference. The value (y-axis) shows the mean expression values of Sodl mRNA relative to Mock treatment after normalizing to Tbp and Hprtl reference levels at both treatment concentrations. FIG. 41 shows the effect, of 2’0me modification used in ODV-si RNAs, as indicated in group (D) of FIG.37, on in vitro knockdown activity in PMH cells. Group D (2’0me modification group) included 7 compounds (Lv, RD-12973, RD-12974, RD-12975, RD-12976, RD-12977, RD-12978 and RD-12979) each with the same 14-nt ACO containing either 2. 4, 6, 8, 10 or 12 substitutions of 2’MOE chemistry for 2’Ome, respectively. RD-12556 and RD-12559 served as duplex control and ODV control, respectively. FIG.41 shows the Sodl mRNA levels in PMH cells after free uptake treatments of ODV-siRNAs at 0.1 pM and 1 pM for 3 days. Mock was treated, in absence of oligonucleotide and not shown. Sodl mRNA levels were quantified by RT-qPCR using gene specific primer sets. Tbp and Hprtl were amplified as internal reference. The value (y-axis) shows the mean expression values of Sodl mRNA relative to Mock treatment after normalizing to Tbp and Hprtl reference levels at both treatment concentrations. FIG. 42 shows the effect of various ACO size used in ODV-siRNAs, as indicated in group (E) of FIG.37, on in vitro knockdown activity in PMH cells. Group E (ACO size group) included 8 compounds (i.e., RD-12980, RD-12981, RD-12982, RD-12983, RD-12984, RD-12985, RD-12986 and RD-12987) derived by truncating the 14-nt ACO in RD-12559 to 13. 12, 11, 10, 9, 8, 7, or 6 nucleotides in length, respectively. RD-12556 and RD-12559 served as duplex control and ODV control, respectively. IK- 42 shows the Sodi mRNA levels in PMH cells after free uptake treatments of ODV-siRNAs at 0.1 pM and 1 pM for 3 days. Mock was treated in absence of oligonucleotide and not shown. Sodi mRN?\ levels w'ere quantified by R.T-qPCR. using gene specific primer sets. Tbp and Hpril were amplified as internal reference. The value (y-axis) show's the mean expression values of Sodi mRNA relative to Mock treatment after normalizing to Tbp and Hprtl reference levels at both treatment con centration s. FIG. 43 shows the effect of Adenine rich used in ODV-siRNAs, as indicated in group (F) of FIG.37, on in vitro knockdown activity in PMH cells. Group F (Adenine rich group) included 5 compounds (i.e., RD-12988, RD-12989, RD-12990, RD-12991, and RD-12992) each with a different 14-nt ACO sequence containing either 5, 6, 7, 8, or 9 total adenine nucleotides, respectively. RD-12556 and RD-12559 served as duplex control and ODV control, respectively. FIG.43 shows the Sodi mRNA levels in PMH cells after free uptake treatments of ODV-siRNAs at 0.1 uM and 1 uM for 3 days. Mock was treated in absence of oligonucleotide and not shown. Sodi mRN A levels were quantified by RT-qPCR using gene specific primer sets. Tbp and Hprtl were amplified as internal reference. The value (y-axis) shows the mean expression values of Sodi mRNA relative to Mock treatment after normalizing to Tbp and Hprtl reference levels at both treatment concentrations. FIG. 44 shows the effect of Cytosine rich used in ODV-siRNAs, as indicated in group (G) of FIG.37, on in vitro knockdown activity in PMH cells. Group G (Cytosine rich group) included 6 compounds RD-12993, RD-12994, RD-12995, RD-12996, RD-12997, and RD-12997) each with a different 14-nt ACO sequence containing either 5, 6, 7, 8, 9, or 10 total cytosine nucleotides, respectively. RD-12556 and RD-12559 served as duplex control and ODV control, respectively. FIG.44 shows the Sodi mRNA levels in PMH cells after free uptake treatments of ODV-siRNAs at 0.1 pM and 1 pM for 3 days. Mock w^as treated in absence of oligonucleotide and not shown. Sodi mRNA levels were quantified by RT-qPCR using gene specific primer sets. Tbp and Hprtl were amplified as internal reference. The value (y-axis) shows the mean expression values of Sodi mRNA relative to Mock treatment after normalizing to Tbp and Hprtl reference levels at both treatment concentrations. FIG. 45 shows the effect of Guanine rich used in ODV-siRNAs, as indicated in group (H) of FIG.37, on in vitro knockdown activity in PMH cells. Group H (Guanine rich group) included 5 compounds (hu, RD-12999, RD-13000, RD-13001, RD-13002, and RD-13003) each with a different 14-nt ACO sequence containing either 5, 6, 7, 8, or 9 total guanine nucleotides, respectively. RD-12556 and RD-12559 served as duplex control and ODV control, respectively. FIG.45 shows the Sodi mRN A levels in PMH cells after free uptake treatments of ODV-siRNAs at 0.1 uM and 1 uM for 3 days. Mock was treated in absence of oligonucleotide and not shown. Sodi mRNA levels were quantified by RT-qPCR using gene specific primer sets. Tbp and Hprtl were amplified as internal reference. The value (y-axis) shows the mean expression values of Sodi mRNA relative to Mock treatment after normalizing to Tbp and Hprtl reference levels at both treatment concentrations. FIG. 46 show's the effect of Uracil rich used in ODV-siRNAs, as indicated in group (I) of FIG.37. on in vitro knockdown activity in PMH cells. Group I (Uracil rich group) included 6 compounds (i.e., RD-13004, RD-13005, RD-13006, RD-13007, RD-13008, and RD-13009) each with a different 14-nt ACO sequence containing either 5, 6, 7, 8, 9, or 10 total uracil nucleotides, respectively. RD-12556 and RD-12559 served as duplex control and ODV control, respectively. F1G.46 shows the Sodl mRNA. levels in PMH cells after free uptake treatments of ODV-siRNAs at 0.1 uM and I uM for 3 days. Mock w'as treated in absence of oligonucleotide and not shown. Sodl mRNA level s were quantified by RT-qPCR. using gene specific primer sets. Tbp and Hprtl were amplified as internal reference. The value (y-axis) shows the mean expression values of Sodl mRNA relative to Mock treatment after normalizing to Tbp and Hprtl reference levels at both treatment concentrations. FIG. 47 show's the effect of Purine rich used in ODV-siRNAs, as indicated in group (J) of FIG.37, on in vitro knockdown activity in PMH cells. Group J (Purine rich group) included 8 compounds each with a different 14-nt ACO sequence containing 9 purines (i.e., RD-13010, RD-13011, and RD-13012), 10 purines (he, RD-13013, RD-13014, and RD-13015), or 11 purines (i.e., RD-13016 and RD-13017) comprised of different amounts of adenosine and guanine. RD-12556 and RD-12559 served as duplex control and ODV control, respectively. FIG.47 shows the Sodl mRNA levels in PMH cells after free uptake treatments of ODV-siRNAs at 0.1 pM and 1 pM for 3 days. Mock was treated in absence of oligonucleotide and not shown. Sodl mRNA levels were quantified by RT-qPCR using gene specific primer sets. Tbp and Hprtl were amplified as internal reference. The value (y-axis) shows the mean expression values of Sodl mRNA relative to Mock treatment after normalizing to Tbp and Hprtl reference levels at both treatment concentrations. FIG. 48 shows the effect of Pyrimidine rich used in ODV-siRNAs, as indicated in group (K) of FIG.37, on in vitro knockdown activity in PMH cells. Group K (Pyrimidine rich group) included 8 compounds each with a different 14-nt ACO sequence containing 9 pyrimidines (i.e., RD-13018, RD-13019, and RD-13020), 10 pyrimidines (tc., RD-13021 and RD-13022), 1.1 pyrimidines {i.e.., RD-13023 and RD-13024), or 12 pyrimidines {i.e., RD-13025) comprised of different amounts of cytosine and uracil. FIG.48 show's the Sodl mRNA levels in PMH cells after free uptake treatments of ODV-siRNAs at 0.1 p.M and 1 p.M for .3 days. Mock was treated in absence of oligonucleotide and not shown. Sodl mRNA levels were quantified by RT-qPCR using gene specific primer sets. Tbp and Hprtl w'ere amplified as internal reference. The value (y-axis) shows the mean expression values of Sodl mRNA relative to Mock treatment after normalizing to Tbp and Hprtl reference levels at both treatment concentrations. FIG. 49 show's the effect of Balanced purpyr used in ODV-siRNAs, as indicated in group (L) of FIG.37, on in vitro knockdown activity in PMH cells. Group L (Balanced pur:pyr group) included 6 compounds {i.e., RD-13026, RD-13027, RD-13028, RD-13029, RD-13030, and RD-13031) each with a different 14-nt ACO sequence containing a fixed 1:1 ratio of purines to pyrimidines, respectively. FIG.49 shows the Sodl mRNA levels in PMH cells after free uptake treatments of ODV-siRNAs at 0.1 pM and 1 pM for 3 days. Mock was treated in absence of oligonucleotide and not shown. Sodl mRNA levels w'ere quantified by RT-qPCR using gene specific primer sets. Tbp and Hprtl were amplified as internal reference. The value (y-axis) show's the mean expression values of Sodl mRNA relative to Mock treatment after normalizing to Tbp and Hprtl reference levels at both treatment concentrations. FIG. 50A-50C show'the in vivo potency of ODV-siRNAs on knocking down Sodl mRNA levels in lung tissue via intratracheal instillation (ITD administration in adult C57BL / 6J mice. The indicated oligonucleotides (i.e., RD-12401, RD-12402, RD-12403, RD-12557, RD-12929 and RD-1.2559) were administered via. ITI at 0.6 mg dose in FIG. 50A. The indicated oligonucleotides (RD-12556, RD-12929 and RD-12559) were administered via IT I at 0.1 mg (FIG.50B) and 0.6 mg (FIG.50C) dose. Saline was administrated as a non-treated negative control. RD-12404 was a non-specific duplex used as negative control. Mice were sacrificed on day 7 and day 21 post-dosing and Sodl mRNA knockdown was quantified in lung tissue via RT-qPCR using gene specific primer sets after RNA isolation and RI' reaction. Tbp was amplified as an internal reference. Mean Sodl mRNA levels in lung tissue of 2-7 animals (n=2-7) are shown relative to mRNA levels in non-treated group after normalizing to Tbp. FIG. 51A-51B show the in vivo potency of ODV-siRNA on knocking dowm SOD1 mRNA. levels in muscle tissue via intravenous (IV) and subcutaneous (SC) injection in adult SOD.l(^iA mice. The indicated siRNA RD-12293 was administered via. IV and SC injection at 20 mg / kg and 50 mg / kg, respectively. Saline was injected as a non-treated negative control. Mice w7ere sacrificed at day 14 post-dosing and SOD I mRNA levels w7ere quantified in muscle and liver tissues via RT-qPCR using gene specific primer sets after RNA isolation and RT reaction. Tbp was amplified as an internal reference. Mean SOD1 mRNA levels in muscle tissue of 2-4 animals in 2 -i) are shown relative to mRNA levels in non-treated group after normalizing to Tbp. FIG. 52 shows in vivo potency of different ODV-siRNA leads on knocking down Sodl mRNA expression via IV injection in adult C57BL / 6J mice. The indicated ODV-siRNAs (i.e., RD-12559, RD-12556, RD-12967, RD-13180, RD-12941, RD-12942, RD-12952, RD-12982, RD-12983, RD-12979, RD-13015, RD-13006 and RD-12998) were administered via IV injection at 20 mg / kg. Saline was injected as a non-treated negative control. RD-12556 sewed as non-ODV duplex control. Mice were sacrificed at day 7 following treatment and Sodl mRNA levels were quantified in different types of muscle tissue (i.e., Forelimb, Hindlimb, Nape and Gluteus) via RT-qPCR using gene specific primer sets after RNA isolation and RT reaction. Tbp was amplified as an internal reference for RNA loading. Mean Sodl mRNA levels in muscle tissue of 3-6 animals (n:::3-6) are shown relative to mRNA levels in non-treated group after normalizing to Tbp. FIG. 53A-53C show7 in vivo potency of different ODV-siRNA leads on knocking down Sodl mRNA expression via ICV injection in adult C57BL / 6J mice. The indicated siRNAs or ODV-siRNAs (Le., RD-12559, RD-1.2556, RD-13334, RD-1.2967, RD-13180, RD-1.2941, RD-12942, RD-12952, RD-12982, RD-12983, RD-12979, RD-13015, RD-13006 and RD-12998) were administered via unilateral ICV injection. Saline was injected as a non-treated negative control. RD-12556 and RD-13334 served as non-ODV duplex, control. FIG.53A shows the Sodl mRNA transcript level in brain-frontal cortex, rest of brain (other than frontal cortex and cerebellum) and brain-cerebellum tissues at 0.2 mg. MGAIB shows the Sodl mRNA transcript level in spinal cord-cervical, spinal cord-thoracic and spinal cord-lumbar tissues at 0.2 mg. FIG.53C shows the Sodl. mRNA transcript level in liver tissue at 0.2 mg. Mice were sacrificed at day 7 following treatment and Sodl mRNA. knockdown was quantified in CNS (i.e., brain-frontal cortex, rest of brain, brain-cerebellum, spinal cord-cervical, spinal cord-thoracic and spinal cord-lumbar) and select peripheral tissues (i.e.. liver) via RT-qPCR.using gene specific primer sets after RNA isolation and RT reaction. Tbp was amplified as an internal reference. Mean Sodl mRNA levels from 3-6 animals (n=3-6) are shown in each of the indicated tissues relative to mRNA levels in non-treated group after normalizing to Tbp. FIG. 54A-54B show m vivo potency of different ODV-siRNA leads on. knocking down Sodl mRNA expression via IV injection in adult C57BL / 6J mice. The indicated siRNAs or ODV-siRNAs (be., RD-12559, RD-12556. RD-13334, RD-1.2967. RD-13180, RD-1.2941. RD- 12942, RD-12952, RD-1.2982, RD-12983, RD-12979, RD-13015, RD-13006 and RD-12998) were administered via IV injection at 20 mg / kg. Saline was injected as a non-treated negative control. RD-12556 and RD-13334 served as non-ODV duplex control. FIG.54A shows the Sodl mRNA transcript level in heart, liver and spleen tissues at 20 mg / kg. FIG.54B shows the Sodl mRNA transcript level in lung, kidney and bladder tissues at 20 mg / kg. Mice were sacrificed on day 7 following treatment and Sodl mRNA knockdown was quantified in select peripheral tissues (he., heart, liver, spleen, lung, kidney and bladder) viaRT-qPCRusing gene specific primer sets after RNA isolation and RT reaction. Tbp was amplified as an internal reference. Mean Sodl mRNA levels from 2~6 animals (0===2-6) are shown in each of the indicated tissues relative to mRNA levels in non-treated group after normalizing to Tbp. FIG. 55A-55D show dose-dependent characterization for internal conjugated ODV (iODV)-siRNA in PMH cells. The indicated siRNAs or ODV-siRNAs (i.e., RD-12559, RD-12556 and RD-13351) were transfected into PMH cells using RNAiMAX in dose escalated concentrations representing approximate multiples of IC50 values (FIG.55A and FIG.55B). The indicated siRNAs (i.e.. RD-12559, RD-13180 and RD-13351) were added into PMH cell culture medium in dose escalated concentrations representing approximate multiples of IC50 values (FIG.55C and FIG.55D). RD-12556 served as non-ODV duplex control. RD-12559 served as ODV-siRNA positive control. Mock treatments were transfected in absence of oligonucleotide (not shown). FIG.55A. and FIG.55C show Sodl mRNA levels and FIG.55B and FIG.55D show ceil viability quantified for each oligonucleotide at every dose by RT-qPCR and CCK8 assay respectively. FIG. 56 interprets some of the in vivo data of siSOD! with ACO variants in Example 28. T he mean average knockdown data (Mean % Reduction) in CNS tissues (brain and spinal cord, compared to liver) are listed in the table. ODV-siSODl variants that had. possible better and worse retention with regards to local and periphery tissues knockdown activity are exemplified. FIG. 57 shows the design of ACO sequence variants derived from the exemplary AC1. The variants include 15 sequences in which the siRNA, linker (L9), 2’MOE modification and PS backbone are fixed, but ACO sequence and length are modified relative to the AC1 sequence. The palindromes, deletions, purine / pyrimidine switches which may impact the delivery efficiency are exemplified. DETAILED D ESCRIPT ION While various embodiments of the invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from Lite invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed. Before the present invention described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lowzer limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the slated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the exemplary' methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. It is understood that the present disclosure supersedes any disclosure of an incorporated publication to the extent there is a contradiction. It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a sample" includes a plurality of such samples and reference to "the molecule" includes reference to one or more molecules and equivalents thereof known to those skilled in the art, and so forth. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed. DEFINITIONS The terms “Amyotrophic lateral sclerosis’'’ or AALS” include, but. are not limited to, familial AES (fALS), sporadic AES (sAES), Lou Gehrig's disease, diseases associated with mutant genes Chromosome 9 Open Reading Frame 72 gene (C9orf72: 40%), superoxide dismutase 1 (SODI; 20%), transactive response DNA-bitiding protein 43 (TDP43\ 4%) and fused in sarcoma / translocated in liposarcoma (FUS / rLS; 4%). The term "oligonucleotide agent" or “oligonucleotide” can be used interchangeably, and refers to polymers of nucleotides, and includes, but is not limited to, single-stranded or double-stranded nucleic acid molecules of DNA, RNA, or DNA / RNA hybrid, oligonucleotide strands containing regularly and irregularly alternating deoxyribosyl portions and ribosyl portions, as well as modified and naturally or unnaturally existing frameworks for such oligonucleotides. Specifically, the oligonucleotide agent for inhibiting mRNA transcript level of target gene described herein is a small inhibiting nucleic acid molecule (siRNA), an antisense oligonucleotide molecule (ASO), or an oligonucleotide delivery vehicle (ODV) conjugated siRNA molecule (siRNA-ACO). Also specifically, the oligonucleotide agent for activating transcription of target gene described herein is a small activating nucleic acid molecule (saRNA), or an oligonucleotide delivery vehicle (ODV) conjugated saRNA molecule (saRNA-ACO). As used herein, the terms “subject” and “individual” are used interchangeably herein to mean any living organism that may be treated with agents of the present application. The term “patient” means a human subject or individual, including disclosure infants, children and adults. A “therapeutically effective amount” of a composition is an amount sufficient to achieve a desired therapeutic effect, and therefore does not require cure or complete remission. In embodiments of the present application, therapeutic efficacy is an improvement in any of the disease indicators, and a. therapeutically effective amount is sufficient to cause an improvement in a clinically significant condition / symptom in the treated individual. The phrases “therapeutically effective amount” and “effective amount” are used herein to mean an amount sufficient to reduce by at least about 15 percent, preferably by at least 50 percent, more preferably by at least 90 percent, or to increase at least about 50 percent, at least about 100 percent, at least about 200 percent, more preferable at least about 500 percent and most preferably prevent, a clinically significant deficit in the activity, function and response of the individual being treated. The effective amount may vary depending on such factors as the size and weight of the subject, the type of illness, or the particular agents of the application. For example, the choice of the agent of the application could affect what constitutes an “effective amount.” One of ordinary skill in lite art would be able to study the factors contained herein and make the determination regarding the effective amount of the agents of the application without undue experimentation. The regime of administration may affect wrhat constitutes an effective amount. The agent of the application can be administered to the subject either prior to or after the disease diagnosis or condition. Further, several divided dosages, as well as staggered dosages, can be administered daily or sequentially, or the dose can be continuously infused, or can be a bolus injection. Further, the dosages of the agent(s) of the application could be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation. The terms “treat,” “treated,” “treating”, or “treatment” as used herein have the meanings commonly understood in the medical arts, and therefore do not require cure or complete remission, and include any beneficial or desired clinical results. Non-limiting examples of such beneficial or desired clinical results are prolonging survival as compared to expected survival without treatment, reduced symptoms including one or more of the followings: weakness and atrophy of proximal skeletal muscles, inability to sit or walk independently, difficulties in swallowing, breathing, etc. As used herein, “preventing” or “delaying” a disease refers to inhibiting the full development of a disease. The term “biological sample” refers to any tissue, cell, fluid, or other material derived from an organism (e.g., human subject). In certain embodiments, the biological sample is serum or blood. As used herein, the term "sequence identity" or "sequence homology" means that one oligonucleotide strand (sense or antisense) of, for example, an saRNA or siRNA has at least 80% similarity with a region on the coding strand or template strand of the promotor, or the sequence of a target gene. In embodiments of the present application, one target gene is SOD1. By "target sequence" is meant a sequence fragment to w'hich the sense strand or antisense oligonucleotide of the siRNA or saRNA is homologous or complementary'. For example, in certain embodiments, a SODI siRNA is homologous or complementary to a target select sequence within human SOD I transcript. As used herein, the term "non-targeting" means that the referenced accessory oligonucleotide (ACO) which conjugates with the targeting oligonucleotide (e.g., siRNA, saRNA, and etc.) does not specifically complement to the target sequence which the targeting oligonucleotide functions, and / or that the referenced oligonucleotide (i.e^ ACO) does not share the same target sequence which the targeting oligonucleotide (e.g.. siRNA, saRNA, and etc. ) specifically attends to function to. The targeting oligonucleotide disclosed herein is a nucleic acid sequence that specifically complements to the target sequence or the region thereof. In some embodiments, the term "non-targeting oligonucleotide" may comprise any referenced oligonucleotide except the “targeting sequence’’. In some case, the “■specifically complementary” may mean that the complementarity between the targeting oligonucleotide and the target sequence or the region thereof is at least about 95%. The non-targeting oligonucleotide (i.e., accessory oligonucleotide, or “ACO’’ used interchangeably) is not to elicit biological activity via any known mechanism, nor intended to elicit activities indicative of ASO (he., “mixmer” or “gapmer”) function onto a complementary nucleic acid sequence (%., mRNA) in a certain subject, an organ of the subject, a tissue of the subject, or a cell of the subject, when the oligonucleotide is administered. The non-targeting oligonucleotide (i.e., ACO) is to facilitate the introduction of the targeting oligonucleotide (e.g., siRNA, saRNA, and etc.) it conjugates into a certain subject, an organ of the subject, a tissue of the subject, a cell of the subject, or a cell nucleus of the subject, when the oligonucleotide conjugate is administered. As used herein, the term "gapmer" refers to a short DNA antisense oligonucleotide (ASO) structure with modified RNA segments on both sides of the central DNA structure. In some embodiments, at least one of the modified RNA segments comprises one or more of modified nucleotides selected from locked nucleic acids (LNA), and 2’-0Me or 2'-F modified nucleotides to increase affinity to the target, increase nuclease resistance, reduce immunogenicity, and / or decrease toxicity. In some embodiments, a gapmer comprises at least one nucleotide modified with a phosphorothioate (PS) group. In some embodiments, the gamper is designed to hybridize to a target piece of RNA and silence the gene transcript through the induction of RNase H cleavage. As an example, the ASO drug "Toferson" is a gapmer that knockdowns SODI mRNA for treatment of ALS. A possible example of a dualaction oligonucleotide (DAO) with a gapmer ASO disclosed in the present application, could be "siSODI-Toferson". As used herein, the term "mixmer" refers to an antisense oligonucleotide (ASO) characterized as a mixture of DNA and chemically modified nucleic acid analogs in structure. Optionally, a mixmer is composed of fully modified nucleotides or nucleic acid analogs. In some embodiments, a mixmer is designed to bind and mask complementary' RNA sequence to sterically block proteins, factors, or other RNAs from interacting with targeted RNA. In some embodiments, a. mixmers is designed to alter pre-mRNA splicing by displacing the spliceosome. In some embodiments, a mixmer is designed to bind and sequester microRNAs (miRN As) in which it is adopt yet another name called an "antagomir" or an "anti-miR". As used herein, the terms "sense strand" or “passenger strand" are interchangeable. The sense strand of dsRNA (e.g., siRN A, saRNA) molecule can include, for example, a first nucleic acid strand of siRNA comprising a fragment of the mRNA sequence of a target gene. As used herein, the terms "antisense strand" or "guide strand" are interchangeable. The antisense strand of an dsRNA molecule can include, for example, a second nucleic acid strand in a duplex of saRNA or siRNA that is complementary to the sense strand. As used herein, the term "first oligonucleotide strand" can be a sense strand or an antisense strand. For example, the sense strand of a saRNA refers to an oligonucleotide strand having homology with the coding strand of the promoter DNA sequence of the target gene of the saRNA. The sense strand of a siRNA refers to an oligonucleotide strand having homologv with the mRNA sequence of the target gene of the siRNA. The antisense strand refers to an oligonucleotide strand complementary with the sense strand in the dsRNA. As used herein, the term "second oligonucleotide strand" can also be a sense strand or an antisense strand. If the first oligonucleotide strand is a sense strand, the second oligonucleotide strand is an antisense strand; and if the first oligonucleotide strand is an antisense strand, the second oligonucleotide strand is a sense strand. The term "promoter" as used herein refers to a nucleic acid sequence, which encodes no proteins and plays a regulatory role for the transcription of a protein-coding or RNA-coding nucleic acid sequence by associating with them spatially. Generally, a eukaryotic promoter contains 100 to 5,000 base pairs, although this length range is not intended to limit the term of "promoter" as used herein. Despite that the promoter sequence is generally located at the 5' terminus of a protein-coding or RNA-coding sequence, it also exists in exon and intron sequences. As used herein, the term "coding strand" refers to the DNA strand in the target gene that cannot be transcribed, the nucleotide sequence of which is identical to the sequence of the RNA produced by transcription (in RNA the T in DNA is replaced by U). The coding strand of the double-stranded DNA sequence of the target gene promoter described in the present disclosure refers to the promoter sequence on the same DNA strand as the DNA coding strand of the target, gene. As used herein, the term "template strand" refers to another strand of double-stranded DNA of a target gene that, is complementary to the coding strand and that can be transcribed as a template into RNA that is complementary to the transcribed RNA base (A-U, G-C). During transcription, RNA polymerase binds to the template strand and moves along the 3 > 5' direction of the template strand, catalyzing RNA synthesis in the 5'—> 3' direction. The template strand of the double-stranded DNA sequence of the target gene promoter described in the present disclosure refers to the promoter sequence on the same DNA strand as the DNA template strand of the target gene. As used herein, the term "transcription start site" or TSS refers to a nucleotide that marks the initiation of transcription on the template strand of a gene. The transcription start, site may be present on the template strand of the promoter region. A gene may have more than one transcription start site. As used herein, the term "overhang" refers to an oligonucleotide strand end (5‘ or 3 ') with non-base paired nucleotide(s) resulting from another strand extending beyond one of the strands within the double stranded oligonucleotide. Single stranded regions extending beyond the 3 'and / or 5' ends of the duplexes are referred to as overhangs. In certain embodiments, the overhang is from 0 to 6 nucleotides in length. It is understood that an overhang of 0 nucleotides means that there is no overhang. As used herein, the terms "gene activation", "activating gene expression", "'gene upregulation” and "'upreguiating gene expression’' can be used interchangeably, and means an increase or upregulation in transcription, translation, expression or activity of a certain nucleic acid sequence as determined by measuring the transcription level, mRNA level, protein level, enzymatic activity, methylation state, chromatin state or configuration, translation level or the activity' or state in a cell or biological system of a gene. These activities or states can be determined directly or indirectly. In addition, "gene activation" or "activating gene expression" refers to an increase in activity associated with a nucleic acid sequence, regardless the mechanism of such activation. For example, gene activation occurs at the transcriptional level to increase transcription into RNA and the RNA is translated into a protein, thereby increasing the expression of the protein. As used herein, the terms "gene silencing", "knockdown of gene expressi on", “gene downregulation” and “downregulating gene expression” can be used interchangeably, and means a decrease or downregulation in transcription, translation, expression or activity of a certain nucleic acid sequence as determined by measuring the transcription level, mRNA level, protein level, enzymatic activity, methylation state, chromatin state or configuration, translation level or the activity or state in a cell or biological system of a gene. These activities or states can be determined directly or indirectly. In addition, "gene down regulation" or "downregulating gene expression" refers to a decrease in activity associated with a nucleic acid sequence, regardless the mechanism of such downregulation. For example, gene downregulation occurs at the transcriptional level to decrease or silence transcription into RNA and the RNA is not translated into a protein, thereby decreasing or silencing the expression of the protein. As used herein, the terms "short, interfering RNA", "siRNA" and “silencing RNA” can be used interchangeably and refer to a ribonucleic acid molecule that can downregulate, knockdown, or silence target gene expression. It can be a double-stranded nucleic acid molecule. It interferes with the expression of specific genes with complementary nucleotide sequences by degrading mRNA after transcription, preventing translation. siRNA binds to target mRNA mainly in the cytoplasm to down-regulate gene expression post-transcriptionally via the RNA interference (RNAi) mechanism. siRNAs may be designed to target a gene’s mRNA sequence to silence its expression via the RNAi mechanism, such as SOD], for maximizing treatment outcomes, e.g., for ALS patients. siRNAs are molecules having endogenous RNA bases or chemically modified nucleotides. The modifications do not abolish cellular activity, but rather impart increased stability and / or increased cellular potency. Examples of chemical modifications include phosphorothioate groups, 2'-deoxynucleotide, 2AdCH3-contaming ribonucleotides, 2'-F-ribonucleotides, 2'-methoxyethyl ribonucleotides, combinations thereof and the like. The siRNA can have varying lengths (e.g., 10-200 bps) and structures (e.g., hairpins, single / double strands, bulges, nicks / gaps, mismatches) and are processed in cells to provide active gene silencing. A double-stranded siRN A can have the same number of nucleotides on each strand (blunt ends) or asymmetric ends (overhangs). An overhang of 1-2 nucleotides, for example, can be present, on the sense and / or the antisense strand, as well as present on the 5'- and / or the 3'-ends of a given strand. The length of the siRNA molecule is typically about 10 to about 60, about 10 to about 50, about 15 to about 30, about 17 to about 29, about 18 to about 28, about. 19 to about 27, about 20 to about 26, about 21 to about 25, and about 2.2 to about 24 base pairs, and typically about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 23, about 25, about 30, about 40, or about 50 base pairs. In addition, the terms "small interfering RNA", “silencing RNA” and “siRNA" also contain nucleic acids other than the ribonucleotide, including, but not limited to, modified nucleotides or analogues. As used herein, the terms “inhibition of gene expression “ or “inhibiting gene expression” and “gene downregulation” or “down-regulating gene expression” can be used interchangeably, and mean an decrease in transcription, translation, expression or activity of a certain nucleic acid as determined by measuring the transcriptional level, mRNA level, protein level, enzymatic activity, methylation state, chromatin state or configuration, translation level or the activity or state in a cell or biological system of a gene. These activities or states can be determined directly or indirectly. In addition, “inhibition of gene expression “, “inhibiting gene expression”, “gene down-regulation” or “dowm-regulating gene expression” refers to a decrease in activity associated with a nucleic acid sequence, regardless of the mechanism of such activation. For example, inhibition of gene expression occurs at the transcriptional level to decrease transcription into RNA and the RNA is translated into a protein, thereby decreasing the expression of the protein. As used herein, the terms "small activating RNA", "saRNA" and "small activating ribonucleic acid" can be used interchangeably and refer to a ribonucleic acid molecule that can upregulate target gene expression. It can be a double-stranded nucleic acid molecule composed of a first nucleic acid strand containing a ribonucleotide sequence with sequence homology with the non-coding nucleic acid sequence (such as a promoter and an enhancer) of a target gene and a second nucleic acid strand containing a nucleotide sequence complementary with the first strand. The saRNA can also be comprised of a synthesized or vector-expressed single-stranded RNA molecule that prone to form a hairpin structure by two complementary regions within the molecule, wherein the first region contains a ribonucleotide sequence having sequence homology with the target sequence of a promoter of a gene, and a ribonucleotide sequence contained in the second region is complementary with the first region. The length of the duplex region of the saRNA molecule is typically about 10 to about 60, about 10 to about 50, about 10 to about 40, about 12 to about 30, about 14 to about 28, about 16 to about 2.6, about 18 to about 24, and about 20 to about 22 base pairs, and typically about 10, about 13, about 15, about 17, about 18, about 19, about 20, about 21, about 22, about 25, about. 30, about 40, about 50, or about 60 base pairs. In addition, the terms "small activating RNA", "saRNA" and "small activating ribonucleic acid" also contain nucleic acids other than the ribonucleotide, including, but not limited to, modified nucleotides or analogues. As used herein, the term “ASO” and “antisense oligonucleotide” can be used interchangeably and refer to single-stranded oligonucleotides which binds to complementary' mRNA to elicit RNase H-dependent knockdown or the mRNA or alter protein binding of the mRNA via steric hindrance. As used herein, the term "hotspot" of siRNAs or ASOs refers to a nucleic acid region of at least 12 bp in length where functional siRNAs / ASOs are enriched, i.e., at least 80%, e.g., about 85%, about 90%, about 95% or about 100% of the siRNAs / ASOs designed to target this region is functional and potent of inhibiting in the mRNA transcript level of the target gene. A “hotspot” herein is defined by a nucleic acid region on the target, sequence of the siRNAs / ASOs, where the 5'-ends of the functional siRNAs or ASOs are located. In a nonlimiting example, a siRNA / ASO is designed according to the following criteria: (1) having a GC content between 35% and 70%, (2) with less than 5 consecutive identical nucleotides, (3) with 3 or less dinucleotide repeats; and (4) with 3 or less trinucleotide repeats. In a nonlimiting example, each of the hotspot sequences disclosed herein comprises at least 4, at least 5, or at least 6 (5’-ends of) functional siRNAs or ASOs. As used herein, the term “functional siRNA” refers to a siRNA, at a 1 rMtreatment concentration free uptake by a cel I, inhibiting the mRNA transcript, level of its intended target gene by at least 80%, as compared to a baseline level of SOD1 mRNA. The term “nonfunctional siRNA” refers to a siRN A, at a 1 nM treatment concentration free uptake by a cell, not capable of inhibiting the mRNA. transcript level by 80%, as compared to a. baseline level of SOD1 mRNA. As used herein, the term “functional ASO” refers to an ASO, at a 200 nM treatment, concentration free uptake by a cell, inhibiting the mRNA transcript level of its intended target gene by at least 60%, as compared to a baseline level of SOD] mRNA. The term “nonfunctional siRNA” refers to an ASO, at a 200 nM treatment concentration free uptake by a cell, not capable of inhibiting the mRNA transcript level by 60%, as compared to a baseline level of SOD] mRNA. As used herein, the term “isolated target site”, “target site” and “isolated polynucleotide" can be used interchangeably, and herein means a nucleic acid target site to which a siRNA has complementarity or hybridizes to. For example, an isolated nucleic acid sequence of a target site can include a nucleic acid sequence to which a region of siRNAs has complementarity or hybridize to. As used herein, the term “complementary” refers to the capability of forming base pairs between two oligonucleotide strands. The base pairs are generally formed through hydrogen bonds between nucleotides in the antiparallel oligonucleotide strands. T he bases of the complementary oligonucleotide strands can be paired in the Watson-Crick manner (such as A to T, A to U, and C to G) or in any other manner allowing the formation of a duplex (such as Hoogsteen or reverse Hoogsteen base pairing). Complementarity includes complete complementarity and incomplete complementarity. “Complete complementarity” or “100% complementarity” means that each nucleotide from the first oligonucleotide strand can form a hydrogen bond with a nucleotide at a corresponding position in the second oligonucleotide strand in the double-stranded region of the siRNA molecule, with no base pair being “mispaired”. “Incomplete complementarity”, “partial complementarity”, or “mismatch” means that not all the nucleotide units of the two strands are bound with each other by hydrogen bonds. For example, for two oligonucleotide strands each of 20 nucleotides in length in the double-stranded region, if only two base pairs in this double-stranded region can be formed through hydrogen bonds, the oligonucleotide strands have a complementarity of 10%. In the same example, if 18 base pairs in this doublestranded region can be formed through hydrogen bonds, the oligonucleotide strands have a complementarity of 90%. Substantial complementarity refers to at least about 75%, about 79%, about 80%, about 85%, about 90%, about 95% or 99% complementarity. As used herein, “3' untranslated region” and “3' UTR” can be used interchangeably, referring to a fragment in 3’ region of a messenger RNA (mRNA) to regulate mRNA-based processes, such as mRN A localization, mRNA stability, and translation. In addition, 3’ UTR may establish 3' UTR-mediated protein-protein interactions (PPIs), and thus can transmit genetic information encoded in 3’ UTR to protein. As used herein, “ODA”’ and “oligonucleotide delivery vehicle” are used interchangeably, which refer to an oligonucleotide molecule comprising a duplex or double-stranded RN A (e.g., siRNA or saRNA) and an ACO which is covalently linked to the duplex RNA via a linker as described in more detail below'. As used herein, “covalent linker”, “linker” and “linking component" are used interchangeably, which refer to a molecule for covalently joining two molecules, e.g., a single-stranded oligonucleotide (e.g. ACO) and a dsRNA (e.g. siRNA or saRNA), two dsRNAs, etc. As described in more detail below, the term can include, e.g., a nucleic acid linker, a peptide linker, and the like and also, includes disulfide linkers. As used herein, the term "synthetic" refers to the manner in which oligonucleotides are synthesized, including any means capable of synthesizing or chemically modifying RNA, such as chemical synthesis, in vitro transcription, vector expression, and the like. As used herein, the term ' LXA" refers to a locked nucleic acid in which the 2’-oxygen and 4’ -carbon atoms are joined by an extra bridge. As used herein, the term “BNA” refers to a 2'-0 and d'-aminoethylene bridged nucleic acid that can contain a five-membered or sixmembered bridged structure with an N-0 linkage. As used herein, the term ‘TN A” refers to a nucleic acid mimic with a pseudopeptide backbone composed of N-(2-aminoethyl) glycine units with the nudeobases attached to the glycine nitrogen via carbonyl methylene linkers. As used herein, the upper cased “SODl” or “SOD / gene” refers to a gene. As used herein, the term '‘SODI mRNA” refers to a message RNA (mRNA) generated from die expression of SODl gene, or the transcription of SODl gene. As used herein, the terms “SODl protein” refers to a protein generated from the expression of SOD1 gene, or translation of the SODl mRN A. Unless otherwise defined, all the technological and scientific terms used therein have the same meanings as those generally understood by those of ordinary skill in the art covering the present application. Overview Aspects of the present application include an oligonucleotide agent comprising oligonucleotide-based delivery vehicle (ODV) to provide improvements in efficient targeting one or more genes associated with a disease or condition, and improvements in the deliver}', chemistry, biodistribution, bioavailability, and other pharmacological properties without compromising oligonucleotide activity. The present application is based on investigations related to compositions and methods that, a targeting oligonucleotide (siRNA, saRNA, etc.), in combination with an ACO, can activate / upregulate a gene expression and increase the amount of expression of full-length gene or protein, or knockout / silence a gene expression and decrease the amount of expression of full-length gene or protein, in order to improve therapeutic effects for genetic conditions. The term “oligonucleotide-delivery vehicle (ODV)” refers to a structure by conjugating an “accessory oligonucleotide (ACO)” to a chemical entity or moiety, e.g., a duplex oligonucleotide, to facilitate the introduction of the molecule into or uptake by a cell, a tissue, or an organ of an individual. The present inventors found that the ODV did not interfere with siRNA knockdown activity (Example 3) and saRNA-induced gene activation (Example 5). The present inventors also found that the length, nucleotide compositions, modifications (e.g., 2'-0me), linking components, palindromes of the sequence, numbers of phosphorothioate (PS) backbone substitution of the ACO had effects on dsRNA activity in vivo. When administered in either brain or spinal cord tissue as compared to a dsRNA without an ODV, ODV-dsRNA shows an improved in vivo activity in the CNS via. local injection. Additional aspects of the present application include methods of treating Amyotrophic lateral sclerosis (ALS) by administering an effective amount of an oligonucleotide agent comprising a SODl -targeting siRNA. The siRNA inhibits the expression of SODl gene through the RNAi silencing mechanism. The present inventors have developed SOD I siRN As with potent inhibitoty effect, for use in the treatment of ALS. Amyotrophic lateral sclerosis (ALS), also referred to as Lou Gehrig's disease, is an adultonset, lethal, paralytic disorder caused by the degeneration of motor neurons. ALS is characterized by progressive, adult-onset degeneration of cranial, brainstem, and spinal motor neurons, leading to death by respiratory failure within 3-5 years of diagnosis. ALS presents as a familial or a sporadic form, depending on whether or not there is a family history of the disease, with sporadic ALS (sALS) accounts for 90% of the ALS patients. The most common mutant genes account for ~75% of ALS in the United States: Chromosome 9 Open Reading Frame 72 gene (C9orf72; 40%), superoxide dismutase 1 (SODI; 20%), transactive response DNA-binding protein 43 (TDP43; 4%) and fused in sarcoma / translocated in liposarcoma (FUS / I’LS; 4%). Mutations in the C9orf72 and SODI genes also account for ~5-8% and ~2-3% of apparently sALS, respectively. To date, most of the studies of gene silencing have been undertaken in the context of the SODI gene models; the high copy number SODJ^^ transgenic mouse model is still a cornerstone of ALS research. Up to now, only two disease-modifying agents, Riluzole and Edaravone, are approved by U.S. Food and Drug Administration (FDA) for ALS treatment. Riluzole inhibits glutamate release from presynaptic terminals and blocks the post-synaptic N-methyl-D-aspartate (NMDA) receptors, which have been shown to increase survival by three to six months on average. Edaravone is a free radical scavenger that lowers the neuronal damage, eliminating the lipid peroxide hydroxyl radicals and transfers the electrons to edaravone (the radical) to ameliorate the oxidative damage. The two drugs only modestly improve survival and disease progression and canh cure the ALS. To date, there is currently no effective therapy available for ALS and new therapies are needed to treat this disease. Among the known genes underlining ALS, SOD I gene still remains a major cause of fALS and has been considered to be an important ALS drug target. The human SODI gene is located on chromosome 21q22.11 and located from base pair 33,031,935 to base pair 33,041,241 with a genomic size of 9307 bp. SODI gene codes for the monomeric SOD1 protein (153 amino acids, molecular weight 16 kDa), and also encodes for the detoxifying copper / zinc binding SOD1 enzyme, which has been found to be localized mainly in the cytosol, as well as in the nucleus, peroxisomes, and mitochondria (Tafuri et al. 2015). The first description of the ALS disease dates back to at least 1824 by Charles Bell, however, SODI as the first risk gene of ALS was discovered in 1993. When the first SODI transgenic mouse model (SODI was established in 1994, indicating that the research on ALS entered a new era. All these lines of evidence indicate that SODI mutants cause disease most probably via a gain-of-function, and reducing its levels may be beneficial. The excessive oxidation of wild-type SODI induces toxic conformational changes SODI silencing significantly attenuated astrocyte-mediated toxicity towards motor neurons. Therefore, silencing SODI expression is an important strategy for the treatment of ALS. OHgmmDeotids Agents Aspects of the present application include an oligonucleotide agent that includes a singlestranded oligonucleotide (e.g., ACO) having at least 6 nucleotides in length and a targeting double-strand oligonucleotide that are covalently finked, wherein the single-stranded oligonucleotide is a non-targeting oligonucleotide. Aspects of the present application include an oligonucleotide agent that includes a singlestranded oligonucleotide (e.g., ACO) having at least 6 nucleotides in length and a targeting double-strand oligonucleotide that are covalently finked, wherein at least one phosphodiester bond between two adjacent nucleotides in the single-stranded oligonucleotide sequence is substituted by a phosph orothioate (PS), mesyl phosphorami date or boranophosphate bond. Aspects of the present application include an oligonucleotide agent that includes a singlestranded oligonucleotide having at least 6 nucleotides in length and a targeting double-strand oligonucleotide that are covalently linked, wherein the single stranded-oligonucleotide comprises a palindrome sequence. Aspects of' the present application include an oligonucleotide agent that includes a singlestranded oligonucleotide having at least 6 nucleotides in length and a targeting double-strand oligonucleotide that are covalently Linked, wherein at least about 14%, at least about 28%, at least about 42%, at least about 57%, at least about 71%, at least about 85%, at least about 92%, or about 100% of the nucleotides of the single-stranded oligonucleotide have a 2 ’-Ome modification. Aspects of the present application include an oligonucleotide agent that includes a singlestranded oligonucleotide having at least 6 nucleotides in length and a targeting double-strand oligonucleotide that are covalently linked, wherein the single-stranded oligonucleotide comprises no more than 72% or no more than 64% of cytosines. Aspects of the present application include an oligonucleotide agent that includes a singlestranded oligonucleotide having 6-22 nucleotides in length and a targeting double-strand oligonucleotide that are covalently linked, wherein the single-stranded oligonucleotide is capable of facilitating delivery of the double-stranded oligonucleotide in the central nervous system (CNS). In some embodiments, the oligonucleotide agent comprises a double-stranded oligonucleotide, wherein the double-stranded oligonucleotide comprises a sense strand and an antisense strand, wherein the antisense strand has complementarity to a target nucleic acid; and a non-targeting single-stranded oligonucleotide, wherein the single-stranded oligonucleotide is 6-22 nucleotides in length. The double stranded oligonucleotide and the single-stranded oligonucleotide are covalently linked, with or without one or more linking components, to form the oligonucleotide agent. In some embodiments, the sense strand of the double stranded targeting oligonucleotide is covalently linked to anon-targeting single-stranded oligonucleotide (NTO). In some embodiments, the antisense strand of the double stranded targeting oligonucleotide is covalently linked to the non-targeting single-stranded oligonucleotide. In certain embodiments, the NTO does not have complementarity to the target nucleic acid of the double stranded oligonucleotide. In certain embodiments, the NTO does not have complementarity to the target gene or target mRNA transcript of the double stranded oligonucleotide. In certain embodiments, the NTO does not have complementarity to a nucleic acid of a subject possessing the target nucleic acid. In some embodiments, the target nucleic acid is a mammalian nucleic acid, e.g., from human. In some embodiments, the oligonucleotide agent has a compound formula of: o: -------- i ----------- o, (Formula la) or o, — t-------------o. (Formula lb), wherein: Oi is a double -stranded oligonucleotide comprising a sense strand and an antisense strand, wherein the antisense strand has complementarity to a target nucleic acid (e.g., mammalian target nucleic acid); Ch is a non-targeting single-stranded oligonucleotide. In some embodiments, the single-stranded oligonucleotide is at least 6 nucleotides in length. L is a Linker for covalently linking the double stranded oligonucleotide and the single-stranded oligonucleotide. In some embodiments, the oligonucleotide agent has a compound formula of: CX---Q ---L---Q2--Qy Cz           (Formula H), wherein Ch is a double stranded oligonucleotide comprising a sense strand and an antisense strand, wherein the antisense strand has complementarity to a target nucleic acid; O? is a nontargeting single-stranded oligonucleotide. In some embodiments, the single-stranded oligonucleotide is 6-22 nucleotides in length; L is a linker for covalently linking the double stranded oligonucleotide and the single-stranded oligonucleotide; and optional components Cx, Cy, and Cz, wherein Cx, Cy, and Cz are independently absence, or conjugation groups selected from one or more of a lipid, a fatty acid, a fluorophore, a ligand, a saccharide, a peptide, an antibody and any other commonly used conjugation groups. In. some embodiments, the compound of Formula II comprises 1 conjugation group. In some embodiments, the compound of Formula II comprises 2 conjugation groups. In some embodiments, the compound of Formula II comprises 3 conjugation groups. In some embodiments, the double-stranded oligonucleotide is a siRNA. In some embodiments, the double-stranded oligonucleotide is a saRNA. In some embodiments, the 5' end, the 3’ end, or an internal nucleotide of the single-stranded oligonucleotide is conjugated to a linking component. In some embodiments, the internal nucleotide in the sense or antisense strand of the double-stranded oligonucleotide is substituted by a linking component, wherein the single-stranded oligonucleotide is covalently conjugated with the linking component. In some embodiments, the single-stranded oligonucleotide is covalently conjugated to the sense strand, the antisense strand, or both the sense and anti sense strands of the second oligonucleoti de by a linking component. In some embodiments, the single-stranded oligonucleotide is covalently conjugated to the 3’ end, or the 5: end, or both the 3’ and 5' ends, or an internal nucleotide of the sense strand of the double-stranded oligonucleotide, as depicted in Figure 1 A, IB or IC. In some embodiments, the single-stranded oligonucleotide is covalently conjugated to the 3’ end, or the 5' end, or both the 3’ and 5’ ends, or an internal nucleotide of the antisense strand of the double-stranded oligonucleotide. In some embodiments, the double stranded targeting oligonucleotides and the single-stranded oligonucleotide that are covalently linked have a total nucleotide length ranging from 10 nucleotides to 500 nucleotides (e.g., 10 nucleotides to 100 nucleotides, 50 nucleotides to 100 nucleotides, 50 nucleotides to 200 nucleotides, 20 nucleotides to 100 nucleotides, 20 nucleotides to 200 nucleotides, 2.0 nucleotides to 300 nucleotides, 50 nucleotides to 300 nucleotides, 20 nucleotides to 80 nucleotides, 100 nucleotides to 300 nucleotides, 300 nucleotides to 500 nucleotides). Accessory oligonucleotides (ACO) Although some prior research proved that siRNAs capable of inhibiting SOD1 mRNA and decreasing SOD I protein expression can be used to treat SOD1 protein-related diseases, e.g.. for amyotrophic lateral sclerosis (ALS) patients, the inventors found there are two unsolved issues: 1) a lack of potency of SOD1 siRNA molecules and 2) a lack of efficient delivery' method to deliver the siRNA molecule to cells of a target organ or tissue. Surprisingly, the current invention found, when the dsRNA agent, e.g. an siRNA, is conjugated to a non-targeting single-stranded accessory oligonucleotide (ACO) as disclosed, bioavailability, biodistribution, and / or cellular uptake and m vivo potency of the dsRNA was significantly improved as compared to an oligonucleotide agent without the ACO. Especially in some in vivo examples in the present application, the ACO of the oligonucleotide agent increased the biodistribution of dsRNA within one, or two, or more target tissues as compared to an oligonucleotide agent without the ACO. “Delivering into a cell,’’ when referring to a targeting double-strand oligonucleotide, e.g., a double-stranded RNA agent (dsRNA) such as a siRNA, a saRNA, or the like, means efficient uptake or absorption by the cell, as is understood by those skilled in the an. Absorption or uptake of an dsRNA can occur through unaided diffusive or active cellular processes, or by auxiliary agents or devices. The meaning of this term is not limited to cells in vitro'. an dsRNA can also be “introduced into a cell,” wherein the cell is part of a living organism. In such an instance, introduction into the cell will include the delivery to the organism. For example, for in vivo delivery', dsRNA can be injected into a tissue site or administered systemically. In vitro introduction into a cell includes methods known in the art such as electroporation, free uptake, and lipofection. Further approaches are described herein below which is not known in the art. The ACO of the oligonucleotide agent is a single-stranded oligonucleotide that is in favor of the oligonucleotide agent by its delivery properties. Therefore, the ACO does not target a nucleic acid in a subject which the dsRNA is targeting, or a “natural”' nucleic acid from the subject, such as a target nucleic acid of the dsRNA. In some embodiments, the ACO does not target a nucleic acid in a subject which the dsRNA is targeting. In some embodiments, the ACO does not have complementarity wdth a nucleic acid which the dsRNA is targeting. In some embodiments, the ACO does not have complementarity with a gene sequence or its mRNA transcript which the dsRN is targeting. In some embodiments, the length of the ACO comprises a nucleotide length ranging from 6 to 22 nucleotides, such as 6 nucleotides or more, 7 nucleotides or more, 8 nucleotides or more, 9 nucleotides or more, 10 nucleotides or more, 11 nucleotides or more, 12 nucleotides or more, 13 nucleotides or more, 14 nucleotides or more,15 nucleotides or more,16 nucleotides or more, 17 nucleotides or more, 18 nucleotides or more, 19 nucleotides or more, 20 nucleotides or more, 21 nucleotides or more, 22 nucleotides or more. In some embodiments, the length of the ACO is 6 to 18 contiguous oligonucleotides. In some embodiments, the length of the ACO is 10-14 nucleotides in length. In some embodiments, the length of the ACO can modulate the activity and / or biodistribution of the oligonucleotide agent within the target tissue or cell of interest. For example, the present inventors found that shorter ACOs demonstrated activity of the oligonucleotide agent throughout the central nervous system, while longer ACOs demonstrated activity of the oligonucleotide agent only in particular regions of the brain, such as the cerebellum. In some embodiments, activity of the oligonucleotide agent throughout the entire central nervous system is desired. In some embodiments, activity of the oligonucleotide agent in particular regions of the brain is desired. The ACO may comprise a sequence that is modified in order to further increase the capacity of the oligonucleotide agent to deliver a second oligonucleotide. In some embodiments, the sequence of the ACO comprises one or more of a chemically modified nucleotide, or at least one phosphodi ester bond between two adjacent nucleotides in the oligonucleotide sequence is substituted by a phosphorothioate or boranophosphate bond. The chemical modifications of the ACC) includes, without, limitation, modification of the 2 -ON of the ribose in the nucleotide, the modification or the absence of a base in the nucleotide, the locking or bridging of a nucleic acid, a nucleotide being a peptide nucleic acid, a nucleotide being a deoxy ribonucleotide (DNA), a nucleotide having a 5'-phosophate moiety, a nucleotide having a 5XE)-viny1phosphonate moiety, a nucleotide having a 5'-methy1 cytosine moiety, etc. Chemical modifications that may be found in ACOs are also further described below. The ACO may comprise at least one phosphodiester bond substituted with phosphorothioate (PS) bond on the backbone of the nucleotide sequence. In some embodiments, the ACO comprises multiple PS backbone modifications, e.g., at least 2 PS, at least 3 PS, at least 4 PS, at least 5 PS, at. least 6 PS, or greater than 6 PS backbone modifications. In some embodiments, the ACO comprises at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at. least 60%, at least 70%, at least 80%, at. least 90%, at least 95%, or 100% phosphodiester bond substituted with phosphorothioate (PS) bond on the backbone of the nucleotide sequence. As a non-limiting example, a 14 nt ACO may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 PS backbone modifications. In some embodiments, the ACO having N nucleotides in length comprises N~1 PS modifications. The ACO may also has a specific composition of nucleotides. In some embodiments, the ACO may have a certain percentage of adenines within the nucleotide sequence of the ACO. The ACO may have any percent composition of adenines. Percent compositions of adenines that find use in the present disclosure include without limitation, 30-35%, 35-40%, 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, greater than 70%, etc. In a preferred embodiment, the percent, composition of adenines is from about 35% to about 65%. In some embodiments, the ACO may have a certain percentage of cytosines within the nucleotide sequence of the ACO. The ACO may have any percent composition of cytosines. Percent compositions of cytosines that find use in the present disclosure include without limitation, 30-35%, 35-40%, 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, 75-80%, greater than 80%, etc. In a preferred embodiment, the percent composition of cytosines is from about 35% to about 72%. In some embodiments, the ACO may ha ve a certain percentage of guanosines within the nucleotide sequence of the ACO. The ACO may have any percent composition of guanosines. Percent compositions of guanosines that find use in the present disclosure include without limitation, 30-35%, 35-40%, 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, greater than 70%, etc. In a preferred embodiment, the percent composition of guanosines is from about 35% to about 65%. In some embodiments, the ACO may have a certain percentage of uracil within the nucleotide sequence of the ACO. The ACO may have any percent composition of uracil. Percent compositions of uracil that find use in the present disclosure include without, limitation, 3035%, 35-40%, 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, 75-80%, greater than 80%, etc. In a preferred embodiment, the percent composition of uracil is from about 35% to about 72%. In some embodiments, the ACO may have a certain percentage of purines within the nucleotide sequence of the ACO. The ACO may have any percent, composition of purines. Percent compositions of purines that find use in the present disclosure include without limitation, 35-40%, 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, 75-80%, greater than 80%, etc. In. a preferred embodiment, the percent composition of purines is from about 65% to about 72%. In some embodiments, the AGO may have a certain percentage of pyrimidines within the nucleotide sequence of the ACO. The ACO may have any percent composition of pyrimidines. Percent compositions of pyrimidines that find use in the present di sclosure include without limitation, 35-40%, 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, 75-86%, greater than 80%, etc. In a preferred embodiment, the percent composition of pyrimidines is from about 42% to about 58%. In some embodiments, the AGO may have a specific combination of purines and pyrimidines. The specific combination of purines and pyrimidines may be any combination desired. Specific combinations of purines and pyrimidines that find use in the present disclosure include without limitation, about 30% purines about 70% pyrimidines, about 40% purines about 60% pyrimidines, about 50% purines about 50¾ pyrimidines, about 60% purines about 40% pyrimidines, about 70% purines about 30% pyrimidines, etc. In a preferred embodiment, the specific combination of purines and pyrimidines is about 42% purines and about 58% pyrimidines. In some embodiments, the nucleotide sequence of the single-stranded oligonucleotide comprises at least 40%, at least 50%, at least 60%, or at least 70% of the nucleotides have 2’-Ome modification. In some embodiments, 70-100% of the nucleotide in ACO have 2'-0me modification. In some embodiments, the nucleotide sequence of the single-stranded oligonucleotide is a palindrome sequence. The term “palindromic sequence” used herein means a nucleic acid sequence in a double-stranded D'NA or RNA molecule whereby reading in a certain direction (e.g., 5' to 3') on one strand is identical to the sequence in the same direction (e g., 5' to 3') on the complementary strand. In some embodiments, the single-stranded oligonucleotide with a palindromic sequence enhances activity the double-stranded oligonucleotide or delivery of the oligonucleotide agent. In some embodiments, palindrome ACOs enhanced the protein binding capacity and knockdown activity of ODV-siRNAs on Sod I mRNA. In some embodiments, the single-stranded oligonucleotide with palindrome sequence is selected from the group of SEQ ID NOs: 1300-1314. Therefore, aspects of the present application further relate to an oligonucleotide agent capable of inhibiting the expression of superoxide dismutase 1 (SOD1) comprising a small interfering RNA (siRNA), and an ACO. In some embodiments, the oligonucleotide agent comprising one or more conjugated ACOs to enhance the biodistribution of the oligonucleotide agent in particular tissues of the oligonucleotide agent, and increase permeability of the oligonucleotide agent and passage through membranes, such as the blood brain barrier. In some embodiments, the ACO is an oligonucleotide comprising a 5’ end and a 3: end. In some embodiments, the dsRNA and the ACO are covalently linked, with or without one or more linking components, to form the oligonucleotide agent. In another aspect of the present application, an oligonucleotide agent comprising a siRN A and a non-targeting ACO is provided. The ACO comprises a single-stranded oligonucleotide sequence comprising a nucleotide sequence that is at least 60% homology (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%), at least 97%, at least 99% homology or 100 % identical) to the nucleotide sequence selected from SEQ ID NOs: 953-954. In some embodiments, wherein the ACO comprises a nucleotide sequence that is at least 90%) identical to the nucleotide sequence selected from SEQ ID NOs: 953-954. In some embodiments, the oligonucleotide agent comprises a single-stranded oligonucleotide (ACO) tethered to a dsRNA. In some embodiments, the dsRNA is a natural nucleic acid. In some embodiments, the natural nucleic acid is a target nucleic acid. In certain embodiments, the natural nucleic acid is an intracellular nucleic acid. In some embodiments, the ACO is anon-targeting oligonucleotide (NTO). In some embodiments, the ACO is a synthetic non-targeting oligonucleotide. In some embodiments, the ACO is a random non-targeting oligonucleotide. In some embodiments, the ACO comprises RNA, DNA, BNA, LNA PAA., or combinations thereof. In some embodiments, the ACO interacts with one or more of: proteins in the plasma membrane, plasma proteins, peptides, ligands, lipids, fatty acids, saccharides, proteoglycan and zwitterionic phosphocholines. Such interaction of the ACO provides for increased biodistribution and enrichment of the targeting double stranded oligonucleotide of the oligonucleotide agent for local delivery to various target issues and cells of interest. Additionally, such interaction reduces or eliminates cytotoxicity of the oligonucleotide agent, confirming strong ‘on-target’ activity without overt effects on cell viability. In certain embodiments, the protein interacting with ACO is selected from one or more of serum albumin, IgG, .Apolipoprotein A-l, Apolipoprotein A-II, Complement factor C3, Transferrin, a-l Antitrypsin, Haptoglobin, Hemopexin, Fibrinogen, a-2-Macroglobulin, Prealbumin / TTR, Antithrombin III, a-l -Antichymotrypsin, p-2-G!ycoprotein, Ceruloplasmin, a-l Acid glycoprotein, Complement component Clq, Complement factor C4, Histidine-rich glycoprotein, Plasminogen, Fibronectin, ApoBlOO, Factor H, Apolipoprotein E, and Factor ' In yet other embodiments, the protein interacting with ACO is selected from one or more of: ASGPR, hGFR I. DLR. M6PR, Tl.R. Stabilin, SRB, NuckNm AP2M1, EEA1, RabSC, Rab7a, STX5, Pl 15, COPII, M6PR, GCC2, ANXA2, TCP1, ALIX, TSG101, VPS28, GLP-1, and HSP-90. In certain embodiments, the interaction of the AGO is through direct binding or mediated by one or more conjugated ligands which is covalently linked to the ACO or the double stranded oligonucleotide, or both. In some embodiments, the one or more conjugated ligands comprise a lipid, a fatty acid, a lluorophore, a saccharide, a peptide, an antibody and any other commonly used conjugation ligands. In certain embodiments, the conjugating ligands is selected from one or more of a cellpenetrating peptide, polyethylene glycol, an alkaloid, a tryptamine, a benzimidazole, a quinolone, an amino acid, a cholesterol, glucose and N-acetylgalactosamine. In certain embodiments, the one or more conjugation ligands is a fatty acid. In some embodiments, the oligonucleotide agent comprising the one or more conjugation ligands enhances the biodisiribution of the oligonucleotide agent in particular tissues, reduce or eliminate cytotoxicity of the oligonucleotide agent, and increase permeability of the oligonucleotide agent and passage through membranes, such as the blood brain barrier. In some embodiments, the ACO comprises a single-stranded oligonucleotide sequence comprising a nucleotide sequence that is at least 60% (e.at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequence selected from SEQ ID NOs: 1-22 In some embodiments, the oligonucleotide agent comprises an ACO. In certain embodiments, the ACO comprises a nucleotide sequence that is at least 60% (c.gw at least 65%), at least 70%), at. least. 75%, at least 80%, at least 85%, at. least. 90%, at least 95%), at least 97%, at. least. 99% or 100%) identical to a nucleotide sequence selected from the group of AC2(N22) (SEQ ID NO: 1), AC2(N20) (SEQ ID NO: 2), AC2(N18) (SEQ ID NO: 3), AC2(N16) (SEQ ID NO: 4), AC2(N15) (SEQ ID NO: 5), AC2(NI 4) (SEQ ID NO: 6), AC2(N12) (SEQ ID NO: 7) AC2(N 12) (SEQ ID NO: 7), AC2(N10) (SEQ ID NO: 8), AC2(N8) (SEQ ID NO: 9), AC2(N6) (SEQ ID NO: 10), AC2(22) (SEO ID NO: 11), AC2(18) (SEQ ID NO: 12), AC2( 16) (SEQ ID NO: 13), AC2(15) (SEQ ID NO: 141. AC2( 14) (SEQ ID NO: 15), 00203) (SEQ ID NO: 16), AC2( 12) (SEQ ID NO: 17), AC2( 11) (SEQ ID NO: 18), AC2(10) (SEQ ID NO: 19), AC2(9) (SEQ ID NO: 20), AC2(8) (SEQ ID NO: 21) and AC2(6) (SEQ ID NO: 22). In certain embodiments, the ACO comprises a chemically modified nucleotide sequence that is at. least. 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to a nucleotide sequence selected from the group of SEQ ID NOs: 12991379. In certain embodiments, the ACO has a chemically modified nucleotide sequence selected from the group of SEQ ID NOs: 1299-1379. In certain embodiments, the ACO has a chemically modified nucleotide sequence and a linker selected from the group of SEQ ID NOs: 1299-1379. In certain embodiments, the ACO has a chemically modified nucleotide sequence that is with 0, 1, 2 or 3 chemical modification differences to a nucleotide sequence selected from the group of SEQ ID NOs: 1299-1379. In some embodiments, the oligonucleotide agent of the present application comprises more than one ACO, for example, 2, 3, 4, 5, 6, 7, 9, 10 ACOs, covalently linked to a dsRNA, with or without one or more linkers in between the ACOs and dsRNA. The amount, of ACO, upon need, can vary from 2 to 10, or 2 to 100, or 2 to 1,000, or 2 to 10,000, linked to dsRNA via a multivalent linker, for example, a polymeric linker, in branch or liner form. In some embodiments, multiple ACOs are covalently linked to 2 or more dsRNAs, for example, 2, 3, 4, 5, 6, 7, 9, 10 or more dsRNAs, including saRNAs and / or siRNAs, in one agent. In some embodiments, the oligonucleotide agent, of the present application composes one ACO and multiple dsRNAs, for example, 2, 3, 4, 5, 6, 7, 9, 10 dsRNAs, linked with or without one or more linkers in between the ACO and dsRNAs. The amount of dsRNA, including saRNAs and / or siRNAs, upon need, can vary from 2 to 10, or 2 to 100, or 2 to 1,000, or 2 to 10,000, linked to ACO via a multivalent linker, for example, a polymeric linker, in branch or liner form. Targeting Oligonucleotide In some embodiments, the targeting oligonucleotide comprises a double stranded oligonucleotide. In some embodiments, the double-stranded oligonucleotide is a doublestranded RNA (dsRNA ). The dsRNA may be any dsRNA deemed useful. dsRN As that find use in the present disclosure include, without limitation, siRNA, saRNA, etc. In some embodiments, the double-stranded oligonucleotide comprises a sense strand and an antisense strand, the antisense strand having complementarity to a. target nucleic acid. In some embodiments, the antisense strand having complementarity' to a target nucleic acid is located in a promotor sequence. In some embodiments, the antisense strand having complementarity to a target nucleic acid is located in a coding or template sequence of a gene. In some embodiments, one of the sense or antisense strands has complementarity to a target nucleic acid which is a gene transcript, e.g., a mRNA or a pre-mRNA. In some embodiments, the dsRNA comprises a sense strand that is at least 17 contiguous nucleotides. In some embodiments, the dsRNA comprises a sense strand that is at least 18 contiguous nucleotides. In some embodiments, the dsRNA comprises a sense strand that is at most 60 contiguous nucleotides. In some embodiments, the sense strand has a length ranging from about 10 nucleotides or more, about 15 nucleotides or more, about 20 nucleotides or more, about 25 nucleotides or more, about 30 nucleotides or more, about 35 nucleotides or more, about 40 nucleotides or more, about 45 nucleotides or more, about 50 nucleotides or more, about 55 nucleotides or more, or about 60 nucleotides or more. In some embodiments, the sense strand is 10-100 nucleotides in length (e.g., 10-20 nucleotides, 10-50 nucleotides, 10-90 nucleotides, 20-95 nucleotides, 30-70 nucleotides, 40-80 nucleotides, 50-100 nucleotides, 10-40 nucleotides, 1030 nucleotides). In some embodiments, the sense strand is 10-60 nucleotides in length (e.g., 10-20 nucleotides, 10-50 nucleotides, 10-40 nucleotides, 10-30 nucleotides). In some embodiments, the sense strand has a nucleotide length ranging from 27-41 nucleotides. In some embodiments, the antisense strand has a length ranging from about 10 nucleotides or more, about 15 nucleotides or more, about 20 nucleotides or more, about 25 nucleotides or more, about 30 nucleotides or more, about 35 nucleotides or more, about 40 nucleotides or more, about 45 nucleotides or more, about 50 nucleotides or more, about 55 nucleotides or more, or about 60 nucleotides or more. In some embodiments, the antisense strand is 10-100 nucleotides in length (e.g., 10-20 nucleotides, 10-50 nucleotides, 10-90 nucleotides, 20-95 nucleotides, 30-70 nucleotides, 40-80 nucleotides, 50-100 nucleotides, 10-40 nucleotides, 1030 nucleotides). In some embodiments, the antisense strand is 19-30 nucleotides in length. In some embodiments, the antisense strand is 18-26 nucleotides in length. The double-stranded oligonucleotide may comprise a sequence that is modified in order to further increase the stability and / or die ability of the double-stranded oligonucleotide to modulate gene expression. In some embodiments, the sequence of the double-stranded oligonucleotide comprises one or more of a chemically modified nucleotide, or at least one phosphodi ester bond between two adjacent nucleotides in die oligonucleotide sequence is substituted by a phosphorothioate or boranophosphate bond. The chemical modifications of the double-stranded oligonucleotide includes, without limitation, modification of the 2 -ON of the ribose in the nucleotide, the modification or the absence of a base in the nucleotide, the locking or bridging of a nucleic acid, a nucleotide being a peptide nucleic acid, a nucleotide being a deoxyribonucleotide (DNA), a nucleotide having a 5-phosophate moiety, a nucleotide having a 5 '-(E)-vinylphosphonate moiety, a nucleotide having a 5'-methyl cytosine moiety, etc. Chemical modifications that may be found in double-stranded oligonucleotides are also further described below. Short interfering RNA (siRNA) Embodiments of the present application are based in part on the surprising discovery that an oligonucleotide agent (for example, siRNA, also referred to as “SODI gene siRNA”, "‘SODI siRNA”, or “siSODl” herein) is capable of inhibiting or downregulating the expression of a SODI gene in a cell. The decrease in functional SODI gene transcript following administration with an oligonucleotide agent of the present application can achieve a significant decrease or downregulation in the levels of SOD1 mRNA and SODI protein in a cell or a mammal. In particular, the inventors discovered that the functional oligonucleotide agents capable of inhibiting expression of superoxide dismutase 1 (SOD1) comprising a siRNA, wherein the siRNA comprises a sense strand and an antisense strand forming a double strand, wherein the antisense strand comprises a nucleotide sequence comprising at least 10 contiguous nucleotides, with 0, 1,2 or 3 mismatches, having at least 85% nucleotide sequence complementarity or homology to a portion of the nucleotide sequence of SODI mRNA. As a beneficial consequence, a target sequence (e.g., an isolated nucleic acid sequence comprising the target, sequence), upon interacting with the siRNA, can inhibit / downregulate the SODI mRNA transcript by at least 10% as compared to a. baseline level of SODI mRNA. Based at least in part on these discoveries, the present application features siRNA, compositions, and pharmaceutical compositions for mhibitmg / downregulating the SODI mRNA transcript by at least 10% as compared to baseline levels of SODI mRNA. In some embodiments, the siRNA inhibits or downregulates the SODI mRNA more than 10%. For instance, the siRNA inhibits or downregulates SODI mRNA by at ieast about 15%, at least about 20%, at ieast about 25%, at ieast about 30%, at ieast about 35%, at ieast about 40%, at ieast about 45%, at ieast about 50%, at ieast about 55%, at ieast about 60%, at ieast about 65%, at ieast about 70%, at ieast about 75%, at ieast about 80%, at ieast about 85%, at ieast about 90%, at least about 95%, at least about 100%, or greater than 100% as compared to baseline levels of SODI mRNA. Also provided herein are methods for preventing or treating a disease or condition induced by over-expression of SOD I protein, a SODI gene mutation, and / or high or abnormal SODI level in an individual comprising administering to the individual any of the siRNA, compositions, and / or pharmaceutical compositions described herein. Embodiments of the present application are also based in part on the discovers- that the SODI mRNA inhibitory oligonucleotide agents comprises a siRNA having a sense strand that is at least 85%, at least 90%, or at least 95% homology to the nucleotide sequence selected from the group of DS 17-0001 (SEQ ID NO: 384), DS 17-0002 (SEQ ID NO: 372), DS17-0003 (SEQ ID NO: 409), DS.17-0004 (SEQ ID NO: 357), DS17-0005 (SEQ ID NO: 486), DS17-0029 (SEQ ID NO: 588), DSI7-01N3 (SEQ ID NO: 912), DS17-02N3 (SEQ ID NO: 914), DS17-03N3 (SEQ ID NO: 916), DS17-04N3 (SEQ ID NO: 918), andDS17-05N3 (SEQ ID NO: 920).                    ' In some other embodiments, the SODI mRNA inhibitory' oligonucleotide agents comprises a siRNA having an antisense strand that is at least 85%, at least 90%, or at least 95% homology to the nucleotide sequence selected from the group of DS 17-0001 (SEQ ID NO: 653), DS17-0002 (SEQ ID NO: 641), DS1.7-0003 (SEQ ID NO: 678), DS17-0004 (SEQ ID NO: 626), DS.17-0005 (SEQ ID NO: 755), DS 17-0029 (SEQ ID NO: 857), DSI7-01N3 (SEQ ID NO: 913), DS 17-02N3 (SEQ ID NO: 915), DSl 7-03N3 (SEQ ID NO: 917), DS N-04N3 (SEQ ID NO: 919), andDS17-05N3 (SEQ ID NO: 921). In some embodiments, the SODI mRNA inhibitory' oligonucleotide agent comprises a siRN A, wherein the sense strand and the antisense strand of the siRNA have nucleotide sequences that is independently at least 85%, at least 90%, or at least 95% homology to the nucleotide sequence pairs selected from the group of: DS17-0001 (SEQ ID NO: 384 and SEQ ID NO: 653), DS 17-0002 (SEQ ID NO: 372*and SEQ ID NO: 641),DS 17-0003 (SEQ ID NO: 409 and SEQ ID NO: 678),DS 17-0004 (SEQ ID NO: 357 and SEQ ID NO: 626), DS17-0005 (SEQ ID NO: 486 and SEQ ID NO: 755),DSl 7-0029 (SEQ ID NO: 588 and SEQ ID NO: 857), DS I7-01N3 (SEQ ID NO : 912 and SEQ ID NO: 913), DS17-02N3 (SEQ ID NO: 914 and SEQ ID NO: 915), DS 17-03N3 (SEQ ID NO: 916 and SEQ ID NO: 917),DS17-04N3 (SEQ ID NO: 918 and SEQ ID NO: 919), and DS17-05N3 (SEQ ID NO: 920 and SEQ ID NO: 921). A siRNA targeting 3’UTR of the SODI gene to inhibit SODI mRN A transcript level in a. cell is also provided by the present disclosure. The siRNA comprises an oligonucleotide sequence having a length ranging from 16 to 35 consecutive nucleotides, wherein the continuous oligonucleotide sequence comprises a nucleotide sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% homology or complementarity to an equal length portion of SEQ ID NO:59, wherein the siRNA inhibits the mRNA transcript of SODI gene by at least 80% as compared to the baseline rA'SODI mRNA level. Surprisingly, the inventors discovered that the functional siRNAs capable of inhibiting the SODI mRNA transcript level were not randomly distributed on the SODI gene or particularly 3’-UTR of the SODI gene but were clustered in certain specific hotspot regions. Only some regions on the 3'~UTR of SOD1 gene are in favor of die siRNAs’ function of inhibiting, for exampie, the regions 549 to 562 (Hl; SEQ ID NO:6l) and 568 to 580 (H2; SEQ ID NO:63) of SOD I gene. Likewise, merely one region on the 3’-UTR of SOD1 gene are in favor of the ASOs’ function of inhibiting, that is, the regions 552 to 566 (H3: SEQ ID NO:65). The regions disclosed herein so called “'hotspots”. Tite inventors also discovered that optimal target sequences / sense strand of an siRNA within the SOD1 gene or particularly 3’-UTR of the SOD1 gene include sequences having: (1) a GC content between 35% and 65%; (2) less than 5 consecutive identical nucleotides; (3) 3 or less dinucleotide repeats; and (4) 3 or less trinucleotide repeats. As a beneficial consequence, a target sequence (e.g,, an isolated nucleic acid sequence comprising the target sequence), upon interacting with the siRNA, can inhibit the SOD1 mRNA transcript level by at least 80% as compared to a baseline level of SOD1 mRNA. Based at least in part on these discoveries, the present disclosure features siRNA, compositions, and pharmaceutical compositions for inhibiting the SOD1 mRNA transcript level by at least 80% as compared to baseline levels of SOD1 mRNA. Also provided herein are methods for preventing or treating a disease or condition induced by elevated level of SOD1 protein in a cell in an individual comprising administering any of the siRNA, compositions, and / or pharmaceutical compositions described herein. Therefore, the present application discloses a hotspot of siRNA in the 3’-UTR of the SOD1 gene, wherein the oligonucleotide agent disclosed in the present application having at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% homology or complementarity to an equal length portion of the hotspot, wherein the oligonucleotide agent inhibits the mRNA transcript of SOD1 gene by at least 80% as compared to the baseline of SOD I mRNA level. The present application further discloses an isolated target site of siRNA in the 3’-UTR of the SOD I gene, wherein the isolated target site has a nucleic acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% homology to a sequence selected from SEQ ID NOs:1068~1113. In some embodiments, the sense strand of the siRNA has a nucleotide sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% identical to the nucleotide sequence selected from SEQ ID NOs: 976-1021. In some embodiments, the antisense strand of the siRNA has a nucleotide sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%), at least 99% or 100% identical to the nucleotide sequence selected, from SEQ ID NOs: 1022-1067. In certain embodiments, the select target region of the SOD1 gene comprises a nucleotide sequence that is at least 75%, at least 80%, at least. 85%, at least 90%), at least 95%, at. least. 97%, at least 99% or 100% identical to the nucleotide sequence selected from group of SEQ ID NOs: 1068-1113. In some embodiments, the SOD1 mRNA inhibitory oligonucleotide agent comprises a siRNA, wherein the siRNA comprises a sense strand and an antisense strand having nucleotide sequences that is independently at least 85%, at least 90%), or at least 95% homology to the nucleotide sequence pairs selected from the group of: DS17-01M3 (SEQ ID NO: 922and SEQ ID NO: 923), DS 17-02M3 (SEQ ID NO: 924and SEQ ID NO: 925), DS17-03X0 (SEQ ID NO: 926 and SEQ ID NO: 927), DS17-04M3 (SEQ ID NO: 928 and SEQ ID NO: 929), and DS17-05M3 (SEQ ID NO: 930 and SEQ ID NO: 931). In addition, the siRNAs provided in Tables 3 and 22 identify a site in a SOD1 transcript that is susceptible to RISC-mediated cleavage. As such, the present invention further features siRNAs that target within one of such sequences. As used herein, a siRNA is said to target within a particular site of an RN A transcript if the siRNA promotes cleavage of the transcript anywhere within that particular site. Such a siRNA will generally include at least 15 contiguous nucleotides from one of the sequences provided in Tables 3 or 22 coupled to additional nucleotide sequences taken from the region contiguous to the selected sequence in a SODI gene. The siRNAs of the oligonucleotide agent described herein include an RNA strand (the antisense strand) having a region which is 60 nucleotides or less in length, i.e., 15-40 nucleotides in length, generally 19-25 nucleotides in length, which region is substantially complementary' to at least part of a mR A A transcript of a SOD] gene. The use of these siRNA s enables the targeted degradation of mR.NAs of genes that are implicated in pathologies associated with SODI expression in mammals. Exceptionally low dosages of SODI siRNAs in particular can specifically and efficiently mediate RNAi, resulting in significant inhibition of expression of a SODI gene. Using cell-based assays, the present inventors have demonstrated that siRNAs targeting SODI can specifically and efficiently mediate RNAi, resulting in significant, inhibition of expression of a SODI gene. Thus, methods and oligonucleotide agents including these siRNAs are useful for treating pathological processes that can be mediated by dowm regulating SODI, such as in the treatment of a disorder that causes elevated SOD] levels, e.g., amyotrophic lateral sclerosis (ALS). The following detailed description discloses how to make and use oligonucleotide agents containing siRN As to inhibit the expression of a SODI gene, as well as oligonucleotide agents and methods for treating diseases and disorders caused by the expression of this gene. In some embodiments, the continuous oligonucleotide sequence of the siRNA has five or less, i.e., 5, 4, 3, 2, 1, or 0 nucleotide differences or mismatches relative to the equal length portion of SODI mRA A hi some embodiments, the continuous oligonucleotide sequence of the sense strand of siRNA has three or less, i.e., 3, 2, 1., or 0 nucleotide differences or mismatches relative to the equal length portion of SOD] mRNA. In some embodiments, the continuous oligonucleotide sequence of the antisense strand of siRNA has three or less, i.e., 3, 2, 1, or 0 nucleotide differences or mismatches relative to the equal length portion of SODI mRNA. In some embodiments, the SODI mRNA disclosed herein does not contain a nucleotide mutation. In some embodiments, the SODI mRNA disclosed herein contains at least one nucleotide mutation. In some embodiments, the SOD] mRNA disclosed herein contains at least one nucleotide mutation on the targeting site of the siRNA. In some embodiments, the SODi mRNA disclosed herein contains at least one nucleotide mutation upper stream and / or downstream the targeting site of the siRNA. In some embodiments, the differences or mismatches locate in the middle or 3’ terminus of the oligonucleotide sequence of the siRNA. Methods and principles of siRNA molecule design are well known to those skilled in the art and are described in detail in, for example, Place et. ah, Molecular Tderapy-Ducleic Acids (2012) 1, el 5; and Li et.al., PNAS, 2006, vol. 103, no. 46, 17337--17342, which are herein incorporated by reference in their entireties. In one aspect, an RNA interference agent includes a single-stranded RNA that interacts with a. target RN A sequence to direct, the clea vage of the target RNA . Without washing to be bound by theory, long double-stranded RNA introduced into plants and invertebrate cells is broken down into siRNA by a Type III endonuclease known as Dicer (Sharp et ah, Genes Dev. 2001, 15:485). Dicer, a ribonuclease-III-like enzyme, processes the dsRNA into 19-23 base pair short interfering RNAs with characteristic two base 3’ overhangs (Bernstein, et al., (2001) Nature 409:363), The siRNAs are then incorporated into an RNA-induced silencing complex (RISC) where one or more helicases unwind the siRNA duplex, enabling the complementary antisense strand to guide target recognition (Nykanen, et al., (2001) Cell 107:309). Upon binding to the appropriate target mRNA, one or more endonucleases within the RISC cleaves the target to induce silencing (Elbashir, et al., (2001) Genes Dev. 15:188). Thus, in one aspect the invention relates to a single-stranded RNA that, promotes the formation of a RISC complex to effect silencing of the target gene. In some embodiments, the siRNA disclosed herein comprises a. sense strand and an antisense strand. The sense strand and the antisense strand comprise complementary regions capable of forming a double-stranded nucleic acid structure that inhibits the SODI transcription in a cell via the RNAi mechanism. The RNAi mechanism (also known as RNA interference) used herein refers to a mechanism that a double-strand nucleic acid structure is capable of downregulating target, genes in a sequence-specific maimer at the transcriptional level. The sense strand and the ami sense strand of the siRNA can exist either on two different nucleic acid strands or on one nucleic acid strand (e.g., a contiguous nucleic acid sequence). When the sense strand and the antisense strand are located on two different strands, at least one strand of the siRNA has a 3' overhang of 0 to 6 nucleotides in length, such that the overhangs of 0, 1, 2, 3, 4, 5 or 6 nucleotides in length, and in some cases, both strands have a 3’ overhang of 2 or 3 nucleotides in length. The nucleotide of the overhang is, in some cases thymine deoxyribonucleotide (dT), or in some cases, natural overhangs which are nucleotides selected from or complementary to the corresponding position on the DNA target. When the sense strand and the antisense strand are located on one nucleic acid strand, in some cases, the siRNA is a hairpin single-stranded nucleic acid molecule, where the complementary regions of the sense strand and the antisense strand form a double-stranded nucleic acid structure with each other. In the siRNA disclosed herein, in some embodiments, the sense strand has a length ranging from 10 to 60 nucleotides. For example, in some embodiments, lite sense strand and the antisense strand, independently comprises a length of 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35 nucleotides. In some embodiments, the antisense strand has a length ranging from 10 to 60 nucleotides. For example, in some embodiments, the sense strand and the antisense strand, independently comprises a length of 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35 nucleotides. In some embodiments, one strand of the siRNA has at least 75% (e.g., at least about 79%, about 80%, about 85%, about 90%, about 95% or about 99%) sequence homology or complementarity to a nucleotide sequence fragment of a SOD1 gene transcript. Specifically, the sense strand of the siRNA disclosed herein has at least 75% (e.g., at least about 79%, about 80%, about 85%, about 90%, about 95% or about 99%) sequence homology to a. nucleotide sequence fragment of a SOD1 gene transcript, and the antisense strand of the siRNA disclosed herein has at least 75% (e.g., at least about 79%, about 80%, about 85%, about 90%, about 95% or about 99%) sequence homology to a nucleotide sequence fragment of a SOD1 gene transcript. In some embodiments, the sense strand of the siRNA disclosed herein has at. least 75% (e.g., at least about 79%, about 80%, about 85%, about 90%, about 95% or about 99%) sequence homology to a nucleotide sequence selected from group of SEQ ID NOs: 976-1021. In some embodiments, the antisense strand of the siRNA disclosed herein has at least 75% (e.g., at least about 79%, about 80%, about 85%, about 90%, about 95% or about 99%) sequence homology to a nucleotide sequence selected from the group of SEQ ID NOs: 1022-1067. In certain embodiments, one strand of the siRNA can have five or less, i.e., 5, 4, 3, 2, L or 0 nucleotide differences or mismatches relative to a nucleotide sequence of any portion of SEQ ID NO: 59. Specifically, the sense strand of the siRNA disclosed herein can have three or less, i.e., 3, 2, L or 0 nucleotide differences relative to the nucleotide sequence selected from the group of SEQ ID NOs: 976-1021, and the antisense strand of the siRN A disclosed herein can have three or less, he., 3, 2, 1, or 0 nucleotide differences relative to the nucleotide sequence selected from the group of SEQ ID NOs: 1022-1067. In some embodiments, the differences or mismatches locate in the middle or 3’ terminus of the sense or antisense strand of the siRNA. In some embodiments, the antisense strand disclosed herein is capable of interacting with a target nucleic acid sequence of a mRNA of a SODI gene in. a sequence specific manner, meaning that the antisense strand is capable of undergoing hybridization to a target nucleic acid through hydrogen bonding. In some embodiments, an antisense strand has a nucleotide sequence that, when written in the 5' to 3‘ direction., comprises the reverse complement of the target portion of a target nucleic acid to which it is targeted. In certain such embodiments, an antisense strand has a nucleotide sequence that, when written in the 5' to 3! direction, comprises the reverse complement of the target portion in a fragment of a SODI gene transcript. Antisense oligonucleotide (ASO) The present disclosure also provides antisense oligonucleotides (ASOs) capable of inhibit SODI mRNA level in a cell. The ASOs modulates aRNAi - SODI mRNA - SODI protein pathway by a RNase H-dependent mechanism of action and thus can be used to treat SODI protein-related disease, e.g., for amyotrophic lateral sclerosis (ALS) patients. Disclosed in the present application is an oligonucleotide agent comprising an antisense oligonucleotide (ASO), which comprises an oligonucleotide sequence having a length ranging from 12 to 30 consecutive nucleotides, wherein the continuous oligonucleotide sequence comprises a nucleotide sequence having at least 75%, at least 80%, at least 85%, at least 90%, at. least 95% or 100% homology or complementarity to an equal length portion of SEQ ID NO:59, wherein the ASO inhibits the mRNA transcript of SODI gene by at least 60% as compared to the baseline of SODI mRNA level. In some embodiments, the ASO inhibits the mRNA transcript of SODI gene by greater 60% as compared to the baseline of SODI mRNA level. For instance, the ASO inhibits the mRNA transcript of SODI gene by at least about 65%, at least about 70%, at least about 75%>, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, or greater than 100% as compared to the baseline of SODI mRNA level. Further discloses in the present application is that the ASOs in the 3’-UTR. of the SODI gene capable of inhibiting the SODI mRNA transcript level wrere not randomly distributed on the SODI gene or particularly 3’-UTR of the SOD I gene but were clustered in certain specific hotspot regions. Only some regions on the 3'-UTR of SODI gene are in favor of the ASOs’ function of inhibiting, for example, the region SEQ ID NO:65 (H3) of SODI gene. In some embodiments, the ASO disclosed herein has at least 75%, at least 80%, at. least 85%, at least 90%, at least 95% or 100% complementarity to an equal length portion of the hotspot SEQ ID NO:65 (H3). In some embodiments, the ASO inhibits the mRNA transcript of SODI gene by at least 60% as compared to the baseline of SODI mRNA level. In some embodiments, the ASO comprising a single-stranded oligonucleotide sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% identical to die nucleotide sequence selected from chemically modified SEQ ID NOs: 1 155-1195. In some embodiments, the ASO comprising a single-stranded oligonucleotide sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% identical to the nucleotide sequence selected from the unmodified naked sequences of SEQIDNOs: 1155-1195. In some embodiments, the ASO is a single-stranded oligonucleotide comprising a 5’ end and a 3 ’ end. In some embodiments, the length of the antisense oligonucleotide comprises a nucleotide length ranging from 12 to 30 nucleotides, such as 13 nucleotides or more, 14 nucleotides or more, 15 nucleotides or more, 16 nucleotides or more, 17 nucleotides or more, 18 nucleotides or more, 19 nucleotides or more, 20 nucleotides or more, 21 nucleotides or more, 22 nucleotides or more, 23 nucleotides or more, 24 nucleotides or more, 25 nucleotides or more. In some embodiments, the length of the ASO is 15 to 25 contiguous oligonucleotides. In some embodiments, the ASO comprises a nucleotide sequence selected from the nucleotide sequence group of SEQ ID NOs: 1155-1195. C hemical m edit lea Eons All nucleotides of the oligonucleotides described herein may be natural, i.e., non-chemically modified, nucleotides or at. least, one nucleotide may be a chemically modified nucleotide. Non-limiting examples of the chemical modification include one or more of a combination of the following: a) modification of a phosphodiester bond of nucleotides in the oligonucleotide sequence; b) modification of 2-OH of the ribose in the nucleotide, c) modification of a base in the nucleotide, d) at least one nucleotide in the oligonucleotide sequence being a locked nucleic acid, and e) at least one nucleotide in the oligonucleotide sequence being a deoxy ri bonucl eotide (DN A). In some embodiments, the nucleotides or oligonucleotides of the present application is chemically modified to enhance stability or other beneficial characteristics. The nucleic acids featured, in the present application may be synthesized, and / or modified by conventional methods, such as those described in “Current protocols in nucleic acid chemistry,” Beaucage, S. L. el al. (Edrs.), John Wiley & Sons, Inc., New York, N.Y., USA, which is hereby incorporated herein by reference. Modifications include, for example, (a) end modifications, e.g., 5’ end modifications (phosphorylation, conjugation, inverted linkages, etc.) 3’ end modifications (conjugation, DNA nucleotides, inverted linkages, etc.), (b) base modifications, e.g., replacement with stabilizing bases, destabilizing bases, or bases that base pair with an expanded repertoire of partners, removal of bases (abasic nucl eotides), or conjugated bases, (c) sugar modifications (e.g., at the 2’ position or 4' position) or replacement of the sugar, as well as (d) backbone modifications, including modification or replacement of the phosphodiester linkages. Specific examples of siRNA molecules that can be used in this present application include but are not limited to RNAs containing modified backbones or no natural internucieoside linkages. In some embodiments, RNAs having modified backbones include, among others, those that do not have a phosphorus atom in the backbone. In some embodiments, modified RNAs that do not have a phosphorus atom in their internudeoside backbone can also be oligonucleosides. In some embodiments, the modified oligonucleotide will have a phosphorus atom in its internudeoside backbone. Chemical modifications of nucleotides or oligonucleotides in the present disclosure are well known io those skilled in the art, and modifications of the phosphodi ester bond refer to modifications of oxygen in the phosphodiester bond, including phosphorothioate modifications and boronated phosphate modifications. The modifications disclosed herein stabilize an oligonucleotide structure, maintaining high specificity and high affinity for base pairing. The modifications disclosed herein also stabilize an ACO structure and maintain its delivering accessory properties including bioavail ability, biodistribution, and / or cellular uptake of the oligonucleotide agent in various tissues prefrontal cortex, cerebellum, spinal cord (e.g., cervical, thoracic, lumber), muscle, liver, and kidney. hi some embodiments, the chemical modification is to substitute the phosphodiester bond with phosphorothioate (PS) bond on the backbone of the nucleotide sequence of the oligonucleotide agent disclosed herein. In some embodiments, the oligonucleotide agent disclosed herein comprises at least one PS backbone modification. In some embodiments, the ACO comprises at least one PS backbone modification. In some embodiments, the oligonucleotide agent comprises at least 2 PS, at least 3 PS, at least 4 PS, at least 5 PS, at least 6 PS, or greater than 6 PS backbone modifications. In some embodiments, about 90% to about 95% of the phosphodi ester backbone bond of ACO are substituted with phosphorothioate (PS) bond. In some embodiments, the oligonucleotide agent comprises at least one PS backbone modification on 5’ end, 3’ end or internal site of the sense strand of the dsRNA. In some embodiments, the oligonucleotide agent comprises at least one PS backbone modification on 5’ end, 3’ end or internal site of the antisense strand of the dsRNA. In some embodiments, the oligonucleotide agent comprises at least one PS backbone modification on 5’ end, 3’ end or internal site of the single strand of the ACO. In some embodiments, the nucleotides or oligonucleotides of the present, appli cati on includes at least one chemically modified nucleotide which is modified at 2'-OH in pentose of a nucleotide, i.e., the introduction of certain substituents at the hydroxyl position of the ribose, such as 2’-fluoromodification, 2'-oxymethyl modification, 2-oxyethylidenemethoxy modification, 2,4Alinitrophenol modification, locked nucleic acid (LNA), 2'-amino modification or 2'-deoxy modification, e.g., a 2AdeoxyAf-fluoro modified nucleotide, a 2’-deoxy -modifi cd n ucl eoti de. In some embodiments, the nucleotides or oligonucleotides of the present application includes at. least, one chemically modified nucleotide which is modified at the base of the nucleotide, e.g., 5 ’-bromouracil modification, 5'-iodouracil modification, N-methyluracil modification, or 2,6-diaminopurine modification. In some embodiments, the chemical modification of the nucleotides or oligonucleotides in the present application is an addition of a (E)-vinylphosphonate moiety7 at the 5’ end of the sense or antisense sequence. In some embodiments, the chemical modification of the at. least, one chemically modified nucleotide is an addition of a 5'-methyl cytosine moiety at the 5’ end of the sense or antisense sequence. In some embodiments, the nucleotides or oligonucleotides in the present application are modified at the base of the nucleotide, e.g., 5 '-bromouracil modification, 5’ -iodouracil modification, N-methyluracil modification, or 2,6-diaminopurine modification. In. some embodiments, at least one oligonucleotide in the oligonucleotide agent includes at least one modified nucleotide, e.g., a 2'-()-methyl modified nucleotide, a nucleotide comprising a 5;-phosphorothioate group, a terminal nucleotide linked to a cholesteryl derivative or dodecanoic acid bisdecylamide group, a 2-deoxy-2-fluoro modified nucleotide, a 2'-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, a 2'-ammo-modified nucleotide, a 2'-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, and a non-natural base comprising nucleotide. In some embodiments, the first and second dsRNAs include “endo-light” modification with 2-O-methyl modified nucleotides and nucleotides comprising a 5'-phosphorothioate group. Modified oligonucleotide backbones include, for example, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoaikyiphosphotriesters, methyl and other alkyl phosphonates including 3'-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including j’-amino phosphorami date and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphoiriesters, and boranophosphates having normal 3’-5’ linkages, 2’-5’ linked analogs of these, and those) having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3’-5’ to 5’-3’ or 2’-5’ to 5’-2’. Various salts, mixed salts and free acid forms are also included. Non-limiting examples of preparation of the phosphoms-containing linkages include, but are not limited to, U.S. Pat. Nos. 3,687,808; 4,469,863; 4,476,301; 5,023,243; 5,177,195; 5,188,897; 5,264,423; 5,276,019; 5,278,302; 5,286,717; 5,321,131; 5,399,676; 5,405^939; 5,453,496; 5,455,233; 5,466,677, 5,476,925; 5,519,126; 5,536,821; 5,541,316, 5,550,111; 5,563,253; 5,571,799; 5,587,361; 5,625,050; 6,028,188; 6,124,445; 6,160,109; 6,169,170; 6,172,209, 6,239,265; 6,277,603; 6,326,199; 6,346,614, 6,444,423; 6,531,590; 6,534,639; 6,608,035, 6,683,167; 6,858,715; 6,867,294; 6,878,805, 7,015,315; 7,041,816; 7,273,933, 7,321,029; and U.S. Pat. RE39464, which are herein specifically each incorporated by reference in their entireties. In some embodiments, the nucleotides or oligonucleotides comprise one or more of RNA, DNA, BN A, LNA or peptide nucleic acid (PNA). The RNA of a siRNA or saRNA can also be modified to include one or more locked nucleic acids (LNA). A locked nucleic acid is a nucleotide having a modified ribose moiety in which die ribose moiety comprises an extra bridge connecting the 2’ and 4’ carbons. This structure effectively “locks” the ribose in the 3’-endo structural conformation. The addition of locked nucleic acids to siRNAs has been shown to increase siRNA stability in serum, and to reduce off-target effects (Elmen, J. et al., (2005) Nucleic Acids Research 33(l):439-447; Mook, O R. et ah, (2007) Mol Cane Ther 6(3):833-843; Grunweher, A. et al., (2003) Nucleic Acids Research 31(12):3185-3193). Representative U.S. patents that teach the preparation of locked nucleic acid nucleotides include, but are not limited to, the following: U.S. Pat. Nos. 6,268,490; 6,670,461; 6,794,499; 6,998,484; 7,053,207; 7,084,125; and 7,399,845, each of which is herein incorporated by reference in its entirety. In other RNA mimetics suitable or contemplated for use in siRNAs, both the sugar and the internucleoside linkage, the backbone, of the nucleotide units are replaced with novel groups. The base units are maintained for hybridization with an appropriate nucleic acid target compound. One such oligomeric compound, an RNA mimetic that has been shown to have excellent hybridization properties, is referred to as a peptide nucleic acid (PNA). In PNA compounds, the sugar backbone of an RNA is replaced with an amide containing backbone, in particular an aminoethylglycine backbone. The nucleobases are retained and are bound directly or indirectly io aza nitrogen atoms of the amide portion of the backbone. Representative U.S. patents that teach the preparation of PNA compounds include, but are not Limited to, U.S. Pat. Nos. 5,539,082, 5,714,331; and 5,719,262, each of which is herein incorporated by reference. Further teaching of PNA compounds can be found, for example, in Nielsen etah, Science, 1991, 254, 1497-1500. In some embodiments, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 9084, or least about 95%, or about 100% nucleotides of the singlestranded oligonucleotide are chemically modified nucleotides. In some embodiments, the sense strand and the antisense strand of the oligonucleotide agent independently comprise at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or about 100% nucleotides which are chemically modified nucieotides. These modifications may increase the bioavail ability of the oligonucleotides, increase affinity for the target sequence, and enhance resistance to nuclease hydrolysis in a cell. In addition, to facilitate entry of the oligonucleotides into a cell, lipophilic groups such as cholesterol may be introduced at the ends of the sense or antisense strands of the oligonucleotides on the basis of the above modifications to facilitate action through a cell membrane composed of lipid bilayers and gene promoter regions within the nuclear membrane and nucleus. In some embodiments, the oligonucleotides of the present application which, upon contact with a cell, are effective in deactivating or dowmregulating the expression of one or more genes in the cell, preferably by at least 10% (e.g., at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%). In some embodiments, the oligonucleotides of the present application which, upon contact with a cell, are effective in activating or upregulating the expression of one or more genes in the cell, preferably by at least 10% (e.g., at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, at least 200%, at least 300%, at least 500%, at least 800%, at least 1000%, at least 2000%, or at least 5000%). One aspect of the application provides a cell comprising an oligonucleotide agent of the present application or a nucleic acid encoding the oligonucleotide agent of the present application. In one embodiment, the cell is a mammalian cell, preferably a human cell. Such cells may be ex vivo, such as cell lines or cell lines, and the like, or may be present in mammalian bodies, such as humans, including infants, children or adults. In some embodiments, the at least one chemical modified oligonucleotide is the non-targeting single-stranded oligonucleotide. In some embodiments, the at least one chemical modified oligonucleotide is the targeting double stranded oligonucleotide. In certain embodiments, the at least one chemical modified oligonucleotide is the non-targeting single-stranded oligonucleotide and the targeting double stranded oligonucleotide. Covalent Linkage Aspects of the present application include an oligonucleotide agent comprising a doublestranded targeting oligonucleotide and a non-targeting single-stranded oligonucleotide, e.g., an ACO, that are covalently linked. In some embodiments, a double-stranded targeting oligonucleotide and a non-targeting single-stranded oligonucleotide are covalently linked by a linking component. In some embodiments, the double-stranded oligonucleotide and the non-targeting singlestranded oligonucleotide are linked with a covalent linker. In some embodiments, the linker is a disulfide linker. Various combinations of strands can be linked, e.g., the first and second dsRNA sense strands are covalently linked or, e.g., the first and second dsRNA antisense strands are covalently linked. In some embodiments, the sense strand of the double stranded targeting oligonucleotide is covalentlv linked to the single-stranded oligonucleotide. In some embodiments, the antisense strand of the double stranded targeting o1igonudeoti.de is covalently linked to die singlestranded oligonucleotide. In some embodiments, any of die oligonucleotides in the oligonucleotide agent of die present application includes a linking component. Linkers typically comprise a direct bond or an atom such as oxygen or sulfur, a unit such as NR1, C(O), C(O)O, C(O)NRd, SO, SO2, SO2NH or a chain of atoms, such as substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, arylalkyl, ary 1 alkenyl, aiylalkynyl, heteroaiylalkyl, heteroaryl alkenyl, heteroaryl alkynyl, heterocyclyi alky I, heterocycly I alkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyi, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkyl aryl alkenyl, alkylarylalkynyl, alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alkynyl arylal kynyl, alkylheteroarylalkyd, alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl, alkynylheteroaiylalkyl, alkynylheteroarylalkenyl, alkynylheteroarylalkynyl, alkyl heterocycly I alkyd, alkyl heterocyclyi alkenyl, alkylhererocyciylalkynyl, alkenylheterocyclylalkyl, alkenylheterocyclylalkenyk alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl, alkenyl heteroaryl, alkynylhereroaryl, where one or more methylenes can be interrupted or terminated by O, S, S(O), SO?, N(R‘h, C(O), cleavable linking group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic; where R1 is hydrogen, acyl, aliphatic or substituted aliphatic. Without limitations, various types of linker functionality can be included in the subject conjugates, including but not limited to cleavable linkers, and non-cleavable linkers, as well as reversible linkers and irreversible linkers. In some embodiments, the linker is a cleavable linker. Cleavable linkers are those that rely on processes inside a target cell to liberate the tw7o parts the linker is holding together, e.g.. the ACO and the dsRNA, as reduction in the cytoplasm, exposure to acidic conditions in a lysosome or endosome, or cleavage by specific enzymes (e.g., proteases) within the cell. As such, cleavable linkers allow7 the dsRNA to be released in its original form after the conjugate has been internalized and processed inside a target cell. Cleavable linkers include, but are not limited to, those whose bonds can be cleaved by enzymes (e.g., peptide linkers); reducing conditions (e.g., disulfide linkers); or acidic conditions (e.g., hydrazones and carbonates). In some embodiments, the linking component is selected from one or more of ethylene glycol chain, an alkyl chain, a peptide, nucleic acid, carbohydrates, thiol linkage, a phosphodiester, a phosphorothioate, a phosphorami date, an amide, and a carbamate. In some embodiments, the linking component includes, but is not limited to: a) LI or S18 (spacer-18 linker) (l,l-bis(4-methoxyphenyl)-l~phenyl~2,5,8,.ll,14,]7-hexaoxanonadecan-19-yl (2-cyanoethyl) diisopropylphosphoramidite); b) L4 or C6 (spacer-C6 linker) (6-(bis(4-methoxyphenyl)(phenyl)methoxy)hexyl (2-cyanoethyl) diisopropylphosphoramidite); c) L6 (1,1 -bis(4-methoxyphenyl)-I-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl (2-cyanoethyl) diisopropylphosphoramidite); d) L9 or S9 (spacer-9 linker) (2-(2-(2-(bis(4-methoxyphenyl)(phenyl)methoxy)ethoxy)ethoxy)ethyl (2-cyanoethyl) diisopropylphosphoramidite); e)L10 orC3 (spacer-C3 linker) (3-(bis(4-methoxyphenyl)(phenyl)meihoxy)propyI (2-cyanoethyl) diisopropylphosphoramidite); f) Ll2(d spacer) ((2R,3S)~2-((bis(4~ methoxyphenyl)(phenyl)methoxy)methyl)tetrahydrofuran-3-yl (2-cyanoethyl) diisopropylphosphoramidite); g) Li3 or C12 (spacer-C12 linker) (12-(bis(4- methoxyphenyl)(phenyl)methoxy)dodecyl (2-cyanoethyl) diisopropylphosphoramidite); h) L14 (spacer-L14 linker) (((lr,4r)-4-((bis(4- methoxyphenyl)(phenyl)methoxy)methyl)cyclohexyl)methyl (2-cyanoethyl) diisopropylphosphoramidite); i) LI 5 (spacer-L15 linker) (4-(2-(bis(4-methoxyphenyl)(phenyl)methoxy)ethyl)phenethyl (2-cyanoethyl) diisopropylphosphoramidite); j) L16 (spacer-L16 linker) (2-(l-(2-(bis(4~ methoxyphenyl)(phenyl)methoxy)ethyl)cyclohexyl)ethyl (2-cyanoethyl) diisopropylphosphoramidite); k) C6x 1 ((2S,3 S,4S,5S)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methy I )-5-inethoxy-4-(pent-4~yn-l-yloxy)tetrahydrofuran-3-yI (2-cyanoethyl) diisopropylphosphoramidite); 1) C6x2 ((2S,3 S,4S,5S)~5-((bis(4~methoxyphenyl)(phenyl)methoxy)methyl )-2-methoxy-4-(pent-4 -yn-1 -yloxy)tetrahy drofuran-3-yl (2-cyanoethyl) diisopropylphosphoramidite); m) C6x5 (2-((2-(bis(4-methoxyphenyl)(phenyl)methoxy)ethyl)(pent-4-yn-1 - y l)ami no)ethy I (2-cyanoethy 1) dii sopropy Iphosp horami dite), and n) C6x7 ((9H-fluoren-9-yl)methyl (4-((2S,4R)-2-((bis(4- methoxyphenyl)(phenyl)methoxy)methyl)-4- ((bis(diisopropylatnino)phosphanyl)ox.y)pyn;olidin-l-yl)-4-ox.obutyl)carbamate). In certain embodiments, the linking component comprises a compound structure shown in Table 1. In certain embodiments, the linking component conjugates to a nucleotide in the single-stranded oligonucleotide or the double-stranded oligonucleotide. In certain embodiments, the linking component conjugates at a nucleoside position selected from 5’-phosphate, 3\ base and 2’-H / OH of a nucleotide in the single-stranded oligonucleotide or the double-stranded oligonucleotide. In certain embodiments, the linking component is Spacer phosphoramidite 18 (Phosphoramidous acid, N,N~bis(l-methylethy!R I9,19-bis(4-methoxyphenyl)-!.9-phenyl-3,6,9,12,15,18-hexaoxanonadec-l-yl 2-cyanoethyl ester). Ui Ui Table 1. Linkers used in oligonucleotide agents Name Formula Structure LI or SIS (spacer-18 linker) 1,1 -bi s(4-methoxy phenyl)-! -pheny 1- 2,5,8,11,14,17-hexaoxan.onadecan- 19-yl (2-cyanoethyl) diisopropylphosphoramidite DMTrO'” L4 or C6 (spacer-C6 linker) 6-(bis(4-methoxyphenyl)(phenyl)methoxy)hexyl (2-cyanoethyl) diisopropylphosphoramidite L6 1,1 -bis(4-meihoxyphenyT)-1 -phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl (2-cyanoethyl) di i sopropyl ph osphoramidi te DMTrO. 1 d o < o o b ■>' g L9 or S9 (spacer-9 linker) 2-(2-(2-(bis(4- methoxyphenyl)(phenyl)methoxy)ethoxy)ethoxy)e thy! (2-cyanoethyl) diisopropylphosphoramidite DMTrOx -•'X'X L10 or C3 (spacer-C3 linker) 3 -(bi s(4-m ethoxy pheny l)(p heny 1 )m ethoxy )propy 1 (2-cyanoethyl) diisopropylphosphoramidite DMTrO^ X-NX. ,CN L12(d spacer) (2R,3S)-2-((bis(4- methoxy phenyl)(phenyl)methoxy )methy l)tetrahy d rofuran-3 -yl (2-cyanoethyl) di i sopropyl ph osphoramidi te O"\ DMTrO-^k^ / °-F> \ ' L13 or C12 (spacer-Cl 2 linker) 12-( bi s(4~ methoxyphenyl)(phenyl)methoxy)dodecyl (2-cyanoethyl) di i sopropyl ph osph oramidite 1 LI 4 (spacer-L14 linker) ((lr,4r)-4-((bi s(4- methoxyphenyl)(phenyl)methoxy)methyl)cyclohe xyl)methyl (2-cyanoethyl) di i sopropylph osphoramidi te DMTrO^ z o / ° V CL" 2 d — (J WO 2023 / 280190                                                 PCT / CN2022 / 104037 L15 (spacer-L15 linker) 4-(2-(bis(4- methoxyphenyl)(phenyl)methoxy)ethyl)phenethyl (2-cyanoethyl) diisopropylphosphoramidite o s -1 o —( p Z-T3 —b o z L16 (spacer-L16 linker) 2-( 1-(2-(bis(4- methoxyphenyl)(phenyl)methoxy)ethyl)cyclohexy bedn 1 (2-cyanoethyl) diisopropylphosphoramidite / --CN \ P DMTrO        O-Px / __\ C6xl (2S,3S,4S,5S)-2-((bis(4-methoxyphenyl)(phenyl)m ethoxy )methy 1)-5-methoxy-4-(pent"4-yn-1 -yloxy)tetrahydrofuran~3 -yl (2-cyanoethyl) diisopropylphosphoramidite DMTrO NO—y    l'<., / Qx.,sOMe "% / “A \  P-0   0 / -N C6x2 (2S,3S,4S,5S)-5-((bis(4- methoxyphenyr)(phenyl)methoxy)methyl)-2-methoxy-4-(pent-4-yn-l-yloxy)tetrahydrofuran-3-yl (2-cyanoethyl) diisopropylphosphoramidite DMTrO NG Cox 5 2-((2-(bis(4- methoxyphenyr)(phenyr)methoxy)ethyl)(pent-4-yn-l~yl)amino)ethyl (2-cyanoethyl) diisopropylphosphoramidite \'Xp,O^.N / ^.ODMTr 6      k WO 2023 / 280190                                                 PCT / CN2022 / 104037 tn / o o E ESgSMay^ ___ /   , \>s!ia: \     / X $ o DMTrO ' V 7 J M "X ' O O t-d z:—t J.illO—c / \ J z o ■5 • *£ b5 O s s ri 'S x‘ o p S 3? t? S3 O 6 Q £ mate "S C^E O tZ . yDcarbai or other O' pr^ O' £ o Q £ G" O-i o s x> o X o 4OE, or ~F, (9H met ((bit -1-y o -OM -OH or -H or eosi cd' Nucl 9¾ In some embodiments, the double-stranded targeting oligonucleotide and the single-stranded oligonucleotide are covalently linked by a phosphodiester bond. In some embodiments, the double-stranded targeting oligonucleotide and the single-stranded oligonucleotide are covalently linked by a phosphorothioate bond. In some embodiments, the double-stranded targeting oligonucleotide comprises a sense strand that is covalently linked to the single-stranded oligonucleotide. In some embodiments, the double-stranded targeting oligonucleotide comprises an antisense strand that is covalently linked to the single-stranded oligonucleotide. In some embodiments, the double-stranded targeting oligonucleotide and the single-stranded oligonucleotide are covalently linked by one or more nucleotides. Non-limiting examples of covalent linkers can be found in U.S. Patent Application Publication No.: 20200332292, which is hereby incorporated by reference in its entirety. The covalent linker can join the double-stranded targeting oligonucleotide and the single-stranded oligonucleotide. In some embodiments, the covalent linker can join two sense strands, two antisense strands, one sense and one antisense strand, two sense strands and one antisense strand, two antisense strands and one sense strand, two sense and two antisense strands, an antisense strand and single-stranded oligonucleotide, a sense strand and inactivated oligonucleotide, and the like. In certain embodiments, the covalent linker includes a nucleic acid (e.g., RNA and / or DNA) and / or a peptide. The linker can be single-stranded, double-stranded, partially single-strands, or partially double-stranded. In some embodiments the linker includes a disulfide bond. The linker can be cleavable or non-cleavable. In certain embodiments, the covalent linker includes, e.g., dTsdTmm(5'~2 / deoxythymidyl-3'~ thiophosphate-5'-2'deoxythymidyl-3'-phosphate-5'-uri dyi-3''-phosphate-5''-uridyl-3 phosphate); rUsrU (a thiophosphate linker: 5’-uridyl-3'-thiophosphate~5'-uridyl-3’~ phosphate); an rUrU linker; dTsdTaa (aadTsdT, 5'-2'deoxythymidyl-3'-tiiiophosphate-5'-2’deoxythymidyl-3'-phosphate-5'-adenyl-3 -phosphate-5 -adeny 1-3’'-phosphate); dTsdT (5-2’deoxythym.idyl-3'-thiophosphate-5'-2' deoxythymidyl-3’'-phosphate); or dTsdTuu:=uudTsdT=:5'~2'deoxythymidyl-3'~thiophosphate-5'-2'deoxythymidyl-3'-phosphate-5 '-uri dy 1 -3 ’-phosphate-5 '-uridyl-3 '-phosphate. When the covalent linker is a RNA, the RNA linker may be composed of any combination of nucleotides. The combination of nucleotides may be adenine, uracil, guanosine, cytosine, or any combination thereof. The RNA linker may be any length. In some embodiments, the RN A linker is 2-50 nucleotides in length. When the RNA linker is 2-50 nucleotides in length, the RNA linker may be any intervening length such as 5-10, 10-15, or 15-20 nucleotides in length. In some embodiments, the covalent linker includes a polyRNA, such as poly(5’-adenyl-3 ’ -phosphate.......A A AA AA AA) or poly(5 ’ -cytidyl-3' -phosphate-5' -uridyl-3 phosphate.......CUCUCUCU)), e.g., Xc single- stranded poly RNA linker wherein n is an integer from 2-50 inclusive, preferable 4-15 inclusive, most, preferably 7-8 inclusive. Modified nucleotides or a mixture of nucleotides can also be present in said. polyRNA linker. When the covalent tinker is a DNA, the DNA linker may be composed of any combination of nucleotides. The combination of nucleotides may be adenine, thymine, guanosine, cytosine, or any combination thereof. The DNA linker may be any length. In some embodiments, the DNA linker is 1-50 nucleotides in length. When the DNA linker is 1-50 nucleotides in length, the DNA linker may be any intervening length such as 5-10, 10-15, or 15-20 nucleotides in length. The covalent linker can be a polyDNA, such as poly(5'-2'deoxythymidyl-3’-phosphate—TTTTTTTT), e.g., wherein n is an integer from 2-5() inclusive, preferable 4-15 inclusive, most preferably 7-8 inclusive. Modified nucleotides or a mixture of nucleotides can. also be present in said polyDNA linker, a single- stranded polyDNA linker wherein n is an integer from 2-50 inclusive, preferable 4-15 inclusive, most preferably 7-8 inclusive. Modified nucleotides or a mixture of nucleotides can also be present in said polyDN A linker. In some embodiments, the covalent, linker includes a disulfide bond, optionally a bis-hexyldisulfide linker. In one embodiment, the disulfide linker is C12H26O4PS2 Exact Mass: 329.1010 MoL Wt.: .329.4362 In some embodiments, the covalent linker includes a peptide bond, e.g., include amino acids. In one embodiment, the covalent linker is a 1-10 amino acid long linker, preferably comprising 4-5 amino acids, optionally X-Gly-Phe-Gly-Y wherein X and Y represent any amino acid. In some embodiments, the covalent linker includes HEG, a hexaethylenglycol linker. Orientation and position of covalent linkage Aspects of the present application include covalently linking the double-stranded targeting oligonucleotide and. the non-targeting single-stranded oligonucleotide, e.g., an ACO, to form an oligonucleotide agent. In some embodiments, the orientation of the linkage and positioning of the double-stranded targeting oligonucleotide and the single-stranded oligonucleotide may enhance stability, oligonucleotide activity, or other beneficial characteristics, such as maximized target gene output, increased or decreased activity or expression (e.g., mRNA expression, protein expression, etc.) of one or more target genes. In some embodiments, the single-stranded oligonucleotide is covalently linked to a 3’ end of the sense or antisense strand of the double-stranded target oligonucleotide: b) the singlestranded oligonucleotide is covalently linked to a 5’ end of the sense or antisense strand of the double-stranded targeting oligonucleotide, or c) the single-stranded oligonucleotide is covalently finked to an internal nucleotide between the 5’ end and the 3’ end of the sense or antisense strand of the double-stranded targeting oligonucleotide. In some embodiments, the internal nucleotide of the sense or antisense strand of the double-stranded targeting oligonucleotide is located at nucleotide position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 from 5’ end of the sense or antisense strand; or located at nucleotide position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, .12, or 13 from 3’ end of the sense or antisense strand. In some embodiments, an internal nucleotide of the sense or antisense strand of the doublestranded targeting oligonucleotide is substituted by one or more linking component or spacer which is covalently linked to the single-stranded oligonucleotide on its 5’ end or 3’ end (Le., internal conjugated ODV). In some embodiments, the internal conjugated ODV has enhanced potency as compared to the .L or 5’ end conjugated ODV (Le., .ACO conjugated on 3’ or 5’ end of the sense or antisense strand of the double stranded oligonucleotide). In certain embodiments, the 5’ end of the single-stranded oligonucleotide is conjugated to a linking component. In some embodiments, the 3: end of the single-stranded oligonucleotide is conjugated to a linking component. In certain embodiments, the linking component or spacer comprises a compound shown in Table 1. .Agents that decrease the expression of the SODI gene or protein In some embodiments, the oligonucleotide agent decreases the expression of a SODI gene or protein. Administration of the oligonucleotide agent to a patient treats or delays the onset of ALS, such as familial or sporadic ALS or Leu Lou Gehrig’s disease. In certain embodiments, the described oligonucleotide agent decreases the amount of a full-length SODI protein by, for example, deactivating / downregulating SODI transcription to decrease the amount of fulllength SODI mRNA. In certain embodiments, full-length SODI protein is decreased in an amount sufficient to reduce the symptoms associated with an ALS. In certain embodiments, full-length SODI protein is decreased by at least 10% (e.g., at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%). The administration may be performed in any route of administration deemed useful. In some embodiments, the administration route is locally at the site of a central nervous system location. In some embodiments, the administration route is systemic. In certain embodiments, a double-stranded targeting oligonucleotide of the oligonucleotide agent that decreases the expression of the SOD1 gene or protein is an siRNA. The SOD1 siRNA deactivates or downregulates the expression of an SODI gene, its mRN A transcript or SODI protein in a cell in which the SODI gene, its mRNA. transcript or SODI protein is normally or over-expressed. In typical embodiments, a first strand of the SODI siRNA comprises a segment that has at least 75% sequence identity or sequence complementarity to a 6-60 nucleotide fragments of a select target region of the SODI mRNA transcript thereby effecting deactivation or dowmregulation of expression of the SOD I protein. In the present application, the SODI siRNA comprises a sense nucleic acid fragment and an antisense nucleic acid fragment. The sense nucleic acid fragment and the antisense nucleic acid fragment comprise complementary regions capable of forming a double-stranded nucleic acid structure that knocks down expression of the SODI gene in a cell by the RN A interference mechanism. Sense nucleic acid fragments and antisense nucleic acid fragments of siRNAs may be present on two different nucleic acid strands or may be present on the same nucleic acid strand. When the sense and antisense nucleic acid fragments are present on two strands, at least one strand of the siRNA has a 3’ overhang of 0-6 nucleotides in length, preferably both strands have a 3' overhang of 2 or 3 nucleotides in length, and preferably the nucleotides of the overhang are deoxythymine (dT). When a sense nucleic acid fragment and an antisense nucleic acid fragment of an siRNA are present on the same nucleic acid strand, preferably the siRNA is a single-stranded hairpin-structured nucleic acid molecule, wherein the complementary regions of the sense nucleic acid fragment and the antisense nucleic acid fragment form a double-stranded nucleic acid structure. In such an siRNA, the sense nucleic acid fragment and antisense nucleic acid fragment are 16-60 nucleotides in length, respectively and may be 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 3L 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 nucleotides. In certain embodiments of the present application, the SOD1 siRNA comprises a sense nucleic acid strand and an antisense nucleic acid strand, the sense nucleic acid strand comprising at least one region that is complementary to at least one region on the antisense nucleic acid strand to form a double-stranded nucleic acid structure capable of deactivating expression of the SOD1 protein in a cell. In certain embodiments of the present application, the sense nucleic acid strand and the antisense nucleic acid strand are located on two different nucleic acid strands. In certain embodiments of the present application, the sense nucleic acid fragment and the antisense nucleic acid fragment are located on the same nucleic acid strand, forming a hairpin singlestranded nucleic acid molecule, wherein the complementary regions of the sense nucleic acid fragment and the antisense nucleic acid fragment form a double-stranded nucleic acid structure. In certain embodiments of the present application, at least one of the nucleic acid strands has a 3’overhang of 0 to 6 nucleotides in length. In certain embodiments of the present application, both of the nucleic acid strands have 3'overhangs of 2-3 nucleotides in length. In certain embodiments of the present application, the sense and antisense nucleic acid strands are 16 to 35 nucleotides in length, respectively. In some embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of DS17-01M3-AC1 (me!4)-L9V3 whose antisense strand has a nucleotide sequence of SEQ ID NO: 933 that has complementarity with a fragment the of the ODV structured sense strand of SEQ ID NO: 928. In some embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% {e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of DS17-02M3-AC1 (me!4)-L9V3 whose antisense strand has a nucleotide sequence of SEQ ID NO: 935 that has complementarity with a fragment of the ODV structured sense strand of SEQ ID NO: 928.                    '           '                                                   ' In some embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of DS17-03M3-AC1 (mel4)-L9V3 whose antisense strand has a nucleotide sequence of SEQ ID NO: 937 that has complementarity with a fragment of the ODV structured sense strand of SEQ ID NO: 936. In some embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of D S 17-04M3-AC1 (mel4)-L9V3 whose anti sense strand has a nucleotide sequence of SEQ ID NO: 939 that, has complementarity with a fragment the of the ODV structured sense strand of SEQ ID NO: 938.              ' In some embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of DS17-04M3v-ACl (me 14)-1,9 V3 whose antisense strand has a nucleotide sequence of SEQ ID NO: 950 that has complementarity with a fragment the of the ODV structured sense strand of SEQ ID NO: 938.                '           "                                                    ’ In some embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) Identical to the nucleotide sequences of DS17-05M3-AC1 (me!4)-L9V3 whose antisense strand has a nucleotide sequence of SEQ ID NO: 941 that has complementarity with a fragment the of the ODV structured sense strand of SEQ ID NO: 940. In some embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 10056) identical to the nucleotide sequences of DS17-29M2-ACI (mel4)-L9V3 whose antisense strand has a nucleotide sequence of SEQ ID NO: 47 that has complementarity with a fragment the of the ODV structured sense strand of SEQ ID NO: 942.              "          " In some embodiments, the oligonucleotide agent has a nucleotide sequence that Is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at. least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of DS17-01M3v-ACl (me!4)-L9V3 whose antisense strand has a nucleotide sequence of SEQ ID NO: 47 that has complementarity with a fragment the of the ODV structured sense strand of SEQ ID NO: 932. In some embodiments, the oligonucleotide agent has a nucleotide sequence that, is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 8556, at least 90%, at least 95%, at least 9756, at least 995-6 or I00%') identical to the nucleotide sequences of DS17-02M3v-ACl (me14)-L9V3 whose antisense strand has a nucleotide sequence of SEQ ID NO: 943 that has complementarity with a fragment the of the ODV structured sense strand of SEQ ID NO: 934.                '           '                                                    ' In some embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 6556, at least 70%, at least 7556, at least 80%), at least 85%, at least 9056, at least 95%, at. least. 9756, at least 99% or 100%) identical to the nucleotide sequences of DS17-03M3v-ACl (me!4)-L9V3 whose antisense strand has a nucleotide sequence of SEQ ID NO: 944 that has complementarity with a fragment the of the ODV structured sense strand of SEQ ID NO: 936.                '           ' In some embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 6056 (e.g., at least 65%, at least 70%, at least 75%, at least 8056, at least 85%, at least 9056, at least 9556, at least 97%, at least 9956 or 10056) identical to the nucleotide sequences of DS 17-05M3v-AC1 (me!4)-L9V3 whose antisense strand has a nucleotide sequence of SEQ ID NO: 951 that has complementarity with a fragment the of the ODV structured sense strand of SEQ ID NO: 940. In some embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 6056 (e.g., at least 65%, at least 7056, at least 75%, at least 8056, at least 85%, at least 90%, at least 9556, at least 97%, at least 99% or 10056) identical to the nucleotide sequences of DS17-04M3-asSODl -1 -1,9V3 whose antisense strand has a nucleotide sequence of SEQ ID NO: 939 that, has complementarity with a fragment the of the ODV structured sense strand of SEQ ID NO: 952.              ' In some aspects, the present application provides an isolated SOD1 gene siRNA targeting site having any contiguous 16-35 nucleotide sequence on a select target region of the SOD1 gene (full length SOD1 sequence of SEQ ID NO: 895). In certain embodiments, the select target region of the SODI gene comprises a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequence selected from: at least a nucleotide sequence of SEQ ID NOs: 88-356. In some embodiments, an siRNA includes a nucleotide sequence of a sense strand that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequence selected from: SEQ ID NOs: 357-624. In some embodiments, an siRNA includes a nucleotide sequence of an antisense strand that is at least 60% (e.g., at least 65%, at least 70%, at least 75%>, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequence selected from the group of: SEQ ID NOs: 626893. In some embodiments, an siRNA includes a nucleotide sequence of a sense strand that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequence selected from: SEQ ID NOs: 38, 40, 42, 44, 46, 50, 52, 54, 56, 58, 60, 62, and 64. In some embodiments, an siRNA includes a nucleotide sequence of an antisense strand that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequence selected from the group of: SEQ ID NOs: 39, 41, 43, 45, 47, 49, 51, 53 and 57. In certain embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%>, at least 80%), at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of siHTT-AC2-SlLl (SEQ ID NO: 28) and an antisense strand having a nucleotide sequence of SEQ ID NO: 27 that has partial complementarity with the sense strand of SEQ ID NO: 28. In certain embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%>, at least 80%), at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of siApp-8-SlVl (SEQ ID NO: 30) and an antisense strand having a nucleotide sequence of SEQ ID NO: 31 that has partial complementarity with the sense strand of SEQ ID NO: 30. In certain embodiments, the oligonucleotide agent that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%), at least 85%, at least 90%, at least 95%), at least 97%, at least 99% or 100%) identical to the nucleotide sequences ofsiSOD 1-231-ESC (SEQ ID NO: 38) and an antisense siRNA strand having a nucleotide sequence of SEQ ID NO: 39 that has partial complementarity with the sense strand of SEQ ID NO: 38. In certain embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%>, at least 80%), at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences ofsiSODl-231-TT(SEQ ID NO: 40) and an antisense siRNA strand having a nucleotide sequence of SEQ ID NO: 41 that has partial complementarity with the sense strand of SEQ ID NO: 40.     ' In certain embodiments, die oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of (SEQ ID NO: 42) and an antisense siRNA strand having a nucleotide sequence of SEQ ID NO: 43 that has partial complementarity with the sense strand of SEQ ID NO: 42. In certain embodiments, die oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of (SEQ ID NO: 44) and an antisense siRNA strand having a nucleotide sequence of SEQ ID NO: 45 that has partial complementarity with the sense strand of SEQ ID NO: 44. In certain embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of (SEQ ID NO: 46) and an antisense siRNA strand having a nucleotide sequence of SEQ ID NO: 47 that has partial complementarity with the sense strand of SEQ ID NO: 46. In certain embodiments, the oligonucleotide has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of SEQ ID NO: 46 and an antisense siRNA strand having a nucleotide sequence of SEQ ID NO: 49 that has partial complementarity with the sense strand of SEQ ID NO: 46. In certain embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% Q.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of (SEQ ID NO: 50) and an antisense strand having a nucleotide sequence of SEQ ID NO: 51 that has partial complementarity with the sense strand of SEQ ID NO: 50. In certain embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of (SEQ ID NO: 52) and an antisense siRNA strand having a nucleotide sequence of SEQ ID NO: 53 that has partial complementarity with the sense strand of SEQ ID NO: 52. In certain embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of SEQ ID NO: 54 and an antisense siRNA strand having a nucleotide sequence of SEQ ID NO: 47 that has partial complementarity with the sense strand of SEQ ID NO: 54. In certain embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of SEQ ID NO: 56 and an antisense siRNA strand having a nucleotide sequence of SEQ ID NO: 57 that has partial complementarity with the sense strand of SEQ ID NO: 56. In certain embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of siSOD1M2-AC2(N22)-S I V3v-Qu5(SEQ ID NO: 58) and an antisense siRNA strand having a nucleotide sequence of SEQ ID NO: 57 that has partial complementarity with the sense strand of SEQ ID NO: 58.                                             ' In certain embodiments, die oligonucleotide agent lias a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of siSODlM2-AC2(N15)-SlV3v-Qu5(SEQ ID NO: 60) and an antisense siRNA strand having a nucleotide sequence of SEQ ID NO: 57 that has partial complementarity with the sense strand of SEQIDNO: 60                                          ' In certain embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of siSODlM2-AC2(N12)-Sl V3v-Qu5(SEQ ID NO: 62) and an antisense siRNA strand having a nucleotide sequence of SEQ ID NO: 57 that has partial complementarity with the sense strand of SEQ ID NO: 62. In certain embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of siSODlM2-AC2(N6)-SlV3v-Qu5(SEQ ID NO:64) and an antisense siRNA, strand having a nucleotide sequence of SEQ ID NO: 57 that has partial complementarity with the sense strand of SEQ ID NO: 64.                                             " In certain embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to SEQ ID NOs: 1196-1298, and an antisense siRNA strand having a nucleotide sequence of SEQ ID NO: 57 that has partial complementarity with the sense strand of SEQ ID NOs:l 196-1298. In addition, to facilitate entry of the siRNA into a cell, chemical conjugation groups other than the ACO disclosure herein may be introduced at the ends of the sense or anti sense strands of the siRNA on the basis of the above modifications to facilitate action through a cell membrane composed of lipid bilayers and mRNA regions within the nuclear membrane and nucleus. In some embodiments, siRNAs disclosed in the present application are covalently attached to one or more conjugate groups. In some embodiments, conjugate groups modify one or more properties of the attached oligonucleotide, including but not limited to pharmacodynamics, pharmacokinetics, stability, binding, absorption, tissue distribution, cellular distribution, cellular uptake, charge and clearance. In some embodiments, conjugate groups impart a new property on the attached oligonucleotide, e.g., fluorophores or reporter groups that enable detection of the oligonucleotide. Certain conjugate groups and conjugate moieties have been described previously, for example: cholesterol moiety (Letsinger etal., Proc. Nad. Acad. Sci. USA, 1989, 86, 6553-6556), cholic acid (Manoharan et al., Bioorg. Med, Chern. Lett., 1994, 4, 1053-1060), a thioether, e.g., hexyl-S-trityhhiol (Manoharan et al., Ann. N.Y. Acad. Set., 1992, 660, 306-309; Manoharan eta!., Bioorg. Med. Chem. Lett., 1993, 3, 2765-2770), a thiocholesterol (Oberhauser et al., Nucl. Acids Res., 1992, 20, 533-538), an aliphatic chain, e.g., do-decan-diol or undecyl residues (Sai son -Behm oaras et al., EMBO 1, 1991, 10, 11111118, Kabanov et al., FEBS Lett., 1990, 259, 327-330, Svinarchuk et al., Biochimie, 1993, 75, 49-54), a 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, 3651-3654; Shea et al., Nucl. Acids Res., 1990, 18, 3777-3783), a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides &Nudeotides, 1995, 14, 969-973), or adamantane acetic acid a palmityl moiety (Mishra etal., Biochim. Biaphys. Acta, 1995, 1264, 229-237), an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety (Crooke el al., J. Pharmacol. Exp. Ther., 1996, 277, 923-937), a tocopherol group (Nishina et al., Molecular Therapy Nucleic Acids, 2015, 4, e220; and Nishina et al., Molecular Therapy, 2008, 16, 734-740), or a GalNAc cluster (e.g., WO2014 / 179620). In some embodiments, the siRNA of the present application relates to the sense strand or the antisense strand of the siRNA that is conjugated to one or more conjugation groups selected from: intercalated, reporter molecules, polyamines, polyamides, peptides, carbohydrates, vitamin moi eties, polyethylene glycols, thioethers, poly ethers, cholesterols, thiocholesterols, cholic acid moieties, folate, lipids, phospholipids, biotin, phenazine, phen an thri dine, anthraquinone, adamantane, acridine, fluoresceins, rhodamines, coumarins, fluorophores, and dyes. In some embodiments, a conjugate group comprises an active drug substance, for example, aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fen-bufen, ketoprofen, (8)-(+)-pranoprofen, carprofen, dansyl sarcosine, 2,3,5-triiodobenzoic acid, fmgolimod, flufenamic acid, folinic acid, a benzothiadiazide, chlorothiazide, a diazepine, indo-methicin, a barbiturate, a cephalosporin, a sulfa drug, an antidiabetic, an antibacterial or an antibiotic. In some embodiments, the siRNA of the present application is conjugated to one or more conjugation groups selected from: a lipid, a fatty acid, a fluorophore, a ligand, a saccharide, a peptide, and an antibody. In some embodiments, the siRNA of the present application relates to the sense strand or the antisense strand of the siRNA that is conjugated to one or more conjugation groups selected from a cell-penetrating peptide, polyethylene glycol, an alkaloid, a tryptamine, a benzimidazole, a quinolone, an amino acid, a cholesterol, glucose and N-acety 1 gal actosam i ne. In some embodiments, the siRN A conjugated to one or more conjugation groups disclosed in die embodiments is directly contacted, transferred, delivered or administrated to a cell or a subject. Oligonucleotide agents that increase the expression of the SMN2 gene or SMN2 protein In some embodiments, the oligonucleotide agent including the double-stranded targeting oligonucleotide and the non-targeting single-stranded oligonucleotide, e.g., an ACO, increases the expression of an SMN2 gene or protein. Administration of oligonucleotide agent to a patient treats or delays the onset of an SMN-deficiency-related condition, such as spinal muscular atrophy (SMA). In certain embodiments, the described oligonucleotide agent increases the amount of a full-length SMN protein by, for example, activating / up-regulating SMN2 transcription in conjunction with modulating splicing for exon 7 inclusion to increase the amount of full-length SMN2 mRNA. In certain embodiments, full-length SMN protein is increased in an amount sufficient to reduce the symptoms associated with an SMN-deficiency-related condition. In certain embodiments, full-length SMN protein is increased by at least 10% (e.g., at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%). The administration may be performed in any route of administration deemed useful. In some embodiments, the administration route is locally at the site of a central nervous system location. In some embodiments, the administration route is systemic. In certain embodiments, double-stranded targeting oligonucleotide of the oligonucleotide agent that increases the expression of the SMN2 gene or protein is an saRNA. The SMN2 saRNA activates or upregulates the expression of an SMN2 gene in a cell in which the SMN2 gene is normally, insufficiently, or incorrectly expressed. In typical embodiments, a first strand of the SMN2 saRNA comprises a segment that has at least 75% sequence identity or sequence complementarity to a 16-35 nucleotide fragment of the promoter region of the SMN2 gene thereby effecting activation or upregulation of expression of the gene. In certain embodiments of the present application, the SMN2 saRNA comprises a sense nucleic acid strand and an antisense nucleic acid strand, the sense nucleic acid strand comprising at least one region that is complementary to at least one region on the antisense nucleic acid strand to form a double-stranded nucleic acid structure capable of activating expression of the SMN2 gene in a cell. In certain embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to any one of the saRNA sense strand sequences SEQ ID NOs: 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, and 86, and an antisense saRNA strand having a nucleotide sequence selected from SEQ ID NO: 67, that has partial complementarity with the sense strand SEQ ID NOs: 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, and 86, respectively. In certain embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to any one of the saRNA sense strand sequence of SEQ ID NO: 66, and an antisense saRNA strand having a nucleotide sequence selected from SEQ ID NO: 67, that has partial complementarity with the sense strand selected from SEQ If) NO: 66.^ In certain embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99'% or 100%) identical to the nucleotide sequences ofR6-04M1-AC2(16)-S1L1 V3v (SEQ ID NO: 70) and an antisense siRNA strand having a nucleotide sequence of SEQ ID NO: 67 that has partial complementarity with the sense strand of SEQ ID NO: 70.^ In certain embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of R6-04M4-AC2(15)-SlLl V3v (SEQ ID NO: 72) and an antisense siRN A strand having a nucleotide sequence of SEQ ID NO: 67 that has partial complementarity with the sense strand of SEQ ID NO: 72.U In certain embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of R6-04M1-AC2(14)-S1L1 V3v (SEQ ID NO: 74 ) and an antisense siRNA strand having a nucleotide sequence of SEQ ID NO: 67 that has partial complementarity with the sense strand of SEQ ID NO: 74.^ In certain embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of R.6-04M4-AC2(13)-SlLl V3v (SEQ ID NO: 76) and an antisense siRNA strand having a nucleotide sequence of SEQ ID NO: 67 that has partial complementarity with the sense strand of SEQ ID NO: 76,fl In certain embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of R6-04M1-z\C2(12)-S1L1V3v (SEQ ID NO: 78) and an antisense siRNA strand having a nucleotide sequence of SEQ ID NO: 67 that has partial complementarity with the sense strand of SEQ ID NO: 78.fl In certain embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of R6-04M1-AC2(11)~SILI V3v (SEQ ID NO: 80) and an antisense siRNA strand having a nucleotide sequence of SEQ ID NO: 67 that has partial complementarity with the sense strand of SEQ ID NO: 80.fl                                                ’ In certain embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of R6-04M1-z\C2(10)-S1L1V3v (SEQ ID NO: 82) and an antisense siRN A strand having a nucleotide sequence of SEQ ID NO: 67 that has partial complementarity with the sense strand of SEQ ID NO: 82.fl In certain embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of R6-O4M1-AC2(9)-S1L1 V3v (SEQ ID NO: 84) and an antisense siRNA strand having a nucleotide sequence of SEQ ID NO: 67 that has partial complementarity with the sense strand of SEQ ID NO:. 84.                                            ' In certain embodiments, the oligonucleotide agent has a nucleotide sequence that is at least 60% (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100%) identical to the nucleotide sequences of R6-04Ml-AC2(8)-SlLlV3v (SEQ ID NO: 86) and an antisense siRNA strand having a nucleotide sequence of SEQ ID NO: 67 that has partial complementarity with the sense strand of SEQ ID NO: 86.                                             " Methods of modulating gene expression In some aspects, oligonucleotide agents of the present application can be useful for therapeutic approaches to treating diseases such as spinal muscular atrophy (SMA) or ALS. By non-limiting embodiments, the present application provides a method of decreasing or silencing the levels of mRNA transcript of a SOD1 gene or SOD1 protein in a cell or individual, comprising administering to a subject a pharmaceutical composition disclosed herein. In some embodiments, the present application relates to a method for treating or delaying the onset or progression of Amyotrophic lateral sclerosis (ALS) in a subject, the method comprising: administering to the subject a pharmaceutical composition disclosed herein. In some embodiments, the subject has sporadic ALS (sALS). In some embodiments, the subject has familial ALS (fALS). In some embodiments, the pharmaceutical composition decreases or silences the levels of mRNA transcript of a SOD] gene or SODI protein in a cell or individual. In some embodiments, the AGO of the oligonucleotide agent improves the stability, bioavailability, biodistribution, and / or cellular uptake of the siRNA as compared to an oligonucleotide agent without the ACO. In some embodiments, the ACO of the oligonucleotide agent increases the biodistribution of siRNA within one or more target tissues as compared to an oligonucleotide agent without the ACO. In some embodiments, the ACO of the oligonucleotide agent increases the biodistribution of siRNA within two or more target tissues as compared to an oligonucleotide agent without the ACO. In some embodiments, the one or more target tissues is selected from tissues of brain, spinal cord, muscle, spleen, lung, heart, liver, bladder, and kidney. In some embodiments, the one or more target tissues is selected from the group of: prefrontal cortex, cerebellum, and rest of brain; cervical, thoracic and lumbar in spinal cord; heart, forelimb, hindlimb, nape, and gluteus. In some embodiments, the oligonucleotide agent of the present application achieves a decrease in full-length SODI protein that is less than the amount achieved by administration of the same amount of double stranded oligonucleotide such as a siRNA substance without an ODV structure used individually, with higher potency, reduced toxicity, or unwanted side effects. In some embodiments, the oligonucleotide agent of the present application achieves a decrease in full-length SOD 1 protein that is less than the additive effect of treatment with the same amount of the double-stranded targeting oligonucleotide used individually. Specifically, the oligonucleotide agent of the present application inhibits / dowm-regulates the SODI mRNA transcript by at least 10% at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% as compared to baseline SODI mRNA transcript). In some embodiments, upon administering the oligonucleotide agent disclosed in the embodiments, e.g., to a ceil or a subject, the SODI mRNA transcript is inhibited / downreguiated by at least 50%, 60%, 70%, 77%, 79%, 81%, 84%, 85%, and 88% at. 10 nM treatment compared to baseline SODI mRNA transcript in control group) in an in vitro cell line. In some embodiments, an oligonucleotide agent inhibits or downregulates the SOD] mRN A transcript by about 90%. In some embodiments, the expression of SODI gene is inhibited / downreguiated by administering the oligonucleotide agent, disclosed in the embodiments to a cell at a concentration of at least 0.01 nM e.g., 0.02 nM, 0.05 nM, 0.08 nM, 0.1 nM, 0.2 nM, 0.3 nM, 0.4 nM, 0.5 nM, 0.6 nM. 0.8 nM, I nM, 5 nM. 10 nM, 25 nM, 50 A! 75 nM, 100 nM, or 150 nM. In some embodiments, the SODI gene coded protein (SODI protein) is inhibited / downreguiated bv administering the oligonucleotide aeent disclosed in the embodiments, e.g., to a cell or a. subject. The knockdown of the SODI protein by at least at least 10% (e.g., at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100%, as compared to baseline expression of the SODI protein). In some embodiments, an oligonucleotide agent inhibits or downregulates the expression of the SOD I protein by about 90%. In some embodiments, the SODI protein is inhibited / down-regulated by administering die oligonucleotide agent disclosed in the embodiments to a cell at a concentration of at least 0.01 nM, e.g., 0.02 nM, 0.05 nM, 0.08 nM, 0.1 nM, 0.2 nM, 0.3 nM, 0.4 nM, 0.5 nM, 0.6 nM, 0.8 nM, I nM, 2 nM, 3 nM, 4nM, 5 nM, 10 nM, 25 nM, 50 nM, 75 nM, 100 nM, or 150 nM. In some embodiments, the oligonucleotide agents disclosed in the embodiments have a dosedependent knockdown activity in cells. In some embodiments, the oligonucleotide agents knockdown the SODl mRNA transcript in cells with a IC50 of less than 10 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.8 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM. 0.1 nM, 0.08 nM, 0.06 nM, 0.04 nM, 0.02 nM, 0.01 nM, 0.008 nM, or 0.005 nM. Another aspect of the present application relates to a method for preventing or treating a disorder or condition induced by over-expression of SODl protein, a SODl gene mutation, and / or high SODl mRNA levels in an individual comprising: administering an effective amount of the siRNA, the oligonucleotide agent, or the composition comprising the oligonucleotide agent disclosed herein to the individual. In some embodiments, the effective amount of the siRNA, disclosed herein, can be a concentration ranging from 0.01 nM to 50 nM, e.g., 0.01 nM, 0.02 nM, 0.05 nM, 0.08 nM, 0.1 nM, 0.2 nM, 0.3 nM, 0.4 nM, 0.5 nM, 0.6 nM, 0.8 nM, 1 nM, 5 nM, 10 nM, 25 nMi, 50 nM, 75 nM, 100 nMi, or 150 nM. In some embodiments, the disorder or condition is ALS. In some embodiments, the individual is a mammal. In some embodiments, the individual is a human. In any of the embodiments provided herein, such cells may be ex. vivo, such as cell lines, and the like, or may be present in mammalian bodies, such as humans. In some embodiments, the human is a subject or individual suffering from a SODl protein related condition or ALS. Another aspect of the application relates to the use of an oligonucleotide agent of the present application, a nucleic acid encoding two or more oligonucleotides of the oligonucleotide agent of the present application or a composition comprising the oligonucleotide agent of the present application or a nucleic acid encoding two or more oligonucleotides of the oligonucleotide agent, of the present for the preparation of a medicament for the treatment or delaying the onset of an SMN-defidency-related condition or ALS. The subject may be a mammal, such as a human. The subject may be an infant, a child or an adult. In certain embodiments, die oligonucleotide agent of the present application achieves a decrease in full-length SODl protein that is less than the amount achieved by administration of the same amount, of double stranded oligonucleotide substance used individually, with reduced toxicity or unwanted side effects. In certain embodiments, the oligonucleotide agent of the present application achieves a decrease in full-length SODl protein that is less than the additive effect of treatment with the same amount of the double stranded targeting oligonucleotide used individually. In certain embodiments, the effect of the oligonucleotide agent of the present application achieves a greater clinical improvement compared to the effect of the same amount of either substance used individually. In certain embodiments, the effect of the oligonucleotide agent achieves a greater than additive clinical improvement compared to the effect of the same amount of double-stranded oligonucleotide used individually. In any of the embodiments provided herein, such oligonucleotide agent, nucleic acids encoding the oligonucleotide agent of the present application, or compositions comprising such oligonucleotide agent or nucleic acids encoding oligonucleotide agent of the present application may be introduced directly into a cell, or may be produced, intracellularly upon introduction of a nucleotide sequence encoding the oligonucleotide agent into a cell, preferably a mammalian cell, more preferably a human cell. Such cells may be ex vivo, such as cell lines, and the like, or may be present in mammalian bodies, such as humans. In some embodiments, the human is a patient or individual suffering from a SMN-deficiency-related condition or ALS. In certain embodiments, a nucleic acid encoding an oligonucleotide agent, or a composition comprising the aforementioned oligonucleotide agent or a nucleic acid encoding an oligonucleotide agent of the application, in respective amounts sufficient to effect treatment of ALS. In certain embodiments, the baseline measurement is obtained from a biological sample, as defined herein, obtained from an individual prior to administering the therapy described herein. In certain embodiments, the biological sample is peripheral blood mononuclear cells, blood plasma, serum, skin tissue, cerebrospinal fluid (CSF). Methods of treating A LS Aspects of the present methods include methods of treating ALS in a subject comprising administering to the subject a pharmaceutical composition comprising an oligonucleotide agent of the present application and a pharmaceutically acceptable carrier. Among the known genes underlining ALS, SODl gene still remains a major cause of fALS and has been considered to be an important ALS drug target. The human SODl gene is located on chromosome 21q22.11 and located from base pair 33,031,935 to base pair 33,041,241 with a genomic size of 9307 bp. SOD] gene codes for the monomeric SODl protein (153 amino acids, molecular weight 16 kDa), and also encodes for the detoxifying copper / zinc binding SODl enzyme, which has been found to be localized mainly in the cytosol, as well as in the nucleus, peroxisomes, and mitochondria. The first description of the ALS disease dates back to at least 1824 by Charles Bell, however, SOD1 as the first risk gene of ALS was discovered in 1993. When the first SODl transgenic mouse model (SODl G9iA) was established in 1994, indicating that the research on ALS entered a new era. All these lines of evidence indicate that SODl mutants cause disease most probably via a gain-of-function, and reducing its levels may be beneficial. The excessive oxidation of wild-type SODl induces toxic conformational changes SODl silencing significantly attenuated astrocyte-mediated toxicity towards motor neurons. Therefore, silencing SODl expression is an important strategy for the treatment of ALS. The present application provides an oligonucleotide agent with an efficient and effective oligonucleotide delivery vehicle. The agent comprising a double-stranded siRNA targeting oligonucleotide is observed to treat ALS by inhibiting the expression of SODl gene through the RNAi silencing mechanism. The present application provides SODl siRNAs with potent inhibitory effect, when covalently linked with an ODV (ACO), which was found by the inventors to be beneficial for use in lite treatment of ALS. In some embodiments, the subject has sporadic ALS tsALS). In some embodiments, the subject has familial ALS (fALS). In some embodiments, the subject with ALS has increased or abnormal SODl full length protein expression. In some embodiments, the double-stranded oligonucleotide of the oligonucleotide agent decreases or silences the expression of the SODl gene or SODl protein. In certain embodiments, the ACO of the oligonucleotide agent improves the stability, bioavailability, biodistribution, and / or cellular uptake of the double-stranded oligonucleotide as compared to an oligonucleotide agent without the ACO. In some embodiments, the ACO of the oligonucleotide agent increases the biodistribution of double stranded oligonucleotide the within one or more target tissues as compared to an oligonucleotide agent without the .ACO. In some embodiments, the ACO of the oligonucleotide agent increases the biodistribution of double stranded oligonucleotide the within two or more target tissues as compared to an oligonucleotide agent without the ACO. In some embodiments, the one or more target tissues is selected from: prefrontal cortex, cerebellum, muscle, liver, and kidney. Cells com prising siRNA After contacting a cell, the oligonucleotide agent disclosed herein can effectively inhibit or downregulate the expression of SODl gene in a cell, for example downregulate the expression by at least 10% (e.g., as compared to baseline SODl transcription). In some embodiments, the present application relates to a cell comprising the oligonucleotide agent disclosed herein. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell, such as a human cell in various tissues in organs including brain, spinal cord, muscle, spleen, lung, heart, liver, bladder, and kidney. In some embodiments, the cell in target tissues is selected from the group of: prefrontal cortex, cerebellum, and rest of brain, cervical, thoracic and lumbar in spinal cord; heart, forelimb, hindlimb, nape, and gluteus muscles. The cell disclosed herein may be in vitro, or ex vivo, such as a cell line or a cell strain, or may exist in a mammalian body, such as a human, body. The human body disclosed herein is a subject suffering from a disease or symptom caused by a SODl gene mutation, abnormal SODl mRNA level, and / or overexpression of SOD 1 protein in CNS. In some embodiments, the cell is from a CNS tissue of a subject suffering from ALS. In some embodiments, the cell is from a subject suffering from / M.S. Compositions of an oligonucleotide agent Another aspect of the present application provides a pharmaceutical composition comprising the double stranded targeting oligonucleotide and the non-targeting single-stranded oligonucleotide as described in the present application. The present application provides a composition or pharmaceutical composition capable of downregulated the level of SODl mRNA transcript by the mechanism of action (MoA) of RNA interference, comprising the oligonucleotide agent disclosed herein, to treat or prevent onset of a SOD l related disease (particularly ALS). In some embodiments, the present application relates to a composition or pharmaceutical composition comprising the siRNA of the present application. In some embodiments, the present application relates to a composition or pharmaceutical composition comprising the siRNA and the ACO as described herein. In. some embodiments, the present application relates to a composition or pharmaceutical composition comprising the siRNA and the ACO covalently linked by a linking component as described herein. In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier. In one embodiment, the pharmaceutically acceptable carrier includes one or more of an aqueous carrier, liposome or LNP, polymer, micelle, colloid, metal nanoparticle, non-metallic nanoparticle, bioconjugates (e.g., GalNAc), and polypeptide. In one embodiment, the aqueous carrier may be, for example, RNase-free water, or RNase-free buffer. The composition may contain 1-150 nM, for example 1-100 nM, for example 1-50 nM, for example 1-20 nM, for example 10-100 nM, 10-50 nM, 20-50 nM, 20100 nM, for example 50 nM of the aforementioned oligonucleotides or nucleic acid encoding the oligonucleotides according to the present application. In some embodiments, the composition comprises 1-150 nM of the oligonucleotide agent of the present application. Another aspect of the present application relates to the use of the oligonucleotide agent as described herein, a nucleic acid encoding the oligonucleotides agent as described herein, or a composition comprising such oligonucleotide agent or a nucleic acid encoding the oligonucleotide agent as described herein, where the double-stranded targeting oligonucleotide and the single-stranded oligonucleotide are covalently linked, for the preparation of one or more compositions for modulate the expression of one or more genes or proteins expressed by a cell. Another embodiment provides pharmaceutical compositions or medicaments comprising the agents of the present application and a therapeutically inert, carrier, diluent or pharmaceutically acceptable excipient as well as methods of using the agents of the present application to prepare such compositions and medicaments. For the oligonucleotide agent compositions of the present application, the delivery' can be optionally through parenteral infusions including intrathecal, intramuscular, intravenous, intraarterial, intraperitoneal, intravesical, intracerebroventricular, intravitreal or subcutaneous administration; or through oral administration, intranasal administration, inhaled administration, vaginal administration, or rectal administration. A typical formulation is prepared by mixing an agent of the present application and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g.. Ansel H. C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery7 Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; Gennaro A. R. et al., Remington : The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe R. C, Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (he., an agent, of the present application or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product ( / . e., medicament). Compositions of the present application are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. In another aspect, the application provides use of the oligonucleotide agent, according to any one of the embodiments described herein, or a composition according to any one of the embodiments described herein, in the manufacture of a medicament for the treatment of gene or protein-related condition in an individual. The use according to certain embodiments, the condition can include a SMN-deficiency-related condition that comprises ALS. The use according to certain embodiments, the condition can include a SMN-deficiency-related condition that comprises a hereditary7 neuromuscular disease, preferably spinal muscular atrophy. In other embodiments, the condition can include an immune-related condition, such as cancer. Also provided is the use according to certain embodiments wherein the individual is a mammal, preferably a human. Dose regiments and route of administration Aspects of the present application relate to a pharmaceutical composition comprising the oligonucleotide agent of the present, application. In some embodiments, the pharmaceutical composition comprising die oligonucleotide agent of the present application and a pharmaceutically acceptable carrier, a therapeutically inert carrier, diluent or pharmaceutically acceptable excipient. The pharmaceutical composition disclosed herein is to be developed into a medicament preventing or treating the SODI protein related condition or ALS.                                " Aspects of the present application also relate to methods of using the oligonucleotide agents of the present application to prepare such compositions. Another aspect of the present application relates to use of the oligonucleotide agent of the present, application in manufacturing the pharmaceutical composition disclosed herein. Another aspect of the present application relates to use of the oligonucleotide agent, according to any one of the embodiments described herein, or a composition according to any one of the embodiments described herein, in the manufacture of a medicament for the prevention or treatment of gene or protein-related symptom induced by the over-expression of SOD1 protein, a SODI gene mutation, and / or high SOD I protein levels in an individual. For the use according to certain embodiments, the condition can include a SODI proteinmutation-related disorder or condition that comprises ALS. For the use according to certain embodiments, the symptom induced by over-expression of abnormal SODI protein is ALS. Also related is the use according to certain embodiments wherein the individual is a mammal, for example a human. The dosage at which the oligonucleotide agents or compositions of the present application can be administered can vary' within wide limits and will be fitted to the individual requirements in each case. In some embodiments, a first dose of a pharmaceutical composition according to the present application is administered when the subject is less than one week old, less than one month old, less than 3 months old, less than 6 months old, less than one-year-old, less than 2 years old, less than 15 years old, or older than 15 years old. The single dose of the oligonucleotide agent can be a single dose ranging from 0.01 mg / kg to 1000 mg / kg for example, about 0.01,0.02, 0.05, 0.1, 0.2, 0.5, I, 2, 2.5, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 30, 40, 50, 75, 100, 120, 150, 200, 250, 300, 400, 500, 750, or 1000 mg / kg. The doses described herein may contain two or more of any of the oligonucleotide agent sequences described herein. In some embodiments, the proposed dose frequency is approximate. For example, in some embodiments if the proposed dose frequency is a dose at. day 1 and a second dose at day 29, an ALS patient may receive a second dose 25, 26, 27, 28, 29, 30, 31, 32, 33, or 34 days after receipt, of the first dose. In some embodiments, if the proposed dose frequency is a dose at. day 1 and a second dose at day 15, an ALS patient, may receive a second dose 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days after receipt of the first dose. In some embodiments, if the proposed dose frequency is a dose at. day I and a second dose at day 85, an ALS patient may receive a second dose 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90 days after receipt of the first dose. In some embodiments, the dose and / or the volume of the injection will be adjusted based on the subject’s age, the subject's body weight, and / or other factors that may require adjustment of the parameters of the injection. In some embodiments, pharmaceutical compositions comprise a co-soivent system. Certain of such co-solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. In some embodiments, such cosolvent systems are used for hydrophobic compounds. A non-limiting example of such a cosolvent system is the VPD co-solvent system, which is a solution of absolute ethanol comprising 3% w / v benzyl alcohol, 8% w / v of the nonpolar surfactant Polysorbate 80™ and 65% w / v polyethylene glycol 300. The proportions of such co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics. Furthermore, the identity of co-solvent components may be varied: for example, other surfactants may be used instead of Polysorbate 80™; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose. Examples of other compositions or components associated with the oligonucleotide agent, compositions, pharmaceutical compositions, and methods described herein include, but are not limited to: diluents, salts, buffers, chelating agents, preservatives, drying agents, antimicrobials, needles, syringes, packaging materials, tubes, bottles, flasks, beakers, and the like, for example, for using, modifying, assembling, storing, packaging, preparing, mixing, diluting, and / or preserving the components for a particular use. In embodiments where liquid forms of any of the components are used, the liquid form may be concentrated or ready to use. In some embodiments, lipid moieties used in nucleic acid therapies can be applied in the present application for delivery of the oligonucleotide agent molecules disclosed herein. In such methods, the nucleic acid (e.g., one or more oligonucleotide agents described herein) is introduced into preformed liposomes or lipoplexes made of mixtures of cationic lipids and neutral lipids. In certain methods, oligonucleotide agent complexes with mono- or polycationic lipids are formed without the presence of a neutral lipid. In some embodiments, a lipid moiety is selected to increase distribution of a pharmaceutical agent to a particular cell or tissue. In some embodiments, a lipid moiety is selected to increase distribution of a pharmaceutical agent to fat tissue. In some embodiments, a lipid moiety is selected to increase distribution of a pharmaceutical agent to muscle tissue. In some embodiments, pharmaceutical compositions comprise a delivery system. Examples of delivery systems include, but are not limited to, liposomes and emulsions. Certain delivery7 systems are useful for preparing certain pharmaceutical compositions including those comprising hydrophobic compounds. In some embodiments, certain organic solvents such as dimethylsulfoxide are used. In some embodiments, pharmaceutical compositions comprise one or more tissue-specific delivery7 molecules designed to deliver the one or more pharmaceutical agents of the present application to specific tissues or cell types. For example, in some embodiments, pharmaceutical compositions include liposomes coated with a tissue-specific antibody. In some embodiments, the oligonucleotide agent can be delivered or administered via a vector. Any vectors that may be used for gene delivery7 may be used. In some embodiments, a viral vector may be used. Non-limiting examples of viral vectors that may be used in the present application include, but are not limited to, human immunodeficiency virus: HSV, herpes simplex virus; MMSV, Moloney murine sarcoma virus; MSCV, murine stern cell virus; SFV, Semliki Forest virus, SIN, Sindbis virus, VEE, Venezuelan equine encephalitis virus; VSV, vesicular stomatitis virus; W, vaccinia virus, AAV, adeno-associated virus; adenovirus; lent!virus; and retrovirus. In some embodiments, the vector is a recombinant AAV vector. AAV vectors are DNA viruses of relatively small size that can integrate, in a stable and site-specific manner, into the genome of the cells that they infect. They are able to infect a wide spectrum of cells without inducing any effects on cellular growth, morphology7 or differentiation, and they do not appear to be involved in human pathologies. The AAV genome has been cloned, sequenced and characterized. It encompasses approximately 4700 bases and contains an inverted terminal repeat (ITR) region of approximately 145 bases at each end, which serves as an origin of replication for the virus. The remainder of the genome is divided into two essential regions that carry the encapsulation functions: the left-hand part of the genome, that contains the rep gene involved in viral replication and expression of the viral genes, and the right-hand part of the genome, which contains the cap gene encoding die capsid proteins of die virus. AAV vectors may be prepared using standard methods in the art. Adeno-associated viruses of any serotype are suitable (see, e.g., Blacklow, pp. 165-174 of "Parvoviruses and Human Disease" J. R. Pattison, ed. (1988); Rose, Comprehensive Virology 3:1, 1974; P. Tattersall "The Evolution of Parvovirus Taxonomy" In Parvoviruses (J RKerr, S F Cotmore. ME Bloom, R M Linden, C R Parrish, Eds.) p 5-14, Hudder Arnold, London, UK (2006); and D E Bowles, J E Rabinowitz, R J Samulski "The Genus Dependovims" (J R Kerr, S F Cotmore. M E Bloom, R M Linden, C R Parrish, Eds.) p 15-23, Hudder Arnold, London, UK (2006), the disclosures of which are hereby incorporated by reference herein in their entireties). Methods for purifying for vectors may be found in, for example, U.S. Pat. Nos. 6,566,118, 6,989,264, and 6.995,006 and WO / 1999 / 011764 titled "Methods for Generating High Titer Helper-free Preparation of Recombinant AAV Vectors", the disclosures of which are herein incorporated by reference in their entirety. Preparation of hybrid vectors is described in, for example, PCT Application No. PCT / US2005 / 027091, the disclosure of which is herein incorporated by reference in its entirety. The use of vectors derived from the AAVs for transferring genes m vriro and in vivo has been described (See e.g., International Patent Application Publication Nos: 91 / 18088 and WO 93 / 09239; U.S. Pat. Nos. 4,797,368, 6,596,535, and 5,139,941; and European Patent No: 0488528, ail of which are herein incorporated by reference in their entirety). These publications describe various AAV-derived constructs in which the rep and / or cap genes are deleted and replaced by a gene of interest, and the use of these constructs for transferring the gene of interest in vitro (into cultured cells) or in vivo (directly into an organism), The replication defective recombinant AAVs according to the application can be prepared by co-transfecting a plasmid containing the nucleic acid sequence of interest flanked by two AAV inverted terminal repeat. (ITR) regions, and a plasmid carrying the AAV encapsulation genes (rep and cap genes), into a cell line that is infected with a human helper vims (for example an adenovirus). ’The .AAV recombinants that are produced are then purified by standard techniques. In some embodiments, the vector(s) for use in the methods of the application are encapsulated into a virus particle (e.g., AAV virus particle including, but not limited to, AAVl, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, A AV.10, AAVl.I, AAV12, AAV13, AAV14, AAVl 5, and AAV16). Accordingly, the application may include a recombinant virus particle (recombinant because it contains a recombinant polynucleotide) comprising any of the vectors described herein. Methods of producing such particles are known in the art and are described in U.S. Pat. No. 6,596,535. In a particular embodiment, the oligonucleotide agent shows a greater than additive effect or synergy in the treatment, prevention, delaying progression and / or amelioration of diseases caused by the SOD] gene, and additionally for the protection of cells implicated in the pathophysiology of the disease, particularly for the treatment, prevention, delaying progression and / or amelioration ALS. In some embodiments, the delivery of the pharmaceutical composition comprising the oligonucleotide agent can be through parenteral infusions including intrathecal, intramuscular, intravenous, intraarterial, intraperitoneal, intravesical, intracerebrovemricular, intravitreal or subcutaneous administration, or through oral administration, intranasal administration, inhaled administration, vaginal administration, or rectal administration. In certain embodiments, where a dose of the oligonucleotide agent is administered as an intrathecal injection by lumbar puncture, the use of a smaller gauge needle may reduce or ameliorate one or more symptoms associated with a lumbar puncture procedure. In certain embodiments, symptoms associated with a lumbar puncture include, but are not limited to, post-lumbar puncture syndrome, headache, back pain, pyrexia, constipation, nausea, vomiting, and puncture site pain. In certain embodiments, use of a 24- or 25-gauge needle for the lumbar puncture reduces or ameliorates one or more post lumbar puncture symptoms. In certain embodiments, use of a 21 -, 22-, 23-, 24- or 25-gauge needle for the lumbar puncture reduces or ameliorates post-lumbar puncture syndrome, headache, back pain, pyrexia, constipation, nausea, vomiting, and / or puncture site pain. In certain embodiments, die dose and / or the volume of the injection will be adjusted based on the patient's age, the patient's CSF volume, or the patient's age and / or estimated CSF volume. (For example, see Matsuzawa J, Matsui M, Konishi T, Noguchi K, Gur R C, Bilker W, Miyawaki T. Age-related volumetric changes of brain gray and white matter in healthy infants and children. Cereb Cortex 2001 April; 11(4):335-342, which is hereby incorporated by reference in its entirety). Kits In another aspect, any of the compositions described herein can be provided in one or more kits, optionally including instructions for use of the compositions. That is, the kit can include a description of use of an oligonucleotide agent or composition in any method described herein. A "kit," as used herein, typically defines a package, assembly, or container (such as an insulated container) including one or more of the components or embodiments of the application, and / or other components associated with the application, for example, as previously described. Any of the antes or components of the kit may be provided in liquid form (e.g., in solution), or in solid form (e.g., a dried powder, frozen, etc.). In some cases, the kit includes one or more components, which may be within the same or in two or more receptacles, and / or in any combination thereof. The receptacle is able to contain a liquid, and non-limiting examples include bottles, vials, jars, tubes, flasks, beakers, or the like. In some cases, the receptacle is spill-proof (when closed, liquid cannot exit the receptacle, regardless of orientation of the receptacle). Examples of other compositions or components associated with the agents, compounds and methods described herein include, but are not limited to: diluents, salts, buffers, chelating agents, preservatives, drying agents, antimicrobials, needles, syringes, packaging materials, tubes, bottles, flasks, beakers, and the like, for example, for using, modifying, assembling, storing, packaging, preparing, mixing, diluting, and / or preserving the components for a particular use. In embodiments where liquid forms of any of the components are used, the liquid form may be concentrated or ready to use. In additional embodiments, a. kit can include instructions or instructions to a website or other source in any form that are provided for using the kit in connection with the components and / or methods described herein. For instance, the instructions may include instructions for the use, modification, mixing, diluting, preserving, assembly, storage, packaging, and / or preparation of the components and / or other components associated with the kit. In some cases, the instructions may also include instructions for the delivery of the components, for example, for shipping or storage at room temperature, sub-zero temperatures, cryogenic temperatures, etc. The instructions may be provided in any form that is useful to the user of the kit, such as written or oral (e.g., telephonic), digital, optical, visual (e.g., videotape, DVD, etc.) and / or electronic communications (including Internet or web-based communications), provided in any manner. Materials and methods General methods Starting materials, reagents and solvents for organic synthesis were purchased from commercial sources and used as received unless stated otherwise. Purification of reactions products was performed by column chromatography using silica gel (200-300 mesh) and eluting with hexane / ethyl acetate, DCM / MeOH. Thin layer chromatography (TLC) was carried out using precoated silica Gel GF plates and visualized using KMnO4 stains. 1H-NMR spectra were recorded at 400 or 500 MHz (Varian) using CDC13 with TMS. Mass spectra (MS) were recorded on LC / MS (Agilent. Technologies 1260 Infinity 11 / 6120 Quadrupole) and a time-of-flight mass spectrometer by ESI or matrix assisted laser desorption / ionization (MALDI). Oligonucleotide Synthesis The oligonucleotides used were synthesized on a K&A. DNA synthesizer (K&ALaborgeraete GbR, Schaafheim, Germany) by using solid phase technique. Briefly, during solid phase synthesis, phosphoramidite monomers including various linkers and conjugations (0. IM in acetonitrile or dichloromethane), were added sequentially onto a solid support to generate die desired full-length oligonucleotides. Each cycle of base addition consisted of four chemical reactions including detritylation, coupling, oxidation / thiolation and capping. Detritylations were performed using 3% di chloroacetic acid (TCA) in DCM for 45 seconds and capping was done with a 16% N-methylimidazole in THF (CAP A) and THF:acetic anhydride:2,6-lutidine, (80:10:10, v / v / v) (CAP B) for 20 seconds . Sulfurizations were carried out with 0.1 M solution of xanthane hydride in pyridine / ACN (50:50, v / v) for 3 minutes. Oxidation was performed using 0.02 M iodine in THF'.pyridine:water (70:20:10, v / v / v) for 60 seconds. Phosphoramidite coupling times were 360 s for all amidites. Deprotection I (Nucleoba.se Deprotection): After completion of synthesis, the solid support was then irans.fen.-ed to a screw-cap microcentrifuge tube. For a 1 pM synthesis scale, a mixture of 33% methylamine in ethanol and 1 mi of ammonium hydroxide was added. The tube containing the solid support was then heated in an oven at 60°C to 65°C for 15 min and then allowed to cool to room temperature. The cleavage solution was collected and evaporated to dryness in a speedvac. Deprotection II (Removal of 2’-TBDMS Group): The crude RNA oligonucleotide, still carrying the 2’-TBDMS groups, was dissolved in 0.1 ml of DMSO. After adding 1 ml of Triethylamine 3HF, the tube was capped, and the mixture was shaken vigorously to ensure complete dissolution. The bottle was heated in an oven at 60°C to 65QC for 3 to 3.5 hours. The tube was removed from the oven and cooled to room temperature. The solution containing the completely desilyl ated oligonucleotide was cooled on dry ice. 2 mis of icecold n-butanol (-20^0) were carefully added in 0.5 ml portions to precipitate the oligonucleotide. The precipitate was filtered, washed with 1 ml ice-cold n-butanol, and subsequently dissolved in 2M TEAA (triethylammonium acetate). The crude oligonucleotides were then purified by exchange (IEX) HPLC using a source 15Q column. Purity of the fractions were analyzed by ion exchange (IEX) HPLC using Column DN A Pac™ PA100. Following the generation of desalted purified single-strand solutions, a duplex was made by annealing two complimentary single-stranded oligonucleotides, which were subsequently lyophilized to powder. RP-HPLC and ESI-MS Oligonucleotides were analyzed via reverse phase chromatography (i.e., RP-HPLC) (Waters XBridge oligonucleotide BEH Cl8 I30A) using an acetonitrile grant and detection wavelength of 260 nm to qualify oligonucleotide purity. Electrospray ionization mass spectrometry (ESI-MS) was performed on desalted oligonucleotides resuspended in water / acetonitrile (50:50) containing 1% (vol / vol) triethylamine in. negative ion mode. Cell culture and treatment SMA patient-derived fibroblasts including GM03813 (SMA type II with 3 copies of SMN2 gene) and GM09677 (SMA type I with 3 copies of SMN2 gene) cells were obtained from Coriell Institute (Camden, NJ, USA). Both cultures were maintained at 37®C with 5% CO? in modified MEM medium (Gibco, Thermo Fisher Scientific, Carlsbad, CA) supplemented with 15% bovine calf serum (Sigma-Aldrich), 1% NEAA (Gibco), and 1% peniciHin / streptomycin (Gibco). Mouse neural stem cell line NSC-34 (BNCC341122, Beijing, China), HEK293A (Cobioer / CBP60436, Nanjing, China), and NSC-34 (BNCC341122, Beijing, China) cells were cultured at 37°C with 5% CO? in DMEMi (Gibco) medium supplemented with 10% bovine calf serum (Sigma-Aldrich) and 1% penicillin / streptomycin (Gibco). Primary mouse hepatocytes (PMH) were isolated from the liver of Type III SMA (Smnl"7', SMN2+ / +) mice. PMH cells were cultured at 37°C with 5% CO2 in modified DMEM medium (Gibco, Thermo Fisher Scientific, Carlsbad, CA) supplemented with 10% bovine calf serum (Sigma-Aldrich) and 1% penicillin / streptomycin (Gibco). SH-SY5Y ceils (SCSP-5014, Chinese Academy of Sciences, Shanghai, China) were cultured at 5% CO? and 37°C in MEM medium (Gibco, Thermo Fisher Scientific, Carlsbad, CA) supplemented with 10% bovine calf serum (Sigma-Aldrich) and 1% peniciHin / streptomycin (Gibco). Neuro-2a (N-2a, BNCC338529, Beijing, China) were cultured at 5% CO? and 37°C in E.MEM medium (Gibco, Thermo Fisher Scientific, Carlsbad, CA) supplemented with 10% bovine calf serum (Sigma-Aldrich) and 1% peniciHin / streptomycin (Gibco). Human glioma cell line T98G (ATCC) cells were cultured at. 37°C with 5% CO2 in modified MEM medium (Gibco, Thermo Fisher Scientific, Carlsbad, CA) supplemented with 10% bovine calf serum (Sigma-Aldrich) and 1% peniciHin / streptomycin (Gibco). Human cervical carcinoma cell HeLa (ATCC) cells were cultured at 37°C with 5% CO2 in modified RPMI 1640 medium (Gibco, Thermo Fisher Scientific, Carlsbad, CA) supplemented with 10% bovine calf serum (Sigma-Aldrich) and 1% peniciHin / streptomycin (Gibco). The T98G, HeLa. and HEK293 A cells were seeded into 24-well plates at 10x10*4 cells / well. siRNAs (note: the oligonucleotide agents in the present invention are simplified as “’siRNA” in the description of materials, methods and examples hereafter) were individually transfected into the cells in each well at indicated concentration, or any other concentrations with 0.3 uL of RNAiMAX (Invitrogen, Carlsbad, CA) by following the reverse transfection protocol respectively, and the transfection duration was 24 hours. Other cells were seeded into 6- and 96-well plates at. a final density of 1-2 x ] 0s and 6000 cells / well, respectively. Mock (blank control) was transfected in the absence of an oligonucleotide. dsCon2 duplex was transfected as a non-specific duplex control. AH oligonucleotide sequences including RNA duplexes and ODV constructs used for cell treatments are listed in Table 2, Table 3 and Table 8. ACO sequence are listed in Table 7. Table 2. Oligonucleotide strand sequences and duplex compositions Oligonucleotide name Category Target gene(s) SEQ ID NO Sequence (5'-3') Size (nt) dsCon2 Neg. Control dsRNA 24 ACUACUGAGUGACAGUAGATT 21 25 UCUACUGUCACUCAGUAGUTT 21 siHTT-SIVl siRNA HTT 26 mU*mA*mUmCmAmGfUmALAfAfGmAmGmAmUmU*mA*mA 18 27 VPmU*fU*mAmAmUfCmUmCmUmUfL!mAfCmUmGmAmUmA*mU*mA 20 siHTT-AC2-SlLl ODV-siRNA HTT 28 mU*inA*mUmCmAmGfUmAfAfAfGmAmGmAmUmU*mA*mA-S18-meU*meA*meG*meA*meC*meU*meA*meG*meA*meU*meC*meA*meU* meA*meU*meG*meA*meG 36 27 VPmU*fU*mAmAmUfCmUmCmUmUfL!mAfCmUmGmAmUmA*mU*mA 20 siApp-8-SlVlv siRNA App 30 fC*mC*fCmAfGmAfAmUfCfAfGmCfUmAfCmGfGmAfA 19 31 WmU*fU*mCfCmGlLTmAfGmCfUmGfAmUfUmCfUmGfGmG*fC*mU 21 si App-8-AC2(N18)-S 1L1V3 v ODV-siRNA App 32 fC*mC*fCmAfGmAfAmUfCfAfGmCflJmAfCmGfGmAfA-S18-U*A*G*A*C*U*A*G*AW*C*A*U*A*U*G*A*G 37 31 VPmU*fU*mCfCmGfUinAfGmCfUmGfAmUfUmCfUmGfGmG*fC*mU 21 siApp-8-AC2(N 15)-S IL 1 V3v ODV-siRNA App 34 fC*mC*fCmAfGmAfAmUfCfAfGmCfUmAfCmGfGmAfA-S18-U*A*G*A*C*U*A*G*A*U*C*A*U*A*U 34 31 VPmU*fU*mCfCmGfUmAfGmCfUmGfAmUfUmCfUmGfGmG*fC*mU 21 siApp-8-AC2(N12)-SlLlV3v ODV- siRNA App 36 fC*mC*fCmAfGmAfAmUfCfAfGmCfUmAfCmGfGmAfA-S 18-U*A*G*A*C*U*A*G*A*U*C*A 32 31 VPmU*fU*mCfCmGfUmAfGmCfUmGfAmUfUmCfUmGfGmG*fC*mU 21 siSODl-231-E siRNA SOD1 38 fU*mG*fAmAfGmAfGmAfGfGfCmAfUmGfUmUfG*mG*fA 19 39 mU*fC*mCfAmAfCmAfUmGfCmCfUmCfUmCfUmUfCmA*fU*mC 21 siSODl-231-TT siRNA SOD1 40 fU*mG*fAmAfGmAfGmAfGfGfCmAfUmGfUmUfG*mG*fA 19 41 mU*fC*mCfAmAfCmAfUmGfCmCfUmCfUmCfUmUfCinA*T*T 21 siSOD 1-231-Ml siRNA SOD1 42 mG*TA*niAfGmAfGmAfGfGfCJAfUmGfl!mUfG*mG*£A 18 43 mU*fC*mCfAmAfCmAfUmGfCmCfUmC*fU*mC*fU*mU*fC*mA*fU 20 siSOD 1-231-S2 siRNA SOD1 44 fG*mA*fGmAfGmGfCmAfUmGfUmUfG*mG*fA 15 45 mU*fC*mCfAmAfCmAfUmGfCmCfUmC*fU*mC*fU*mU*fC*mA*fU 20 siSOD 1-388-E siRNA SOD1 46 fG*mG*fUmGtGmAfAmAfUfGfAmAtGmAfAniAf*GmU*tA 19 WO 2023 / 280190                                                 PCT / CN2022 / 104037 47 mU*fA*mCfUmUfUmCfUmUfCmAfUmUfUmCfCmAfCinC*fU*mU 21 siSODl-388-TT siRNA SOD1 48 fG*mG*fUmGfGmAfAmAfUfGfAmAfGmAfAmAf*GmU*fA 19 49 mU*fA*mCfUmUfUmCfUmUfCmAfUmUfUmCfCmAfCmC*T*T 21 siSODl-388-Ml siRNA SOD1 50 mG*fU*mGfGmAfAmAfUfGfAfAfGmAfAmAfG*mU*fA 18 51 mU*fA*mCfUmUfUmCfUmUfCmAfUmU*fU*mC*fC*mA*fC*inC*fU 20 siSOD 1-388-S2 siRNA SOD1 52 fG*mA*fAmAflJmGf.AmAfGmAfAmAfG*mU*fA 15 53 mU*fA*mCfUmUfUmCfUmUfCniAfUmU*fU*mC*fC*mA*fC*mC*fU 20 siSOD 1M2-L1 siRNA SOD I 54 fG*mG*fUmGfGmAfAmAfUfGfAmAfGmAfAtnAf*GmU*fA-S18 19 47 mU*fA*mCfUmUfUmCflJmUfCniAfUmUfUmCfCmAfCinC*fU*mU 21 siSOD 1M2-SIV Iv-Qu5 siRNA SOD1 56 fG*mG*fUmGfGmAfAmAfUfGfAmAfGmAfAmAf*GmU*fA-Qu5 19 57 VPmU*fA*mCfUmUfUmCfUmUfCmAfUmUfUmCfCmAfCmC*fU*mU 21 siSOD 1M2-AC2(N22)-S1 V3v-Qu5 ODV- siRNA SOD1 58 Qu5-fG*mG*fUmGfGmAfAmAfUfGfAmAfGmAfAmAfG*mU*fA-S18-U*A*G*A*C*U*A*G*A*U*C*A*U*A*U*G*A*G*U*A*G*A 41 57 VPmU*fA*mCfUmUfUmCfUmUfCmAfUmUfUmCfCmAfCmC*fU*mU 21 siSOD 1M2-AC2(N 15)-S 1 V3v-Qu5 ODV-siRNA SOD1 60 Qu5-fG*mG*fUmGfGmAfAmAfUfGfAmAfGmAfAmAfG*mU*fA-Sl 8- U*A*G*A*C*U*A*G*A*U*C*A*U*A*U 34 57 VPmU*fA*mCfUmUfUmCfUmUfCmAfUmUfUmCfCmAfCmC*fL!*mU 21 siSOD 1M2-AC2(N 12)-81 V3v-Qu5 ODV- siRNA SOD1 62 Qu5-fG*mG*fUmGfGmAfAmAfUfGfAmAfGmAfAmAfG*mU*fA-S18- U*A*G*A*C*U*A*G*A*U*C*A 31 57 WmU*fA*mCflJmUfUmCfUmUfCmAfL!mUfUmCfCmAfCmC*fU*mU 21 siSOD 1M2-AC2(N6)-S 1V3 v-Qu5 ODV- siRNA SOD1 64 Qu5-fG*mG*flJmGfGmAfAmAlUfGlAmAfGmAfAmAlG*mU*fA-S18-U*A*G*A*C*U 25 57 VPinU*fA*mCfUmUfUmCfUmUfCmAfUinUfUmCfCinAfCinC*fU*mU 21 R6-04(20)-S IV lv(CM-4) saRNA SAIN 2 66 mG*fA*mCfGmAfGmGfCfCfUfAfAniGfCmAfA*mC*tA 18 67 VPmU*fG*mUfUmGfCmUfUmAfGmGfCmC*lLr*mC*fG*mU*fC*mU*fC 20 R6-04M1-AC2 (18)-S IL 1 V3v ODV- saRNA SMN2 68 mG*fA*mCfGmAfGmGfCfCfUfAfAmGfCmAfA*mC*fA-S18- meU*meA*meG*meA*meC*meU*meA*meG*meA*meU*meC*meA*meU* meA*meU*meG*meA*meG 36 67 VPmU*fG*mUfUmGfCmUfUmAfGmGfCmC*lLr*mC*fG*mU*fC*mU*fC 20 WO 2023 / 280190                                                 PCT / CN2022 / 104037 34 20 CO 20 p! 20 31 20 o 20 20 28 20 20 20 mG*fA*mCfGmAfGmGfCfCfUfAfAmGfCmAfA*mC *fA-S18-meU*meA*meG*meA*meC*meU*meA*meG*meA*meU*meC*meA*meU* me A *meU * meG VPmU*fG*mUfUmGfCmUfL'mAfGmGfCmC*W*mC*fG*mU*fC*mU*fC mG*fA*mCfGmAfGmGfCfCfUfAfAmGfCmAfA*mC*fA-S 18-meU*meA*meG*meA*meC*meU*meA*meG*meA*meU*meC*meA*me]J* meA*meU VPmU*fG*mUfUmGfCmUfL'mAfGmGfCmC*W*mC*fG*mU*fC*mU*fC mG*fA*mCfGmAfGmGfCfCfUfAfAmGfCmAfA*mC*fA-S 18-meU*meA*meG*meA*meC*meU*meA*meG*meA*meU*meC*meA*me]J* me A VPmU*fG*mUfUmGfCmUfL'mAfGmGfCmC*W*mC*fG*mU*fC*mU*fC a > bi t>0 CZ3 J5 < 01 -fr £ g < * o < g id is o g Q p 8 0 < g g < 01 B § a < o y si s ■" a b a g O ■" s < •0 y <*-> * PI "s * •IT* JS s 2 a a a § ’g ’g § •s* g <s 8 * o £ °? -r < a b S s ■< «■ u s S- S o b s G <£ a o < a jS bl ei a S U g y C 1 P S P £ C -X-g O O £3 O -X-£ <3^ •f y g G «” * Gl a a WmU*fG*mUfUmGfCmUfL!mAfGmGfCmC*fU*mC*fG*mU*fC*mU*fC mG*fA*mCfGmAfGmGfCfCfUfAfAmGfCmAfA*mC*fA-S 18-meU*meA*meG*meA*meC*meU*meA*meG*meA*meU*meC \7PmU*fG*mUfUmGfCmU:RTmAfGmGfCmC*fU*mC*fG*mU*fC*mU*fC mG*fA*mCfGmAfGmGfCfCtGfAfAmGfCmAfA*mC*fA-S18-meU*meA*meG*meA*meC*meU*nieA*meG*meA*meIJ VPmU*fG*mUfUmGfCmUfUinAfGmGfCmC*fU*mC*fG*mU*fC*mU*fC mG*fA*mCfGmAfGmGfCfCfUfAfAmGfCmAfA*mC *fA-S 18-meU*meA*meG*meA*meC*meU*meA*meG*meA VPmU*fG*mUfUmGfCmUfL'mAfGmGfCmC*lLr*mC*fG*mU*fC*mU*fC mG*fA*mCfGmAfGmGfCfCfUfAfAmGfCmAfA*mC*fA-S 18-meU*meA*meG*meA*meC*meU*meA*meG WmU*fG*mUfUmGfCmUfL!mAfGmGfCmC*fU*mC*fG*mU*fC*mU*fC 70 67 72 67 74 67 r? 67 00 r- 67 o co 82 SO 84 67 86 67 ZNIAS SMN2 SMN2 SMN2 SMN2 SMN2 SMN2 ZNIAS SMN2 ODV-saRNA ODV-saRNA ODV-saRNA ODV-saRNA ODV-saRNA ODV-saRNA ODV-saRNA ODV-saRNA ODV-saRNA R6-04M1-AC2(16)-S1L1V3v R6-04M1-AC2 (15)-S IL 1 V3v R6-04M1 -AC2(14)-S 1LI V3v R6-04M1-AC2(13)-S1L1V3v R6-04M1 -AC2( 12)-S IL 1V3 v R6-04M1 -AC2(11)-S 1LI V3v R6-04M1 - AC2( 10)-S IL 1 V3v R6-04M1 -AC2(9)-S IL 1V3 v R6-04M1 -AC2(8)-S 1L1 V3v n.b.: upper case, RNA; *. phosphorothioate (PS) backbone modification; f, 2'-fluoro, m, 2'-O-m.ethyl (2'-0Me); me, 2'-O-methoxyethy1 (2’ MOE); VP, 5'-(E)-vinylphosphonate, C, 5'-methvl cytosine: U, 5'-methvl uracil, SI8, spacer-18 linker: Qu5, Quasar570 Table 3. Oligonucleotide strand sequences and duplex compositions siRNA SEQID NO Target sequence (5’-3') SEQID NO Sense (5'-3') SEQID NO Antisense (5’-3') siSODl-5 88 cgacgaaggccgtgtgcgt 357 CGACGAAGGCCGUGUGCGUTT 626 ACGCACACGGCCUUCGUCGTT siSODl-8 89 cgaaggccgtgtgcgtgcl 358 CGAAGGCCGUGUGCGUGCUTT 627 AGCACGCACACGGCCUUCGTT siSODl-10 90 aaggccgtgtgcgtgctga 359 AAGGCCGUGUGCGUGCUGATT 628 UCAGCACGCACACGGCCUUTT siSODl-11 91 aggccgtgtgcgtgctgaa 360 AGGCCGUGUGCGUGCUGAATT 629 UUCAGCACGCACACGGCCUTT siSODl-17 92 tgtgcgtgctgaagggcga 361 UGUGCGUGCUGAAGGGCGATT 630 UCGCCCUUCAGCACGCACATT siSODl-35 93 acggcccagtgcagggcat 362 ACGGCCCAGUGCAGGGCAUTT 631 AUGCCCUGCACUGGGCCGUTT siSODl-37 94 ggcccagtgcagggcatca 363 GGCCCAGUGCAGGGCAUCATT 632 UGAUGCCCUGCACUGGGCCTT siSODl-38 95 gcccagtgcagggcatcat 364 GCCCAGUGCAGGGCAUCAUTT 633 AUGAUGCCCUGCACUGGGCTT siSODl-40 96 ccagtgcagggcatcatca 365 CCAGUGCAGGGCAUCAUCATT 634 UGAUGAUGCCCUGCACUGGTT siSODl-41 97 cagtgcagggcatcatcaa 366 CAGUGCAGGGCAUCAUCAATT 635 UUGAUGAUGCCCUGCACUGTT siSODl-42 98 agtgcagggcatcatcaat 367 AGUGCAGGGCAUCAUCAAUTT 636 AUUGAUGAUGCCCUGCACUTT siSODl-43 99 gtgcagggcatcatcaatt 368 GUGCAGGGCAUCAUCAAUUTT 637 AAUUGAUGAUGCCCUGCACTT siSODl-44 100 tgcagggcatcatcaattt 369 UGCAGGGCAUCAUCAAUUUTT 638 AAAUUGAUGAUGCCCUGCATT siSODl-45 101 gcagggcatcatcaatttc 370 GCAGGGCAUCAUCAAUUUCTT 639 GAAAUUGAUGAUGCCCUGCTT siSODl-46 102 cagggcatcatcaatltcg 371 CAGGGCAUCAUCAAUUUCGTT 640 CGAAAUUGAUGAUGCCCUGTT siSODl-47 103 agggcat cat caatttcga 372 AGGGCAUCAUCAAUUUCGATT 641 UCGAAAUUGAUGAUGCCCUTT siSODl-50 104 gcatcatcaatttcgagca 373 GCAUCAUCAAUUUCGAGCATT 642 U GCU CGAAAUU GAU GAUGCTT siSODl-51 105 catcatcaatttcgagcag 374 CAUCAUCAAUUUCGAGCAGTT 643 CUGCUCGAAAUUGAUGAUGTT siSODl-52 106 atcatcaatttcgagcaga 375 AUCAUCAAUUUCGAGCAGATT 644 UCUGCUCGAAAUUGAUGAUTT siSODl-53 107 tcatcaatttcgagcagaa 376 UCAUCAAUUUCGAGCAGAATT 645 UUCUGCUCGAAAUUGAUGATT siSODl-56 108 tcaatttcgagcagaagga 377 UCAAUUUCGAGCAGAAGGATT 646 UCCUUCUGCUCGAAAUUGATT siSODl-57 109 caatttcgagcagaaggaa 378 CAAUUUCGAGCAGAAGGAATT 647 UUCCUUCUGCUCGAAAUUGTT siSODl-58 110 aatttcgagcagaaggaaa 379 AAUUUCGAGCAGAAGGAAATT 648 UUUCCUUCUGCUCGAAAUUTT siSODl-59 111 atttcgagcagaaggaaag 380 AUUUCGAGCAGAAGGAAAGTT 649 CUUUCCUUCUGCUCGAAAUTT WO 2023 / 280190                                                 PCT / CN2022 / 104037 siSOD 1-60 112 ttlcgagcagaaggaaagt 381 UUUCGAGCAGAAGGAAAGUTT 650 ACUUUCCUUCUGCUCGAAATT siSOD 1-61 113 ttcgagcagaaggaaagta 382 UUCGAGCAGAAGGAAAGUATT 651 UACUUUCCUUCUGCUCGAATT siSOD 1-62 114 tcgagcagaaggaaa gtaa 383 UCGAGCAGAAGGAAAGUAATT 652 UUACUUUCCUUCUGCUCGATT siSOD 1-63 115 cgagcagaaggaaagtaat 384 CGAGCAGAAGGAAAGUAAUTT 653 AUUACUUUCCUUCUGCUCGTT siSOD 1-64 116 gagcagaaggaaagtaatg 385 GAGCAGAAGGAAAGUAAUGl T 654 CAUUACUUUCCUUCUGCUCTT siSOD 1-66 117 gcagaaggaaagtaatgga 386 GCAGAAGGAAAGUAAUGGATT 655 UCCAUUACUUUCCUUCUGCTT siSOD 1-69 118 gaaggaaagtaatggacca 387 GAAGGAAAGUAAUGGACCATT 656 UGGUCCAUUACUUUCCUUCTT siSOD 1-72 119 ggaaagtaatggaccagtg 388 GGAAAGUAAUGGACCAGUGTT 657 CACUGGUCCAUUACUUUCCTT siSOD 1-73 120 gaaagtaatggaccagtga 389 GAAAGUAAUGGACCAGUGATT 658 UCACUGGUCCAUUACUUUCTT siSODl-74 121 aaagtaatggaccagtgaa 390 AAAGUAAUGGACCAGUGAATT 659 UUCACUGGUCCAUUACUUUTT siSOD 1-75 122 aagtaatggaccagtgaag 391 AAGUAAUGGACCAGUGAAGTT 660 CUUCACUGGUCCAUUACUUTT siSOD 1-77 123 gtaatggaccagtgaaggt 392 GUAAUGGACCAGUGAAGGUTT 661 ACCUUCACUGGUCCAUUACTT siSOD 1-79 124 aatggaccagtgaaggtgt 393 AAUGGACCAGUGAAGGUGUTT 662 ACACCUUCACUGGUCCAUUTT siSOD 1-80 125 atggaccagtgaaggtgtg 394 AUGGACCAGUGAAGGUGUGTT 663 CACACCUUCACUGGUCCAUTT siSODl-85 126 ccagtgaaggtgtggggaa 395 CC AGUG A AGGLi GUGGGG A ATT 664 UUCCCCACACCUUCACUGGTT siSOD 1-88 127 gtgaaggtgtggggaagca 396 GUGAAGGUGUGGGGAAGCATT 665 UGCUUCCCCACACCUUCACTT siSOD 1 ’89 128 tgaaggtgtggggaagcat 397 UGAAGGUGUGGGGAAGCAUTT 666 AUGCUUCCCCAC ACCUUCATT siSOD 1-90 129 gaaggtgtggggaagcatt 398 GAAGGUGUGGGGAAGCAUUTT 667 AAUGCUUCCCCACACCUUCTT siSOD 1-91 130 aaggtgtggggaagcatta 399 AAGGUGUGGGGAAGCAUUATT 668 UAAUGCUUCCCCACACCUUTT siSODl-92 131 aggtgtggggaagcattaa 400 AGGUGUGGGGAAGCAUUAATT 669 UUAAUGCUUCCCCACACCUTT siSOD 1-93 132 ggtgtggggaa gcattaaa 401 GGUGUGGGGAAGCAUUAAATT 670 UUUAAUGCUUCCCCACACCTT siSOD 1 ’94 133 gtgtggggaagcattaaag 402 GUGUGGGGAAGCAUUAAAGTT 671 CUUUAAUGCUUCCCCACACTT siSOD 1-95 134 tgtggggaagcattaaagg 403 UGUGGGGAAGCAUUAAAGGTT 672 CCUUUAAUGCUUCCCCACATT siSOD 1-96 135 gtggggaagcattaaagga 404 GUGGGGAAGCAUUAAAGGATT 673 UCCUUUAAUGCUUCCCCACTT siSODl-98 136 ggggaagcattaaaggact 405 GGGGAAGCAUUAAAGGACUTT 674 AGUCCUUUAAUGCUUCCCCTT siSOD 1-99 137 gggaagcattaaaggactg 406 GGGAAGCAUUAAAGGACUGTT 675 CAGUCCUUUAAUGCUUCCCTT siSOD 1-100 138 ggaagcattaaaggactga 407 GGAAGCAUUAAAGGACUGATT 676 UCAGUCCUUUAAUGCUUCCTT siSODl-102 139 aagcattaaaggactgact 408 AAGCAUUAAAGGACUGAUU 1’1 677 AGUCAGUCCUUUAAUGCUUTT siSODl-104 140 gcattaaaggactgactga 409 GCAUUAAAGGACUGACUGATT 678 UCAGUCAGUCCUUUAAUGCTT siSODl-105 141 cattaaaggactgactgaa 410 CAUUAAAGGACUGACUGAATT 679 UUCAGUCAGUCCUUUAAUGTT WO 2023 / 280190                                                 PCT / CN2022 / 104037 Ui siSODl-106 142 attaaaggactgactgaag 411 AUUAAAGGACUGACUGAAGTT 680 CUUCAGUCAGUCCUUUAAUTT siSODl-107 143 ttaaaggactgactgaagg 412 UUAAAGGACUGACUGAAGGTT 681 CCUUCAGUCAGUCCUUUAATT siSOD 1-108 144 taaaggactgactgaaggc 413 UAAAGGACUGACUGAAGGCTT 682 GCCUUCAGU CAGUCCUUUATT siSODl-114 145 actgactgaaggcctgcat 414 ACUGACUGAAGGCCUGCAUTT 683 AUGCAGGCCUUCAGUCAGUTT siSODl-117 146 gactgaaggcctgcatgga 415 GACUGAAGGCCUGCAUGGATT 684 UCCAU GCAGGCCU UCAGUCTT siSODl-118 147 actgaaggcctgcatggat 416 ACUGAAGGCCUGCAUGGAUTT 685 AUCCAUGCAGGCCUUCAGUTT siSODl-119 148 ctgaaggcctgcatggatt 417 CUGAAGGCCUGCAUGGAUUTT 686 AAUCCAUGCAGGCCUUCAGTT siSODI-120 149 tgaaggcctgcatggattc 418 UGAAGGCCUGCAUGGAUUCTT 687 GAAUCCAUGCAGGCCUUCATT siSODl-122 150 aaggcctgcatggattcca 419 AAGGCCUGCAUGGAUUCCATT 688 UGGAAUCCAUGCAGGCCUUTT siSODl-123 151 aggcctgcatggattccat 420 AGGCCUGCAUGGAUUCCAUTT 689 AUGGAAUCCAUGCAGGCCUTT siSODl-125 152 gcctgcalggaltccatgt 421 GCCUGCAUGGAUUCCAUGUTT 690 ACAUGGAAUCCAUGCAGGCTT siSOD 1-126 153 cctgcatggattccatgtt 422 CCUGCAUGGAUUCCAUGUUTT 691 AACAUGGAAUCCAUGCAGGTT siSODI-127 154 ctgcatggattccatgttc 423 CUGCAUGGAUUCCAUGUUCTT 692 GAACAUGGAAUCCAUGCAGTT siSODl-128 155 tgcatggattccatgttca 424 UGCAUGGAUUCCAUGUUCATT 693 UGAACAUGGAAUCCAUGCATT siSODl-129 156 gcatggattccatgttcat 425 GCAUGGAUUCCAUGUUCAUTT 694 AUGAACAUGGAAUCCAUGCTT siSODl-131 157 atggattccatgttcatga 426 AUGGAUUCCAUGUUCAUGATT 695 UCAUGAACAUGGAAUCCAUTT siSODl-132 158 tggattccatgttcatgag 427 UGGAUUCCAUGUUCAUGAGTT 696 CUCAUGAACAUGGAAUCCATT siSODI-133 159 ggattccatgttcatgagt 428 GGAUUCCAUGUUCAUGAGUTT 697 ACUCAUGAACAUGGAAUCCTT siSODl-134 160 gattccatgttcatgagtt 429 GAUUCCAUGUUCAUGAGUUTT 698 AACUCAUGAACAUGGAAUCTT siSODl-137 161 tccatgttcatgagtttgg 430 UCCAUGUUCAUGAGUUUGGTT 699 CCAAACUCAUGAACAUGGATT siSODl-138 162 ccatgttcatgagtttgga 431 CCAUGUUCAUGAGUUUGGATT 700 UCCAAACU CAUGAACAU GGTT siSOD 1-140 163 atgttcatgagtttggaga 432 AUGUUCAUGAGUUUGGAGATT 701 UCUCCAAACUCAUGAACAUTT siSOD 1-141 164 tgttcatgagtttggagat 433 UGUUCAUGAGUUUGGAGAUTT 702 AUCUCCAAACUCAUGAACATT siSODl-142 165 gttcatgagtttggagata 434 GUUCAUGAGUUUGGAGAUATT 703 UAUCUCCAAACUCAUGAACTT siSODl-148 166 gagtttggagataatacag 435 GAGUUUGGAGAUAAUACAGTT 704 CUGUAUUAUCUCCAAACUCTT siSODl-150 167 gtttggagataatacagca 436 GUUU GGAGAUAAUACAGCATT 705 UGCUGUAUUAUCUCCAAACTT siSOD 1-154 168 ggagataatacagcaggct 437 GGAGAUAAUACAGCAGGCUTT 706 AGCCUGCUGUAUUAUCUCCTT siSODl-156 169 agataatacagcaggctgt 438 AGAUAAUACAGCAGGCUGUTT 707 ACAGCCUGCUGUAUUAUCUTT siSODl-157 170 gataatacagcaggc tgta 439 GAUAAUACAGCAGGCUGUATT 708 UACAGCCUGCUGUAUUAUCTT siSODl-158 171 ataatacagcaggctgtac 440 AUAAUACAGCAGGCUGUACTT 709 GUACAGCCUGCUGUAUUAUTT WO 2023 / 280190                                                 PCT / CN2022 / 104037 oe siSODl-159 172 taatacagcaggctgtacc 441 UAAUACAGCAGGCUGUACCTT 710 GGUACAGCCUGCUGUAUUATT siSODl-160 173 aatacagcaggctgtacca 442 AAUACAGCAGGCUGUACCATT 711 UGGUACAGCCUGCUGUAUUTT siSOD 1-162 174 tacagcaggctgtaccagt 443 UACAGCAGGCUGUACCAGUTT 712 ACUGGUACAGCCUGCUGUATT siSODl-163 175 acagcaggctgtaccagtg 444 ACAGCAGGCUGUACCAGUGTT 713 CACUGGUACAGCCUGCUGUTT siSODl-165 176 agcaggctgtaccagtgca 445 AGCAGGCUGUACCAGUGCATT 714 UGCACUGGUACAGCCUGCUTT siSODl-171 177 ctgtaccagtgcaggtcc t 446 CUGUACCAGU GCAGGUCCUTT 715 AGGACCUGCACUGGUACAGTT siSODl-173 178 gtaccagtgcaggtcctca 447 GUACCAGUGCAGGUCCUCATT 716 UG AGGACCUGC A CUGGU ACTT siSOD 1-175 179 accagtgcaggtcctcact 448 ACCAGUGCAGGUCCUCACUTT 717 AGUGAGGACCUGCACUGGUTT siSODl-176 180 ccagtgcaggtcctcactt 449 CCAGUGCAGGUCCUCACUUTT 718 AAGUGAGGACCUGCACUGGTT siSODl-177 181 cagtgcaggtcctcacttt 450 CAGUGCAGGUCCUCACUUUTT 719 AAAGUGAGGACCUGCACUGTT siSODl-178 182 aglgcaggtcctcacttta 451 AGUGCAGGUCCUCACUUUATT 720 UAAAGUGAGGACCUGCACUTT siSOD 1-179 183 gtgcaggtcctcactttaa 452 GUGCAGGUCCUCACUUUAATT 721 UUAAAGUGAGGACCUGCACTT siSODl-180 184 tgcaggtcctcactttaat 453 UGCAGGUCCUCACUUUAAUTT 722 AUUAAAGUGAGGACCUGCATT siSODl-181 185 gcaggtcctcactttaatc 454 GCAGGUCCUCACUUUAAUCTT 723 GAUUAAAGUGAGGACCUGCTT siSODl-182 186 caggtcctcactttaatcc 455 CAGGUCCUCACUUUAAUCCTT 724 GGAUUAAAGUGAGGACCUGTT siSODl-183 187 aggtcc tcactttaalcct 456 AGGUCCUCACUUUAAUCCUTT 725 AGGAUUAAAGUGAGGACCUTT siSOD 1-184 188 ggtcctcactttaatcctc 457 GGUCCUCACUUUAAUCCUCTT 726 GAGGAUUAAAGUGAGGACCTT siSODl-185 189 gtcctcactttaatcctct 458 GUCCUCACUUUAAUCCUCUTT 727 AGAGGAUUAAAGUGAGGACTT siSODl-186 190 tcctcacltiaalcclcta 459 UCCUCACUUUAAUCCUCUATT 728 UAGAGGAUUAAAGUGAGGATT siSODl-187 191 cctcactttaatcctctat 460 CCUCACUUUAAUCCUCUAUTT 729 AUAGAGGAUUAAAGUGAGGTT siSODl-188 192 ctcactttaatcctctatc 461 CUCACUUUAAUCCUCUAUCTT 730 GAUAGAGGAUUAAAGUGAGTT siSOD 1-189 193 tcactttaatcctctatcc 462 UCACUUUAAUCCUCUAUCCTT 731 GGAUAGAGGAUUAAAGUGATT siSODl-190 194 cactttaatcctctatcca 463 CACUUUAAUCCUCUAUCCATT 732 UGGAUAGAGGAUUAAAGUGTT siSODl-192 195 citiaaicclctatccaga 464 CUUUAAUCCUCUAU CCAGATT 733 UCUGGAUAGAGGAUUAAAGTT siSODl-196 196 aatcctctatccagaaaac 465 AAUCCUCUAUCCAGAAAACTT 734 GUUUUCUGGAUAGAGGAUUTT siSODl-197 197 atcctctatccagaaaaca 466 AUCCUCUAUCCAGAAAACATT 735 UGUUUUCUGGAUAGAGGAUTT siSOD 1-198 198 tcctctatccagaaaacac 467 UCCUCUAUCCAGAAAACACTT 736 GUGUUUUCUGGAUAGAGGATT siSOD 1-201 199 tctatc...

Claims

1. An oligonucleotide agent comprising a non-targeting single-stranded oligonucleotide, wherein the single-stranded oligonucleotide is at least 6 nucleotides in length, wherein the single-stranded oligonucleotide is capable of facilitating delivery of a double-stranded oligonucleotide, wherein at least one phosphodiester bond between two adjacent nucleotides in the single-stranded oligonucleotide sequence is substituted by a phosphorothioate (PS), mesyl phosphoramidate or boranophosphate bond.

2. The oligonucleotide agent according to claim 1, wherein the double-stranded oligonucleotide comprises a sense strand and an antisense strand.

3. The oligonucleotide agent according to any one of claims 1-2, wherein the singlestranded oligonucleotide is conjugated to the double-stranded oligonucleotide.

4. The oligonucleotide agent according to any one of claims 1-3, wherein the singlestranded oligonucleotide and the double-stranded oligonucleotide is conjugated with zero, one or more linking components.

5. The oligonucleotide agent according to any one of claims 1-4, wherein all nucleotides of the single-stranded oligonucleotide are non-chemically modified nucleotides, or at least one nucleotide is a chemically modified nucleotide.

6. The oligonucleotide agent according to any one of claims 2-5, wherein all nucleotides of the double-stranded oligonucleotide are non-chemically modified nucleotides, or at least one nucleotide is a chemically modified nucleotide, or at least one phosphodiester bond between two adjacent nucleotides in the nucleotide sequence is substituted by a phosphorothioate, mesyl phosphoramidate or boranopho sphate bond.

7. The oligonucleotide agent according to any one of claims 5-6, wherein the chemically modified nucleotide comprises one or more of the following modifications:a) modification of 2'-OH of the ribose in the nucleotide;b) modification or absence of a base moiety on the nucleoside ring in the nucleotide;c) a nucleotide being a locked or bridged nucleic acid, andd) a nucleotide being a deoxyribonucleotide (DNA).

8. The oligonucleotide agent according to claim 7, wherein the chemically modified nucleotide has a 2’-OH ribose modification selected from: a 2'-fluoro-2'-deoxynucleoside (2'-F) modification, a 2'-O-methyl (2'-O-Me) modification, and a 2'-O-(2-methoxyethyl) (2'-0-M0E) modification.

9. The oligonucleotide agent according to any of claims 5 and 7, wherein the singlestranded oligonucleotide is composed of one or more nucleotides selected from the group of RNA, DNA, bridged nucleic acid (BNA), locked nucleic acid (LNA) and peptide nucleic acid (PNA).

10. The oligonucleotide agent according to claim 1, wherein the single-stranded oligonucleotide comprises at least one phosphorothioate (PS) backbone substitution.

11. The oligonucleotide agent according to claim 10, wherein the single-stranded oligonucleotide has at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%' of the phosphodiester bonds substituted with phosphorothioate (PS) bond on the backbone of the nucleotide sequence.

12. The oligonucleotide agent according to claim 11, wherein the single-stranded oligonucleotide has 85-95% or 95-100% of the phosphodiester bond substituted with PS bond on the backbone of the nucleotide sequence.

13. The oligonucleotide agent according to any one of claims 5-6, wherein the at least one chemically modified nucleotide is a nucleotide having an addition of a 5'-phosophate moiety at the 5’ end of the nucleotide sequence.

14. The oligonucleotide agent according to claim 13, wherein at least one chemically modified nucleotide is a nucleotide having an addition of a 5’-(E)-vinyIphosphonate moiety.

15. The oligonucleotide agent according to any one of claims 5-6, wherein the at least one chemically modified nucleotide is a nucleotide having an addition of a 5'-methyl cytosine moiety at the 5’ end of the nucleotide sequence.

16. The oligonucleotide agent according to any one of claims 1-15, wherein the single-stranded oligonucleotide is 6-22 nucleotides in length.

17. The oligonucleotide agent according to claim 16, wherein the single-stranded oligonucleotide is 8-16 nucleotides in length.

18. The oligonucleotide agent according to claim 17, wherein the single-stranded oligonucleotide is 10-14 nucleotides in length.

19. The oligonucleotide agent according to any one of claims 1-18, wherein the single strand oligonucleotide comprises a nucleotide sequence that is at least 90% identical to the nucleotide sequence selected from the group consisting of SEQ ID NOs: 1-22.

20. The oligonucleotide agent according to any one of claims 1-18, wherein the nucleotide sequence of the single-stranded oligonucleotide comprises 35-65% adenines.

21. The oligonucleotide agent according to any one of claims 1-18, wherein the nucleotide sequence of the single-stranded oligonucleotide comprises 35-72% cytosines.

22. The oligonucleotide agent according to any one of claims 1-18, wherein the nucleotide sequence of the single-stranded oligonucleotide comprises 35-65% guanosines.

23. The oligonucleotide agent according to any one of claims 1-18, wherein the nucleotide sequence of the single-stranded oligonucleotide comprises 35-72% uracil.

24. The oligonucleotide agent according to any one of claims 1-18, wherein the nucleotide sequence of the single-stranded oligonucleotide comprises 64-78% purines.

25. The oligonucleotide agent according to any one of claims 1-18, wherein the nucleotide sequence of the single-stranded oligonucleotide comprises 64-86% pyrimidines.

26. The oligonucleotide agent according to any one of claims 1-18, wherein the nucleotide sequence of the single-stranded oligonucleotide comprises 42-58% purines and 42-58% pyrimidines.

27. The oligonucleotide agent according to any one of claims 1-26, wherein the nucleotide sequence of the single-stranded oligonucleotide comprises at least about 14%, at least about 28%, at least about 42%, at least about 57%, at least about 71%, at least about 85%, at least about 92%, or about 100% of the nucleotides having a 2’0me modification.

28. The oligonucleotide agent according to any one of claims 1-27, wherein the nucleotide sequence of the single-stranded oligonucleotide is a palindrome sequence.

29. The oligonucleotide agent according to any one of claims 1-28, wherein the single-stranded oligonucleotide comprises a chemically modified nucleotide sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% homology, or 100% identical to a nucleotide sequence selected from the group of SEQ ID NOs: 1299-1379.

30. The oligonucleotide agent according to claim 29, wherein the single-stranded oligonucleotide comprises a chemically modified nucleotide sequence having 0, 1, 2 or 3 different chemical modifications than a. nucleotide sequence selected from the group consisting of SEQ ID NOs: 1299-1379.

31. The oligonucleotide agent according to any one of claims 1-30, wherein the double-stranded oligonucleotide and the single-stranded oligonucleotide are covalently conjugated by a linking component.

32. The oligonucleotide agent according to claim 31, wherein the single-stranded oligonucleotide is conjugated to a linking component.

33. The oligonucleotide agent according to claim 32, wherein the 5’ end, the 3’ end, or an internal nucleotide of the single-stranded oligonucleotide is conjugated to the linking component.

34. The oligonucleotide agent according to any one of claims 31-3.3, wherein the double-stranded oligonucleotide comprises a sense strand and an antisense strand, and the single-stranded oligonucleotide is covalently conjugated to the sense strand, the antisense strand, or both the sense and the antisense strands of the double-stranded oligonucleotide by a linking component.

35. The oligonucleotide agent according to claim 34, wherein the single-stranded oligonucleotide is covalently conjugated to the 3’ end, the 5’ end, both the 3’ and the 5’ ends, or an internal nucleotide of the sense strand of the double-stranded oligon ucleoti de.

36. The oligonucleotide agent according to claim 34, wherein the single-stranded oligonucleotide is covalently conjugated to the 3’ end, the 5’ end, both the 3’ and the 5’ ends, or an internal nucleotide of the antisense strand of the doubles trended oligonucleotide.

37. The oligonucleotide agent according to any one of claims 35-36, wherein the internal nucleotide in the sense or antisense strand of the double-stranded oligonucleotide is substituted by a linking component, wherein the singlestranded oligonucleotide is covalently conjugated with the linking component.

38. The oligonucleotide agent according to any one of claims 31-37, wherein more than one single-stranded oligonucleotides are covalently conjugated to the double- stranded oligonucleotide.

39. The oligonucleotide agent according to claim 38, wherein about 2-10 singlestranded oligonucleotides are covalently conjugated to the double-stranded oligonucleotide.

40. The oligonucleotide agent according to any one of claims .31-37, wherein more than one said double-stranded oligonucleotides are covalently conjugated to the single-strended oligonucleotides.

41. The oligonucleotide agent according to claim 40, wherein about 2-10 said doublestranded oligonucleotides are covalently conjugated to the single-stranded oligonucleotides.

42. The oligonucleotide agent according to any one of claims 31-41, wherein the linking component conjugated with the nucleotide in the single-stranded oligonucleotide or the double-stranded oligonucleotide, or both the singlestranded oligonucleotide and the double-stranded oligonucleotide through a phosphorothioate (PS) bond.

43. The oligonucleotide agent according to any one of claims 37 and 42, wherein the single-stranded oligonucleotide is covalently conjugated with the linking component through a phosphorothioate (PS) bond.

44. The oligonucleotide agent according to any one of claims 37 and 42, wherein the double-stranded oligonucleotide is covalently conjugated with the linking component through phosphorothioate (PS) bond on either or both ends of the linking component.

45. The oligonucleotide agent according to any one of claims 4-44, wherein the linking component comprises a direct bond, or an oxygen or sulfur atom, or a unit selected from the following group: NR1, C(O), C(O)O, C(O)NR1, SO, SO2, and SO2NH; where RI is hydrogen, acyl, aliphatic or substituted aliphatic.

46. The oligonucleotide agent according to any one of claims 4-44, wherein the linking component is selected from the group consisting of: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl alkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl, alkynylheteroarylalkyl, alkynylheteroarylalkenyl, alkynylheteroarylalkynyl, alkylheterocyclylalkyl, alkylheterocyclylalkenyl, alkylhererocyclylalkynyl, alkenylheterocyclylalkyl, alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl, alkynyIheterocyclylalkenyl, alkynylheterocyclylalkyny 1, alkylary 1, alkenylaryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl, alkynylhereroaryl, wherein one or more methylenes are interrupted or terminated by O, S, S(O), SO2, N(R')2, C(O), cleavable linking group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclic.

47. The oligonucleotide agent according to any one of claims 4-44, wherein the linking component is selected from one or more of an ethylene glycol chain, an alkyl chain, an alkenyl chain, an alkynyl chain, a peptide, carbohydrates, thiol linkage, a phosphodiester, a phosphorothioate, a phosphoramidate, an amide, a carbamate, a. tetrazole linkage, and a benzimidazole linkage.

48. The oligonucleotide agent according to any one of claims 4-44, wherein the linking component is selected from the group consisting of:a) LI or S18 (spacer-18 linker) (1,1-bis(4-methoxypheny 1)-1-phenyl-2,5,8,1 1,14,17-hexaoxanonadecan-19-yl (2-cyanoethyl) diisopropylphosphoramidite);b) L4 or C6 (spacer-C6 linker) (6-(bis(4-methoxyphenyl)(phenyl)methoxy)hexyl (2-cyanoethyl) diisopropylphosphoramidite);c) L6 (l,l-bis(4-methoxyphenyl)-l-phenyl-2,5,8,ll,14-pentaoxahexadecan-16-yl (2-cyanoethyl) diisopropylphosphoramidite):d) L9 or S9 (spacer-9 linker) (2-(2-(2-(bis(4-methoxyphenyl)(phenyl)methoxy)ethoxy)ethoxy)ethyl (2-cyanoethyl) diisopropylphosphoramidite);e) LIO or C3 (spacer-C3 linker) (3-(bis(4-methoxyphenyl)(phenyl)methoxy)propyl (2-cyanoethyl) diisopropylphosphoramidite);f) L12(d spacer) ((2R,3S)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)tetrahydrofuran-3-yl (2-cyanoethyl) diisopropylphosphoramidite);g) L13 or Cl 2 (spacer-C12 linker) (12-(bis(4-methoxyphenyl)(phenyl)methoxy)dodecyl (2-cyanoethyl) diisopropylphosphoramidite);h) L14 (spacer-L14 linker) (((lr,4r)-4-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)cyclohexyl)methyl (2-cyanoethyl) diisopropylphosphoramidite);i) LI 5 (spacer-L15 linker) (4-(2-(bis(4-methoxyphenyl)(phenyl)methoxy)ethyl)phenethyl (2-cyanoethyl) diisopropylphosphoramidite);j) L16 (spacer-L16 linker) (2-(l-(2-(bis(4-methoxyphenyl)(phenyl)methoxy)ethyl)cyclohexyl)ethyl (2-cyanoethyl) diisopropylphosphoramidite);k) C6xl ((2S,3S,4S,5S)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-5-methoxy-4-(pent-4-yn-l-yloxy)tetrahydrofuran-3-yl (2-cyanoethyl) diisopropylphosphoramidite);1) C6x2 ((2S,3S,4S,5S)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-2-methoxy-4-(pent-4-yn-l-yloxy)tetrahydrofuran-3-yl (2-cyanoethyl) diisopropylphosphoramidite);m) C6x5 (2-((2-(bis(4-methoxyphenyl)(phenyl)methoxy)ethyl)(pent-4-yn-l-yl)amino)ethyl (2-cyanoethyl) diisopropylphosphoramidite); andn) C6x7 ((9H-fluoren-9-yl)methyl (4-((2S,4R)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-((bis(diisopropylamino)phosphanyl)oxy)pyrrolidin- l-yl)-4-oxobutyl)carbamate).

49. The oligonucleotide agent of any one of claims 1-48, wherein the oligonucleotide agent comprises a nucleotide sequence that is at least 90% identical to the nucleotide sequences selected from the group consisting of:a) siSOD!M2-AC2(N22)-SlV3v-Qu5 (SEQ ID NO: 58) and an antisense strand having a nucleotide sequence of SEQ ID NO: 57 that has partial complementarity with the sense strand of siSOD!M2-AC2(N22)-SlV3v-Qu5 (SEQ ID NO: 58);b) siSODlM2-AC2(N15)-Sl V3v-Qu5 (SEQ ID NO: 60) and an antisense strand having a nucleotide sequence of SEQ ID NO: 57 that has partial complementarity with the sense strand of siSODlM2-AC2(N15)-SlV3v-Qu5 (SEQ ID NO: 60);c) siSODlM2-AC2(N12)-Sl V3v-Qu5 (SEQ ID NO: 62) and an antisense strand having a nucleotide sequence of SEQ ID NO: 57 that has partial complementarity with the sense strand of siSODlM2-AC2(N12)-Sl¥3v-Qu5 (SEQ ID NO: 62); andd) siSODlM2-AC2(N6)-SlV3v-Qu5 (SEQ ID NO: 64) and an antisense strand having a nucleotide sequence of SEQ ID NO: 57 that has partial complementarity with the sense strand of siSODlM2-AC2(N6)-SlV3v-Qu5 (SEQ ID NO: 64).

50. The oligonucleotide agent of any one of claims 1-48, wherein the oligonucleotide agent comprises a nucleotide sequence that is at least 90% identical to the following nucleotide sequence:siHTT-AC2-SlLl (SEQ ID NO: 28) and an antisense strand having a nucleotide sequence of SEQ ID NO: 27 that has partial complementarity with the sense strand of sd H I- AC2-S Nd (SEQ ID NO: 28).5I. The oligonucleotide agent of any one of claims 1 -48, wherein the oligonucleotide agent comprises a nucleotide sequence that is at least 90% identical to the nucleotide sequences selected from the group of:a) siApp-8-AC2(N18)-SlLl V3v (SEQ ID NO: 32) and an antisense strand having a nucleotide sequence of SEQ ID NO: 31 that has partial complementarity with the sense strand of siApp-8-AC2(N18)-SlLlV3v (SEQ ID NO: 32);b) siApp-8-AC2(N15)-S!Ll V3v (SEQ ID NO: 34) and an antisense strand having a nucleotide sequence of SEQ ID NO: 31 that has partial complementarity with the sense strand of siApp-8-AC2(N15)-SlLlV3v (SEQ ID NO: 34); andc) siApp-8-AC2(N12)-SlLl V3v (SEQ ID NO: 36) and an antisense strand having a nucleotide sequence of SEQ ID NO: 31 that has partial complementarity with the sense strand of siApp-8-AC2(N12)-SlLlV3v (SEQ ID NO: 36).

52. The oligonucleotide agent according to any one of claims 1-48, wherein the sense or antisense strand of the double-stranded oligonucleotide has a nucleotide sequence that is at least 90% identical to the nucleotide sequence selected from the group of: R6-04(20)-SlVlv(CM-4) (SEQ ID NO: 66) or R6-04(20)-S1 Vlv(CM-4) (SEQ ID NO: 67).

53. The oligonucleotide agent of any one of claims 1-48, wherein the oligonucleotide agent comprises a nucleotide sequence that is at least 90% identical to the nucleotide sequences selected from the group of:a) R6-04Ml-AC2(18)-SlLlV3v (SEQ ID NO: 68) and an antisense strand having a nucleotide sequence of SEQ ID NO: 67 that has partial complementarity with the sense strand of R6-04Ml-AC2(18)-SlLlV3v (SEQ ID NO: 68);b) R6-04MhAC2(16)-SHJ V3v (SEQ ID NO: 70) and an antisense strand having a nucleotide sequence of SEQ ID NO: 67 that has partial complementarity with the sense strand of R6-04M1-AC2(16)-S1L1V3v (SEQ ID NO: 70);c) R6-04Ml-AC2(15)-SlLlV3v (SEQ ID NO: 72) and an antisense strand having a nucleotide sequence of SEQ ID NO: 67 that has partial complementarity with the sense strand of R6-04Ml-AC2(15)-SlLlV3v (SEQ ID NO: 72);d) R6-04M1-AC2(14)-S1L1V3v (SEQ ID NO: 74) and an antisense strand having a nucleotide sequence of SEQ ID NO: 67 that has partial complementarity with the sense strand of R6-04M1-AC2(14)-S1L1V3v (SEQ ID NO: 74);e) R6A)4MDAC2(13)-S1L1 V3v (SEQ ID NO: 76) and an antisense strand having a nucleotide sequence of SEQ ID NO: 67 that has partial complementarity with the sense strand of R6-04Ml-AC2(13)-SlLlV3v (SEQ ID NO: 76);f) R6-04M1-AC2(12)-S1L1V3v (SEQ ID NO: 78) and an antisense strand having a nucleotide sequence of SEQ ID NO: 67 that has partial complementarity with the sense strand of R6-04Ml-AC2(12)-SlLlV3v (SEQ ID NO: 78);g) R6-O4M1-AC2(1 1)-S1L1V3v (SEQ ID NO: 80) and an antisense strand having a nucleotide sequence of SEQ ID NO: 67 that has partial complementarity with the sense strand of R6-04Ml-AC2(ll)-SlLlV3v (SEQ ID NO: 80);h) R6-O4MDAC2(1O)-S1IJ V3v (SEQ ID NO: 82) and an antisense strand having a nucleotide sequence of SEQ ID NO: 67 that has partial complementarity with the sense strand of R6-04Ml-AC2(10)-SlLlV3v (SEQ ID NO: 82);i) R6-O4M1-AC2(9)-S1L1 V3v (SEQ ID NO:84) and an antisense strand having a nucleotide sequence of SEQ ID NO: 67 that has partial complementarity with the sense strand of R6-04Ml-AC2(9)-SlLlV3v (SEQ ID NO: 84); andj) R6-04Ml-AC2(8)-SlLlV3v (SEQ ID NO: 86) and an antisense strand having a nucleotide sequence of SEQ ID NO: 67 that has partial complementarity with the sense strand of R6-04M1-AC2(8)-S1L1V3v (SEQ ID NO: 86).

54. The oligonucleotide agent according to any one of claims 1-53, wherein the single-stranded oligonucleotide is conjugated to one or more conjugation groups.

55. The oligonucleotide agent according to any one of claims 1-53, wherein the double-stranded oligonucleotide is conjugated to one or more conjugation groups.

56. The oligonucleotide agent according to claim 55, wherein the sense strand or the antisense strand of the double-stranded oligonucleotide is conjugated to one or more conjugation groups.

57. The oligonucleotide agent according to any one of claims 54-56, wherein the conjugation groups is selected from one or more of: a lipid, a fatty acid, a fluorophore, a ligand, a saccharide, a peptide, and an antibody.

58. The oligonucleotide agent according to any one of claims 54-57, wherein the one or more conjugation groups is selected from: a cell-penetrating peptide,polyethylene glycol, an alkaloid, a tryptamine, a benzimidazole, a quinolone, an amino acid, a. cholesterol, glucose and N-acetylgalactosamine.

59. The oligonucleotide agent according to any one of claims 2-58, wherein the double-stranded oligonucleotide is a small interfering RNA (siRNA) or a small activating RNA (saRNA).

60. The oligonucleotide agent according to any one of claims 2-58, wherein the sense or antisense strand of the double-stranded oligonucleotide has a nucleotide sequence that is at least 90% identical to the nucleotide sequence siApp-8-Sl VI (SEQ ID NO: 28) or siApp-8-SlVl (SEQ ID NO: 27).

61. The oligonucleotide agent according to any one of claims 1-59, wherein the oligonucleotide agent comprises a small interfering RNA (siRNA), wherein the siRNA comprises a sense strand and an antisense strand to form a duplex structure, wherein the antisense strand comprises a nucleotide sequence comprising at least 10 contiguous nucleotides, with 0, 1,2 or 3 mismatches, and having at least 85% nucleotide sequence complementarity or homology to a portion of the nucleotide sequence of SEQ ID NO: 895, wherein the oligonucleotide agent is capable of inhibiting expression of superoxide dismutase 1 (SOD1) in a cell.

62. The oligonucleotide agent according to claim 60, wherein the sense strand of the double-stranded oligonucleotide has a nucleotide sequence that is at least 90%' identical to the nucleotide sequence selected from the group consisting of: siSODl-5 (SEQ ID NO: 357), siSODl-8 (SEQ ID NO: 358), siSODl-10 (SEQ ID NO: 359), siSODl-11 (SEQ ID NO: 360), siSOD-17 (SEQ ID NO: 357), siSODl-35 (SEQ ID NO: 362), and siSODl-37 through siSODl-447 (SEQ ID NOs: 363-624).

63. The oligonucleotide agent according to any one of claims 61-62, wherein the antisense strand of the double-stranded oligonucleotide has a nucleotide sequence that is at least 90% identical to the nucleotide sequence selected from the group consisting of: siSODl-5 (SEQ ID NO: 626), siSODl-8 (SEQ ID NO: 627), siSODl-10 (SEQ ID NO: 628), siSODl-11 (SEQ ID NO: 629), siSOD-17 (SEQ ID NO: 630), siSODl-35 (SEQ ID NO: 631), and siSODl-37- through siSODl-447 (SEQ ID NOs: 632-893).

64. The oligonucleotide agent according to any one of claims 61-63, wherein the sense strand of the double-stranded oligonucleotide has a nucleotide sequence that is at least 90% identical to the nucleotide sequence selected from the group consisting of:a) siSODl-231-E (SEQ ID NO: 38);b) siSODl-231-TT (SEQ ID NO: 40);c) siSODl-231-Ml (SEQ ID NO: 42);d) siSODl-231-S2 (SEQ ID NO: 44);e) siSODl-388-E (SEQ ID NO: 46);f) siSODl-388-TT (SEQ ID NO: 48);g) siSODl-388-Ml (SEQ ID NO: 50);h) siSODl-388-S2 (SEQ ID NO: 52);i) siSOD1.M2-Ll (SEQ ID NO: 54); andj) siSODlM2-SlV5 (SEQ ID NO: 56).

65. The oligonucleotide agent according to any one of claims 61-64, wherein the antisense strand of the double-stranded oligonucleotide has a nucleotide sequence that is at least 90% identical to the nucleotide sequence selected from the group of:a) siSODl-231-E (SEQ ID NO: 39);b) siSODl-231-TT (SEQ ID NO: 41);c) siSODl-231-Ml (SEQ ID NO: 43);d) siSODl-231-S2 (SEQ ID NO: 45);e) siSODl-388-E (SEQ ID NO: 47);f) siSOD 1-388-TT (SEQ ID NO: 49):g) siSODl-388-Ml (SEQ ID NO: 51);h) siSODl-388-S2 (SEQ ID NO: 53);i) siSOD 1M2-L1 (SEQ ID NO: 47); andj) siSODlM2-SlVlv-Qu5 (SEQ ID NO: 57).

66. The oligonucleotide agent according to claim 60, wherein the sense strand of the siRNA has a nucleotide sequence that has at least 85% homology to the nucleotide sequence selected from the group consisting of: DS 17-0001 (SEQ ID NO: 384), DS17-0002 (SEQ ID NO: 372), DS17-0003 (SEQ ID NO: 409), DS17-0004 (SEQ ID NO: 357), DS 17-0005 (SEQ ID NO: 486), DS 17-0029 (SEQ ID NO: 588), DS17-01N3 (SEQ ID NO: 912), DS17-02N3 (SEQ ID NO: 914), DS17-03N3 (SEQ ID NO: 916), DS17-04N3 (SEQ ID NO: 918), DS17-05N3 (SEQ ID NO: 920) and SEQ ID NOs: 976-1021.

67. The oligonucleotide agent according to claim 61 or 66, wherein the antisense strand of the siRNA has a nucleotide sequence that has at least 85% homology to the nucleotide sequence selected from the group consisting of: DS 17-0001 (SEQ ID NO: 653), DS 17-0002 (SEQ ID NO: 641), DS 17-0003 (SEQ ID NO: 678), DS 17-0004 (SEQ ID NO: 626), DS 17-0005 (SEQ ID NO: 755), DS 17-0029 (SEQ ID NO: 857), DS17-01N3 (SEQ ID NO: 913). DS17-02N3 (SEQ ID NO: 915), DS17-03N3 (SEQ ID NO: 917), DS17-04N3 (SEQ ID NO: 919), DS 17-O5N3 (SEQ ID NO: 921), and SEQ ID NOs: 1022-1067.

68. The oligonucleotide agent according to claim 61, wherein the sense strand and the antisense strand of the siRNA have nucleotide sequences that are independently at least 85% homologous to the nucleotide sequence pairs selected from the following groups:(a) DS 17-0001 (SEQ ID NO: 384 and SEQ ID NO: 653).(b) DS 17-0002 (SEQ ID NO: 372 and SEQ ID NO: 641),(c) DS 17-0003 (SEQ ID NO: 409 and SEQ ID NO: 678),(d) DS 17-0004 (SEQ ID NO: 357 and SEQ ID NO: 626),(e) DS 17-0005 (SEQ ID NO: 486 and SEQ ID NO: 755).(f) DS 17-0029 (SEQ ID NO: 588 and SEQ ID NO: 857),(g) DS 17-01N3 (SEQ ID NO: 912 and SEQ ID NO: 913),(h) DS17-02N3 (SEQ ID NO: 914 and SEQ ID NO: 915),(i) DS17-03N3 (SEQ ID NO: 916 and SEQ ID NO: 917),(j) DS 17-04N3 (SEQ ID NO: 918 and SEQ ID NO: 919), and(k) DS17-05N3 (SEQ ID NO: 920 and SEQ ID NO: 921).

69. The oligonucleotide agent according to claim 61, wherein the sense strand and the antisense strand of the siRN A have nucleotide sequences that is independently at least 85% homologous to the nucleotide sequence pairs selected from the following groups:a) DS17-01M3 (SEQ ID NO: 922 and SEQ ID NO: 923),b) DS 17-02M3 (SEQ ID NO: 924 and SEQ ID NO: 925).c) DS 17-03M3 (SEQ ID NO: 926 and SEQ ID NO: 927),d) DS 17-04M3 (SEQ ID NO: 928 and SEQ ID NO: 929), ande) DS 17-05M3 (SEQ ID NO: 930 and SEQ ID NO: 931).

70. The oligonucleotide agent according to claim I, wherein the oligonucleotide agent comprises an siRNA and a non-targeting ACO, wherein the ACO comprises a nucleotide sequence that is at least 90%, at least 95%, or 100% identical to SEQ I D NO: 954, and the oligonucleotide agent is capable of inhibiting the expression of superoxide dismutase 1 (SOD1) in a cell.

71. The oligonucleotide agent according to claim 70, wherein the sense strand and the antisense strand of the siRNA have nucleotide sequences that independently are at least 85% homologous to the nucleotide sequence pairs selected from the following groups:a) DS 17-01 M3 (SEQ ID NO: 922 and SEQ ID NO: 923),b) DS 17-02M3 (SEQ ID NO: 924 and SEQ ID NO: 925),c) DS 17-03M3 (SEQ ID NO: 926 and SEQ ID NO: 927),d) DS 17-04M3 (SEQ ID NO: 928 and SEQ ID NO: 929),e) DS 17-05M3 (SEQ ID NO: 930 and SEQ ID NO: 931),f)  DS 17-01M3-AC1 (mel 4)-L9V3 (SEQ ID NO: 932 and SEQ ID NO: 933),g) DS17-02M3-AC1 (me!4)-L9V3 (SEQ ID NO: 934 and SEQ ID NO: 935),h) DS17-03M3-AC1 (me!4)-L9V3 (SEQ ID NO: 936 and SEQ ID NO: 937),i)  DS17-04M3-AC1 (me!4)-L9V3 (SEQ ID NO: 938 and SEQ ID NO: 939),j)  DS17-05M3-AC1 (me!4)-L9V3 (SEQ ID NO: 940 and SEQ ID NO: 941),k) DS17-29M2-AC1 (me!4)-L9V3 (SEQ ID NO: 942 and SEQ ID NO: 47),I) DS17-01M3v-ACl (mel4)-L9V3 (SEQ ID NO: 932 and SEQ ID NO: 47), m) DS17-02M3v-ACl (mel4)-L9V3 (SEQ ID NO: 934 and SEQ ID NO: 943),n) DS 17-03M3v-AC 1 (mel4)-L9V3 (SEQ ID NO: 936 and SEQ ID NO: 944),o) DS17-04M3v-ACl (mel4)-L9V3 (SEQ ID NO: 938 and SEQ ID NO: 950),p)  DS 17-05M3v-AC 1 (mel4)-L9V3 (SEQ ID NO: 940 and SEQ ID NO: 951),andq) DS17-04M3-asSODl-l-L9V3 (SEQ ID NO: 952 and SEQ ID NO: 939).

72. The oligonucleotide agent according to claim 1, wherein the oligonucleotide agent comprises a non-targeting ACO conjugated sense strand of a siRNA and an antisense strand of the siRNA, wherein the non-targeting ACO conjugated sense strand comprises a linking component covalently conjugating the ACO and the sense strand, wherein the antisense strand comprises a nucleotide sequence that is at least 90%, at least 95% homology, or 100% identical to SEQ ID NO: 57.

73. The oligonucleotide agent according to the claim 72, wherein the non-targeting ACO conjugated sense strand comprises a nucleotide sequence that is at least 90%, at least 95%, or 100% identical to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1197-1288 and SEQ ID NOs: 1291-1298.

74. The oligonucleotide agent according to any one of claims 72-73, wherein the linking component is selected from the linking component group listed in SEQ ID NOs: 1197-1288 in Table 28 and SEQ ID NOs: 1291-1298 in Table 30.

75. The oligonucleotide agent according to any one of claims 1-74, wherein the single-stranded oligonucleotide of the oligonucleotide agent improves the stability, bioavailability, biodistribution, and / or cellular uptake of the doublestranded oligonucleotide as compared to an oligonucleotide agent without the single-stranded oligonucleotide.

76. The oligonucleotide agent according to any one of claims 2-74, wherein the single-stranded oligonucleotide of the oligonucleotide agent increases the biodistribution of double-stranded oligonucleotide within one or more targettissues as compared to an oligonucleotide agent without the single-stranded oligonucleotide.

77. The oligonucleotide agent according to claim 76, wherein the one or more target tissues is selected from tissues of brain, spinal cord, muscle, spleen, lung, heart, liver, bladder, and kidney.

78. The oligonucleotide agent according to claim 77, wherein the one or more target tissues is selected from the group consisting of: prefrontal cortex, cerebellum, and rest of brain; cervical, thoracic and lumbar in spinal cord; heart, forelimb, hindlimb, nape, and gluteus.

79. A vector, comprising the oligonucleotide agent of any one of claims 1-78.

80. A cell, comprising the oligonucleotide agent of any one of claims 1-78.

81. The cell according to claim 80, wherein the cell is a mammalian cell, optionally a human cell.

82. The cell according to any one of claims 80-81, wherein the cell is a host cell.

83. The cell according to any one of claims 80-82, wherein the cell is in vitro.

84. The cell according to any one of claims 80-82, wherein the cell exists in a mammalian body.

85. A pharmaceutical composition, comprising the oligonucleotide agent of any one of claims 1-78 and / or the cell of any one of claims 80-84.

86. The pharmaceutical composition according to claim 85, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier selected from an aqueous carrier, liposome or LNP, polymer, micelle, colloid, metal nanoparticle, non-metallic nanoparticle, bioconjugates, and polypeptide.

87. The pharmaceutical composition according to any one of claims 85-86, wherein the pharmaceutical composition silences the SOD1 gene expression or decreases the SOD1 protein.

88. The pharmaceutical composition according to any one of claims 85-86, wherein the pharmaceutical composition decreases the expression of the HIT or App gene, or inhibits HTT or APP protein.

89. The pharmaceutical composition according to any one of claims 85-86, wherein the pharmaceutical composition increases or activates the expression of the SMN2 gene or SMN2 protein.

90. A kit, comprising the oligonucleotide agent of any one of claims 1-78.

91. A kit comprising a pharmaceutical composition of any one of claims 85-89.

92. A method of silencing the SOD1 gene expression or decreases the SOD1 protein, comprising administering to a subject a pharmaceutical composition of any one of claims 85-89.

93. A method for treating or delaying the onset or progression of Amyotrophic lateral sclerosis (ALS) in a subject, the method comprising: administering to a subject a pharmaceutical composition of any one of claims 85-87.

94. The method according to claim 93, wherein the subject has sporadic ALS (sALS).

95. The method according to claim 93, wherein the subject has familial ALS (fALS).

96. A method of decreasing or inhibiting the expression of a HTT gene or huntingtin protein, the method comprising administering to a subject a pharmaceutical composition of any one of claims 85, 86 and 88.

97. A method for treating or delaying the onset or progression of Huntington's disease (HD) in a subject, the method comprising: administering to a subject a pharmaceutical composition of any one of claims 85, 86 and 88.

98. A method of increasing or activating the expression of an App gene or amyloid precursor protein ( APP), the method comprising administering to a subject a pharmaceutical composition of any one of claims 85, 86 and 88.

99. A method for treating or delaying the onset or progression of APP associated diseases including Cerebral Amyloid Angiopathy App-related (CAA-APP) and Alzheimer Disease (AD) in a subject, the method comprising: administering to a subject a pharmaceutical composition of any one of claims 85, 86 and 88.100.A method of increasing or activating the expression of an SMN2 gene or SMN2 protein, the method comprising administering to a subject a pharmaceutical composition of any one of claims 85, 8€) and 89.101.A method for treating or delaying the onset or progression of spinal muscular atrophy (SMA) in a subject, the method comprising: administering to a subject a pharmaceutical composition of any one of claims 85, 86 and 89.102.The method according to any one of claims 92-101, wherein the single-stranded oligonucleotide of the oligonucleotide agent improves the stability, bioavailability, biodistribution, and / or cellular uptake of the double-stranded oligonucleotide as compared to an oligonucleotide agent without the singlestranded oligonucleotide.103.The method according to any one of claims 92-101, wherein the single-stranded oligonucleotide of the oligonucleotide agent increases the biodistribution of double-stranded oligonucleotide within one or more target tissues as compared to an oligonucleotide agent without the single-stranded oligonucleotide.104.The method according to any one of claims 92-101, wherein the single-stranded oligonucleotide of the oligonucleotide agent increases the biodistribution of double-stranded oligonucleotide within two or more target cell types in a tissue as compared to an oligonucleotide agent without the single-stranded oligonucleotide.1O5.The method according to claim 103, wherein the one or more target tissues is selected from the tissues from brain, spinal cord, muscle, spleen, lung, heart, liver, bladder, and kidney.106.The method according to claim 103, wherein the one or more target tissues is selected from the group consisting of: prefrontal cortex, cerebellum, and rest of brain; cervical, thoracic and lumbar in spinal cord; heard, forelimb, hindlimb, nape, and gluteus.107.A use of the oligonucleotide agent of any one of claims 1-78, in manufacturing a medicament for treating or delaying the onset or progression of Amyotrophic lateral sclerosis (ALS).108.A use of the pharmaceutical composition of any one of claims 85-89 in manufacturing a medicament for treating or delaying the onset or progression of Amyotrophic lateral sclerosis (ALS).109.The use according to any of claims 107-108, wherein the ALS comprises sporadic ALS (sALS) and / or familial ALS (fALS).1 lO.The oligonucleotide agent of any one of claims 1 -78 for use in treating or delaying the onset or progression of Amyotrophic lateral sclerosis (ALS), optionally, the ALS comprises sporadic ALS (sALS) and / or familial ALS (fALS).11 l.The pharmaceutical composition of any one of claims 85-89 for use in treating or delaying the onset or progression of Amyotrophic lateral sclerosis (ALS), optionally, the ALS comprises sporadic ALS (sALS) and / or familial ALS (fALS).

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