Oligonucleotide, oligonucleotide conjugate and composition, and use

Abstract

Provided is a single-stranded oligonucleotide having a length of 16-30 nucleotides. The single-stranded oligonucleotide has complementarity to FXI mRNA sufficient to mediate the RNAi effect. Each nucleotide in the single-stranded oligonucleotide is either modified or unmodified, wherein in the single-stranded oligonucleotide, at least one nucleotide is nucleotide X and at least one nucleotide is a fluoro-modified nucleotide. Furthermore, in the direction from the 5' end to the 3' end, at least one nucleotide X is located after the 8th nucleotide of the single-stranded oligonucleotide and is spaced apart from the 8th nucleotide of the single-stranded oligonucleotide by 4 to 7 nucleotides; and each nucleotide X is either a deoxynucleotide or an unmodified nucleotide. Further provided are a double-stranded oligonucleotide, an oligonucleotide conjugate and a pharmaceutical composition that comprise the single-stranded oligonucleotide as an antisense strand.

Description

Oligonucleotides, oligonucleotide conjugates, and compositions and uses TECHNICAL FIELD The present disclosure relates to a single-stranded oligonucleotide, in particular to an antisense strand of a double-stranded oligonucleotide, and further relates to a double-stranded oligonucleotide, an oligonucleotide conjugate, a pharmaceutical composition comprising the antisense strand, uses and methods of preparation thereof. BACKGROUND SOD1 (Superoxide Dismutase 1) is best known for its role in the familial form of amyotrophic lateral sclerosis (fALS), and many SOD1 mutations increase the propensity of SOD1 to aggregate, which is thought to ultimately induce motor neuron death. Amyotrophic lateral sclerosis (ALS) is a common fatal disease that progresses through the degeneration of upper and lower motor neurons, leading to progressive paralysis, respiratory failure, and death within 2-5 years. It is also the most common adult motor neuron disease, with a prevalence of 5 per 100,000 people and a lifetime risk of 1:400-1:800. Two types of small non-coding RNAs, small hairpin RNAs (shRNAs) and artificial microRNAs (miRNAs), are increasingly being used as therapeutic strategies for neurodegenerative diseases, with miRNAs in particular due to their more favorable safety profile. In addition, SOD1 is overexpressed in many cancer types, including lung cancer, non-small cell lung cancer, and 70% of primary breast cancers. SOD1 overexpression in cancer can gain a growth advantage by providing protection from oxidative damage. In the drug discovery of oligonucleotides, including single-stranded oligonucleotides and double-stranded oligonucleotides, the improvement of modifications of oligonucleotides has never stopped. In single-stranded oligonucleotides, such as ASOs, ssRNAis, and antisense strands of double-stranded oligonucleotides, such as siRNAs, according to the type, position, and number of modifications, the key performance of the oligonucleotides, such as pharmacological activity, stability, and long-acting, can be significantly affected. Although a large number of modification schemes of oligonucleotides are disclosed in the prior art, how to improve the modification of oligonucleotides, in particular single-stranded oligonucleotides and antisense strands of double-stranded oligonucleotides, to obtain oligonucleotides with higher activity, higher stability, and / or long-acting is still the direction of research and development in the field. SUMMARY The present disclosure provides a single-stranded oligonucleotide, a double-stranded oligonucleotide comprising the single-stranded oligonucleotide as an antisense strand, and an oligonucleotide conjugate, all of which exhibit good pharmacological activity and stability when targeting SOD1 mRNA. In an aspect, the present disclosure provides a single-stranded oligonucleotide having a length of 16-30 nucleotides, the single-stranded oligonucleotide having a complementarity with SOD1 mRNA sufficient to mediate an RNAi effect; each nucleotide in the single-stranded oligonucleotide being a modified or unmodified nucleotide, wherein, in the single-stranded oligonucleotide, at least one nucleotide is a nucleotide X, at least one nucleotide is a fluorinated modified nucleotide; and, in a direction from 5' end to 3' end, at least 1 nucleotide X is located after the 8th nucleotide of the single-stranded oligonucleotide, and the 8th nucleotide is spaced by 4-7 nucleotides; And, in a direction from 5' end to 3' end, if the 14th nucleotide of the single-stranded oligonucleotide is a nucleotide X, and all the nucleotides from the 15th nucleotide and after of the single-stranded oligonucleotide are modified nucleotides, then the 13th nucleotide of the single-stranded oligonucleotide is selected from one of alkoxy-modified nucleotide, alkyl-modified nucleotide, substituted alkyl-modified nucleotide, amine-modified nucleotide, thermally unstable nucleotide and BNA; Each nucleotide X is a deoxynucleotide or an unmodified nucleotide. In yet another aspect, the present disclosure provides a double-stranded oligonucleotide containing a sense strand and an antisense strand, each nucleotide in the sense strand and the antisense strand being a modified or unmodified nucleotide, the sense strand and the antisense strand being at least partially reverse-complementary to form a double-stranded region, wherein the antisense strand is the single-stranded oligonucleotide as described in the present disclosure. In yet another aspect, the present disclosure also provides an oligonucleotide conjugate containing an oligonucleotide group and a delivery group conjugated to the oligonucleotide group, the oligonucleotide group being a group formed by removing one or more atoms or atom groups from any one of the single-stranded oligonucleotide and the double-stranded oligonucleotide provided in the present disclosure. In yet another aspect, the present disclosure also provides a pharmaceutically acceptable salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide or the oligonucleotide conjugate as described in the present disclosure. In yet another aspect, the present disclosure also provides a pharmaceutical composition containing one or more of the single-stranded oligonucleotide, the double-stranded oligonucleotide, the oligonucleotide conjugate and the pharmaceutically acceptable salt as described in the present disclosure, and a pharmaceutically acceptable excipient. In yet another aspect, the present disclosure also provides a use of one or more of the single-stranded oligonucleotide, the double-stranded oligonucleotide, the oligonucleotide conjugate, the pharmaceutically acceptable salt and the pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating and / or preventing a disease or a symptom associated with the level of SOD1 mRNA. In yet another aspect, the present disclosure also provides a method of treating and / or preventing a disease or a symptom associated with SOD1 mRNA level, comprising administering to a subject in need thereof one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the present disclosure. In yet another aspect, the present disclosure also provides a method of modulating SOD1 mRNA in a cell in vivo or in vitro, comprising contacting an effective amount of one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the present disclosure with the cell in vitro or in vivo. In yet another aspect, the present disclosure also provides one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the present disclosure for use as a medicament. In yet another aspect, the present disclosure also provides a cell expressing SOD1 mRNA, comprising one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the present disclosure. In addition, the present disclosure also provides a kit comprising one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the present disclosure. All publications, including patents, patent applications, or any other All publications, including patents, patent applications, or any other Advantages The double-stranded oligonucleotides, oligonucleotide conjugates, and / or pharmaceutical compositions comprising the single-stranded oligonucleotides of the present disclosure as antisense strands have high activity in modulating SOD1 mRNA, for example, good stability and SOD1 mRNA inhibitory activity in cells and / or in subjects, and thus have good application prospects. In one aspect, the double-stranded oligonucleotides (such as siRNA), conjugates, and / or pharmaceutical compositions containing the single-stranded oligonucleotides of the present disclosure as antisense strands show excellent SOD1 mRNA inhibitory effect. For example, in in vitro tests, the siRNA of the present disclosure can achieve effective inhibition of SOD1 mRNA, and at a concentration of 50 nM, the siRNA provided by the present disclosure has an inhibition rate of SOD1 mRNA in mouse liver primary cells of more than 95%, and can even be as high as 99%. On the other hand, the siRNA of the present disclosure containing the antisense strand of the present disclosure, the conjugate of the present disclosure and / or the pharmaceutical composition of the present disclosure all showed good inhibition of SOD1 mRNA in mice administered with the conjugate of the present disclosure throughout the experimental period. The conjugate of the present disclosure maintained the inhibition rate of SOD1 mRNA in mice at 64% or even 78% or more. The conjugate of the present disclosure showed at least 7.76% or even 18% or more higher inhibition rate of SOD1 mRNA than the reference conjugate with the same sequence but different modification. For another example, the siRNA of the present disclosure significantly inhibited the expression of SOD1 mRNA in different parts of the spinal cord of rats. The inhibition rate of SOD1 mRNA increased over time in the lumbar segment and thoracic segment of the spinal cord. The inhibition rate of SOD1 mRNA in the thoracic segment of the spinal cord was 81.0% on day 29, and the inhibition rate of SOD1 mRNA in the lumbar segment of the spinal cord was even 86.5%. This showed the long-acting inhibition of SOD1 mRNA in rats by the siRNA of the present disclosure. Thus, the conjugate of the present disclosure has good SOD1 mRNA regulating activity, shows significant pharmaceutical activity in the preparation of drugs for the treatment and / or prevention of diseases or symptoms related to SOD1 mRNA expression, and has excellent development prospects. DETAILED DESCRIPTION The detailed description of the present disclosure is described in detail below. It should be understood that the detailed description described herein is only used to illustrate and explain the present disclosure, and is not used to limit the present disclosure. In the present disclosure, SOD1 mRNA refers to SOD1 mRNA expressed in mammalian cells. In the present disclosure, SOD1 mRNA refers to mRNA of the sequence shown in Genbank accession number NM_000454.5. Further, unless otherwise specified, the term "SOD1 gene" used in the present disclosure refers to a gene transcribing the above-mentioned SOD1 mRNA. DEFINITIONS In the context of this document, the expressions "complementary" or "reverse complementary" are used interchangeably and have the meaning well known to those skilled in the art, i.e. in a double-stranded nucleic acid structure, the bases of one strand each form a hydrogen bond between base pairs in a complementary manner with the bases on the other strand, effecting base pairing, forming Watson-Crick base pairs. A "base pair" refers to two bases that form a base pair. In DNA, the purine base adenine (A) always pairs with the pyrimidine base thymine (T) (or in RNA with uracil (U)); the purine base guanine (G) always pairs with the pyrimidine base cytosine (C). Each base pair comprises one purine and one pyrimidine. When adenine on one strand always pairs with thymine (or uracil) on the other strand and guanine always pairs with cytosine, the two strands are considered to be complementary to each other and the sequence of one strand can be deduced from the sequence of its complementary strand. When the bases are modified, as long as the purine-pyrimidine pairing relationship described above is not affected (including but not limited to the number and strength of hydrogen bonds between the bases), the modified bases are also considered to be able to form complementary pairs. Accordingly, "mismatch" or "base mismatch" in the art means that the bases at the corresponding positions between the two single-stranded nucleic acids involved do not pair in a complementary manner; when the corresponding position includes an abasic nucleotide, it is also considered to form a mismatch with the base on the other strand. In the above and below, "nucleotide sequence A is substantially reverse complementary, substantially reverse complementary or completely reverse complementary to nucleotide sequence B over a span of X nucleotides" means that there is a continuous nucleotide sequence A' of length X in nucleotide sequence A which is substantially reverse complementary, substantially reverse complementary or completely reverse complementary to a continuous nucleotide sequence B' of the same length X in nucleotide sequence B. Unless specifically stated, in the context of this document, a reference to an oligonucleotide and / or oligonucleotide conjugate described in the applications or methods provided by the present disclosure, including but not limited to an oligonucleotide and / or oligonucleotide conjugate represented by any of the structural formulae described in the applications or methods provided by the present disclosure, also refers to a pharmaceutically acceptable salt of the oligonucleotide and / or the conjugate, depending on the context. In the foregoing and hereinafter, particularly in describing the preparation of a single-stranded oligonucleotide, double-stranded oligonucleotide, pharmaceutical composition, or oligonucleotide conjugate of the disclosure, unless otherwise specified, the nucleoside monomer refers to modified or unmodified nucleoside phosphoramidite monomers (unmodified or modified RNA phosphoramidites, sometimes also referred to as Nucleoside phosphoramidites) used in the phosphoramidite solid phase synthesis according to the kind and order of nucleotides in the single-stranded oligonucleotide, double-stranded oligonucleotide, or oligonucleotide conjugate to be prepared. The phosphoramidite solid phase synthesis is a method commonly known to those skilled in the art for use in RNA synthesis. The nucleoside monomers used in the disclosure are all commercially available. Various protecting groups, such as hydroxyl protecting groups or amino protecting groups, can be used in the disclosure. In the foregoing and hereinafter, a protecting group renders a chemical functionality insensitive to specific reaction conditions, and can be added to and removed from that functionality in a molecule without substantially damaging the rest of the molecule. Representative hydroxyl protecting groups are disclosed in Peter G. M. Wuts, Greene’s Protective Groups in Organic Synthesis, Chapter 2, 5th edition, John Wiley & Sons, Inc., New Jersey, 2014, each of which is incorporated herein by reference in its entirety. In some embodiments, the protecting group is stable under basic conditions, but can be removed under acidic conditions. In some embodiments, nonexclusive examples of hydroxyl protecting groups that can be used herein include dimethoxytrityl (DMT), monomethoxytrityl, 9-phenylxanthyl (Pixyl), and 9-(p- methoxyphenyl)xanthyl (Mox). In some embodiments, nonexclusive examples of hydroxyl protecting groups that can be used herein include Tr (trityl), MMTr (4-methoxytrityl), DMTr (4,4'-dimethoxytrityl), and TMTr (4,4',4"-trimethoxytrityl). The term “subject,” as used herein, refers to any animal, such as a mammal or a marsupial. Subjects of the disclosure include, but are not limited to, humans, non-human primates (e.g., rhesus or other types of macaques), mice, pigs, horses, donkeys, cows, rabbits, sheep, rats, and any species of poultry. As used herein, "treatment" refers to an approach for obtaining beneficial or desired results, including but not limited to therapeutic benefit. "Therapeutic benefit" means eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the observation of improvement in a subject, even though the subject can still be afflicted with the underlying disorder, by eradicating or ameliorating one or more of the signs or symptoms of the underlying disorder. As used herein, "prevention" refers to an approach for obtaining beneficial or desired results, including but not limited to prophylactic benefit. To obtain "prophylactic benefit", a single-stranded oligonucleotide, a double-stranded oligonucleotide, a pharmaceutical composition or an oligonucleotide conjugate of the present disclosure can be administered to a subject at risk of developing a disease associated with SOD1 mRNA, or to a subject reporting one or more physiological symptoms of the disease, even though the diagnosis of the disease can not have been made. In some embodiments, "prevention" includes reducing or eliminating the risk of a disease associated with SOD1 mRNA by administering a single-stranded oligonucleotide, a double-stranded oligonucleotide, a pharmaceutical composition or an oligonucleotide conjugate to a subject at risk of developing the disease associated with SOD1 mRNA, before the risk of the disease associated with SOD1 mRNA progresses to an explicit disease process, to intervene in the level of SOD1 mRNA or SOD1 protein, so as to reduce or eliminate the risk of the disease. Single-stranded oligonucleotide of the present disclosure The present disclosure provides a single-stranded oligonucleotide, the length of which is 16-30 nucleotides, the single-stranded oligonucleotide having sufficient complementarity with SOD1 mRNA to mediate an RNAi effect; each nucleotide in the single-stranded oligonucleotide is a modified or unmodified nucleotide, wherein, in the single-stranded oligonucleotide, at least one nucleotide is a nucleotide X, and at least one nucleotide is a fluorine-modified nucleotide; and, in the direction from the 5' end to the 3' end, at least 1 nucleotide X is located after the 8th nucleotide of the single-stranded oligonucleotide, and is spaced apart from the 8th nucleotide by 4-7 nucleotides; And, in the direction from the 5' end to the 3' end, if the 14th nucleotide of the single-stranded oligonucleotide is a nucleotide X, and all the nucleotides from the 15th nucleotide and thereafter of the single-stranded oligonucleotide are modified nucleotides, then the 13th nucleotide of the single-stranded oligonucleotide is selected from one of an alkoxy-modified nucleotide, an alkyl-modified nucleotide, a substituted alkyl-modified nucleotide, an amine-modified nucleotide, a thermally unstable nucleotide and a BNA; Each nucleotide X is a deoxynucleotide or an unmodified nucleotide. In the present disclosure, by regulating the expression level of SOD1 mRNA and / or changing the protein level, diseases associated with the expression level and / or protein level of SOD1 mRNA can be treated or prevented. The inventors surprisingly found that the single-stranded oligonucleotide, the double-stranded oligonucleotide comprising the single-stranded oligonucleotide as the antisense strand and the oligonucleotide conjugate of the present disclosure have good stability and SOD1 mRNA inhibitory activity in cells and / or in vivo in a subject, and thus have good application prospects. To exert the RNAi effect, the single-stranded oligonucleotide of the present disclosure has a length of 16-30 nucleotides. In some embodiments, the single-stranded oligonucleotide of the present disclosure has a length of 17-28, 19-26, or 20-24 nucleotides. In some embodiments, the single-stranded oligonucleotide of the present disclosure has a length of 19, 21 or 23 nucleotides. In this case, the single-stranded oligonucleotide, the double-stranded oligonucleotide comprising the single-stranded oligonucleotide as the antisense strand and the oligonucleotide conjugate of the present disclosure have a better balance of synthesis cost, stability and RNAi activity. In the single-stranded oligonucleotide of the present disclosure, at least one nucleotide X is located after the 8th nucleotide of the single-stranded oligonucleotide and is spaced 4-7 nucleotides from the 8th nucleotide of the single-stranded oligonucleotide; and, in the direction from the 5' end to the 3' end, if the 14th nucleotide of the single-stranded oligonucleotide is a nucleotide X, and all the nucleotides after the 15th nucleotide of the single-stranded oligonucleotide are modified nucleotides, then the 13th nucleotide of the single-stranded oligonucleotide is selected from one of an alkoxy-modified nucleotide, an alkyl-modified nucleotide, a substituted alkyl-modified nucleotide, an amine-modified nucleotide, a thermally unstable nucleotide and a BNA. The inventors have particularly found that the single-stranded oligonucleotide conjugate of the present disclosure can effectively maintain the high inhibitory activity of the single-stranded oligonucleotide, the double-stranded oligonucleotide and the oligonucleotide conjugate on SOD1 mRNA while maintaining stability by comprising a fluorine-modified nucleotide and a nucleotide X. In some embodiments, the number of nucleotides X in the single-stranded oligonucleotide is 1-3, for example 1, 2 or 3. In some embodiments, each nucleotide X is located after the 8th nucleotide in the single-stranded oligonucleotide; and in the direction from the 5' end to the 3' end, each nucleotide X is spaced 3, 5, 7 or 10 nucleotides from the 8th nucleotide in the single-stranded oligonucleotide. In some embodiments, each nucleotide X in the single-stranded oligonucleotide is located after the 8th nucleotide in the single-stranded oligonucleotide, and one of the nucleotides X is spaced 5 nucleotides from the 8th nucleotide, i.e. in the direction from the 5' end to the 3' end, the 14th nucleotide of the single-stranded oligonucleotide is a nucleotide X. In some embodiments, there is only one nucleotide X in the single-stranded oligonucleotide, which is spaced 5 nucleotides from the 8th nucleotide in the single-stranded oligonucleotide in the 5' end to 3' end direction. In some embodiments, there are 2 nucleotides X in the single-stranded oligonucleotide, in which 1 nucleotide X is spaced 5 nucleotides from the 8th nucleotide in the single-stranded oligonucleotide in the 5' end to 3' end direction, and the other nucleotide X is spaced 3, 7, or 10 nucleotides from the 8th nucleotide in the single-stranded oligonucleotide in the 5' end to 3' end direction. In some embodiments, the 12th and 14th nucleotides, or the 14th and 16th nucleotides, or the 14th and 19th nucleotides in the single-stranded oligonucleotide in the 5' end to 3' end direction are nucleotides X. Each nucleotide X is independently selected from a deoxynucleotide or an unmodified nucleotide. In the present context, "unmodified nucleotide" refers to a ribonucleotide (RNA) in which both the base and the ribose are unmodified, i.e., the nucleotide base is a natural ribose base (one of A, U, C, G, T), and the 2' position of the nucleotide ribose is an unprotected hydroxyl group (2'-OH). Correspondingly, "modified nucleotide" refers to a nucleotide in which the base is modified, a nucleotide in which the hydroxyl group at the 2' position of the nucleotide ribose is replaced by another atom or group, or a nucleotide analog. In some embodiments, the 14th nucleotide or the 12th and 14th nucleotides in the single-stranded oligonucleotide in the 5' end to 3' end direction are deoxynucleotides, and the other nucleotide X is an unmodified nucleotide. In some embodiments, the 14th nucleotide in the single-stranded oligonucleotide in the 5' end to 3' end direction is a deoxynucleotide, and the other nucleotides are modified nucleotides. In some embodiments, the number of modified nucleotides is more than 50%, more than 70%, or more than 85% of the total number of nucleotides in the single-stranded oligonucleotide of the present disclosure; or, the number of unmodified nucleotides in the single-stranded oligonucleotide is no more than 5, no more than 4, no more than 3, no more than 2, or no more than 1. In some embodiments, the number of unmodified nucleotides in the single-stranded oligonucleotide is 2 or 1. In some embodiments, each of the total number of nucleotides in the single-stranded oligonucleotide is independently a modified nucleotide. As previously described, the single-stranded oligonucleotide described herein can include fluorine-modified nucleotides in addition to nucleotide X. In some embodiments, the number of fluorine-modified nucleotides is 2-7. In some embodiments, the fluorine-modified nucleotides refer to 1 or 2 of the 2nd and 12th, 1 or 2 of the 5th-7th, and 0-2 of the 16th-19th nucleotides in the single-stranded oligonucleotide in the 5' end to 3' end direction. In some embodiments, the fluorine-modified nucleotides refer to 2-5 of the 2nd, 5th, 6th, 7th, 12th, 16th, 18th, and 19th nucleotides in the single-stranded oligonucleotide in the 5' end to 3' end direction. In some embodiments, the fluorine-modified nucleotides refer to the 2nd and 6th nucleotides in the single-stranded oligonucleotide in the 5' end to 3' end direction. In some embodiments, the fluorine-modified nucleotides refer to the 2nd, 6th, and 16th nucleotides in the single-stranded oligonucleotide in the 5' end to 3' end direction. In some embodiments, the fluorine-modified nucleotides refer to the 2nd, 5th, 7th, 12th, and 16th nucleotides in the single-stranded oligonucleotide in the 5' end to 3' end direction. In some embodiments, the fluorine-modified nucleotides refer to the 2nd, 7th, 12th, 16th, and 19th nucleotides in the single-stranded oligonucleotide in the 5' end to 3' end direction. In some embodiments, the fluorine-modified nucleotides refer to the 2nd, 6th, 12th, 16th, and 19th nucleotides in the single-stranded oligonucleotide in the 5' end to 3' end direction. In some embodiments, each modified nucleotide in the single-stranded oligonucleotide other than nucleotide X and the fluorine-modified nucleotide is independently selected from one of an alkoxy-modified nucleotide, a substituted alkoxy-modified nucleotide, an alkyl-modified nucleotide, a substituted alkyl-modified nucleotide, an amine-modified nucleotide, a thermally unstable nucleotide, and a BNA. In some embodiments, the number of substituted alkoxy-modified nucleotides in the single-stranded oligonucleotide is no more than 3. In some embodiments, the number of substituted alkoxy-modified nucleotides in the single-stranded oligonucleotide is no more than 2. In some embodiments, the number of substituted alkoxy-modified nucleotides in the single-stranded oligonucleotide is 1. In some embodiments, there is no substituted alkoxy-modified nucleotide in the single-stranded oligonucleotide. In some embodiments, each modified nucleotide in the single stranded oligonucleotide, other than nucleotide X and the fluorine-modified nucleotide, is selected from an alkoxy-modified nucleotide, a substituted alkoxy-modified nucleotide, or a thermally unstable nucleotide. In some embodiments, the number of thermally unstable nucleotides in the single stranded oligonucleotide is 0-2. In some embodiments, there is no thermally unstable nucleotide in the single stranded oligonucleotide. In some embodiments, the number of thermally unstable nucleotides in the single stranded oligonucleotide is no more than 2. In some embodiments, the number of thermally unstable nucleotides in the single stranded oligonucleotide is 1 or 2. In some embodiments, the single stranded oligonucleotide contains only 1 thermally unstable nucleotide. In some embodiments, each modified nucleotide in the single stranded oligonucleotide, other than nucleotide X and the fluorine-modified nucleotide and the thermally unstable nucleotide, is selected from an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide. In the present context, a “thermally unstable nucleotide” refers to a nucleotide having a thermally unstable modification, which is a modification that results in a decrease in the thermal dissociation temperature of a duplex of an oligonucleotide having the modification at the corresponding position by at least 0.5 °C as compared to a duplex of an oligonucleotide having an unmodified nucleotide at the corresponding position. Exemplary thermally unstable modifications can be found in the specification of PCT publication WO2018 / 098328A1

[0236] -

[0251] The thermally unstable modification described in the paragraph. In some embodiments, the thermally unstable modification nucleotide is one of an acyclic nucleotide or an iso-nucleotide. An acyclic nucleotide is a class of nucleotides in which the sugar ring of the nucleotide is opened. In some embodiments, the acyclic nucleotide can be an unlocked nucleic acid (UNA) or a glycerol nucleic acid (GNA), wherein the UNA is shown in formula (15) and the GNA is shown in formula (16): In the above formula (15) and formula (16), R is selected from H, OH, or alkoxy (O-alkyl), and Base represents a nucleic acid base, such as A, U, G, C, or T. An iso-nucleotide refers to a compound in which the position of the base on the ribose ring is changed. In some embodiments, the iso-nucleotide can be a compound in which the base is moved from the 1'-position to the 2'-position or the 3'-position on the ribose ring, as shown in formula (17) or (18). In the above formula (17)-(18) compounds, Base represents a nucleic acid base, such as A, U, G, C, or T; and R is selected from H, OH, F, or a non-fluorine group as described above. In some embodiments, the thermally unstable modified nucleotide is selected from one of GNA as shown in formula (27A), 2'-OMe abasic nucleotide as shown in formula (27B), 3'-OMe modified nucleotide as shown in formula (27C), 5'-Me modified nucleotide as shown in formula (27D), SNA as shown in formula (27E), hGNA as shown in formula (27F), hhGNA as shown in formula (27G), mGNA as shown in formula (27H), TNA as shown in formula (27I), h'GNA as shown in formula (27J), UNA as shown in formula (27K), and Hyp-spacer as shown in formula (27L): In the above compounds of formula (27A)-(27L), Base represents a nucleic acid base, such as A, U, G, C, or T; R 27 is selected from H, OH, F, alkoxy, alkyl, or alkoxy-substituted alkyl. The * indicates that the carbon atom has chirality at that carbon atom, and the compound can be in the R configuration, the S configuration, or a racemic mixture of the R and S configurations. In some embodiments, each thermally unstable modified nucleotide is independently a GNA as shown in formula (27A). In the above context, BNA refers to a constrained or inaccessible nucleotide. A BNA can contain a five-, six-, or seven-membered ring bridged structure with a "fixed" C3'-endo sugar conformation. The bridge is typically incorporated at the 2'-, 4'-position of the ribose to provide a 2',4'-BNA nucleotide. In some embodiments, the BNA can be a LNA, an ENA, a cET BNA, etc., where the LNA is shown in formula (12), the ENA is shown in formula (13), and the cET BNA is shown in formula (14): In some embodiments, for ease of synthesis, each alkoxyl-modified nucleotide is independently a 2'-methoxyl-modified nucleotide (2'-OMe), which is shown in formula (8). In some embodiments, the 2'-amino-modified nucleotide (2'-NH2) is shown in formula (9). In some embodiments, the 2'-deoxynucleotide (DNA) is shown in formula (10): In the above compounds of formula (7)-(10) and formula (12)-(14), Base represents a nucleic acid base, such as A, U, G, C, or T. In the foregoing and hereinafter, "fluoro-modified nucleotide", "2'-fluoro-modified nucleotide", "nucleotide whose 2'-hydroxyl of the ribose group is replaced by fluorine", and "nucleotide having a 2'-fluoro-ribosyl group" have the same meaning and refer to a compound having a structure as shown in Formula (7) in which the 2'-hydroxyl of the nucleotide is replaced by fluorine; "methoxy-modified nucleotide", "2'-methoxy-modified nucleotide", "nucleotide whose 2'-hydroxyl of the ribose group is replaced by methoxy", and "nucleotide having a 2'-methoxy-ribosyl group" have the same meaning and refer to a compound having a structure as shown in Formula (8) in which the 2'-hydroxyl of the ribose group of the nucleotide is replaced by methoxy. In some embodiments, the single stranded oligonucleotide of the present disclosure is 19-23 nucleotides in length and, in the 5' end to 3' end direction, the 14th nucleotide is a nucleotide X, 2 of the 5th-7th nucleotides and the 19th nucleotide and the 2nd, 12th and 16th nucleotides are fluorinated nucleotides, the 3rd nucleotide is an alkoxy modified nucleotide or a substituted alkoxy modified nucleotide, the 5th nucleotide is an alkoxy modified nucleotide or a substituted alkoxy modified nucleotide when it is not a fluorinated nucleotide, and each of the remaining nucleotides of the single stranded oligonucleotide is an alkoxy modified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 19-23 nucleotides in length and, in the 5' end to 3' end direction, the 12th and 14th nucleotides are nucleotide X, the 2nd, 7th and 16th nucleotides are fluorinated nucleotides, the 3rd or 5th nucleotide is an alkoxy modified nucleotide or a substituted alkoxy modified nucleotide, and each of the remaining nucleotides of the single stranded oligonucleotide is an alkoxy modified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 19-23 nucleotides in length and, in the 5' end to 3' end direction, the 14th and 16th nucleotides are nucleotide X, the 2nd and 6th nucleotides are fluorinated nucleotides, the 13th nucleotide is a substituted alkoxy modified nucleotide or a BNA, and the 3rd or 5th nucleotide is an alkoxy modified nucleotide or a substituted alkoxy modified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 19-23 nucleotides in length and, in the 3' end to 5' end direction, 1 of the 1st-2nd nucleotides of the single stranded oligonucleotide is a thermally unstable nucleotide, and each of the remaining nucleotides of the single stranded oligonucleotide is an alkoxy modified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 19-23 nucleotides in length and, in the 5' end to 3' end direction, 1 of the 16th-19th nucleotides and the 14th nucleotide is a nucleotide X, the 2nd and 6th nucleotides are fluorinated nucleotides, the 16th nucleotide is a fluorinated nucleotide when it is not a nucleotide X, the 13th nucleotide is a substituted alkoxy modified nucleotide or a BNA, the 3rd or 5th nucleotide is an alkoxy modified nucleotide or a substituted alkoxy modified nucleotide, the 20th nucleotide is an alkoxy modified nucleotide or a thermally unstable nucleotide, and each of the remaining nucleotides of the single stranded oligonucleotide is an alkoxy modified nucleotide. In some embodiments, the single stranded oligonucleotide is 21 nucleotides in length, wherein the 16th or 19th nucleotide and the 14th nucleotide is a nucleotide X, and wherein the 14th nucleotide is a deoxynucleotide or an unmodified nucleotide, and the 16th or 19th nucleotide is an unmodified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 21 nucleotides in length and, in the 5' end to 3' end direction, the 14thnucleotide is a deoxy nucleotide, the 2nd, 5th, 7th, 12th, and 16thnucleotides are fluoro-modified nucleotides, the 3rdnucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the single stranded oligonucleotide is an alkoxy-modified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 21 nucleotides in length and, in the 5' end to 3' end direction, the 14thnucleotide is a deoxy nucleotide, the 2nd, 7th, 12th, 16th, and 19thnucleotides are fluoro-modified nucleotides, and each of the remaining nucleotides in the single stranded oligonucleotide is an alkoxy-modified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 21 nucleotides in length and, in the 5' end to 3' end direction, the 14thnucleotide is a deoxy nucleotide, the 2nd, 6th, 12th, 16th, and 19thnucleotides are fluoro-modified nucleotides, and each of the remaining nucleotides in the single stranded oligonucleotide is an alkoxy-modified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 21 nucleotides in length and, in the 5' end to 3' end direction, the 12thand 14thnucleotides are deoxy nucleotides, the 2nd, 7th, and 16thnucleotides are fluoro-modified nucleotides, and each of the remaining nucleotides in the single stranded oligonucleotide is an alkoxy-modified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 21 nucleotides in length and, in the 5' end to 3' end direction, the 14thnucleotide is a deoxy nucleotide, the 16thnucleotide is an unmodified nucleotide, the 2ndand 6thnucleotides are fluoro-modified nucleotides, the 13thnucleotide is a substituted alkoxy-modified nucleotide, the 2ndnucleotide of the single stranded oligonucleotide is a thermally unstable nucleotide in the 3' end to 5' end direction, and each of the remaining nucleotides in the single stranded oligonucleotide is an alkoxy-modified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 21 nucleotides in length and, in the 5' end to 3' end direction, the 14thnucleotide is a deoxy nucleotide, the 19thnucleotide is an unmodified nucleotide, the 2nd, 6th, and 16thnucleotides are fluoro-modified nucleotides, the 13thnucleotide is a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the single stranded oligonucleotide is an alkoxy-modified nucleotide. In some embodiments, each nucleotide X in the single stranded oligonucleotide of the present disclosure is a deoxynucleotide. In some embodiments, each alkoxy-modified nucleotide in the single stranded oligonucleotide of the present disclosure is a methoxy-modified nucleotide. In some embodiments, each substituted alkoxy-modified nucleotide in the single stranded oligonucleotide of the present disclosure is a 2'-0-methoxyethyl-modified nucleotide. In some embodiments, each BNA in the single stranded oligonucleotide of the present disclosure is a LNA, ENA, or cET BNA. In some embodiments, each hot unstable nucleotide in the single stranded oligonucleotide of the present disclosure is a GNA. In some embodiments, each of at least 2 of the linking groups between adjacent nucleotides in the single stranded oligonucleotide of the present disclosure is independently a phosphorothioate group with a modification group. In some embodiments, each of 1-4 of the linking groups between adjacent nucleotides in the first 5 nucleotides at the 5' end in the single stranded oligonucleotide of the present disclosure is independently a phosphorothioate group with a modification group. In some embodiments, each of 1-4 of the linking groups between adjacent nucleotides in the first 5 nucleotides at the 3' end in the single stranded oligonucleotide of the present disclosure is independently a phosphorothioate group with a modification group. In some embodiments, each of 2 of the linking groups between adjacent nucleotides in the first 3 nucleotides at the 5' end or 4 of the linking groups between adjacent nucleotides in the first 5 nucleotides at the 5' end in the single stranded oligonucleotide of the present disclosure is independently a phosphorothioate group with a modification group. In some embodiments, each of 2 of the linking groups between adjacent nucleotides in the first 3 nucleotides at the 3' end or 4 of the linking groups between adjacent nucleotides in the first 5 nucleotides at the 3' end in the single stranded oligonucleotide of the present disclosure is independently a phosphorothioate group with a modification group. In some embodiments, if there is an unmodified nucleotide in the single stranded oligonucleotide of the present disclosure, each of 1 or 2 of the 2 linking groups between the unmodified nucleotide and the adjacent nucleotides is independently a phosphorothioate group with a modification group. The modified phosphorothioate group can make the single stranded oligonucleotide of the present disclosure better resistant to exonuclease, and enhance the stability of the oligonucleotide in a subject. In some embodiments, at least 2, or each of 2-6, of the linking groups between adjacent nucleotides in the single stranded oligonucleotide of the present disclosure is independently a phosphorothioate group with a modification group. In some embodiments, each of 2-6 of the linking groups between adjacent nucleotides in the single stranded oligonucleotide is independently a phosphorothioate group with a modification group. In some embodiments, each of 3 or 4 of the linking groups between adjacent nucleotides in the single stranded oligonucleotide is independently a phosphorothioate group with a modification group. In some embodiments, each of the linking groups between adjacent nucleotides in the first 1-3 nucleotides at the 5' end, and the first 1-3 nucleotides at the 3' end of the single stranded oligonucleotide is independently a phosphorothioate group with a modification group. In some embodiments, if there is an unmodified nucleotide in the single stranded oligonucleotide, each of the unmodified nucleotide and one or two of the two linking groups between the unmodified nucleotide and the adjacent nucleotides is independently a phosphorothioate group with a modification group. In some embodiments, the phosphorothioate group with a modification group is a phosphorothioate group with a structure as shown in formula (28): In some embodiments, the 5' terminal nucleotide of the single stranded oligonucleotide is a 5'-hydroxyl nucleotide with a structure as shown in formula (29), a 5'-phosphate nucleotide with a structure as shown in formula (30), or a 5'-phosphate analog modified nucleotide with a structure selected from one of formula (31) to formula (34): wherein R is selected from one of H, OH, OCH3, and F; Base represents a nucleic acid base selected from A, U, C, G, or T. In some embodiments, the 5'-phosphate nucleotide is a 5'-phosphate modified nucleotide as shown in formula (30), the 5'-phosphate analog modified nucleotide is a nucleotide with a vinyl phosphonate (5'-(E)-vinylphosphonate, E-VP) modification as shown in formula (31), or a 5'-phosphorothioate modification as shown in formula (33). In some embodiments, the 5' terminal nucleotide of the single stranded oligonucleotide is a 5'-hydroxyl nucleotide or a nucleotide with a vinyl phosphonate (5'-(E)-vinylphosphonate, E-VP) modification. In some embodiments, the 5' terminal nucleotide is a nucleotide with a vinyl phosphonate (5'-(E)-vinylphosphonate, E-VP) modification, which can further increase one or more of the stability, the pharmacodynamic activity in a subject, and the long-acting property of the single stranded oligonucleotide, the double stranded oligonucleotide comprising the single stranded oligonucleotide, and the oligonucleotide conjugate of the present disclosure. In some embodiments, the single-stranded oligonucleotide has a length of 21 nucleotides, and in a 5' end to 3' end direction, the 14th nucleotide is a deoxy nucleotide, the 2nd, 5th, 7th, 12th, and 16th nucleotides are fluoro-modified nucleotides, the 3rd nucleotide is a methoxy-modified nucleotide, each of the remaining nucleotides in the single-stranded oligonucleotide is a methoxy-modified nucleotide; the linking group between any two adjacent nucleotides of the 1st to 3rd nucleotides at the 5' end and the linking group between any two adjacent nucleotides of the 1st to 3rd nucleotides at the 3' end are phosphorothioate groups; the 5' end nucleotide is a 5'-hydroxyl nucleotide of Formula (29) or a 5'-vinylphosphonate-modified nucleotide of Formula (31). As previously described, the single-stranded oligonucleotides of the present disclosure have sufficient complementarity to SOD1 mRNA to mediate an RNAi effect. In some embodiments, the single-stranded oligonucleotides of the present disclosure are sufficiently complementary to SOD1 mRNA. In the context of the present disclosure, "sufficiently complementary" means that the single-stranded oligonucleotides of the present disclosure have sufficient complementarity to SOD1 mRNA such that the single-stranded oligonucleotides reduce or eliminate the production of a protein encoded by the SOD1 mRNA through an RNAi effect. In some embodiments, "sufficiently complementary" means that the single-stranded oligonucleotides of the present disclosure are substantially reverse complementary, substantially reverse complementary, or completely reverse complementary to SOD1 mRNA over a length of at least 16 nucleotides, for example, over a length of 16-25 nucleotides, over a length of 18-23 nucleotides, or over a length of 19-21 nucleotides. In some embodiments, the single-stranded oligonucleotides of the present disclosure are completely reverse complementary to SOD1 mRNA. In the preceding and following text, "at least partially anticomplementary," "substantially anticomplementary," "truly anticomplementary," and "completely anticomplementary" can be used to refer to the base pairing between two single-stranded nucleotide sequences: between a single-stranded oligonucleotide and SOD1 mRNA, between the sense and antisense strands of a double-stranded oligonucleotide (such as siRNA), and between the antisense strand of a double-stranded oligonucleotide and SOD1 mRNA. Unless otherwise specified, "at least partially anticomplementary" means that within a given length of nucleotide sequence, there is no more than 50% base mismatch between the two nucleotide sequences; "substantially anticomplementary" means that within a given length of nucleotide sequence, there is no more than 3 base mismatches between the two nucleotide sequences; "truly anticomplementary" means that within a given length of nucleotide sequence, there is 1 base mismatch between the two nucleotide sequences; and "completely anticomplementary" means that within a given length of nucleotide sequence, there are no base mismatches between the two nucleotide sequences. When two nucleotide sequences are completely anticomplementary within a given length of nucleotide sequence, they can anneal to form a double-stranded hybrid uniquely composed of Watson-Crick base pairs within the given length of nucleotide sequence. Unless otherwise stated, when referring to a shorter nucleotide sequence as "completely anticomplementary" to a longer nucleotide sequence, it means that the two nucleotide sequences are completely anticomplementary over the entire length of the shorter nucleotide sequence. For example, the complete anticomplementary relationship between the single-stranded oligonucleotide and SOD1 mRNA described in this disclosure means that the single-stranded oligonucleotide is completely anticomplementary over its entire length; in other words, the single-stranded oligonucleotide can form a double-stranded hybrid by each nucleotide uniquely forming a Watson-Crick base pair with a nucleotide on SOD1 mRNA. In some embodiments, the two "fully complementary" nucleotide sequences may include completely anticomplementary internal regions (e.g., completely anticomplementary across a length of at least 6, 8, or 10 nucleotides). In some embodiments, the single-stranded oligonucleotide of this disclosure is completely anticomplementary to SOD1 mRNA at least within a seed region. The "seed region" refers to the region of nucleotides 2-8 of the single-stranded oligonucleotide of this disclosure, where the single-stranded oligonucleotide of this disclosure can better mediate RNAi action and inhibit SOD1 mRNA levels. In some embodiments, the single-stranded oligonucleotide is substantially or completely complementary to the SOD1 mRNA over a stretch of at least 16 nucleotides. In some embodiments, the nucleotide sequence of positions 2-19 of the single-stranded oligonucleotide is completely complementary to the SOD1 mRNA in the 5' to 3' direction. In some embodiments, the nucleotide sequence of the single-stranded oligonucleotide, except for the first position at the 5' end, is completely complementary to the SOD1 mRNA in the 5' to 3' direction. In some embodiments, all of the nucleotides of the single-stranded oligonucleotide are completely complementary to the SOD1 mRNA. In some embodiments, the single-stranded oligonucleotide of the present disclosure can be the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh single-stranded oligonucleotide described below, each of which is described herein. The first single-stranded oligonucleotide In some embodiments, the present disclosure provides the first single-stranded oligonucleotide, wherein the single-stranded oligonucleotide comprises a nucleotide sequence II, which is equal in length to the nucleotide sequence set forth in SEQ ID NO: 2, and has no more than 3 base differences: 5'-Z2 UUACUUUCCUUCUGCUCG-3' (SEQ ID NO: 2), wherein Z2 is A or U, and the nucleotide sequence II comprises a nucleotide Z'2 at a position corresponding to Z2, which is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence. In the foregoing and hereinafter of the present disclosure, "corresponding to" means being at the same position in a nucleotide sequence, counting from the same end of the nucleotide sequence, for example, the first nucleotide at the 5' end of the nucleotide sequence II is the nucleotide corresponding to the first nucleotide of SEQ ID NO: 2. In some embodiments, each U in the nucleotide sequence of the single-stranded oligonucleotide, double-stranded oligonucleotide, oligonucleotide conjugate of the present disclosure can be optionally replaced by T. These base differences do not significantly reduce the SOD1 mRNA inhibition ability of the single-stranded oligonucleotide, double-stranded oligonucleotide, oligonucleotide conjugate or increase its off-target effect. These single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates comprising base differences are also within the scope of the present disclosure. In some embodiments, there is no more than 1 base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2 comprises a difference at position Z'2 and / or a base difference at any other nucleotide position in nucleotide sequence II. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2 comprises a difference at position Z'2 and / or a base difference at a nucleotide position adjacent to Z'2. In some embodiments, there is no base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2 comprises a difference at position Z'2, and Z'2 is selected from C, U, or G. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2 is a difference at position Z'2, and Z'2 is selected from C, U, or G. In some embodiments, the single-stranded oligonucleotide further comprises nucleotide sequence IV, which is linked to the 3' end of nucleotide sequence II, has a length of 1, 2, 3, or 4 nucleotides, each nucleotide in nucleotide sequence IV is independently one of non-fluoro-modified nucleotides, nucleotide sequence IV is substantially or completely reverse-complementary to SOD1 mRNA, and each of the non-fluoro-modified nucleotides is independently selected from one of 2'-methoxy-modified nucleotide, 2'-alkyl-modified nucleotide having an alkyl group of 1-3 carbon atoms, 2'-amino-modified nucleotide, 2'-substituted amino-modified nucleotide, and heat unstable nucleotide. In some embodiments, the length of nucleotide sequence IV is 2 nucleotides. In some embodiments, the length of nucleotide sequence IV is 1 nucleotide, and the base is A; or, the length of nucleotide sequence IV is 2 nucleotides, and the base composition is AA from 5' end to 3' end; or, the length of nucleotide sequence IV is 3 nucleotides, and the base composition is AAU from 5' end to 3' end; or, the length of nucleotide sequence IV is 4 nucleotides, and the base composition is AAAAA from 5' end to 3' end. In some embodiments, the single-stranded oligonucleotide of the present disclosure further comprises nucleotide sequence V, each nucleotide in nucleotide sequence V is independently a non-fluoro-modified nucleotide, the length of nucleotide sequence V is 1-3 nucleotides, and nucleotide sequence V is linked to the 3' end of nucleotide sequence IV or nucleotide sequence II; after the single-stranded oligonucleotide forms a double-stranded oligonucleotide with a sense strand, nucleotide sequence V constitutes a 3' overhang end of the antisense strand of the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V of the present disclosure has a length of 2 nucleotides, and in a 5' end to 3' end direction, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or fully reverse complementary to the SOD1 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and in a 5' end to 3' end direction, the base composition of the nucleotide sequence V is selected from AA or UU. In some embodiments, the single-stranded oligonucleotide comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 2, and the base composition of the nucleotide sequence V is AA. A second single-stranded oligonucleotide In some embodiments, the present disclosure provides a second single-stranded oligonucleotide, wherein the single-stranded oligonucleotide contains a nucleotide sequence II, the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 4, and differs by no more than 3 bases: 5'-Z4 CUUUCUUCAUUUCCACCU-3' (SEQ ID NO: 4), wherein Z4 is A or U, the nucleotide sequence II comprises a nucleotide Z'4 at a position corresponding to Z4, and Z'4 is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence. In some embodiments, the nucleotide sequence II differs by no more than 1 base from the nucleotide sequence set forth in SEQ ID NO: 4. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 4 comprises a difference at the Z'4 position and / or a base difference at any other nucleotide position in the nucleotide sequence II. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 4 comprises a difference at the Z'4 position and / or a difference at a nucleotide position adjacent to Z'4. In some embodiments, there is no base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 4. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 4 comprises a difference at the Z'4 position, and Z'4 is selected from C, U, or G. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 4 is a difference at the Z'4 position, and Z'4 is selected from C, U, or G. In some embodiments, the single-stranded oligonucleotide further comprises nucleotide sequence IV, which is 1, 2, 3, or 4 nucleotides in length, is linked to the 3' end of nucleotide sequence II, and each nucleotide in nucleotide sequence IV is independently one of the non-fluoro-modified nucleotides, and nucleotide sequence IV is substantially or completely reverse-complementary to SOD1 mRNA. Each of the non-fluoro-modified nucleotides is independently selected from one of 2'-methoxy-modified nucleotide, 2'-alkyl-modified nucleotide with carbon number of 1-3, 2'-amino-modified nucleotide, 2'-substituted amino-modified nucleotide, and heat unstable nucleotide. In some embodiments, the length of nucleotide sequence IV is 2 nucleotides. In some embodiments, the length of nucleotide sequence IV is 1 nucleotide, and the base is U; or, the length of nucleotide sequence IV is 2 nucleotides, and the base composition is UU from 5' end to 3' end; or, the length of nucleotide sequence IV is 3 nucleotides, and the base composition is UUG from 5' end to 3' end; or, the length of nucleotide sequence IV is 4 nucleotides, and the base composition is UUGC from 5' end to 3' end. In some embodiments, the single-stranded oligonucleotide of the present disclosure further comprises nucleotide sequence V, each nucleotide of which is independently a non-fluoro-modified nucleotide, and the length of nucleotide sequence V is 1-3 nucleotides, which is linked to the 3' end of nucleotide sequence IV or nucleotide sequence II; and, after the single-stranded oligonucleotide forms a double-stranded oligonucleotide with the sense strand, nucleotide sequence V constitutes the 3' overhang end of the antisense strand of the double-stranded oligonucleotide. In some embodiments, the length of nucleotide sequence V of the present disclosure is 2 nucleotides, and, from 5' end to 3' end, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or completely reverse-complementary to SOD1 mRNA. In some embodiments, nucleotide sequence V is linked to the 3' end of nucleotide sequence II, and, from 5' end to 3' end, the base composition of nucleotide sequence V is selected from UU. In some embodiments, the single-stranded oligonucleotide comprises only nucleotide sequence II and nucleotide sequence V, nucleotide sequence II consists of SEQ ID NO: 4, and the base composition of nucleotide sequence V is UU. The third single-stranded oligonucleotide In some embodiments, the present disclosure provides a third single-stranded oligonucleotide, wherein the single-stranded oligonucleotide comprises nucleotide sequence II, which is equal in length to the nucleotide sequence set forth in SEQ ID NO: 6, and has no more than 3 base differences. 5'-Z6UGAACAUGGAAUCCAUGC-3' (SEQ ID NO: 6), wherein Z6 is A or U, and nucleotide sequence II comprises a nucleotide Z'6 at a position corresponding to Z6, and Z'6 is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence. In some embodiments, there is no more than 1 base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 6. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 6 comprises a difference at the Z'6 position and / or a base difference at any other nucleotide position in nucleotide sequence II. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 6 comprises a difference at the Z'6 position and / or a base difference at a nucleotide position adjacent to Z'6. In some embodiments, there is no base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 6. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 6 comprises a difference at the Z'6 position, and Z'6 is selected from C, U, or G. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 6 is a difference at the Z'6 position, and Z'6 is selected from C, U, or G. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence IV linked to the 3' end of nucleotide sequence II, the nucleotide sequence IV having a length of 1, 2, 3, or 4 nucleotides, each nucleotide in the nucleotide sequence IV being independently one of a non-fluoro-modified nucleotide, the nucleotide sequence IV being substantially or completely reverse-complementary to SOD1 mRNA, each of the non-fluoro-modified nucleotides being independently selected from one of a 2'-methoxy-modified nucleotide, a 2'-alkyl-modified nucleotide having an alkyl group of 1-3 carbon atoms, a 2'-amino-modified nucleotide, a 2'-substituted amino-modified nucleotide, and a thermally unstable nucleotide. In some embodiments, the nucleotide sequence IV has a length of 2 nucleotides. In some embodiments, the nucleotide sequence IV has a length of 1 nucleotide, and the base is A; or, the nucleotide sequence IV has a length of 2 nucleotides, and the base composition is AG from the 5' end to the 3' end; or, the nucleotide sequence IV has a length of 3 nucleotides, and the base composition is AGG from the 5' end to the 3' end; or, the nucleotide sequence IV has a length of 4 nucleotides, and the base composition is AGGC from the 5' end to the 3' end. In some embodiments, the single-stranded oligonucleotide of the present disclosure further contains a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluorinated modified nucleotide, the nucleotide sequence V has a length of 1 to 3 nucleotides, is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II; after the single-stranded oligonucleotide forms a double-stranded oligonucleotide with the sense strand, the nucleotide sequence V constitutes the 3' overhang end of the antisense strand of the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V has a length of 2 nucleotides, and in the direction from the 5' end to the 3' end, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or is fully reverse complementary to the SOD1 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and in the direction from the 5' end to the 3' end, the base composition of the nucleotide sequence V is selected from AG or UU. In some embodiments, the single-stranded oligonucleotide only contains the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 6, and the base composition of the nucleotide sequence V is AG. A fourth single-stranded oligonucleotide In some embodiments, the present disclosure provides a fourth single-stranded oligonucleotide, wherein the single-stranded oligonucleotide contains a nucleotide sequence II, the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 8, and has no more than 3 base differences from the nucleotide sequence set forth in SEQ ID NO: 8: 5'-Z8CUGGAUAGAGGAUUAAAG-3' (SEQ ID NO: 8), wherein Z8 is A or U, the nucleotide sequence II contains a nucleotide Z8 at a position corresponding to Z'8, Z'8 is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence. In some embodiments, the nucleotide sequence II has no more than 1 base difference from the nucleotide sequence set forth in SEQ ID NO: 8. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 8 includes a difference at the Z'8 position and / or a base difference at any other nucleotide position in the nucleotide sequence II. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 8 includes a difference at the Z'8 position and / or a difference at a nucleotide position adjacent to Z'8. In some embodiments, there is no base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 8. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 8 comprises a difference at position Z'8, and Z'8 is selected from C, U, or G. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 8 is a difference at position Z'8, and Z'8 is selected from C, U, or G. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence IV, which is linked to the 3' end of the nucleotide sequence II, has a length of 1, 2, 3, or 4 nucleotides, each nucleotide in the nucleotide sequence IV is independently one of non-fluoro-modified nucleotides, the nucleotide sequence IV is substantially or completely reverse-complementary to the SOD1 mRNA, and each of the non-fluoro-modified nucleotides is independently selected from one of 2'-methoxy-modified nucleotides, 2'-alkyl-modified nucleotides having an alkyl group of 1-3 carbon atoms, 2'-amino-modified nucleotides, 2'-substituted amino-modified nucleotides, and heat unstable nucleotides. In some embodiments, the nucleotide sequence IV has a length of 2 nucleotides. In some embodiments, the nucleotide sequence IV has a length of 1 nucleotide, and the base is U; or, the nucleotide sequence IV has a length of 2 nucleotides, and the base composition is UG from the 5' end to the 3' end; or, the nucleotide sequence IV has a length of 3 nucleotides, and the base composition is UGA from the 5' end to the 3' end; or, the nucleotide sequence IV has a length of 4 nucleotides, and the base composition is UGAG from the 5' end to the 3' end. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence V, each nucleotide in the nucleotide sequence V is independently a non-fluoro-modified nucleotide, the nucleotide sequence V has a length of 1-3 nucleotides, and is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II; after the single-stranded oligonucleotide forms a double-stranded oligonucleotide with a sense strand, the nucleotide sequence V constitutes a 3' overhang end of the antisense strand of the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V has a length of 2 nucleotides, and from the 5' end to the 3' end, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or is completely reverse-complementary to the SOD1 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and from the 5' end to the 3' end, the base composition of the nucleotide sequence V is selected from UG or UU. In some embodiments, the single-stranded oligonucleotide comprises only nucleotide sequence II and nucleotide sequence V, nucleotide sequence II consists of SEQ ID NO: 8, and nucleotide sequence V has a base composition of UG. A fifth single-stranded oligonucleotide In some embodiments, the present disclosure provides a fifth single-stranded oligonucleotide, wherein the single-stranded oligonucleotide contains nucleotide sequence II, nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 10, and differs by no more than 3 bases from the nucleotide sequence set forth in SEQ ID NO: 10: 5'-Z 10 UCAUUUCCACCUUUGCCC-3' (SEQ ID NO: 10), wherein Z 10 is A or U, nucleotide sequence II comprises a nucleotide Z' 10 at a position corresponding to Z 10 , and Z' 10 is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence. In some embodiments, nucleotide sequence II differs by no more than 1 base from the nucleotide sequence set forth in SEQ ID NO: 10. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 10 comprises a difference at position Z' 10 and / or a base difference at any other nucleotide position in nucleotide sequence II. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 10 comprises a difference at position Z' 10 and / or a base difference at an adjacent nucleotide position to Z' 10 . In some embodiments, there is no base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 10. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 10 comprises a difference at position Z' 10 , and Z' 10 is selected from C, U, or G. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 10 is a difference at position Z' 10 , and Z' 10 is selected from C, U, or G. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence IV, which is linked to the 3' end of the nucleotide sequence II, has a length of 1, 2, 3, or 4 nucleotides, each nucleotide in the nucleotide sequence IV is independently one of the non-fluoro-modified nucleotides, the nucleotide sequence IV is substantially or completely reverse-complementary to the SOD1 mRNA, and each of the non-fluoro-modified nucleotides is independently selected from one of 2'-methoxy-modified nucleotide, 2'-alkyl-modified nucleotide with an alkyl group having a carbon number of 1-3, 2'-amino-modified nucleotide, 2'-substituted amino-modified nucleotide, and heat-unstable nucleotide. In some embodiments, the nucleotide sequence IV has a length of 2 nucleotides. In some embodiments, the nucleotide sequence IV has a length of 1 nucleotide, and the base is A; or, the nucleotide sequence IV has a length of 2 nucleotides, and the base composition is AA in the direction from the 5' end to the 3' end; or, the nucleotide sequence IV has a length of 3 nucleotides, and the base composition is AAG in the direction from the 5' end to the 3' end; or, the nucleotide sequence IV has a length of 4 nucleotides, and the base composition is AAGU in the direction from the 5' end to the 3' end. In some embodiments, the single-stranded oligonucleotide of the present disclosure further comprises a nucleotide sequence V, each nucleotide in the nucleotide sequence V is independently a non-fluoro-modified nucleotide, the nucleotide sequence V has a length of 1-3 nucleotides, and is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II; after the single-stranded oligonucleotide forms a double-stranded oligonucleotide with the sense strand, the nucleotide sequence V constitutes the 3' overhang end of the antisense strand of the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V has a length of 2 nucleotides, and in the direction from the 5' end to the 3' end, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or is completely reverse-complementary to the SOD1 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and in the direction from the 5' end to the 3' end, the base composition of the nucleotide sequence V is selected from AA or UU. In some embodiments, the single-stranded oligonucleotide comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 10, and the base composition of the nucleotide sequence V is AA. Sixth single-stranded oligonucleotide In some embodiments, the present disclosure provides a sixth single-stranded oligonucleotide, wherein the single-stranded oligonucleotide comprises a nucleotide sequence II that is equal in length to the nucleotide sequence set forth in SEQ ID NO: 12 and differs by no more than 3 bases: 5'-Z 12 ACAUGCCUCUCUUCAUCC-3' (SEQ ID NO: 12), wherein Z 12 is A or U, and nucleotide sequence II comprises a nucleotide Z' 12 at a position corresponding to Z 12 , and Z' 12 is the first nucleotide of the 5' end of the single-stranded oligonucleotide sequence; In some embodiments, there is no more than 1 base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 12. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 12 comprises a difference at position Z' 12 and / or a base difference at any other nucleotide position in nucleotide sequence II. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 12 comprises a difference at position Z' 12 and / or a base difference at an adjacent nucleotide position to Z' 12 . In some embodiments, there is no base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 12. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 12 comprises a difference at position Z' 12 , and Z' 12 is selected from C, U, or G. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 12 is a difference at position Z' 12 , and Z' 12 is selected from C, U, or G. In some embodiments, the single-stranded oligonucleotide further comprises nucleotide sequence IV, which is linked to the 3' end of nucleotide sequence II, has a length of 1, 2, 3, or 4 nucleotides, each nucleotide in the nucleotide sequence IV is independently one of non-fluoro-modified nucleotides, the nucleotide sequence IV is substantially or completely reverse-complementary to SOD1 mRNA, and each of the non-fluoro-modified nucleotides is independently selected from one of 2'-methoxy-modified nucleotide, 2'-alkyl-modified nucleotide with carbon number of 1-3, 2'-amino-modified nucleotide, 2'-substituted amino-modified nucleotide, and heat-unstable nucleotide. In some embodiments, the nucleotide sequence IV has a length of 2 nucleotides. In some embodiments, the nucleotide sequence IV has a length of 1 nucleotide, and the base is U; or, the nucleotide sequence IV has a length of 2 nucleotides, and the base composition is UU from 5' end to 3' end; or, the nucleotide sequence IV has a length of 3 nucleotides, and the base composition is UUU from 5' end to 3' end; or, the nucleotide sequence IV has a length of 4 nucleotides, and the base composition is UUUG from 5' end to 3' end. In some embodiments, the single-stranded oligonucleotide of the present disclosure further comprises nucleotide sequence V, each nucleotide in the nucleotide sequence V is independently a non-fluoro-modified nucleotide, the nucleotide sequence V has a length of 1-3 nucleotides, and is linked to the 3' end of nucleotide sequence IV or nucleotide sequence II; after the single-stranded oligonucleotide forms a double-stranded oligonucleotide with the positive strand, the nucleotide sequence V constitutes the 3' overhanging end of the antisense strand of the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V has a length of 2 nucleotides, and from 5' end to 3' end, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or is completely reverse-complementary to SOD1 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of nucleotide sequence II, and from 5' end to 3' end, the base composition of the nucleotide sequence V is selected from UU. In some embodiments, the single-stranded oligonucleotide comprises only nucleotide sequence II and nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 12, and the base composition of the nucleotide sequence V is UU. The seventh single-stranded oligonucleotide In some embodiments, the present disclosure provides the seventh single-stranded oligonucleotide, wherein the single-stranded oligonucleotide comprises nucleotide sequence II, the nucleotide sequence II is equal in length to the nucleotide sequence shown in SEQ ID NO: 14, and has no more than 3 base differences. 5'-Z 14 CCAACAUGCCUCUCUUCA-3'(SEQ ID NO:14), Among them, Z 14 For A or U, the position in nucleotide sequence II corresponds to Z. 14 nucleotide Z' 14 Z' 14 It is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence. In some embodiments, nucleotide sequence II differs from the nucleotide sequence shown in SEQ ID NO:14 by no more than one base. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:14 includes Z'. 14 Differences at positions and / or base differences at any other nucleotide position in nucleotide sequence II. In some embodiments, the base differences between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:14 include Z'. 14 Location and / or Z' 14 Base differences at adjacent nucleotide positions. In some embodiments, there are no base differences between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:14. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:14 includes Z' 14 The difference in position, and Z' 14 Selected from C, U, or G. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:14 is Z'. 14 The difference in position, and Z' 14 Choose from C, U, or G. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence IV linked to the 3' end of nucleotide sequence II, and having a length of 1, 2, 3, or 4 nucleotides. Each nucleotide in nucleotide sequence IV is independently one of a non-fluorinated nucleotide. Nucleotide sequence IV is substantially anticomplementary or completely anticomplementary to SOD1 mRNA. Each of the non-fluorinated nucleotides is independently selected from one of a 2'-methoxy-modified nucleotide, a 2'-alkyl-modified nucleotide having 1-3 carbon atoms, a 2'-amino-modified nucleotide, a 2'-substituted amino-modified nucleotide, and a heat-labile nucleotide. In some embodiments, the length of nucleotide sequence IV is 2 nucleotides. In some embodiments, the nucleotide sequence IV has a length of 1 nucleotide, and the base is U; or, the nucleotide sequence IV has a length of 2 nucleotides, and the base composition is UC from 5' end to 3' end; or, the nucleotide sequence IV has a length of 3 nucleotides, and the base composition is UCC from 5' end to 3' end; or, the nucleotide sequence IV has a length of 4 nucleotides, and the base composition is UCCU from 5' end to 3' end. In some embodiments, the single-stranded oligonucleotide of the present disclosure further contains a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluorinated modified nucleotide, the nucleotide sequence V has a length of 1 to 3 nucleotides, and is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II; after the single-stranded oligonucleotide forms a double-stranded oligonucleotide with the sense strand, the nucleotide sequence V constitutes the 3' overhang end of the antisense strand of the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V has a length of 2 nucleotides, and from 5' end to 3' end, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or fully reverse complementary to the SOD1 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and from 5' end to 3' end, the base composition of the nucleotide sequence V is selected from UC or UU. In some embodiments, the single-stranded oligonucleotide only contains the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 14, and the base composition of the nucleotide sequence V is UC. The eighth single-stranded oligonucleotide In some embodiments, the present disclosure provides the eighth single-stranded oligonucleotide, wherein the single-stranded oligonucleotide contains a nucleotide sequence II, the nucleotide sequence II is equal in length to the nucleotide sequence shown in SEQ ID NO: 16, and has no more than 3 base differences: 5'-Z 16 CACCUUCACUGGUCCAUU-3' (SEQ ID NO: 16), wherein Z 16 is A or U, and the nucleotide Z' 16 in the nucleotide sequence II comprises a nucleotide corresponding to Z 16 , Z' 16 is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence. In some embodiments, there is no more than 1 base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 16. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 16 comprises a difference at position Z 16 and / or a base difference at any one other nucleotide position in nucleotide sequence II. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 16 comprises a difference at position Z 16 and / or a base difference at an adjacent nucleotide position to Z 16 In some embodiments, there is no base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 16. In some embodiments, there is no more than 1 base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 16. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 16 comprises a difference at position Z 16 and Z 16 is selected from C, U, or G. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 16 is a difference at position Z 16 and Z 16 is selected from C, U, or G. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence IV linked to the 3' end of nucleotide sequence II, the nucleotide sequence IV having a length of 1, 2, 3, or 4 nucleotides, each nucleotide in the nucleotide sequence IV being independently one of a non-fluoro-modified nucleotide, the nucleotide sequence IV being substantially reverse-complementary or fully reverse-complementary to SOD1 mRNA, each of the non-fluoro-modified nucleotides being independently selected from one of a 2'-methoxy-modified nucleotide, a 2'-alkyl-modified nucleotide having an alkyl group having a carbon number of 1-3, a 2'-amino-modified nucleotide, a 2'-substituted amino-modified nucleotide, and a thermally unstable nucleotide. In some embodiments, the nucleotide sequence IV has a length of 2 nucleotides. In some embodiments, the nucleotide sequence IV has a length of 1 nucleotide, and the base is A; or, the nucleotide sequence IV has a length of 2 nucleotides, and the base composition is AC from the 5' end to the 3' end; or, the nucleotide sequence IV has a length of 3 nucleotides, and the base composition is ACU from the 5' end to the 3' end; or, the nucleotide sequence IV has a length of 4 nucleotides, and the base composition is ACUU from the 5' end to the 3' end. In some embodiments, the single-stranded oligonucleotide of the present disclosure further contains a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluorinated modified nucleotide, the nucleotide sequence V has a length of 1 to 3 nucleotides, is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II; after the single-stranded oligonucleotide forms a double-stranded oligonucleotide with the sense strand, the nucleotide sequence V constitutes the 3' overhang end of the antisense strand of the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V has a length of 2 nucleotides, and in the direction from the 5' end to the 3' end, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or fully reverse complementary to the SOD1 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and in the direction from the 5' end to the 3' end, the base composition of the nucleotide sequence V is selected from AC or UU. In some embodiments, the single-stranded oligonucleotide only contains the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 16, and the base composition of the nucleotide sequence V is AC. The ninth single-stranded oligonucleotide In some embodiments, the present disclosure provides the ninth single-stranded oligonucleotide, wherein the single-stranded oligonucleotide contains a nucleotide sequence II, the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 18, and has no more than 3 base differences: 5'-Z 18 AUCCAUGCAGGCCUUCAG-3' (SEQ ID NO: 18), wherein Z 18 is A or U, the nucleotide Z' 18 in the nucleotide sequence II corresponds to the position of Z 18 , and Z' 18 is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence. In some embodiments, there is no more than 1 base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 18. The base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 18 includes the difference at the position of Z' 18 , and / or the base difference at any other nucleotide position in the nucleotide sequence II. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 18 includes the difference at the position of Z' 18 , and / or the difference at the position of Z' 18a base difference at the nucleotide position. In some embodiments, there is no base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 18. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 18 comprises Z 18 a difference at the nucleotide position, and Z 18 is selected from C, U, or G. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 18 is Z 18 a difference at the nucleotide position, and Z 18 is selected from C, U, or G. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence IV, which is linked to the 3' end of the nucleotide sequence II, has a length of 1, 2, 3, or 4 nucleotides, each nucleotide in the nucleotide sequence IV is independently one of non-fluoro-modified nucleotides, the nucleotide sequence IV is substantially or completely reverse-complementary to the SOD1 mRNA, and each of the non-fluoro-modified nucleotides is independently selected from one of 2'-methoxy-modified nucleotides, 2'-alkyl-modified nucleotides having an alkyl group of 1-3 carbon atoms, 2'-amino-modified nucleotides, 2'-substituted amino-modified nucleotides, and heat unstable nucleotides. In some embodiments, the nucleotide sequence IV has a length of 2 nucleotides. In some embodiments, the nucleotide sequence IV has a length of 1 nucleotide, and the base is U; or, the nucleotide sequence IV has a length of 2 nucleotides, and the base composition, from the 5' end to the 3' end, is UC; or, the nucleotide sequence IV has a length of 3 nucleotides, and the base composition, from the 5' end to the 3' end, is UCA; or, the nucleotide sequence IV has a length of 4 nucleotides, and the base composition, from the 5' end to the 3' end, is UCAG. In some embodiments, the single-stranded oligonucleotide of the present disclosure further comprises a nucleotide sequence V, each nucleotide in the nucleotide sequence V is independently a non-fluoro-modified nucleotide, the nucleotide sequence V has a length of 1-3 nucleotides, and is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II; after the single-stranded oligonucleotide forms a double-stranded oligonucleotide with a sense strand, the nucleotide sequence V constitutes a 3' overhang end of the antisense strand of the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V of the present disclosure has a length of 2 nucleotides, and, from the 5' end to the 3' end, the nucleotide sequence V is two consecutive thymine deoxynucleotides, two consecutive uracil nucleotides, or is completely reverse-complementary to the SOD1 mRNA. In some embodiments, nucleotide sequence V is linked at the 3' end of nucleotide sequence II, and the base composition of said nucleotide sequence V, in the 5' end to 3' end direction, is selected from UC or UU. In some embodiments, the single-stranded oligonucleotide comprises only nucleotide sequence II and nucleotide sequence V, nucleotide sequence II consists of SEQ ID NO: 18, and the base composition of nucleotide sequence V is UC. A tenth single-stranded oligonucleotide In some embodiments, the present disclosure provides a tenth single-stranded oligonucleotide, wherein the single-stranded oligonucleotide contains nucleotide sequence II, nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 20, and differs from the nucleotide sequence set forth in SEQ ID NO: 20 by no more than 3 bases: 5'-Z 20 UUUCCACCUUUGCCCAAG-3' (SEQ ID NO: 20), wherein Z 20 is A or U, nucleotide sequence II comprises a nucleotide Z' 20 at a position corresponding to Z 20 , and Z' 20 is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence. In some embodiments, nucleotide sequence II differs from the nucleotide sequence set forth in SEQ ID NO: 20 by no more than 1 base. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 20 comprises a difference at position Z' 20 and / or a base difference at any other nucleotide position in nucleotide sequence II. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 20 comprises a difference at position Z' 20 and / or a base difference at an adjacent nucleotide position to Z' 20 . In some embodiments, there is no base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 20. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 20 comprises a difference at position Z' 20 , and Z' 20 is selected from C, U, or G. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 20 is a difference at position Z' 20 , and Z' 20 is selected from C, U, or G. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence IV, which is linked to the 3' end of the nucleotide sequence II, has a length of 1, 2, 3, or 4 nucleotides, each nucleotide in the nucleotide sequence IV is independently one of the non-fluoro-modified nucleotides, the nucleotide sequence IV is substantially or completely reverse-complementary to the SOD1 mRNA, and each of the non-fluoro-modified nucleotides is independently selected from one of 2'-methoxy-modified nucleotide, 2'-alkyl-modified nucleotide having an alkyl group of 1-3 carbon atoms, 2'-amino-modified nucleotide, 2'-substituted amino-modified nucleotide, and heat unstable nucleotide. In some embodiments, the nucleotide sequence IV has a length of 2 nucleotides. In some embodiments, the nucleotide sequence IV has a length of 1 nucleotide, and the base is UC; or, the nucleotide sequence IV has a length of 2 nucleotides, and the base composition is UC from the 5' end to the 3' end; or, the nucleotide sequence IV has a length of 3 nucleotides, and the base composition is UCA from the 5' end to the 3' end; or, the nucleotide sequence IV has a length of 4 nucleotides, and the base composition is UCAU from the 5' end to the 3' end. In some embodiments, the single-stranded oligonucleotide of the present disclosure further comprises a nucleotide sequence V, each nucleotide in the nucleotide sequence V is independently a non-fluoro-modified nucleotide, the nucleotide sequence V has a length of 1-3 nucleotides, and is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II; after the single-stranded oligonucleotide forms a double-stranded oligonucleotide with the sense strand, the nucleotide sequence V constitutes the 3' overhang end of the antisense strand of the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V has a length of 2 nucleotides, and from the 5' end to the 3' end, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or is completely reverse-complementary to the SOD1 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and from the 5' end to the 3' end, the base composition of the nucleotide sequence V is selected from UC or UU. In some embodiments, the single-stranded oligonucleotide comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 20, and the base composition of the nucleotide sequence V is UC. Eleventh single-stranded oligonucleotide In some embodiments, the present disclosure provides an eleventh single stranded oligonucleotide, wherein the single stranded oligonucleotide comprises a nucleotide sequence II that is equal in length to the nucleotide sequence set forth in SEQ ID NO: 22 and differs by no more than 3 bases: 5'-Z 22 CUUUGCCCAAGUCAUCUG-3' (SEQ ID NO: 22), wherein Z 22 is G or C, and nucleotide sequence II comprises a nucleotide Z' 22 corresponding to Z 22 at the position. 22 Z' is the first nucleotide at the 5' end of the single stranded oligonucleotide sequence. In some embodiments, the nucleotide sequence II differs by no more than 1 base from the nucleotide sequence set forth in SEQ ID NO: 22. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 22 comprises a difference at Z' 22 and / or a base difference at any other nucleotide position in nucleotide sequence II. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 22 comprises a difference at Z' 22 and / or a base difference at a nucleotide position adjacent to Z' 22 . In some embodiments, there is no base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 22. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 22 comprises a difference at Z' 22 , and Z' 22 is selected from C, U, or G. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 22 is a difference at Z' 22 , and Z' 22 is selected from C, U, or G. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence IV, which is linked to the 3' end of the nucleotide sequence II, has a length of 1, 2, 3, or 4 nucleotides, each nucleotide in the nucleotide sequence IV is independently one of the non-fluoro-modified nucleotides, the nucleotide sequence IV is substantially or completely reverse-complementary to the SOD1 mRNA, and each of the non-fluoro-modified nucleotides is independently selected from one of 2'-methoxy-modified nucleotide, 2'-alkyl-modified nucleotide with carbon number of 1-3, 2'-amino-modified nucleotide, 2'-substituted amino-modified nucleotide, and heat-unstable nucleotide. In some embodiments, the nucleotide sequence IV has a length of 2 nucleotides. In some embodiments, the nucleotide sequence IV has a length of 1 nucleotide, and the base is C; or, the nucleotide sequence IV has a length of 2 nucleotides, and the base composition is CU from 5' end to 3' end; or, the nucleotide sequence IV has a length of 3 nucleotides, and the base composition is CUU from 5' end to 3' end; or, the nucleotide sequence IV has a length of 4 nucleotides, and the base composition is CUUU from 5' end to 3' end. In some embodiments, the single-stranded oligonucleotide of the present disclosure further comprises a nucleotide sequence V, each nucleotide in the nucleotide sequence V is independently a non-fluoro-modified nucleotide, the nucleotide sequence V has a length of 1-3 nucleotides, and is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II; after the single-stranded oligonucleotide forms a double-stranded oligonucleotide with the positive strand, the nucleotide sequence V constitutes the 3' overhang end of the antisense strand of the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V has a length of 2 nucleotides, and from 5' end to 3' end, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or is completely reverse-complementary to the SOD1 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and from 5' end to 3' end, the base composition of the nucleotide sequence V is selected from CU or UU. In some embodiments, the single-stranded oligonucleotide comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 22, and the base composition of the nucleotide sequence V is CU. In some embodiments, the single-stranded oligonucleotide is the antisense strand of any one of siRNA1-siRNA11 shown in Table 1; In some embodiments, the single-stranded oligonucleotide is an antisense strand of any one of siRNAa1-siRNAa12 shown in Table 2; or, the single-stranded oligonucleotide is an antisense strand of any one of conjugate 1 or conjugate 2 shown in Table 3. In some embodiments, the single-stranded oligonucleotide of the present disclosure can independently exert a pharmacodynamic activity. In some embodiments, the single-stranded oligonucleotide of the present disclosure is an antisense oligonucleotide (ASO). In some embodiments, the single-stranded oligonucleotide of the present disclosure is a single-stranded RNAi (ssRNAi) compound. In some embodiments, the single-stranded oligonucleotide of the present disclosure exerts a pharmacodynamic activity as a single strand (e.g., an antisense strand) of a double-stranded oligonucleotide. Double-stranded oligonucleotide of the present disclosure The present disclosure also provides a double-stranded oligonucleotide comprising a sense strand and an antisense strand, each nucleotide in the sense strand being a modified or unmodified nucleotide, the sense strand and the antisense strand being at least partially reverse complementary to form a double-stranded region, wherein the antisense strand is a single-stranded oligonucleotide as described in the present disclosure above. In some embodiments, the length of the antisense strand is not less than the length of the sense strand. In some embodiments, the length of the sense strand is 19-23 nucleotides. Thus, the ratio of the length of the sense strand and the antisense strand of the double-stranded oligonucleotide of the present disclosure can be 19 / 19, 19 / 20, 19 / 21, 19 / 22, 19 / 23, 19 / 24, 20 / 20, 20 / 21, 20 / 22, 20 / 23, 20 / 24, 21 / 21, 21 / 22, 21 / 23, 21 / 24, 22 / 22, 22 / 23, 22 / 24, 22 / 25, 23 / 23, 23 / 24, 23 / 25, or 23 / 26. In some embodiments, for the convenience of synthesis, the length of the sense strand is 19-21 nucleotides, and the length of the antisense strand is 19-23 nucleotides. In some embodiments, the length of the sense strand and the antisense strand is the same, both being 19, 20, or 21 nucleotides. In some embodiments, the length of the sense strand is 19 nucleotides, and the length of the antisense strand is 20-24 nucleotides. In some embodiments, the length of the sense strand is 20 nucleotides, and the length of the antisense strand is 21-24 nucleotides. In some embodiments, the length of the sense strand is 21 nucleotides, and the length of the antisense strand is 22-24 nucleotides. In some embodiments, the length of the sense strand is 19 nucleotides, and the length of the antisense strand is 21 nucleotides. In some embodiments, the length of the sense strand is 21 nucleotides, and the length of the antisense strand is 23 nucleotides. In some embodiments, in the sense strand of the double stranded oligonucleotide of the present disclosure, 2-3 of the 11th-13th nucleotides from the 3' end to the 5' end are fluorine-modified nucleotides, and the 1st nucleotide and / or the last nucleotide of the sense strand is an alkoxy-modified nucleotide or an inverted abasic deoxyribonucleotide (abbreviated as invab or ia, having a structure as shown in formula (35)). In some embodiments, the 1st nucleotide of the sense strand from the 3' end to the 5' end is an alkoxy-modified nucleotide or an inverted abasic deoxyribonucleotide. In some embodiments, in addition to the above-mentioned fluorine-modified and inverted abasic deoxyribonucleotide, the nucleotides at the remaining positions of the sense strand are non-fluorine-modified nucleotides, each of which is independently selected from one of an alkoxy-modified nucleotide, an alkyl-modified nucleotide, an amine-modified nucleotide, and a thermally unstable nucleotide; In some embodiments, the oxygen atom shown in formula (35) directly connected to the ribose ring can be connected to the 3' phosphate group of the 2nd last nucleotide from the 3' end of the sense strand. In some embodiments, the oxygen atom shown in formula (35) directly connected to the ribose ring can be connected to the 3' phosphate group of the 3' terminal nucleotide of the sense strand, and the oxygen atom shown in formula (35) connected to the ribose ring via methylene can be connected to a hydrogen atom, a hydroxyl protecting group, or a delivery group described below. In some embodiments, the oxygen atom shown in formula (35) connected to the ribose ring via methylene can be connected to the 5' phosphate group of the 2nd last nucleotide from the 5' end of the sense strand. In some embodiments, the oxygen atom shown in formula (35) connected to the ribose ring via methylene is connected to the 5' phosphate group of the 2nd last nucleotide from the 5' end of the sense strand, and the oxygen atom shown in formula (35) directly connected to the ribose ring can be connected to a hydrogen atom, a hydroxyl protecting group, or a delivery group described below. In some embodiments, the sense strand comprises 19-21 nucleotides, and the antisense strand comprises 21-23 nucleotides; the 11th and 13th nucleotides, or the 11th-13th nucleotides of the sense strand from the 3' end to the 5' end are fluorine-modified nucleotides, the 1st nucleotide and / or the last nucleotide of the sense strand is an alkoxy-modified nucleotide or an inverted abasic deoxynucleotide, and the nucleotides at the remaining positions are all alkoxy-modified nucleotides. In this case, the double-stranded oligonucleotide of the present disclosure has better stability and / or activity of forming RISC complex through the position matching of the modified nucleotides of the sense strand and the antisense strand, thereby showing stable and efficient SOD1 mRNA inhibitory activity. In some embodiments, each of the alkoxy-modified nucleotides is a methoxy-modified nucleotide. In some embodiments, in the sense strand, at least one of the linking groups connecting adjacent two nucleotides is a phosphate group with a modification group, which exists between adjacent nucleotides of the 1st-5th nucleotides at the 5' end of the sense strand and between adjacent nucleotides of the 1st-5th nucleotides at the 3' end of the sense strand. In this case, the double-stranded oligonucleotide of the present disclosure has the ability to resist nucleic acid exonuclease and good balance of SOD1 mRNA, thereby having high efficient SOD1 mRNA inhibitory activity while improving stability. In some embodiments, 1-4 of the linking groups between adjacent nucleotides of the 1st-5th nucleotides at the 5' end of the sense strand, and / or 1-4 of the linking groups between adjacent nucleotides of the 1st-5th nucleotides at the 3' end of the sense strand are each independently a phosphate group with a modification group. In some embodiments, all 4 of the linking groups between adjacent nucleotides of the 1st-5th nucleotides at the 5' end of the sense strand are each independently a phosphate group with a modification group. In some embodiments, all 4 of the linking groups between adjacent nucleotides of the 1st-5th nucleotides at the 3' end of the sense strand are each independently a phosphate group with a modification group. In some embodiments, the linking groups connecting adjacent nucleotides of the 1st-3rd, 1st-4th or 1st-5th nucleotides at the 5' end and / or 3' end of the sense strand are phosphate groups with a modification group. In some embodiments, the linking groups between adjacent nucleotides of the 1st-3rd nucleotides at the 5' end of the sense strand are phosphate groups with a modification group. The definition and selection range of the phosphate group with a modification group are the same as those of the phosphate group with a modification group described in the antisense strand of the present disclosure above. In some embodiments, each of the phosphate groups with a modification group is a phosphorothioate group having a structure as shown in formula (28). In some embodiments, the sense strand is the sense strand of any one of siRNA1 - siRNA11 shown in Table 1 ; or, the sense strand is the sense strand of any one of siRNAa1 - siRNAa12 shown in Table 2; or, the sense strand is the sense strand of any one of Conjugate 1 - Conjugate 2 shown in Table 3. In some embodiments, the sense strand comprises 19-21 nucleotides, the antisense strand comprises 21-23 nucleotides; the 11th and 13th nucleotides, or the 11th-13th nucleotides, from the 3' end to the 5' end of the sense strand are fluoro-modified nucleotides, the 1st and / or the last nucleotide of the sense strand is a methoxy-modified nucleotide or an inverted abasic deoxynucleotide, and the remaining nucleotides are alkoxy-modified nucleotides; 1-4 of the linking groups between adjacent nucleotides in the 1st-5th nucleotides from the 5' end of the sense strand, and / or 1-4 of the linking groups between adjacent nucleotides in the 1st-5th nucleotides from the 3' end of the sense strand, are each independently phosphates having a modification group. In some embodiments, the linking group between every two adjacent nucleotides in the 1st-2nd, 1st-3rd, 1st-4th, or 1st-5th nucleotides from the 5' end and / or the 3' end of the sense strand are phosphates having a modification group, and the linking group between the remaining adjacent nucleotides in the sense strand are phosphates. In some embodiments, the linking group between every two adjacent nucleotides in the 1st-3rd, 1st-4th, or 1st-5th nucleotides from the 5' end of the sense strand are phosphates having a modification group, and the linking group between the remaining adjacent nucleotides in the sense strand are phosphates. In some embodiments, the linking group between every two adjacent nucleotides in the 1st-2nd, 1st-3rd, 1st-4th, or 1st-5th nucleotides from the 3' end of the sense strand are phosphates having a modification group, and the linking group between the remaining adjacent nucleotides in the sense strand are phosphates. In some embodiments, all adjacent nucleotides in the sense strand are linked by phosphates. In some embodiments, the phosphate having a modification group is a phosphorothioate group having the structure shown in formula (28), and the alkoxy-modified nucleotide is a 2'-methoxy-modified nucleotide. In some embodiments, in the double-stranded oligonucleotide of the present disclosure, the sense strand comprises 19-21 nucleotides, and the antisense strand comprises 21-23 nucleotides; in the sense strand, the 11th and 13th nucleotides from the 3' end to the 5' end are fluorine-modified nucleotides, the 1st nucleotide is an inverted abasic deoxynucleotide, and the nucleotides at the remaining positions are all alkoxy-modified nucleotides; the linking groups between adjacent nucleotides at the 1st-3rd nucleotides from the 5' end of the sense strand and / or the linking groups between adjacent nucleotides at the 1st-3rd nucleotides from the 3' end of the sense strand are phosphate groups with a modification group; in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 2nd, 5th, 7th, 12th and 16th nucleotides are fluorine-modified nucleotides, the 3rd nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 2nd, 7th, 12th, 16th and 19th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 2nd, 6th, 12th, 16th and 19th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 12th and 14th nucleotides from the 5' end to the 3' end are deoxynucleotides, the 2nd, 7th and 16th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 16th nucleotide is an unmodified nucleotide, the 2nd and 6th nucleotides are fluorine-modified nucleotides, the 13th nucleotide is a substituted alkoxy-modified nucleotide, the 2nd nucleotide from the 3' end to the 5' end of the antisense strand is a thermally unstable nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 19th nucleotide is an unmodified nucleotide, the 2nd, 6th and 16th nucleotides are fluorine-modified nucleotides, the 13th nucleotide is a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide.The linking groups between adjacent nucleotides in the 1st to 3rd nucleotides from the 5' end of the antisense strand and the linking groups between adjacent nucleotides in the 1st to 3rd nucleotides from the 3' end are both phosphates with a modification group, and if there are unmodified nucleotides, 1-2 of the 2 linking groups between each unmodified nucleotide and the adjacent nucleotide are phosphates with a modification group; and the 5' terminal nucleotide of the antisense strand is a 5'-hydroxyl nucleotide represented by formula (29) or a 5'-vinyl phosphate modified nucleotide represented by formula (31). In some embodiments, the sense strand comprises 19 nucleotides, and the antisense strand comprises 21 nucleotides; in the sense strand, the 11th and 13th nucleotides from the 3' end to the 5' end are fluorine-modified nucleotides, the 1st nucleotide is an inverted dealkylated deoxynucleotide, and the nucleotides at the remaining positions are methoxy-modified nucleotides; the linking groups between adjacent nucleotides in the 1st to 3rd nucleotides from the 5' end and the 3' end of the sense strand are phosphothioate groups; in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 2nd, 5th, 7th, 12th, and 16th nucleotides are fluorine-modified nucleotides, and the remaining nucleotides in the antisense strand are methoxy-modified nucleotides; the linking groups between adjacent nucleotides in the 1st to 3rd nucleotides from the 5' end and the 3' end of the antisense strand are phosphothioate groups; and the 5' terminal nucleotide of the antisense strand is a 5'-hydroxyl nucleotide represented by formula (29) or a 5'-vinyl phosphate modified nucleotide represented by formula (31). The double-stranded oligonucleotide of the present disclosure can achieve a good balance between SOD1 mRNA expression regulation activity and in vivo stability by having the above-mentioned modification scheme. In the context of the present disclosure, the "modification scheme" refers to a combination of different numbers, positions, and types of nucleotide ribose modifications, phosphate modifications, 5' end modifications, and / or base modifications that are not or weakly related to specific sequences. In some embodiments, the double-stranded oligonucleotide of the present disclosure can maintain excellent stability while not significantly reducing the original drug activity of the double-stranded oligonucleotide by having the above-mentioned modification scheme, thereby achieving a good balance between SOD1 mRNA expression regulation activity and in vivo stability. In some embodiments, the double-stranded oligonucleotide of the present disclosure is an siRNA. The double-stranded oligonucleotide of the present disclosure can maintain excellent stability while not significantly reducing the original RNAi activity of the siRNA by having the above-mentioned modification scheme, thereby achieving a good balance between SOD1 mRNA inhibition activity and in vivo stability. In some embodiments, the double-stranded oligonucleotide described in the present disclosure consists of a double-stranded region that is substantially reverse-complementary or fully reverse-complementary, and one or two overhanging ends of the sense strand and / or one or two overhanging ends of the antisense strand. In some embodiments, the double-stranded oligonucleotide described in the present disclosure consists of a double-stranded region that is substantially reverse-complementary or fully reverse-complementary and one overhanging end of the antisense strand. In the context of the present disclosure, a "double-stranded region" is a double-stranded structure formed between the shortest nucleotide sequences of each single strand in a double-stranded nucleic acid structure, including all base pairs and all base mismatches located between the base pairs. In some embodiments, the number of base mismatches is no more than 20%, 15%, 10%, or 5% of the total number of base pairs forming the double-stranded region. In some embodiments, the number of base mismatches in the double-stranded region is no more than 3, no more than 2, or no more than 1. In some embodiments, the double-stranded nucleic acid structure includes the double-stranded region and one or more overhanging ends consisting of nucleotides that do not form base pairs on one or both single strands. In some embodiments, the double-stranded nucleic acid structure includes only the double-stranded region. In some embodiments, the sense strand and the antisense strand form a double-stranded region spanning at least 16 nucleotide positions, i.e., the double-stranded region formed by the sense strand and the antisense strand includes at least 16 base pairs. In the context of the present disclosure, each base pair forming the double-stranded region is independently complementary or mismatched. In some embodiments, the sense strand and the antisense strand form a double-stranded region spanning 16-23 nucleotide positions, i.e., the double-stranded region formed by the sense strand and the antisense strand includes 16-23 base pairs. In some embodiments, the sense strand and the antisense strand form a double-stranded region spanning 18, 19, 20, or 21 nucleotide positions, i.e., the double-stranded region formed by the sense strand and the antisense strand includes 18, 19, 20, or 21 base pairs. In some embodiments, the sense strand and the antisense strand are substantially reverse-complementary or fully reverse-complementary within the double-stranded region. In some embodiments, the sense strand and the antisense strand of the double-stranded oligonucleotide described in the present disclosure are substantially reverse-complementary or fully reverse-complementary over the entire length of nucleotides. In some embodiments, the number of base differences between the sense strand and the SOD1 mRNA is no more than 3, no more than 2, or no more than 1. In some embodiments, there are no base differences between the sense strand and the SOD1 mRNA. In the foregoing and hereinafter, a nucleotide sequence and another nucleotide sequence have a "base difference" if the base type of a nucleotide at the same position in the former is different from that in the latter, e.g., if the base type of a nucleotide in the latter is A, and the base type of a corresponding nucleotide in the former is U, C, G, or T, then the two nucleotide sequences are deemed to have a base difference at that position. When a base is modified, as long as the modified base does not affect the purine-pyrimidine pairing relationship when forming the double-stranded nucleic acid structure described above, the modified base and the original base are deemed to have no base difference. In some embodiments, U and T are deemed to have no base difference. In some embodiments, C and 5-methylcytosine (5mC) are deemed to have no base difference. In some embodiments, a nucleotide at a position is replaced with an abasic nucleotide or an equivalent thereof, and the replacement is deemed to result in a base difference at that position. When aligning two nucleotide sequences to determine the number of base differences, the alignment is performed in a manner that has the least number of base differences among all possible alignments, and the base differences are determined based on the alignment. In this case, "the same position" refers to the corresponding position between the two nucleotide sequences in the alignment. For example, when nucleotide sequence A positions 1-5 are aligned with nucleotide sequence B positions 2-6 in the same direction, and the number of base differences is the least compared to other alignments, then "the same position" refers to nucleotide sequence A position 1 aligned with nucleotide sequence B position 2, nucleotide sequence A position 2 aligned with nucleotide sequence B position 3, and so on. In some embodiments, the number of base differences between two nucleotide sequences of different lengths is the total number of base differences between the first nucleotide to the last nucleotide of the shorter nucleotide sequence and each corresponding nucleotide of the other nucleotide sequence, in the same orientation. In some embodiments, the number of base differences between two nucleotide sequences of the same length is the total number of base differences between the first nucleotide to the last nucleotide of either nucleotide sequence and the first nucleotide to the last nucleotide of the other nucleotide sequence, in the same orientation. In some embodiments, the absence of base differences between two nucleotide sequences of different lengths is the absence of base differences between the first nucleotide to the last nucleotide of the shorter nucleotide sequence and each corresponding nucleotide of the other nucleotide sequence, in the same orientation. In some embodiments, the absence of base differences between two nucleotide sequences of the same length is the absence of base differences between the first nucleotide to the last nucleotide of one nucleotide sequence and the first nucleotide to the last nucleotide of the other nucleotide sequence, in the same orientation. The double-stranded oligonucleotide of the present disclosure can be various double-stranded oligonucleotides that modulate SOD1 mRNA expression. In some embodiments, it can be a double-stranded oligonucleotide that inhibits or down-regulates SOD1 mRNA expression, such as an siRNA; in some embodiments, it can be a double-stranded oligonucleotide that activates or up-regulates SOD1 mRNA expression, such as a saRNA. In some embodiments, the double-stranded oligonucleotide is an siRNA. In some embodiments, the double-stranded oligonucleotide of the present disclosure can be the following first-eleventh double-stranded oligonucleotides, each of which is described below. First double-stranded oligonucleotide The present disclosure provides a first double-stranded oligonucleotide, which contains a sense strand and an antisense strand, the sense strand contains a nucleotide sequence I, which is equal in length to the nucleotide sequence shown in SEQ ID NO: 1, and has no more than 3 base differences; the antisense strand contains a nucleotide sequence II, which is equal in length to the nucleotide sequence shown in SEQ ID NO: 2, and has no more than 3 base differences: 5'-CGAGCAGAAGGAAAGUAAZ1 -3' (SEQ ID NO: 1); 5'-Z2UUACUUUCCUUCUGCUCG-3' (SEQ ID NO: 2), wherein Z1 is U, A or an inverted abasic deoxy nucleotide (ia), Z2 is A or U, nucleotide sequence I comprises a nucleotide Z'1 at a position corresponding to Z1, nucleotide sequence II comprises a nucleotide Z'2 at a position corresponding to Z2, and Z'2 is the first nucleotide at the 5' end of the antisense strand. In some embodiments, the sense strand comprises only nucleotide sequence I, and the antisense strand comprises only nucleotide sequence II. In some embodiments, there is no more than 1 base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 1, and / or no more than 1 base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 1 can include a difference at Z'1 position and / or a base difference at any other nucleotide position in nucleotide sequence I. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 1 can include a difference at Z'1 position and / or a base difference at a nucleotide position adjacent to Z'1. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 1 is a base difference at Z'1 position, preferably Z'1 is an inverted abasic deoxy nucleotide. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2 includes a difference at Z'2 position, and Z'2 is selected from C, U or G. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2 is a difference at Z'2 position, and Z'2 is selected from C, U or G. In some embodiments, the nucleotide at position 2-19 of the nucleotide sequence II is fully reverse complementary to SOD1 mRNA in the direction from 5' end to 3' end. In some embodiments, the nucleotide sequence II is fully reverse complementary to the nucleotide sequence I. In some embodiments, there is a base mismatch between the 2nd nucleotide in the nucleotide sequence II in the direction from 5' end to 3' end and the 2nd nucleotide in the nucleotide sequence I in the direction from 3' end to 5' end. By including this base mismatch, one can have higher SOD1 mRNA inhibitory activity while maintaining low off-target effect. In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, the nucleotide sequence III has a length of 1, 2, 3, or 4 nucleotides, the nucleotide sequence IV and the nucleotide sequence III have equal length, and the nucleotide sequence IV and the nucleotide sequence III are substantially reverse complementary or fully reverse complementary, and the nucleotide sequence III is linked to the 5' end of the nucleotide sequence I. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 1 nucleotide, the nucleotide sequence III has a base of U, and the nucleotide sequence IV has a base of A, in the direction from the 5' end to the 3' end. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 2 nucleotides, the nucleotide sequence III has a base composition of UU, and the nucleotide sequence IV has a base composition of AA, in the direction from the 5' end to the 3' end. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 3 nucleotides, the nucleotide sequence III has a base composition of UUU, and the nucleotide sequence IV has a base composition of AAA, in the direction from the 5' end to the 3' end. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 4 nucleotides, the nucleotide sequence III has a base composition of AUUU, and the nucleotide sequence IV has a base composition of AAUU, in the direction from the 5' end to the 3' end. In some embodiments, the antisense strand further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluorinated modified nucleotide, the nucleotide sequence V has a length of 1 to 3 nucleotides, and the nucleotide sequence V is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II, and forms a 3' overhang end of the antisense strand after forming the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V has a length of 2 nucleotides, and in the direction from the 5' end to the 3' end, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or fully reverse complementary to the SOD1 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and in the direction from the 5' end to the 3' end, the base composition of the nucleotide sequence V is selected from AA or UU. In some embodiments, the sense strand comprises only the nucleotide sequence I, the antisense strand comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 2, the nucleotide sequence I consists of SEQ ID NO: 1, the nucleotide sequence V is linked at the 3' end of the nucleotide sequence II, and the base composition of the nucleotide sequence V, in the direction from the 5' end to the 3' end, is AA. The second double-stranded oligonucleotide The present disclosure provides a second double-stranded oligonucleotide, which contains a sense strand and an antisense strand, the sense strand contains a nucleotide sequence I, the nucleotide sequence I is equal in length to the nucleotide sequence shown in SEQ ID NO: 3, and has no more than 3 base differences; the antisense strand contains a nucleotide sequence II, the nucleotide sequence II is equal in length to the nucleotide sequence shown in SEQ ID NO: 4, and has no more than 3 base differences: 5'-AGGUGGAAAUGAAGAAAGZ3 -3'(SEQ ID NO: 3); 5'-Z4CUUUCUUCAUUUCCACCU-3'(SEQ ID NO: 4), wherein, the Z3 is U, A or inverted abasic deoxynucleotide (ia), Z4 is A or U, the nucleotide sequence I contains a nucleotide Z'3 at the position corresponding to Z3, the nucleotide sequence II contains a nucleotide Z'4 at the position corresponding to Z4, Z'4 is the first nucleotide at the 5' end of the antisense strand. In some embodiments, the sense strand comprises only the nucleotide sequence I, the antisense strand comprises only the nucleotide sequence II. In some embodiments, there are no more than 1 base difference between the nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO: 3, and / or no more than 1 base difference between the nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO: 4. Wherein, the base difference between the nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO: 3 can include the difference at the position of Z'3 and / or the base difference at any other nucleotide position in the nucleotide sequence I. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO: 3 can include the base difference at the position of Z'3 and / or the nucleotide position adjacent to Z'3. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO: 3 is the base difference at the position of Z'3, preferably, Z'3 is an inverted abasic deoxynucleotide. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 4 comprises a difference at position Z'4, and Z'4 is selected from C, U, or G. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 4 is a difference at position Z'4, and Z'4 is selected from C, U, or G. In some embodiments, the nucleotide sequence II is fully reverse-complementary to the nucleotide sequence I. In some embodiments, the 2nd nucleotide in the nucleotide sequence II is base-mismatched with the 2nd nucleotide in the nucleotide sequence I, in the direction from 5' end to 3' end. By including the base-mismatch, one can have a higher SOD1 mRNA inhibitory activity while maintaining a low off-target effect. In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, the nucleotide sequence III has a length of 1, 2, 3, or 4 nucleotides, the nucleotide sequence IV and the nucleotide sequence III have an equal length, and the nucleotide sequence IV and the nucleotide sequence III are substantially reverse-complementary or fully reverse-complementary, and the nucleotide sequence III is linked to the 5' end of the nucleotide sequence I. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 1 nucleotide, in the direction from 5' end to 3' end, the nucleotide sequence III has a base of A, and the nucleotide sequence IV has a base of U; in this case, the length ratio of the sense strand and the antisense strand is 20 / 20. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 2 nucleotides, in the direction from 5' end to 3' end, the nucleotide sequence III has a base composition of AA, and the nucleotide sequence IV has a base composition of UU; in this case, the length ratio of the sense strand and the antisense strand is 21 / 21. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 3 nucleotides, in the direction from 5' end to 3' end, the nucleotide sequence III has a base composition of CAA, and the nucleotide sequence IV has a base composition of UUG; in this case, the length ratio of the sense strand and the antisense strand is 22 / 22. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 4 nucleotides, in the direction from 5' end to 3' end, the nucleotide sequence III has a base composition of GCAA, and the nucleotide sequence IV has a base composition of UUGC; in this case, the length ratio of the sense strand and the antisense strand is 23 / 23. In some embodiments, the antisense strand further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluoro-modified nucleotide, the nucleotide sequence V has a length of 1 to 3 nucleotides, is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II, and forms a 3' overhang end of the antisense strand after forming the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V has a length of 2 nucleotides, and in the direction from the 5' end to the 3' end, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or fully reverse complementary to the SOD1 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and in the direction from the 5' end to the 3' end, the base composition of the nucleotide sequence V is UU. In some embodiments, the sense strand only comprises the nucleotide sequence I, the antisense strand only comprises the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 4, the nucleotide sequence I consists of SEQ ID NO: 3, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and in the direction from the 5' end to the 3' end, the base composition of the nucleotide sequence V is UU. A third double-stranded oligonucleotide The present disclosure provides a third double-stranded oligonucleotide, which comprises a sense strand and an antisense strand, the sense strand comprises a nucleotide sequence I, the nucleotide sequence I is equal in length to the nucleotide sequence set forth in SEQ ID NO: 5, and has no more than 3 base differences; the antisense strand comprises a nucleotide sequence II, the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 6, and has no more than 3 base differences: 5'-GCAUGGAUUCCAUGUUCAZ5 -3' (SEQ ID NO: 5); 5'-Z6UGAACAUGGAAUCCAUGC-3' (SEQ ID NO: 6), wherein, the Z5 is U, A or an inverted abasic deoxynucleotide (ia), Z6 is A or U, the nucleotide sequence I comprises a nucleotide Z'5 at a position corresponding to Z5, the nucleotide sequence II comprises a nucleotide Z'6 at a position corresponding to Z6, and Z'6 is the first nucleotide at the 5' end of the antisense strand. In some embodiments, the sense strand only comprises the nucleotide sequence I, the antisense strand only comprises the nucleotide sequence II. In some embodiments, there is no more than 1 base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 5, and / or no more than 1 base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 6. Among them, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 5 can include a difference at the Z'5 position and / or a base difference at any other nucleotide position in the nucleotide sequence I. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 5 can include a base difference at the Z'5 position and / or at a nucleotide position adjacent to Z'5. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 5 is a base difference at the Z'5 position, preferably, Z'5 is an inverted dealkylated deoxynucleotide. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 6 includes a difference at the Z'6 position, and Z'6 is selected from C, U or G. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 6 is a difference at the Z'6 position, and Z'6 is selected from C, U or G. In some embodiments, the 2nd-19th nucleotides of the nucleotide sequence II are fully reverse complementary to the SOD1 mRNA in the direction from 5' end to 3' end. In some embodiments, the nucleotide sequence II is fully reverse complementary to the nucleotide sequence I. In some embodiments, there is a base mismatch between the 2nd nucleotide in the nucleotide sequence II in the direction from 5' end to 3' end and the 2nd nucleotide in the nucleotide sequence I in the direction from 3' end to 5' end. By including the base mismatch, a higher SOD1 mRNA inhibitory activity can be achieved while maintaining a low off-target effect. In some embodiments, the sense strand further contains a nucleotide sequence III, the antisense strand further contains a nucleotide sequence IV, the length of the nucleotide sequence III is 1, 2, 3 or 4 nucleotides, the length of the nucleotide sequence IV is equal to that of the nucleotide sequence III, and the nucleotide sequence IV and the nucleotide sequence III are substantially reverse complementary or fully reverse complementary, and the nucleotide sequence III is connected to the 5' end of the nucleotide sequence I. In some embodiments, the length of each of nucleotide sequence III and nucleotide sequence IV is 1 nucleotide, the base of nucleotide sequence III is U, and the base of nucleotide sequence IV is A, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 20 / 20. In some embodiments, the length of each of nucleotide sequence III and IV is 2 nucleotides, the base composition of nucleotide sequence III is CU, and the base composition of nucleotide sequence IV is AG, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 21 / 21. In some embodiments, the length of each of nucleotide sequence III and IV is 3 nucleotides, the base composition of nucleotide sequence III is CCU, and the base composition of nucleotide sequence IV is AGG, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 22 / 22. In some embodiments, the length of each of nucleotide sequence III and IV is 4 nucleotides, the base composition of nucleotide sequence III is GCCU, and the base composition of nucleotide sequence IV is AGGC, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 23 / 23. In some embodiments, the antisense strand further comprises nucleotide sequence V, each nucleotide of nucleotide sequence V is independently a non-fluorinated modified nucleotide, the length of nucleotide sequence V is 1 to 3 nucleotides, and nucleotide sequence V is linked to the 3' end of nucleotide sequence IV or nucleotide sequence II, to form a 3' overhang end of the antisense strand after forming the double-stranded oligonucleotide. In some embodiments, the length of nucleotide sequence V is 2 nucleotides, and nucleotide sequence V is, in the direction from the 5' end to the 3' end, 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or fully reverse complementary to SOD1 mRNA. In some embodiments, nucleotide sequence V is linked to the 3' end of nucleotide sequence II, and the base composition of nucleotide sequence V is AG or UU, in the direction from the 5' end to the 3' end. In some embodiments, the sense strand comprises only nucleotide sequence I, the antisense strand comprises only nucleotide sequence II and nucleotide sequence V, nucleotide sequence II consists of SEQ ID NO: 6, nucleotide sequence I consists of SEQ ID NO: 5, nucleotide sequence V is linked to the 3' end of nucleotide sequence II, and the base composition of nucleotide sequence V is AG, in the direction from the 5' end to the 3' end. A fourth double-stranded oligonucleotide The present disclosure provides a fourth double-stranded oligonucleotide comprising a sense strand and an antisense strand, the sense strand comprising a nucleotide sequence I which is identical in length to and differs from the nucleotide sequence set forth in SEQ ID NO: 7 by no more than 3 bases; the antisense strand comprising a nucleotide sequence II which is identical in length to and differs from the nucleotide sequence set forth in SEQ ID NO: 8 by no more than 3 bases: 5'-CUUUAAUCCUCUAUCCAGZ7 -3' (SEQ ID NO: 7); 5'-Z8CUGGAUAGAGGAUUAAAG-3' (SEQ ID NO: 8), wherein Z7 is U, A or inverted abasic deoxynucleotide (ia), Z8 is A or U, nucleotide sequence I comprises a nucleotide Z'7 at a position corresponding to Z7, nucleotide sequence II comprises a nucleotide Z'8 at a position corresponding to Z8, and Z'8 is the first nucleotide at the 5' end of the antisense strand. In some embodiments, the sense strand comprises only nucleotide sequence I, and the antisense strand comprises only nucleotide sequence II. In some embodiments, there is no more than 1 base difference between nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 7, and / or no more than 1 base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 8. In some embodiments, the base difference between nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 7 can include a difference at Z'7 position and / or a base difference at any other nucleotide position in nucleotide sequence I. In some embodiments, the base difference between nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 7 can include a difference at Z'7 position and / or a difference at a nucleotide position adjacent to Z'7. In some embodiments, the base difference between nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 7 is a difference at Z'7 position, and preferably Z'7 is an inverted abasic deoxynucleotide. In some embodiments, the difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 8 includes a difference at Z'8 position, and Z'8 is selected from C, U or G. In some embodiments, the difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 8 is a difference at Z'8 position, and Z'8 is selected from C, U or G. In some embodiments, the 2nd to 19th nucleotides of the nucleotide sequence II are fully reverse-complementary to the SOD1 mRNA in the 5' end to 3' end direction. In some embodiments, the nucleotide sequence II is fully reverse-complementary to the nucleotide sequence I. Alternatively, there is a base mismatch between the 2nd nucleotide in the nucleotide sequence II and the 2nd nucleotide in the nucleotide sequence I in the 5' end to 3' end direction. By including the base mismatch, one can have higher SOD1 mRNA inhibitory activity while maintaining low off-target effects. In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, the nucleotide sequence III has a length of 1, 2, 3, or 4 nucleotides, the nucleotide sequence IV has the same length as the nucleotide sequence III, and the nucleotide sequence IV and the nucleotide sequence III are substantially reverse-complementary or fully reverse-complementary, and the nucleotide sequence III is linked to the 5' end of the nucleotide sequence I. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 1 nucleotide in the 5' end to 3' end direction, the nucleotide sequence III has a base of A, and the nucleotide sequence IV has a base of U; in this case, the length ratio of the sense strand and the antisense strand is 20 / 20. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 2 nucleotides, the nucleotide sequence III has a base composition of CA in the 5' end to 3' end direction, and the nucleotide sequence IV has a base composition of UG; in this case, the length ratio of the sense strand and the antisense strand is 21 / 21. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 3 nucleotides, the nucleotide sequence III has a base composition of UCA in the 5' end to 3' end direction, and the nucleotide sequence IV has a base composition of UGA; in this case, the length ratio of the sense strand and the antisense strand is 22 / 22. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 4 nucleotides, the nucleotide sequence III has a base composition of CUCA in the 5' end to 3' end direction, and the nucleotide sequence IV has a base composition of UGAG; in this case, the length ratio of the sense strand and the antisense strand is 23 / 23. In some embodiments, the antisense strand further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluorinated modified nucleotide, the nucleotide sequence V has a length of 1 to 3 nucleotides, and the nucleotide sequence V is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II to form a 3' overhang end of the antisense strand after forming the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V has a length of 2 nucleotides, and in the 5' end to 3' end direction, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or fully reverse-complementary to the SOD1 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and in the 5' end to 3' end direction, the base composition of the nucleotide sequence V is UG or UU. In some embodiments, the sense strand only contains the nucleotide sequence I, the antisense strand only contains the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 8, the nucleotide sequence I consists of SEQ ID NO: 7, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and in the 5' end to 3' end direction, the base composition of the nucleotide sequence V is UG. A fifth double-stranded oligonucleotide The present disclosure provides a fifth double-stranded oligonucleotide, which contains a sense strand and an antisense strand, the sense strand contains a nucleotide sequence I, the nucleotide sequence I is equal in length to the nucleotide sequence set forth in SEQ ID NO: 9, and has no more than 3 base differences; the antisense strand contains a nucleotide sequence II, the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 10, and has no more than 3 base differences: 5'-GGGCAAAGGUGGAAAUGAZ9 -3' (SEQ ID NO: 9); 5'-Z 10 UCAUUUCCACCUUUGCCC-3' (SEQ ID NO: 10), wherein the Z9 is U, A or an inverted abasic deoxynucleotide (ia), Z 10 is A or U, the nucleotide sequence I contains a nucleotide Z'9 at a position corresponding to Z9, the nucleotide sequence II contains a nucleotide Z'9 at a position corresponding to Z 10 10 10 is the first nucleotide at the 5' end of the antisense strand sequence. In some embodiments, the sense strand only contains the nucleotide sequence I, the antisense strand only contains the nucleotide sequence II. ​​In some embodiments, there is no more than 1 base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 9, and / or no more than 1 base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 10. Among them, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 9 can include the difference at the Z'9 position and / or the base difference at any other nucleotide position in the nucleotide sequence I. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 9 can include the base difference at the Z'9 position and / or the base difference at the nucleotide position adjacent to Z'9. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 9 is the base difference at the Z'9 position, preferably, Z'9 is an inverted abasic deoxynucleotide. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 10 includes the difference at the Z' 10 position, and Z' 10 is selected from C, U or G. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 10 is the difference at the Z' 10 position, and Z' 10 is selected from C, U or G. In some embodiments, the 23rd-19th nucleotide of the nucleotide sequence II is fully reverse complementary to the SOD1 mRNA in the direction from 5' end to 3' end. In some embodiments, the nucleotide sequence II is fully reverse complementary to the nucleotide sequence I. In some embodiments, there is a base mismatch between the 2nd nucleotide in the nucleotide sequence II in the direction from 5' end to 3' end and the 2nd nucleotide in the nucleotide sequence I in the direction from 3' end to 5' end. By including the base mismatch, it is possible to have higher SOD1 mRNA inhibitory activity while maintaining low off-target effect. In some embodiments, the sense strand further contains a nucleotide sequence III, the antisense strand further contains a nucleotide sequence IV, the length of the nucleotide sequence III is 1, 2, 3 or 4 nucleotides, the length of the nucleotide sequence IV is equal to that of the nucleotide sequence III, and the nucleotide sequence IV and the nucleotide sequence III are substantially reverse complementary or fully reverse complementary, and the nucleotide sequence III is connected to the 5' end of the nucleotide sequence I. In some embodiments, the length of each of the nucleotide sequence III and the nucleotide sequence IV is 1 nucleotide, the base of the nucleotide sequence III is U, and the base of the nucleotide sequence IV is A, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 20 / 20. In some embodiments, the length of each of the nucleotide sequence III and the nucleotide sequence IV is 2 nucleotides, the base composition of the nucleotide sequence III is UU, and the base composition of the nucleotide sequence IV is AA, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 21 / 21. In some embodiments, the length of each of the nucleotide sequence III and the nucleotide sequence IV is 3 nucleotides, the base composition of the nucleotide sequence III is CUU, and the base composition of the nucleotide sequence IV is AAG, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 22 / 22. In some embodiments, the length of each of the nucleotide sequence III and the nucleotide sequence IV is 4 nucleotides, the base composition of the nucleotide sequence III is ACUU, and the base composition of the nucleotide sequence IV is AAGU, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 23 / 23. In some embodiments, the antisense strand further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluorinated modified nucleotide, the length of the nucleotide sequence V is 1 to 3 nucleotides, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II, and forms a 3' overhang end of the antisense strand after the double-stranded oligonucleotide is formed. In some embodiments, the length of the nucleotide sequence V is 2 nucleotides, and the nucleotide sequence V is, in the direction from the 5' end to the 3' end, 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or fully reverse complementary to the SOD1 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and the base composition of the nucleotide sequence V is AA or UU, in the direction from the 5' end to the 3' end. In some embodiments, the sense strand comprises only the nucleotide sequence I, the antisense strand comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 10, the nucleotide sequence I consists of SEQ ID NO: 9, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and the base composition of the nucleotide sequence V is AA, in the direction from the 5' end to the 3' end. Sixth double-stranded oligonucleotide The present disclosure provides a sixth double-stranded oligonucleotide comprising a sense strand and an antisense strand, the sense strand comprising a nucleotide sequence I which is identical in length to and differs from the nucleotide sequence set forth in SEQ ID NO: 11 by no more than 3 bases; the antisense strand comprising a nucleotide sequence II which is identical in length to and differs from the nucleotide sequence set forth in SEQ ID NO: 12 by no more than 3 bases: 5'-GGAUGAAGAGAGGCAUGUZ 11 -3'(SEQ ID NO: 11); 5'-Z 12 ACAUGCCUCUCUUCAUCC-3'(SEQ ID NO: 12), wherein the Z 11 is U, A or inverted abasic deoxynucleotide (ia), Z 12 is A or U, the nucleotide sequence I comprises a nucleotide Z' 11 at a position corresponding to Z 11 , the nucleotide sequence II comprises a nucleotide Z' 12 at a position corresponding to Z 12 , Z' 12 is the first nucleotide of the 5' end of the antisense strand. In some embodiments, the sense strand comprises only the nucleotide sequence I, and the antisense strand comprises only the nucleotide sequence II. In some embodiments, there is no more than 1 base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 11, and / or no more than 1 base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 12. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 11 can include a difference at the Z' 11 position and / or a base difference at any other nucleotide position in the nucleotide sequence I. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 11 can include a difference at the Z' 11 position and / or a base difference at a nucleotide position adjacent to Z' 11 . In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 11 is a base difference at the Z' 11 position, preferably, Z' 11 is an inverted abasic deoxynucleotide. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 12 includes a difference at the Z' 12a difference at position Z' selected from C, U or G. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 12 is a difference at position Z' selected from C, U or G. 12 a difference at position Z' selected from C, U or G. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 12 is a difference at position Z' selected from C, U or G. 12 a difference at position Z' selected from C, U or G. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 12 is a difference at position Z' selected from C, U or G. 12 a difference at position Z' selected from C, U or G. In some embodiments, the nucleotide at position 2-19 of the nucleotide sequence II is fully reverse-complementary to the SOD1 mRNA in the 5' end to 3' end direction. In some embodiments, the nucleotide sequence II is fully reverse-complementary to the nucleotide sequence I. In some embodiments, there is a base mismatch between the 2ndnucleotide in the nucleotide sequence II in the 5' end to 3' end direction and the 2ndnucleotide in the nucleotide sequence I in the 3' end to 5' end direction. By including the base mismatch, one can have higher SOD1 mRNA inhibitory activity while maintaining low off-target effects. In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, the nucleotide sequence III has a length of 1, 2, 3 or 4 nucleotides, the nucleotide sequence IV and the nucleotide sequence III have the same length, and the nucleotide sequence IV and the nucleotide sequence III are substantially reverse-complementary or fully reverse-complementary, and the nucleotide sequence III is linked to the 5' end of the nucleotide sequence I. In some embodiments, the length of the nucleotide sequence III and the nucleotide sequence IV is 1 nucleotide, the base of the nucleotide sequence III is A, and the base of the nucleotide sequence IV is U, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand and the antisense strand is 20 / 20. In some embodiments, the length of the nucleotide sequence III and the nucleotide sequence IV is 2 nucleotides, the base composition of the nucleotide sequence III is AA, and the base composition of the nucleotide sequence IV is UU, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand and the antisense strand is 21 / 21. In some embodiments, the length of the nucleotide sequence III and the nucleotide sequence IV is 3 nucleotides, the base composition of the nucleotide sequence III is AAA, and the base composition of the nucleotide sequence IV is UUU, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand and the antisense strand is 22 / 22. In some embodiments, the length of the nucleotide sequence III and the nucleotide sequence IV is 4 nucleotides, the base composition of the nucleotide sequence III is CAAA, and the base composition of the nucleotide sequence IV is UUUG, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand and the antisense strand is 23 / 23. In some embodiments, the length of the nucleotide sequence III and the nucleotide sequence IV is 2 nucleotides, the base composition of the nucleotide sequence III is UU, and the base composition of the nucleotide sequence IV is AA, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand and the antisense strand is 21 / 21. In some embodiments, the antisense strand further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluorinated modified nucleotide, the length of the nucleotide sequence V is 1 to 3 nucleotides, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II, and forms a 3' overhang end of the antisense strand after the double-stranded oligonucleotide is formed. In some embodiments, the length of the nucleotide sequence V is 2 nucleotides, and the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or fully reverse complementary to the SOD1 mRNA, in the direction from the 5' end to the 3' end. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and the base composition of the nucleotide sequence V is AA or UU, in the direction from the 5' end to the 3' end. In some embodiments, the sense strand comprises only the nucleotide sequence I, the antisense strand comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 12, the nucleotide sequence I consists of SEQ ID NO: 11, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and the base composition of the nucleotide sequence V is AA, in the direction from the 5' end to the 3' end. A seventh double stranded oligonucleotide The present disclosure provides a seventh double stranded oligonucleotide, comprising a sense strand and an antisense strand, the sense strand comprising a nucleotide sequence I which is equal in length to and differs from the nucleotide sequence set forth in SEQ ID NO: 13 by no more than 3 bases; the antisense strand comprising a nucleotide sequence II which is equal in length to and differs from the nucleotide sequence set forth in SEQ ID NO: 14 by no more than 3 bases: 5'-UGAAGAGAGGCAUGUUGGZ 13 -3' (SEQ ID NO: 13); 5'-Z 14 CCAACAUGCCUCUCUUCA-3' (SEQ ID NO: 14), wherein the Z 13 is U, A or an inverted abasic deoxynucleotide (ia), Z 14 is A or U, the nucleotide sequence I comprises a nucleotide Z' 13 corresponding to the position of Z 13 , and the nucleotide sequence II comprises a nucleotide Z' 14 corresponding to the position of Z 14 , Z' 14 is the first nucleotide of the 5' end of the antisense strand. In some embodiments, the sense strand comprises only the nucleotide sequence I, and the antisense strand comprises only the nucleotide sequence II. In some embodiments, there are no more than 1 base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 13, and / or no more than 1 base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 14. Where there are base differences between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 13, the base differences can include a difference at the position of Z' 13 and / or a base difference at any other nucleotide position in the nucleotide sequence I. In some embodiments, there are base differences between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 13, which include a difference at the position of Z' 13 and / or a base difference at a nucleotide position adjacent to Z' 13 . In some embodiments, there is a base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 13, which is a difference at the position of Z' 13 , preferably, Z' 13 is an inverted abasic deoxynucleotide. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 14 comprises a difference at position Z 14 selected from C, U, or G. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 14 is a difference at position Z 14 selected from C, U, or G. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 14 is a difference at position Z 14 selected from C, U, or G. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 14 is a difference at position Z 14 selected from C, U, or G. In some embodiments, the nucleotide sequence II is fully reverse-complementary to the nucleotide sequence I, in the 5' end to 3' end direction, from the 2nd to the 19th nucleotide of the nucleotide sequence II. In some embodiments, the nucleotide sequence II is fully reverse-complementary to the nucleotide sequence I. In some embodiments, there is a base mismatch between the 2nd nucleotide in the nucleotide sequence II and the 2nd nucleotide in the nucleotide sequence I, in the 5' end to 3' end direction and the 3' end to 5' end direction, respectively. By including the base mismatch, one can have a higher SOD1 mRNA inhibitory activity while maintaining a low off-target effect. In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, the nucleotide sequence III has a length of 1, 2, 3, or 4 nucleotides, the nucleotide sequence IV and the nucleotide sequence III have the same length, and the nucleotide sequence IV and the nucleotide sequence III are substantially reverse-complementary or fully reverse-complementary to each other, and the nucleotide sequence III is linked to the 5' end of the nucleotide sequence I. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 1 nucleotide, in the 5' end to 3' end direction, the nucleotide sequence III has a base of A, and the nucleotide sequence IV has a base of U; in this case, the length ratio of the sense strand and the antisense strand is 20 / 20. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 2 nucleotides, in the 5' end to 3' end direction, the nucleotide sequence III has a base composition of GA, and the nucleotide sequence IV has a base composition of UC; in this case, the length ratio of the sense strand and the antisense strand is 21 / 21. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 3 nucleotides, in the 5' end to 3' end direction, the nucleotide sequence III has a base composition of GGA, and the nucleotide sequence IV has a base composition of UCC; in this case, the length ratio of the sense strand and the antisense strand is 22 / 22. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 4 nucleotides, in the 5' end to 3' end direction, the nucleotide sequence III has a base composition of AGGA, and the nucleotide sequence IV has a base composition of UCCU; in this case, the length ratio of the sense strand and the antisense strand is 23 / 23. In some embodiments, the antisense strand further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluorinated modified nucleotide, the nucleotide sequence V has a length of 1 to 3 nucleotides, is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II, and forms a 3' overhang end of the antisense strand after forming the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V has a length of 2 nucleotides, and in the direction from the 5' end to the 3' end, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or fully reverse complementary to the SOD1 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and in the direction from the 5' end to the 3' end, the base composition of the nucleotide sequence V is UC or UU. In some embodiments, the sense strand comprises only the nucleotide sequence I, the antisense strand comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 14, the nucleotide sequence I consists of SEQ ID NO: 13, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and in the direction from the 5' end to the 3' end, the base composition of the nucleotide sequence V is UC. The eighth double-stranded oligonucleotide The present disclosure provides the eighth double-stranded oligonucleotide, which comprises a sense strand and an antisense strand, the sense strand comprises a nucleotide sequence I, the nucleotide sequence I is equal in length to the nucleotide sequence shown in SEQ ID NO: 15, and has no more than 3 base differences; the antisense strand comprises a nucleotide sequence II, the nucleotide sequence II is equal in length to the nucleotide sequence shown in SEQ ID NO: 16, and has no more than 3 base differences: 5'-AAUGGACCAGUGAAGGUGZ 15 -3' (SEQ ID NO: 15); 5'-Z 16 CACCUUCACUGGUCCAUU-3' (SEQ ID NO: 16), wherein the Z 15 is U, A, or an inverted abasic deoxynucleotide (ia), Z 16 is A or U, the nucleotide sequence I comprises a nucleotide Z' 15 corresponding to the position of Z 15 , the nucleotide sequence II comprises a nucleotide Z' 16 corresponding to the position of Z 16 , Z' 16 is the first nucleotide at the 5' end of the antisense strand. In some embodiments, the sense strand comprises only the nucleotide sequence I, and the antisense strand comprises only the nucleotide sequence II. In some embodiments, there is no more than 1 base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 15, and / or no more than 1 base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 16. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 15 can comprise Z' 15 at the position and / or a base difference at any one of the other nucleotide positions in the nucleotide sequence I. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 15 can comprise Z' 15 at the position and / or a base difference at the adjacent nucleotide position to Z' 15 In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 15 is Z' 15 at the position, preferably, Z' 15 is a reverse dealkylated deoxynucleotide. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 16 comprises Z' 16 at the position, and Z' 16 is selected from C, U or G. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 16 is Z' 16 at the position, and Z' 16 is selected from C, U or G. In some embodiments, the 2nd-19th nucleotides of the nucleotide sequence II are fully reverse complementary to the SOD1 mRNA in the direction from 5' end to 3' end. In some embodiments, the nucleotide sequence II is fully reverse complementary to the nucleotide sequence I. In some embodiments, there is a base mismatch between the 2nd nucleotide in the nucleotide sequence II in the direction from 5' end to 3' end and the 2nd nucleotide in the nucleotide sequence I in the direction from 3' end to 5' end. By comprising the base mismatch, it is possible to have higher SOD1 mRNA inhibitory activity while maintaining low off-target effect. In some embodiments, the sense strand further comprises a nucleotide sequence III, the anti-sense strand further comprises a nucleotide sequence IV, the nucleotide sequence III has a length of 1, 2, 3, or 4 nucleotides, the nucleotide sequence IV and the nucleotide sequence III have the same length, and the nucleotide sequence IV and the nucleotide sequence III are substantially reverse complementary or completely reverse complementary, and the nucleotide sequence III is linked to the 5' end of the nucleotide sequence I. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 1 nucleotide, the nucleotide sequence III has a base of U, and the nucleotide sequence IV has a base of A, in the direction from the 5' end to the 3' end. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 2 nucleotides, the nucleotide sequence III has a base composition of GU, and the nucleotide sequence IV has a base composition of AC, in the direction from the 5' end to the 3' end. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 3 nucleotides, the nucleotide sequence III has a base composition of AGU, and the nucleotide sequence IV has a base composition of ACU, in the direction from the 5' end to the 3' end. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 4 nucleotides, the nucleotide sequence III has a base composition of AAGU, and the nucleotide sequence IV has a base composition of ACUU, in the direction from the 5' end to the 3' end. In some embodiments, the anti-sense strand further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluorinated modified nucleotide, the nucleotide sequence V has a length of 1 to 3 nucleotides, is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II, and forms a 3' overhang end of the anti-sense strand after forming the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V has a length of 2 nucleotides, and in the direction from the 5' end to the 3' end, the nucleotide sequence V is two consecutive thymine deoxyribonucleotides, two consecutive uracil ribonucleotides, or is completely reverse complementary to the SOD1 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and in the direction from the 5' end to the 3' end, the base composition of the nucleotide sequence V is AC or UU. In some embodiments, the sense strand comprises only the nucleotide sequence I, the antisense strand comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 16, the nucleotide sequence I consists of SEQ ID NO: 15, the nucleotide sequence V is linked at the 3' end of the nucleotide sequence II, and the base composition of the nucleotide sequence V, in the 5' end to 3' end direction, is AC. Ninth double-stranded oligonucleotide The present disclosure provides a ninth double-stranded oligonucleotide containing a sense strand and an antisense strand, the sense strand containing a nucleotide sequence I, the nucleotide sequence I being equal in length to and differing from the nucleotide sequence set forth in SEQ ID NO: 17 by no more than 3 bases; the antisense strand containing a nucleotide sequence II, the nucleotide sequence II being equal in length to and differing from the nucleotide sequence set forth in SEQ ID NO: 18 by no more than 3 bases: 5'-CUGAAGGCCUGCAUGGAUZ 17 -3' (SEQ ID NO: 17); 5'-Z 18 AUCCAUGCAGGCCUUCAG-3' (SEQ ID NO: 18), wherein the Z 17 is U, A or an inverted abasic deoxynucleotide (ia), Z 18 is A or U, the nucleotide sequence I comprising a nucleotide Z' 17 corresponding in position to Z 17 , the nucleotide sequence II comprising a nucleotide Z' 18 corresponding in position to Z 18 , Z' 18 being the first nucleotide of the 5' end of the antisense strand. In some embodiments, the sense strand comprises only the nucleotide sequence I, and the antisense strand comprises only the nucleotide sequence II. In some embodiments, there is no more than 1 base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 17, and / or no more than 1 base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 18. Wherein the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 17 can include the difference at the position of Z' 17 and / or the base difference at any other nucleotide position in the nucleotide sequence I. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 17 can include the difference at the position of Z' 17 and / or the difference at the position of Z' 17a base difference at the nucleotide position. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 17 is Z 17 a base difference at the nucleotide position, preferably, Z 17 is an inverted dealkylated deoxynucleotide. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 18 comprises a difference at the nucleotide position Z 18 a difference at the nucleotide position, and Z 18 is selected from C, U, or G. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 18 is a difference at the nucleotide position Z 18 a difference at the nucleotide position, and Z 18 is selected from C, U, or G. In some embodiments, the nucleotide at position 2-19 of the nucleotide sequence II is fully reverse-complementary to the SOD1 mRNA in the direction from 5' end to 3' end. In some embodiments, the nucleotide sequence II is fully reverse-complementary to the nucleotide sequence I. In some embodiments, there is a base mismatch between the 2ndnucleotide in the nucleotide sequence II in the direction from 5' end to 3' end and the 2ndnucleotide in the nucleotide sequence I in the direction from 3' end to 5' end. By including the base mismatch, one can have higher SOD1 mRNA inhibitory activity while maintaining low off-target effects. In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, the nucleotide sequence III has a length of 1, 2, 3, or 4 nucleotides, the nucleotide sequence IV and the nucleotide sequence III have equal length, and the nucleotide sequence IV and the nucleotide sequence III are substantially reverse-complementary or fully reverse-complementary, and the nucleotide sequence III is linked to the 5' end of the nucleotide sequence I. In some embodiments, the length of each of the nucleotide sequence III and the nucleotide sequence IV is 1 nucleotide, the base of the nucleotide sequence III is A, and the base of the nucleotide sequence IV is U, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 20 / 20. In some embodiments, the length of each of the nucleotide sequence III and the nucleotide sequence IV is 2 nucleotides, the base composition of the nucleotide sequence III is GA, and the base composition of the nucleotide sequence IV is UC, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 21 / 21. In some embodiments, the length of each of the nucleotide sequence III and the nucleotide sequence IV is 3 nucleotides, the base composition of the nucleotide sequence III is UGA, and the base composition of the nucleotide sequence IV is UCA, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 22 / 22. In some embodiments, the length of each of the nucleotide sequence III and the nucleotide sequence IV is 4 nucleotides, the base composition of the nucleotide sequence III is CUGA, and the base composition of the nucleotide sequence IV is UCAG, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 23 / 23. In some embodiments, the antisense strand further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluorinated modified nucleotide, the length of the nucleotide sequence V is 1 to 3 nucleotides, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II, and forms a 3' overhang end of the antisense strand after the double-stranded oligonucleotide is formed. In some embodiments, the length of the nucleotide sequence V is 2 nucleotides, and the nucleotide sequence V is, in the direction from the 5' end to the 3' end, 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or fully reverse complementary to the SOD1 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and the base composition of the nucleotide sequence V is UC or UU, in the direction from the 5' end to the 3' end. In some embodiments, the sense strand comprises only the nucleotide sequence I, the antisense strand comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 18, the nucleotide sequence I consists of SEQ ID NO: 17, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and the base composition of the nucleotide sequence V is UC, in the direction from the 5' end to the 3' end. The tenth double-stranded oligonucleotide The present disclosure provides a tenth double-stranded oligonucleotide comprising a sense strand and an antisense strand, the sense strand comprising a nucleotide sequence I which is identical in length to and differs from the nucleotide sequence set forth in SEQ ID NO: 19 by no more than 3 bases; and the antisense strand comprising a nucleotide sequence II which is identical in length to and differs from the nucleotide sequence set forth in SEQ ID NO: 20 by no more than 3 bases: 5'-CUUGGGCAAAGGUGGAAAZ 19 -3' (SEQ ID NO: 19); 5'-Z 20 UUUCCACCUUUGCCCAAG-3' (SEQ ID NO: 20), wherein the Z 19 is U, A or an inverted abasic deoxynucleotide (ia), Z 20 is A or U, the nucleotide sequence I comprises a nucleotide Z' 19 at a position corresponding to Z 19 , the nucleotide sequence II comprises a nucleotide Z' 20 at a position corresponding to Z 20 , Z' 20 is the first nucleotide of the 5' end of the antisense strand. In some embodiments, the sense strand comprises only the nucleotide sequence I, and the antisense strand comprises only the nucleotide sequence II. In some embodiments, there is no more than 1 base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 19, and / or no more than 1 base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 20. Where there is a base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 19, the base difference can include a difference at the Z' 19 position and / or a base difference at any other nucleotide position in the nucleotide sequence I. In some embodiments, there is a base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 19 at the Z' 19 position and / or at a nucleotide position adjacent to the Z' 19 position. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 19 is at the Z' 19 position, preferably, Z' 19 is an inverted abasic deoxynucleotide. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 20 includes a difference at the Z' 20a difference at position Z' selected from C, U, or G. In some embodiments, the difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 20 is a difference at position Z' selected from C, U, or G. 20 a difference at position Z' selected from C, U, or G. In some embodiments, the difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 20 is a difference at position Z' selected from C, U, or G. 20 a difference at position Z' selected from C, U, or G. In some embodiments, the difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 20 is a difference at position Z' selected from C, U, or G. 20 a difference at position Z' selected from C, U, or G. In some embodiments, the 2nd-19th nucleotides of nucleotide sequence II are fully reverse-complementary to SOD1 mRNA in the 5' end to 3' end direction. In some embodiments, nucleotide sequence II is fully reverse-complementary to the nucleotide sequence I. In some embodiments, there is a base mismatch between the 2nd nucleotide in nucleotide sequence II in the 5' end to 3' end direction and the 2nd nucleotide in nucleotide sequence I in the 3' end to 5' end direction. By including this base mismatch, one can have higher SOD1 mRNA inhibitory activity while maintaining low off-target effects. In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, the length of nucleotide sequence III is 1, 2, 3, or 4 nucleotides, the length of nucleotide sequence IV is equal to the length of nucleotide sequence III, and nucleotide sequence IV and nucleotide sequence III are substantially reverse-complementary or fully reverse-complementary, and nucleotide sequence III is linked to the 5' end of nucleotide sequence I. In some embodiments, the length of nucleotide sequence III and nucleotide sequence IV is 1 nucleotide in the 5' end to 3' end direction, the base of nucleotide sequence III is A, and the base of nucleotide sequence IV is U; in this case, the length ratio of the sense strand and the antisense strand is 20 / 20. In some embodiments, the length of nucleotide sequence III and IV is 2 nucleotides, the base composition of nucleotide sequence III is GA in the 5' end to 3' end direction, and the base composition of nucleotide sequence IV is UC; in this case, the length ratio of the sense strand and the antisense strand is 21 / 21. In some embodiments, the length of nucleotide sequence III and IV is 3 nucleotides, the base composition of nucleotide sequence III is UGA in the 5' end to 3' end direction, and the base composition of nucleotide sequence IV is UCA; in this case, the length ratio of the sense strand and the antisense strand is 22 / 22. In some embodiments, the length of nucleotide sequence III and IV is 4 nucleotides, the base composition of nucleotide sequence III is AUGA in the 5' end to 3' end direction, and the base composition of nucleotide sequence IV is UCAU; in this case, the length ratio of the sense strand and the antisense strand is 23 / 23. In some embodiments, the antisense strand further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluorinated modified nucleotide, the nucleotide sequence V has a length of 1 to 3 nucleotides, is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II, and forms a 3' overhang end of the antisense strand after forming the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V has a length of 2 nucleotides, and in the direction from the 5' end to the 3' end, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or fully reverse complementary to the SOD1 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and in the direction from the 5' end to the 3' end, the base composition of the nucleotide sequence V is UC or UU. In some embodiments, the sense strand comprises only the nucleotide sequence I, the antisense strand comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 20, the nucleotide sequence I consists of SEQ ID NO: 19, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and in the direction from the 5' end to the 3' end, the base composition of the nucleotide sequence V is UC. Eleventh double-stranded oligonucleotide The present disclosure provides an eleventh double-stranded oligonucleotide, which comprises a sense strand and an antisense strand, the sense strand comprises a nucleotide sequence I, the nucleotide sequence I is equal in length to the nucleotide sequence set forth in SEQ ID NO: 21, and has no more than 3 base differences; the antisense strand comprises a nucleotide sequence II, the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 22, and has no more than 3 base differences: 5'-CAGAUGACUUGGGCAAAGZ 21 -3' (SEQ ID NO: 21); 5'-Z 22 CUUUGCCCAAGUCAUCUG-3' (SEQ ID NO: 22), wherein the Z 21 is G, C, or an inverted abasic deoxynucleotide (ia), Z 22 is G or C, the nucleotide Z' 21 in the nucleotide sequence I comprises a nucleotide corresponding in position to Z 21 , the nucleotide Z' 22 in the nucleotide sequence II comprises a nucleotide corresponding in position to Z 22 , and Z' 22 is the first nucleotide of the 5' end of the antisense strand. In some embodiments, the sense strand comprises only the nucleotide sequence I, and the antisense strand comprises only the nucleotide sequence II. In some embodiments, there is no more than 1 base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 21, and / or no more than 1 base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 22. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 21 can comprise a difference at position Z 21 and / or a base difference at any other nucleotide position in the nucleotide sequence I. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 21 can comprise a difference at position Z 21 and / or a base difference at a nucleotide position adjacent to Z 21 In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 21 is a base difference at position Z 21 , preferably, Z 21 is an inverted abasic deoxynucleotide. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 22 comprises a difference at position Z 22 , and Z 22 is selected from C, U or G. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 22 is a difference at position Z 22 , and Z 22 is selected from C, U or G. In some embodiments, the nucleotide at position 2-19 of the nucleotide sequence II is fully reverse complementary to the SOD1 mRNA in the direction from 5' end to 3' end. In some embodiments, the nucleotide sequence II is fully reverse complementary to the nucleotide sequence I. In some embodiments, there is a base mismatch between the 2nd nucleotide in the nucleotide sequence II in the direction from 5' end to 3' end and the 2nd nucleotide in the nucleotide sequence I in the direction from 3' end to 5' end. By including the base mismatch, one can have higher SOD1 mRNA inhibitory activity while maintaining low off-target effect. In some embodiments, the sense strand further comprises a nucleotide sequence III, the anti-sense strand further comprises a nucleotide sequence IV, the nucleotide sequence III has a length of 1, 2, 3, or 4 nucleotides, the nucleotide sequence IV and the nucleotide sequence III have the same length, and the nucleotide sequence IV and the nucleotide sequence III are substantially reverse complementary or completely reverse complementary, and the nucleotide sequence III is linked to the 5' end of the nucleotide sequence I. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 1 nucleotide, the nucleotide sequence III has a base of G, and the nucleotide sequence IV has a base of C, in the direction from the 5' end to the 3' end. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 2 nucleotides, the nucleotide sequence III has a base composition of AG, and the nucleotide sequence IV has a base composition of CU, in the direction from the 5' end to the 3' end. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 3 nucleotides, the nucleotide sequence III has a base composition of AAG, and the nucleotide sequence IV has a base composition of CUU, in the direction from the 5' end to the 3' end. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 4 nucleotides, the nucleotide sequence III has a base composition of AAAG, and the nucleotide sequence IV has a base composition of CUUU, in the direction from the 5' end to the 3' end. In some embodiments, the anti-sense strand further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluorinated modified nucleotide, the nucleotide sequence V has a length of 1 to 3 nucleotides, is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II, and forms a 3' overhang end of the anti-sense strand after forming the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V has a length of 2 nucleotides, and in the direction from the 5' end to the 3' end, the nucleotide sequence V is two consecutive thymine deoxynucleotides, two consecutive uracil nucleotides, or is completely reverse complementary to the SOD1 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and in the direction from the 5' end to the 3' end, the nucleotide sequence V has a base composition of CU or UU. In some embodiments, the sense strand comprises only the nucleotide sequence I, the antisense strand comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 22, the nucleotide sequence I consists of SEQ ID NO: 21, the nucleotide sequence V is linked at the 3' end of the nucleotide sequence II, and the base composition of the nucleotide sequence V, in the 5' end to 3' end direction, is CU. In some embodiments, the double-stranded oligonucleotide is one of siRNA1-siRNA11 shown in Table 1 below: Table 1 siRNA sequences of the present disclosure wherein the capital letters C, G, U, A and T represent the base composition of the nucleotides; the lower case letter o represents that the nucleotide represented by the capital letter adjacent to the left of the letter o is an alkoxy-modified nucleotide; the lower case letter f represents that the nucleotide represented by the capital letter adjacent to the left of the letter f is a fluoro-modified nucleotide; each N is independently U or T; the lower case letter s represents that the linkage between the two nucleotides represented by the two capital letters adjacent to the left and right of the letter s is a phosphorothioate group; the lower case letter d represents that the nucleotide represented by the capital letter adjacent to the right of the letter d is a deoxynucleotide; ia represents an inverted abasic deoxynucleotide. In some embodiments, each alkoxy-modified nucleotide is a 2'-methoxy-modified nucleotide; each P1 is independently a 5'-hydroxyl nucleotide or a 5'-vinylphosphonate (E-VP) modified nucleotide. The single-stranded oligonucleotides and / or double-stranded oligonucleotides provided by the present disclosure can be obtained by the methods of oligonucleotide preparation in the art, such as the methods of solid-phase synthesis and liquid-phase synthesis. Among them, the solid-phase synthesis has been commercialized and customized services. The methods of preparing nucleoside monomers with corresponding modifications and introducing modified nucleotide groups into the single-stranded oligonucleotides and / or double-stranded oligonucleotides described by the present disclosure by using nucleoside monomers with corresponding modifications are also well known to those skilled in the art. All modified nucleoside monomers can be commercially available or prepared by known methods. The single-stranded oligonucleotides, double-stranded oligonucleotides provided by the present disclosure can be used alone, or in combination with a pharmaceutically acceptable carrier to form a pharmaceutical composition, or in combination with a delivery group to form an oligonucleotide conjugate, or in any other suitable form. An effective amount of the single-stranded oligonucleotides / double-stranded oligonucleotides, the pharmaceutical composition or the oligonucleotide conjugate is contacted with cells to modulate the expression of a target gene, or an effective amount of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugate or pharmaceutical composition is administered to a subject to modulate the expression of a target gene, to achieve the purpose of treating a pathological condition or disease associated with the expression level of the target gene. Oligonucleotide conjugate In another aspect, the present disclosure provides an oligonucleotide conjugate, which contains an oligonucleotide group, and a delivery group conjugated to the oligonucleotide group, the oligonucleotide group is independently a group formed by removing one or more atoms or atom groups from the single-stranded oligonucleotide or double-stranded oligonucleotide provided by the present disclosure. In the context of the present disclosure, unless otherwise specified, "conjugation" refers to the connection between two or more chemical moieties each having a specific function in a manner of covalent connection; accordingly, "conjugate" refers to a compound formed by the covalent connection between the respective chemical moieties. Further, "oligonucleotide conjugate" means a compound formed by the covalent connection of one or more chemical moieties having a specific function to an oligonucleotide. Oligonucleotide conjugate should be understood as a general term for a plurality of oligonucleotide conjugates or an oligonucleotide conjugate represented by a certain chemical formula, depending on the context. In the context of the present disclosure, "conjugation molecule" should be understood as a specific compound that can be conjugated to an oligonucleotide by a reaction to ultimately form an oligonucleotide conjugate of the present disclosure. The delivery group is a group for delivering the oligonucleotide group into a cell expressing SOD1 mRNA. In some embodiments, the delivery group comprises a linker group and a pharmaceutically acceptable targeting group, and the oligonucleotide group, the linker group and the targeting group are covalently or non-covalently connected in sequence, each of the targeting groups is independently selected from a ligand group capable of binding to a cell surface receptor or a group capable of increasing compatibility with tissues. In some embodiments, each of the targeting groups is independently targeted to one or more of the central nervous system, liver, kidney, lung, muscle and eye. In some embodiments, each of the targeting groups is independently a group capable of increasing compatibility with tissues in the central nervous system. In some embodiments, the targeting group is 1-6. In one embodiment, the targeting group is 2-4. The oligonucleotide group can be conjugated to the delivery group non- covalently or covalently, for example, can be covalently conjugated to the delivery group. In some embodiments, the oligonucleotide group is a single-stranded oligonucleotide group, the conjugation site of which to the delivery group can be at the 3' end or 5' end of the single-stranded oligonucleotide, or in the internal sequence of the single-stranded oligonucleotide. In some embodiments, the oligonucleotide group is a double-stranded oligonucleotide group, which can be conjugated to the delivery group non-covalently or covalently, for example, can be covalently conjugated to the delivery group. The conjugation site of the double-stranded oligonucleotide group to the delivery group can be at the 3' end or 5' end of the sense strand of the double-stranded oligonucleotide, or at the 5' end of the antisense strand, or in the internal sequence of the double-stranded oligonucleotide. In some embodiments, the conjugation site of the double-stranded oligonucleotide group to the delivery group is at the 3' end of the sense strand of the double-stranded oligonucleotide. In some embodiments, the delivery group can be linked at any position of the nucleotide, for example, the phosphate group, the ribose 2'-, 3'- or 5'-position hydroxyl group, or the base. When the delivery group is linked at the 3'- or 5'-end of the single-stranded oligonucleotide or the sense strand of the double-stranded oligonucleotide, the delivery group is usually linked to the oxygen atom formed after the removal of the hydrogen atom from the 3'- or 5'-hydroxyl group of the nucleotide; when the delivery group is linked in the internal sequence of the single-stranded oligonucleotide or the double-stranded oligonucleotide, the delivery group is usually linked to the phosphate group, the ribose sugar ring, or the base. In some embodiments, the delivery group can be linked to the 3'-position hydroxyl group of the nucleotide in the internal sequence of the single-stranded oligonucleotide or the double-stranded oligonucleotide, at which time the nucleotides are connected by 2'-5' phosphodiester bonds. Various connection modes can be referred to the description in the following non-patent literature: Muthiah Manoharan et. al. siRNA conjugates carrying sequentially assembled trivalent N-acetylgalactosamine linked through nucleosides elicit robust gene silencing in vivo in hepatocytes. ACS Chemical biology, 2015, 10(5): 1181-7. The disclosure thereof is incorporated herein by reference in its entirety. In some embodiments, the oligonucleotide can be linked to the delivery group via an acid-labile or reducible chemical linkage that is degradable in the acidic environment of the endosome of a cell, thereby allowing the double-stranded oligonucleotide group to be converted to a free double-stranded oligonucleotide. For non-degradable conjugation, the delivery group can be linked to the sense strand of the single-stranded oligonucleotide or the double-stranded oligonucleotide group, thereby minimizing the impact of conjugation on the activity of the double-stranded oligonucleotide group. The targeting group can be linked to the oligonucleotide group via a suitable linker, which can be selected by one skilled in the art depending on the specific type of the targeting group. For example, when the targeting group is a group that targets a receptor on the surface of a hepatocyte, the types of linkers, targeting groups, and the manner of linking to the oligonucleotide can be found in the disclosure of WO2015006740A2, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, the targeting group can be a ligand group commonly used in the art of oligonucleotide drug delivery, such as the various ligand groups described in WO2009082607A2, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, at least one or each of the targeting groups is selected from ligand groups that are capable of binding to a receptor on the surface of a cell that expresses SOD1 mRNA. In some embodiments, at least one or each of the targeting groups is selected from small molecule ligand groups that have affinity for an asialoglycoprotein receptor on the surface of a hepatocyte. In some embodiments, at least one or each of the targeting groups is selected from a group consisting of a ligand group capable of binding to a surface receptor of a mammalian liver parenchymal cell. In some embodiments, each of the targeting groups is independently a ligand having affinity for an asialoglycoprotein receptor on the surface of a mammalian liver cell. In some embodiments, each of the targeting groups is independently an asialoglycoprotein or a saccharide. In some embodiments, each of the targeting groups is independently selected from one of the group consisting of D-mannopyranose, L-mannopyranose, D-arabinose, D-xylofuranose, L-xylofuranose, D-glucose, L-glucose, D-galactose, L-galactose, a-D-mannofuranose, β-D-mannofuranose, a-D-mannopyranose, β-D-mannopyranose, a-D-glucopyranose, β-D-glucopyranose, a-D-glucoruranose, β-D-glucoruranose, a-D-fructofuranose, a-D-fructopyranose, a-D-galactopyranose, β-D-galactopyranose, a-D-galactofuranose, β-D-galactofuranose, glucosamine, sialic acid, galactosamine, N-acetylgalactosamine, N-trifluoroacetylgalactosamine, N-propionylgalactosamine, N-n-butyrylgalactosamine, N-isobutyrylgalactosamine, 2-amino-3-0-[(R)-1-carboxyethyl]-2-deoxy-β-D-glucopyranose, 2-deoxy-2-methylamino-L- pyranoglucose, 4,6-dideoxy-4-formamido-2,3-di-0-methyl-D-mannopyranose, 2-deoxy-2- sulfonamido-D-glucopyranose, N-glycolyl-a-neuraminic acid, 5-thio-β-D-glucopyranose, 2,3,4-tri-0-acetyl-1-thio-6-0-trityl-a-D-glucopyranoside methyl ester, 4-thio-β-D- galactopyranose, 3,4,6,7-tetra-0-acetyl-2-deoxy-1,5-dithio-a-D-glucopyranoside ethyl ester, 2,5- anhydro-D-allosonitrile, ribose, D-ribose, D-4-thioribose, L-ribose, L-4-thioribose, and a group formed by removing one atom or group from one of the foregoing. In some embodiments, at least one or each of the targeting groups is a galactosyl group or an N-acetylgalactosamine group. In some embodiments, the double-stranded oligonucleotide group is capable of modulating the expression level of SOD1 mRNA in a liver parenchymal cell. The delivery group in the oligonucleotide conjugates of the present disclosure can be various delivery groups known to those skilled in the art of oligonucleotide drugs. In some embodiments, the linking group in the oligonucleotide conjugates of the present disclosure has a structure as shown in formula (301): wherein k is an integer from 1 to 5, denotes the site of covalent attachment of the group; all L A is attached to LC The same atom in; or, each L A Independently connected to L C Different atoms in it. In some implementations, L C It has -NH-C(H) n301 (CH2O-) k The structure shown is such that k is an integer from 1 to 3, and n301 = 3 - k; L B The length is 5-20 atoms. In some implementations, each L A Independently, it is a straight-chain alkylene group with a length of 5-20 carbon atoms, wherein one or more methylene groups are optionally replaced by any one or more groups selected from the group consisting of: C(O), NH, O, S, 1,2,3-triazolyl, butadieneyl. In some implementations, L A Having a structure containing amide bonds as shown in formula (302), L B It has a structure as shown in equation (303): Where, n 302 q 302 and p 302 Each is an independent integer from 2 to 6; optionally, n 302 q 302 and p 302 Each can be 2 or 3 independently; n 303 n is an integer between 4 and 16, optionally n 303 For integers between 8 and 12, This indicates the site where the group is covalently linked. In some embodiments, the linking group has a structure as shown in formula (304) or formula (305): In the linking group, each L A Each of the target groups is connected via an ether bond and via L C The oxygen atom of the hydroxyl group in some of the middle groups is related to L. C Partially linked by ether bonds; L B Through the carbonyl group in formula (303) and L C The nitrogen atom of the amino group in some of them forms an amide bond and is connected to the double-stranded oligonucleotide group through the oxygen atom in formula (303) by forming a phosphate ester bond or a thiophosphate ester bond. In some embodiments, the oligonucleotide conjugates provided in this disclosure have a structure as shown in formula (305A): wherein, Nu represents a double-stranded oligonucleotide group formed by the single-stranded oligonucleotide or the double-stranded oligonucleotide provided by the present disclosure. In some embodiments, the linking group in the oligonucleotide conjugate of the present disclosure has a structure represented by formula (306): wherein, n 306 is an integer from 0 to 3, each p 306 is independently an integer from 1 to 6, represents the site of covalent attachment of groups; the linking group is attached to the targeting group via an ether linkage through the oxygen atom marked by *; the linking group is attached to the double-stranded oligonucleotide via at least one of the oxygen atoms marked by # to form a phosphonate or phosphorothioate linkage, and the rest of the oxygen atoms marked by # are attached to hydrogen atoms to form hydroxyl groups or to C1-C3 alkyl groups to form C1-C3 alkoxy groups; In some embodiments, the oligonucleotide conjugate of the present disclosure has a structure represented by formula (307): wherein, Nu represents a double-stranded oligonucleotide group formed by the single-stranded oligonucleotide or the double-stranded oligonucleotide provided by the present disclosure. In some embodiments, the oligonucleotide conjugate of the present disclosure has a structure represented by formula (308): wherein, n 308 is an integer selected from 2 to 4; each m 308 is independently an integer selected from 2 to 5; each R 308 is independently a hydrogen atom, a methyl group or an ethyl group, or 2 R 308 on the same carbon atom together form a carbonyl group; one of the groups represented by A0, each independently, is an oligonucleotide group, which is a group formed by removing one atom or group of atoms from the single-stranded oligonucleotide or the double-stranded oligonucleotide described in the present disclosure; all the remaining A0are targeting groups, each of which is the same or different, and the definition and selection range thereof are as described above. In some embodiments, each targeting group is independently selected from one of the ligands having affinity to the asialoglycoprotein receptor on the surface of mammalian liver parenchymal cells. each L1is independently a divalent linking group having a length of 1-70 or 3-25 atoms; represents the site of covalent attachment of groups. In some embodiments, each L1is independently a straight-chain alkylene of 1-70 or 1-20 carbon atoms, wherein one or more carbon atoms are optionally replaced by any one or more from the group consisting of C(O), NH, O, S, CH=N, S(O)2, OP(O)2, OP(O)(S), C2-C 10 alkenylene, C2-C 10 alkynylene, C6-C 10 arylene, C3-C 18 heterocyclylene, and C5-C 10 heteroarylene; and the straight-chain alkylene can optionally have substituents of any one or more from the group consisting of C1-C 10 alkyl, C6-C 10 aryl, C5-C 10 heteroaryl, C1-C 10 haloalkyl, -OC1-C 10 alkyl, OC1-C 10 alkylphenyl, -C1-C 10 alkyl-OH, -OC1-C 10 haloalkyl, -SC1-C 10 alkyl, -SC1-C 10 alkylphenyl, -C1-C 10 alkyl-SH, -SC1-C 10 haloalkyl, halogen substituent, -OH, -SH, -NH2, -C1-C 10 alkyl-NH2, -N(C1-C 10 alkyl)(C1-C 10 alkyl), -NH(C1-C 10 alkyl), N(C1-C 10 alkyl)(C1-C 10 alkylphenyl), NH(C1-C 10 alkylphenyl), cyano, nitro, -CO2H, -C(O)O(C1-C 10 alkyl), -CON(C1-C 10 alkyl)(C1-C 10 alkyl), -CONH(C1-C 10 alkyl), -CONH2, -NHC(O)(C1-C 10 alkyl), -NHC(O)(phenyl), -N(C1-C 10 alkyl)C(O)(C1-C 10 alkyl), -N(C1-C 10 alkyl)C(O)(phenyl), C(O)C1-C 10 alkyl, C(O)C1-C10 alkylphenyl, C(O)C1-C 10 haloalkyl, -OC(O)C1-C 10 alkyl, -SO2(C1-C 10 alkyl), -SO2(phenyl), -SO2(C1-C 10 haloalkyl), -SO2NH2, -SO2NH(C1-C 10 alkyl), -SO2NH(phenyl), -NHSO2(C1-C 10 alkyl), -NHSO2(phenyl), and -NHSO2(C1-C 10 haloalkyl). As used herein, "alkyl" refers to straight and branched chains, typically of 1 to 20 carbon atoms, e.g., 1 to 10 carbon atoms, such as 1 to 8 or 1 to 6 carbon atoms. For example, C1-C6 alkyl includes straight and branched chain alkyl groups of 1 to 6 carbon atoms. When reference is made to an alkyl group having a specific number of carbons, it is intended to encompass all possible branched and straight chain versions having that number of carbons; thus, for example, "butyl" is meant to include n-butyl, sec-butyl, iso-butyl, and t-butyl; "propyl" includes n-propyl and iso-propyl. Alkylene is a subset of alkyl, referring to the same groups as alkyl, but having two points of attachment. As used herein, "alkenyl" refers to an unsaturated branched or straight chain hydrocarbon group having at least one carbon-carbon double bond obtained by the removal of one molecule of hydrogen from a single carbon atom of a parent alkyl group. The group can be in the cis- or trans- configuration with respect to the double bond. Typical alkenyl groups include, but are not limited to, ethenyl; propenyl, such as prop-1 -en-1 -yl, prop-1 -en-2-yl, prop-2-en-1 -yl (allyl), prop-2-en-2-yl; butenyl, for example, but-1 -en-1 -yl, but-1 -en-2-yl, 2-methylprop-1 -en-1 -yl, but-2-en-1 -yl, but-2-en-2-yl, but-1,3-dien-1 -yl, but-1,3-dien-2-yl, and the like. In certain embodiments, alkenyl groups have 2 to 20 carbon atoms, while in other embodiments, 2 to 10, 2 to 8, or 2 to 6 carbon atoms. Alkenylene is a subset of alkenyl, referring to the same groups as alkenyl, but having two points of attachment. As used herein, "alkynyl" refers to an unsaturated branched or straight-chain hydrocarbon group having at least one carbon-carbon triple bond, obtained by removing two hydrogen atoms from adjacent carbon atoms of a parent alkyl group. Typical alkynyl groups include, but are not limited to: ethynyl; propynyl, such as prop-1-yn-1-yl, prop-2-yn-1-yl; butynyl, for example but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, and the like. In certain embodiments, an alkynyl group has 2 to 20 carbon atoms, while in other embodiments, 2 to 10, 2 to 8, or 2 to 6 carbon atoms. Alkynylene is a subset of alkynyl, referring to the same moieties as alkynyl, but with two points of attachment. As used herein, "alkoxy" refers to an alkyl group of the specified number of carbon atoms linked via an oxygen bridge, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, pentoxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, and the like. Alkoxy groups typically have 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms linked via an oxygen bridge. As used herein, "aryl" refers to a radical derived by removing a hydrogen atom from a carbon atom of an aromatic, monocyclic or polycyclic hydrocarbon ring system. The aromatic, monocyclic or polycyclic hydrocarbon ring system contains only carbon and hydrogen atoms of which 6 to 18 carbons, wherein at least one ring in the ring system is completely unsaturated, i.e., contains a cyclic, delocalized (4n+2) pi-electron system, according to Hückel theory. Aryl includes, but is not limited to, phenyl, fluorenyl, and naphthyl groups, and the like. Alkenyl is a subset of aryl, referring to the same moieties as aryl, but with two points of attachment. "Heteroaryl" refers to a radical derived by removal of hydrogen atom from a 3- to 18- membered aromatic ring radical, containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring in the ring system is completely unsaturated, i.e., contains a cyclic delocalized (4n+2) p-electron system according to Hückel theory. Heteroaryl groups include fused or bridged ring systems. In some embodiments, the heteroatoms in the heteroaryl group are oxidized heteroatoms. In some embodiments, the heteroaryl group contains one or more nitrogen atoms. In some embodiments, one or more of the nitrogen atoms in the heteroaryl group is a quaternized nitrogen atom. The heteroaryl group is attached to the rest of the molecule through any ring atom. Examples of heteroaryl groups include, but are not limited to: azepinyl, acridinyl, benzimidazolyl, benzoindolyl, 1,3-benzodioxazolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothiophenyl, benzo-thieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[l,2-c]pyridazinyl, diphenofuranyl, diphenothiophenyl, furanyl, furanonyl, furopyrido[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, dihydroindolyl, isoindolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]oxazinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]dioxepinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]dioxinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]oxazolyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thiazolyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thiadiazolyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]cinnolinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyridazinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyridinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thiophenyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]furanyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyranyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyranonyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]furanonyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thiophenonyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]pyrimidinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]pyridazinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]pyridinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]thiophenyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]furanyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]pyranyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]pyranonyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]furanonyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]thiophenonyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]pyrimidinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]pyridazinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]pyridinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]thiophenyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]furanyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]pyranyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]pyranonyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]furanonyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]thiophenonyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]pyrimidinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]pyridazinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]pyridinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]thiophenyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]furanyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]pyranyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno8-tetrahydroquinazolinyl), naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[H]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl / thienyl. In the foregoing or hereafter, a "substituted" group, such as a substituted alkyl, substituted alkoxy, substituted amino, substituted aliphatic, substituted heteroaliphatic, substituted acyl, substituted aryl, or substituted heteroaryl. Where not otherwise specified, a "substituted" group means that one or more hydrogen atoms of the group are replaced with one or more substituents. For example, a "substituted alkoxy" means an alkoxy group in which one or more of the hydrogen atoms are replaced with a substituent. Those skilled in the art will appreciate that a wide variety of substituents can be present in the compounds useful in the present disclosure, so long as the introduction of the substituent does not unduly adversely affect the functionality of the present disclosure, and so long as the purposes of the present disclosure are achieved. In some embodiments, the substituents are selected from the group consisting of C1-C 10 alkyl, C6-C 10 aryl, C5-C 10 heteroaryl, C1-C 10 haloalkyl, -OC1-C 10 alkyl, -OC1-C 10 alkylphenyl, -C1-C 10 alkyl-OH, -OC1-C 10haloalkyl, -SC1-C 10 alkyl, -SC1-C 10 alkyl, -SC1-C 10 alkyl-SH, -SC1-C 10 haloalkyl, halo substituent, -OH, -SH, -NH2, -C1-C 10 alkyl-NH2, -N(C1-C 10 alkyl)(C1-C 10 alkyl), -NH(C1-C 10 alkyl), -N(C1-C 10 alkyl)(C1-C 10 alkyl), -NH(C1-C 10 alkyl), -CN, -NO2, -CO2H, -C(O)O(C1-C 10 alkyl), -CON(C1-C 10 alkyl)(C1-C 10 alkyl), -CONH(C1-C 10 alkyl), -CONH2, -NHC(O)(C1-C 10 alkyl), -NHC(O)(phenyl), -N(C1-C 10 alkyl)C(O)(C1-C 10 alkyl), -N(C1-C 10 alkyl)C(O)(phenyl), -C(O)C1-C 10 alkyl, -C(O)C1-C 10 alkyl, -C(O)C1-C 10 alkyl, -OC(O)C1-C 10 alkyl, -SO2(C1-C 10 alkyl), -SO2(phenyl), -SO2(C1-C 10 haloalkyl), -SO2NH2, -SO2NH(C1-C 10 alkyl), -SO2NH(phenyl), -NHSO2(C1-C 10 alkyl), -NHSO2(phenyl), and -NHSO2(C1-C 10 haloalkyl). In some embodiments, the substituent is one of -C1-C3alkyl, -C6-C8aryl, -O-C1-C3alkyl, -O-(C1-C3alkyl)phenyl, halo, -OH, -NH2, -CN, or -NO2. It will be understood by those skilled in the art that, for any group containing one or more substituents, the groups are not intended to introduce any substitution or substitution pattern that is sterically impractical, synthetically impractical, and / or unstable per se. A skilled artisan will appreciate that, although L1is defined for convenience as being a linker group formed by the initial replacement or substitution of a linear alkylene, it can not be a linear group or the name different, e.g., an amine or alkenyl group resulting from the above-mentioned replacement and / or substitution. Unless otherwise indicated, the "length" of any group in a chemical structure depicted in this disclosure refers to the number of atoms in the longest chain of atoms in the group, not counting hydrogen atoms; in the case of groups in which there are multiple ways of connecting two atoms (e.g., two atoms belong to the same cyclic group, such that there are at least 2 chains of atoms that include the two atoms), the length is calculated as the shortest chain of atoms between the two atoms. For example, 1,4-cyclohexanediyl, 1,4-piperidinediyl, 1,4-phenylene, 1,4-piperazinediyl are each calculated as 4 atoms in length, while 1,2-cyclopentanediyl is calculated as only 2 atoms in length. The role of L1covalently linked to A0representing the oligonucleotide group is to enable covalent linkage of the oligonucleotide group to the targeting group, to enable entry of the oligonucleotide conjugate comprising the oligonucleotide group into a cell expressing the mRNA via the targeting effect of the targeting group, and not to affect the SOD1 mRNA level modulating effect of the oligonucleotide group upon entry into a cell expressing the SOD1 mRNA. Thus, in some embodiments, L1covalently linked to A0representing the oligonucleotide group has a length of 3-20 atoms, or 4-15 atoms, or 5-12 atoms. In some embodiments, L1covalently linked to A0representing the oligonucleotide group is selected from one or more of the following combinations of A1, A2, A4, A5, A10, A16, A18, and A19: wherein j1is an integer from 2 to 10; denotes the site of covalent linkage of groups. In some embodiments, R2is selected from at least two of the following combinations of A1, A2, A4, A10, and A16linked to a phosphate group or a modified phosphate group; in some embodiments, R2is selected from at least two of the following combinations of A1, A2, A10linked to a phosphate group or a modified phosphate group. In some embodiments, L1covalently linked to A0representing the oligonucleotide group has a structure as shown in formula (B1), (B2), (B3), or (B4): wherein, denotes the site of covalent linkage of groups, L B1 and L B2 are the same or different, independently selected from one or any combination of the following groups: -(CH2) q1-CH(OH)-, -CH(CH2OH)-, -NH-, -O-, -S-, 1,4-cyclohexanediyl, 1,4-piperidinediyl, 1,4- phenylenediyl, 1,4-piperazinediyl, pyrrolidinediyl, wherein q1 is an integer from 1 to 6, L B1 and L B2 each independently is an integer from 1 to 20 atoms. In some embodiments, L B1 and L B2 each independently is an integer from 1 to 10 atoms. In some embodiments, L B1 and L B2 each independently is an integer from 1 to 6 atoms. L B3 is selected from one of a phosphonate group, a thiophosphonate group, a dithiophosphonate group, covalently attached to the oxygen atom remaining after removal of a hydrogen atom from the ribose 5' position hydroxyl group of the 5' terminal nucleotide, or the ribose 3' position hydroxyl group of the 3' terminal nucleotide of the oligonucleotide group sense strand or antisense strand. In some embodiments, L B3 is a phosphonate group, covalently attached to the oxygen atom remaining after removal of a hydrogen atom from the ribose 5' position hydroxyl group of the 5' terminal nucleotide, or the ribose 3' position hydroxyl group of the 3' terminal nucleotide of the oligonucleotide group sense strand. In some embodiments, in the case of preparing the oligonucleotide conjugate of the disclosure by a process of solid phase synthesis, L1covalently attached to A0representing the oligonucleotide group needs to contain simultaneously a linking site to N on the nitrogen-containing backbone, a linking site to the oligonucleotide group and a functional group capable of linking to a solid support. In some embodiments, the site linked to N on the nitrogen-containing backbone in L1covalently attached to A0representing the oligonucleotide group forms an amide bond with N, the oligonucleotide group is covalently attached through a phosphonate bond and the functional group capable of linking to a solid support is a hydroxyl group or an amino group. In some embodiments, R2is B5, B6, B5' or B6': wherein, represents the site of covalent bond linkage of the group. q2may be an integer from 1 to 10, in some embodiments, q2is an integer from 1 to 5. The role of L1 covalently linked to A0 representing a targeting group is to place the targeting group in a suitable spatial position for better binding to the receptor, thus specifically targeting and entering the relevant cell. Therefore, L1 covalently linked to A0 representing a targeting group can be used in the present disclosure as long as it has a suitable length and the chemical properties do not significantly affect the delivery. In some embodiments, each L1 covalently linked to A0 representing a targeting group is independently a divalent linking group of 3-25 atoms in length. In some embodiments, each L1 covalently linked to A0 representing a targeting group is 4-15 atoms in length. In some embodiments, each L1 covalently linked to A0 representing a targeting group is 5-10 atoms in length. In some embodiments, each L1 covalently linked to A0 representing a targeting group is the same. In some embodiments, each L1 covalently linked to A0 representing a targeting group is the same or different, and is independently selected from the group consisting of the groups represented by formulae (L3)-(L18) and any combination of connections thereof: wherein each j1 is an integer from 2 to 10; each R’ is independently a hydrogen atom or a C1-C3 alkyl group, represents the site of covalent attachment of the group. For ease of synthesis and / or chemical stability, in some embodiments, each L1 covalently linked to A0 representing a targeting group is independently a combination of connections of at least 2 connection units, each connection unit independently having a structure represented by any one of formulae (L3)-(L7). In some embodiments, each connection unit independently has a structure represented by any one of formulae (L3), (L4), and (L7). For ease of synthesis, in some embodiments, each L1 covalently linked to A0 representing a targeting group includes a carbonyl group attached to the nitrogen atom represented in formula (308). In some embodiments, each L1 covalently linked to A0 representing a targeting group independently has a structure represented by formula (L20) or (L21): wherein j2 is an integer from 4 to 9, and j3 is 1 or 2. In some embodiments, j2 is 5, 6, or 7, and j3 is 1. In some embodiments, each L1 covalently linked to A0 representing a targeting group is the same. In the conjugate of the present disclosure, the number of targeting groups and the spacing between the targeting groups are such that a proper spatial configuration of multiple targeting groups is provided. To this end, n308and each m308are independently an integer selected from 2-4. In some embodiments, n308is 3 or 4, such that the number of targeting groups in the conjugate of the present disclosure is 3 or 4, which can better bind to the surface receptors of hepatocytes. In some embodiments, n308is 3 and each m308is independently 3 or 4. As understood by one skilled in the art, each R 308 is a hydrogen atom, a methyl group or an ethyl group, without affecting the delivery effect of the oligonucleotide conjugate, and each R 308 is a hydrogen atom. In the conjugate of the present disclosure, each targeting group is the same or different, and is independently selected from a ligand group that binds to a cell surface receptor. In some embodiments, at least one or each targeting group is a group that can target the liver. In some embodiments, at least one or each targeting group is one of ligands that can have affinity to a receptor on the surface of a mammalian hepatocyte. In some embodiments, at least one or each targeting group is one of ligand groups that can have affinity to an asialoglycoprotein receptor (ASGPR) on the surface of a mammalian hepatocyte. In some embodiments, each targeting group is a galactose group or an N-acetylgalactosamine group formed by removing one atom or group from galactose or N-acetylgalactosamine. In some embodiments, the oligonucleotide conjugate of the present disclosure has a structure represented by formula (403), (404), (405), (406), (407), (408), (409), (410), (411), (412), (413), (414), (415), (416), (417), (418), (419), (420), (421) or (422): wherein Nu represents an oligonucleotide group, such as a single-stranded oligonucleotide group or a double-stranded oligonucleotide group formed by a single-stranded oligonucleotide or a double-stranded oligonucleotide provided by the present disclosure. In some embodiments, the oligonucleotide group is a double-stranded oligonucleotide group, and the P atom shown in the above structural formula is covalently linked to the 3' terminal nucleotide of the sense strand of the double-stranded oligonucleotide group. In some embodiments, the 3' terminal nucleotide of the sense strand of the double-stranded oligonucleotide group is an inverted abasic deoxynucleotide, and the P atom shown in the above structural formula is covalently linked to the double-stranded oligonucleotide group by replacing the hydrogen atom in the hydroxyl group of the ribose ring of the 3' terminal inverted abasic deoxynucleotide of the sense strand of the double-stranded oligonucleotide group represented by Nu with a methylene group. In some embodiments, the P atom shown in the above structural formula (403) to (422) is covalently linked to the oxygen atom remaining after removing one hydrogen atom from the 3' position hydroxyl group of the ribose of the 3' terminal nucleotide of the sense strand of the double-stranded oligonucleotide group represented by Nu. In some embodiments, the P atom shown in the above structural formula (403) to (422) is covalently linked to the oxygen atom of the inverted abasic deoxynucleotide (ia) shown in formula (35) of the 3' terminal of the sense strand of the siRNA represented by Nu by a covalent bond, thereby covalently linking to the sense strand of the siRNA. In some embodiments, the oligonucleotide conjugate of the present disclosure comprises an oligonucleotide group that can be an siRNA group formed by removing one atom or atom group from an siRNA, in which case the oligonucleotide conjugate of the present disclosure is also referred to as an siRNA conjugate. In some embodiments, the double-stranded oligonucleotide group comprised by the oligonucleotide conjugate of the present disclosure can be an siRNA group formed by an siRNA listed in Table 1 or Table 2, for example. The siRNA conjugate comprising these siRNA groups exhibits excellent stability and high SOD1 mRNA inhibitory activity. In some embodiments, the oligonucleotide conjugate is one of Conjugate 1 or Conjugate 2 listed in Table 3. Preparation of the oligonucleotide conjugate of the present disclosure The oligonucleotide conjugates described in the present disclosure can be prepared by various suitable methods by those skilled in the art. For example, when the nucleoside monomers are linked one by one according to the sequence and modification scheme of the sense strand and the antisense strand of the single-stranded oligonucleotide or the double-stranded oligonucleotide described in the present disclosure by the solid-phase synthesis method, the synthesis can be carried out by the methods described in detail in the prior art. For example, the preparation methods of various siRNA conjugates are described in detail in WO2015006740A2. In the case of a double-stranded oligonucleotide being an siRNA, the oligonucleotide conjugates of the present disclosure can also be obtained in a manner well known to those skilled in the art. The preparation method of the structure represented by formula (305) is described in WO2014025805A1, and the preparation method of the structure represented by formula (307) is described in Rajeev et al., ChemBioChem 2015, 16, 903-908. The preparation method of the oligonucleotide conjugate represented by formula (308) is also disclosed in detail in Chinese patent application CN110959011A. The contents of the above documents are incorporated herein by reference in their entirety. Pharmaceutically acceptable salt In yet another aspect, the present disclosure also provides a pharmaceutically acceptable salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate described in the present disclosure. The pharmaceutically acceptable salt is known to those skilled in the art. By forming a salt form, the pharmaceutically acceptable salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate of the present disclosure can exhibit better solubility, bioavailability, or stability than the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate itself. In some embodiments, in the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate described in the present disclosure, the non-bridging oxygen atom or the sulfur atom in the phosphodiester bond or the phosphorothioate bond connecting between each adjacent nucleotide carries a negative charge, which can exist in the form of a hydroxyl group or a mercapto group, and the hydrogen ion in the hydroxyl group or the mercapto group can also be partially or completely replaced by a cation. The cation can be any cation, such as a metal cation, an ammonium ion NH4 +, one of the organic ammonium cations. Further, there can also be a salt-forming group in the delivery group, such as a phosphate group. For the consideration of improving solubility and / or improving bioavailability, in some embodiments, the pharmaceutically acceptable salt is a water-soluble salt of part or all of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate. In some embodiments, the water-soluble salt can be an amine salt, an alkali metal salt, or an alkaline earth metal salt, in some embodiments, the amine salt is selected from one or more of an ammonium salt, a methylamine salt, a tertiary amine salt, a quaternary ammonium salt, the alkali metal salt is selected from a potassium salt or a sodium salt, and the alkaline earth metal salt is selected from a magnesium salt or a calcium salt. In some embodiments, the tertiary amine salt is a triethylamine salt, a triisopropylamine salt, or a N,N-diisopropylethylamine salt. In some embodiments, the pharmaceutically acceptable salt is a salt or a partial salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate, the salt being one or more of a methylamine salt, a triethylamine salt, or a sodium salt. In some embodiments, the pharmaceutically acceptable salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate is a sodium salt or a partial sodium salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate. In some embodiments, the pharmaceutically acceptable salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate is a calcium salt or a partial calcium salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate. In some embodiments, the pharmaceutically acceptable salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate is a mixture of a methylamine salt and an ammonium salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate. Pharmaceutical composition In another aspect, the present disclosure also provides a pharmaceutical composition comprising one or more of the single-stranded oligonucleotide, the double-stranded oligonucleotide, the oligonucleotide conjugate, and the pharmaceutically acceptable salts thereof provided by the present disclosure, and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient is one or more of various ingredients conventionally employed in the art, such as one or more of a solvent, a protective agent, an osmotic pressure adjusting agent, and other pharmaceutically acceptable carriers. For example, when the pharmaceutical composition is an injection solution, the pharmaceutically acceptable excipient is a solvent, such as one or more of deionized water, water for injection, physiological saline, ethanol, an aqueous ethanol solution, or a pH buffer. The pH buffer can be a tris-hydroxymethyl aminomethane hydrochloride buffer having a pH value of 7.5-8.5 and / or a phosphate buffer having a pH value of 5.5-8.5, such as a phosphate buffer having a pH value of 5.5-8.5. The amount of the solvent is adjusted according to the desired concentration of the solution, and the concentration of the oligonucleotide conjugate in the injection solution can be 0.01 mg / mL to 20 mg / mL, 0.1 mg / mL to 10 mg / mL, or 0.5 mg / mL to 5 mg / mL, based on the oligonucleotide group. The protective agent can be at least one of inositol, sorbitol, sucrose, trehalose, mannose, maltose, lactose, and glucose. The content of the protective agent can be 0.01 to 30% by weight, based on the total weight of the pharmaceutical composition. The osmotic pressure adjusting agent can be sodium chloride and / or potassium chloride. The content of the osmotic pressure adjusting agent is such that the osmotic pressure of the pharmaceutical composition is 200 to 700 milliosmoles per kilogram (mOsm / kg). The content of the osmotic pressure adjusting agent can be easily determined by one skilled in the art according to the desired osmotic pressure. In some embodiments, the dose of the pharmaceutical composition prepared as a formulation is adjusted according to the administration method during administration. In some embodiments, the pharmaceutical composition can be a liquid formulation, such as an injection solution, or a lyophilized powder formulation that is mixed with a liquid excipient to prepare a liquid formulation for administration. The liquid formulation can be, but is not limited to, used for subcutaneous, intramuscular, or intravenous injection administration, and can be, but is not limited to, delivered to the lung by spraying, or to other organ tissues (e.g., the liver) by pulmonary administration, or by oral administration, etc. In some embodiments, the pharmaceutical composition is administered by subcutaneous injection. The pharmaceutically acceptable other carrier can be one or more of the carriers conventionally used in the field of double-stranded oligonucleotide administration, such as, but not limited to, magnetic nanoparticles (e.g., nanoparticles based on Fe3O4or Fe2O3), carbon nanotubes, mesoporous silicon, calcium phosphate nanoparticles, polyethylenimine (PEI), polyamidoamine (PAMAM) dendrimer, poly(L-lysine) (PLL), chitosan, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), poly(D&L-lactic / glycolic acid) copolymer (PLGA), poly(2-aminoethyl ethylene phosphate) (PPEEA), and poly(2-dimethylaminoethyl methacrylate) (PDMAEMA), and derivatives thereof. In some embodiments, the content of the oligonucleotide and the pharmaceutically acceptable carrier in the pharmaceutical composition is not particularly required, and in some embodiments, the weight ratio of the oligonucleotide or the oligonucleotide in the oligonucleotide conjugate to the pharmaceutically acceptable carrier can be 1:(1-500), and in some embodiments, the above weight ratio is 1:(1-50). In some embodiments, the pharmaceutical composition can be in the form of a liposome preparation. In some embodiments, the pharmaceutically acceptable carrier used in the liposome preparation comprises an amine-containing transfection compound (hereinafter can also be referred to as an organic amine), a helper lipid, and / or a pegylated lipid. Among them, the organic amine, the helper lipid, and the pegylated lipid can be selected from one or more of the amine-containing transfection compounds or pharmaceutically acceptable salts or derivatives thereof, the helper lipids, and the pegylated lipids described in Chinese Patent Application CN103380113A (which is incorporated herein by reference in its entirety). In some embodiments, the organic amine can be a compound represented by formula (201) or a pharmaceutically acceptable salt thereof as described in Chinese Patent Application CN103380113A: wherein: X 101 and X 102 each independently is O, S, N-A, or C-A, wherein A is hydrogen or C1-C 20 hydrocarbon chain; Y 101 and Z 101 each independently is C=0, C=S, S=0, CH-OH, or S02; R 101 , R 102 , R 103 , R 104 , R 105 , R 106 and R 107 each independently is hydrogen, cyclic or acyclic, substituted or unsubstituted, branched or straight chain aliphatic radical, cyclic or acyclic, substituted or unsubstituted, branched or straight chain heteroaliphatic radical, substituted or unsubstituted, branched or straight chain acyl radical, substituted or unsubstituted, branched or straight chain aryl radical, substituted or unsubstituted, branched or straight chain heteroaryl radical; x is an integer from 1 to 10; n is an integer from 1 to 3, m is an integer from 0 to 20, and p is 0 or 1; wherein, if m=p=0, R 102 is hydrogen; and, if at least one of n or m is 2, R 103 and the nitrogen in formula (201) forms a structure as shown in formula (202) or formula (203): wherein g, e, and f are each independently an integer from 1 to 6, "HCC" represents a hydrocarbon chain, and each *N represents a nitrogen atom in formula (201). In some embodiments, R 103 is a polyamine. In other embodiments, R 103 is a ketal. In some embodiments, each of R 101 and R 102 in formula (201) is independently any substituted or unsubstituted, branched or straight chain alkyl or alkenyl radical having from 3 to about 20 carbon atoms, such as from 8 to about 18 carbon atoms, and from 0 to 4 double bonds, such as from 0 to 2 double bonds. In some embodiments, if each of n and m independently has a value of 1 or 3, R 103 may be any one of the following formulae (204)-(213): wherein, in formula (204) - formula (213), g, e, and f are each independently an integer from 1 to 6, each "HCC" represents a hydrocarbon chain, and each * shows R 103 possible points of attachment to the nitrogen atom in formula (201), wherein each H at any position can be replaced to achieve attachment to the nitrogen atom in formula (201). One skilled in the art can obtain the compound shown in formula (201) by any reasonable method. In some embodiments, the compound shown in formula (201) can be prepared according to the description in Chinese patent application CN103380113A. In some embodiments, the organic amine is an organic amine as shown in formula (214) and / or an organic amine as shown in formula (215): The helper lipid is cholesterol, an analog of cholesterol, and / or a derivative of cholesterol; The PEGylated lipid is 1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine-N- [methoxy(polyethylene glycol)]-2000. In some embodiments, the molar ratio among the organic amine, the helper lipid, and the PEGylated lipid in the pharmaceutical composition is (19.7-80):(19.7-80):(0.3-50), for example, it can be (50-70):(20-40):(3-20). In some embodiments, the pharmaceutical composition particles formed by the oligonucleotide or oligonucleotide conjugate of the present disclosure and the above-mentioned amine-containing transfection reagent have an average diameter of about 30 nm to about 200 nm, typically about 40 nm to about 135 nm, more typically, the average diameter of the liposome particles is about 50 nm to about 120 nm, about 50 nm to about 100 nm, about 60 nm to about 90 nm, or about 70 nm to about 90 nm, for example, the average diameter of the liposome particles is about 30, 40, 50, 60, 70, 75, 80, 85, 90, 100, 110, 120, 130, 140, 150, or 160 nm. In some embodiments, in the pharmaceutical composition formed by the oligonucleotide or oligonucleotide conjugate of the present disclosure and the above-mentioned amine-containing transfection reagent, the weight ratio (weight / weight ratio) of the oligonucleotide or oligonucleotide conjugate to the total lipid (e.g., organic amine, helper lipid, and / or PEGylated lipid) is in the range of from about 1:1 to about 1:50, from about 1:1 to about 1:30, from about 1:3 to about 1:20, from about 1:4 to about 1:18, from about 1:5 to about 1:17, from about 1:5 to about 1:15, from about 1:5 to about 1:12, from about 1:6 to about 1:12, or from about 1:6 to about 1:10, for example, the weight ratio of the oligonucleotide or oligonucleotide conjugate of the present disclosure to the total lipid is about 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, or 1:18. In some embodiments, the components of the pharmaceutical composition can exist independently at the time of sale and in the form of a liquid preparation at the time of use. In some embodiments, the pharmaceutical composition formed by the oligonucleotide or oligonucleotide conjugate of the present disclosure and the above-mentioned pharmaceutically acceptable carrier can be prepared according to various known methods, except that the existing siRNA is replaced with the oligonucleotide or oligonucleotide conjugate of the present disclosure; in some embodiments, it can be prepared according to the following method: The organic amine, helper lipid, and PEGylated lipid are suspended in alcohol according to the above-mentioned molar ratio and mixed to obtain a lipid solution; the amount of alcohol is such that the total mass concentration of the obtained lipid solution is 2-25 mg / mL, for example, it can be 8-18 mg / mL. The alcohol is selected from pharmaceutically acceptable alcohols, such as alcohols that are liquid near room temperature, for example, one or more of ethanol, propylene glycol, benzyl alcohol, glycerol, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, for example, it can be ethanol. The oligonucleotide or oligonucleotide conjugate provided by the present disclosure is dissolved in a buffered salt solution to obtain an aqueous solution of the oligonucleotide or oligonucleotide conjugate. The concentration of the buffered salt solution is 0.05-0.5 M, for example, it can be 0.1-0.2 M, the pH of the buffered salt solution is adjusted to 4.0-5.5, for example, it can be 5.0-5.2, the amount of buffered salt solution is such that the concentration of the oligonucleotide in the oligonucleotide or oligonucleotide conjugate does not exceed 0.6 mg / mL, for example, it can be 0.2-0.4 mg / mL. The buffered salt is selected from one or more of soluble acetate, soluble citrate, for example, it can be sodium acetate and / or potassium acetate. The lipid solution and the aqueous solution of the oligonucleotide or oligonucleotide conjugate are mixed, and the product obtained after mixing is incubated at 40-60°C for at least 2 minutes, for example, it can be 5-30 minutes, to obtain the liposome preparation after incubation. The volume ratio of the lipid solution to the aqueous solution of the double-stranded oligonucleotide is 1:(2-5). The liposome preparation after incubation is concentrated or diluted, impurities are removed, and sterilized to obtain the pharmaceutical composition provided by the present disclosure, which has physical and chemical parameters of pH 6.5-8, encapsulation efficiency not less than 80%, particle size 40-200 nm, polydispersity index not higher than 0.30, and osmotic pressure 250-400 mOsm / kg; for example, the physical and chemical parameters can be pH 7.2-7.6, encapsulation efficiency not less than 90%, particle size 60-100 nm, polydispersity index not higher than 0.20, and osmotic pressure 300-400 mOsm / kg. The concentration or dilution can be performed before, after or simultaneously with the removal of impurities. The method for removing impurities can use various existing methods, for example, a tangential flow system, a hollow fiber column, ultrafiltration under the condition of 100 KDa, and the ultrafiltration exchange solution is phosphate buffer solution (PBS) with pH 7.4. The method for sterilization can use various existing methods, for example, sterilization by filtering through a 0.22 μm filter. Use of the single-stranded oligonucleotide, double-stranded oligonucleotide, oligonucleotide conjugate, pharmaceutically acceptable salt and pharmaceutical composition of the present disclosure The present disclosure also provides the use of the single-stranded oligonucleotide, double-stranded oligonucleotide, oligonucleotide conjugate and pharmaceutically acceptable salt thereof of the present disclosure or the pharmaceutical composition of the present disclosure in the preparation of a medicament for treating and / or preventing a disease or symptom associated with the SOD1 mRNA level of a target gene. In some embodiments, the disease or symptom associated with the SOD1 mRNA level is a central nervous system disease or symptom, a cancer-related disease or symptom. In some embodiments, the central nervous system disease or symptom is amyotrophic lateral sclerosis. In some embodiments, the cancer-related symptom includes lung cancer, non-small cell lung cancer, and breast cancer. The present disclosure also provides a method for treating and / or preventing a disease or symptom associated with the SOD1 mRNA level, which comprises administering to a subject in need thereof an effective amount of one or more of the single-stranded oligonucleotide, double-stranded oligonucleotide, oligonucleotide conjugate and pharmaceutically acceptable salt thereof of the present disclosure and the pharmaceutical composition of the present disclosure. In addition, the present disclosure also provides a method for regulating the expression level of the SOD1 gene in a cell, which comprises contacting the cell with an effective amount of one or more of the single-stranded oligonucleotide, double-stranded oligonucleotide, oligonucleotide conjugate and pharmaceutically acceptable salt thereof and the pharmaceutical composition of the present disclosure. As used herein, the term "administration" refers to the delivery of one or more of a single-stranded oligonucleotide, double-stranded oligonucleotide, oligonucleotide conjugate, or pharmaceutically acceptable salt thereof and a pharmaceutical composition to a subject via a method or route that at least partially targets a desired site to produce a desired effect. Routes of administration suitable for the methods of this disclosure include local administration and systemic administration. Generally, local administration results in the delivery of a greater quantity of the single-stranded oligonucleotide, double-stranded oligonucleotide, oligonucleotide conjugate, or pharmaceutically acceptable salt thereof or a pharmaceutical composition to a specific site compared to the entire body of the subject; while systemic administration results in the delivery of the single-stranded oligonucleotide, double-stranded oligonucleotide, oligonucleotide conjugate, or pharmaceutically acceptable salt thereof or a pharmaceutical composition to substantially the entire body of the subject. The medication may be administered to the subject via any suitable route known in the art, including but not limited to: oral or parenteral routes, such as intravenous administration, intramuscular administration, subcutaneous administration, transdermal administration, airway administration (aerosol), pulmonary administration, nasal administration, rectal administration, and local administration (including oral and sublingual administration). Administration frequency may be once or more daily, weekly, bi-weekly, bi-weekly, monthly, or annually. The dosage of one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, and pharmaceutically acceptable salts and pharmaceutical compositions described in this disclosure can be conventional in the art, and the dosage can be determined based on various parameters, particularly the age, weight, and sex of the subject. Toxicity and efficacy can be determined in cell culture or laboratory animals using standard pharmaceutical procedures, such as determining the LD50 (the dose that causes 50% of the population to die) and ED50 (the dose that elicits 50% of the maximum response intensity in a quantitative response, and the dose that elicits a positive response in 50% of the subjects in a qualitative response). The range of human dosages can be derived based on data obtained from cell culture analysis and animal studies. In administering the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and / or pharmaceutical compositions of the disclosure, for example, to a male or female, 6-12 week old, 18-25 g body weight C57BL / 6J or C3H / HeNCrlVr mouse, the amount of siRNA in the siRNA, pharmaceutical composition, and / or siRNA conjugate can be 0.001-100 mg / kg body weight, in some embodiments 0.01-50 mg / kg body weight, in further embodiments 0.05-20 mg / kg body weight, in still further embodiments 0.1-15 mg / kg body weight, and in yet further embodiments 0.1-10 mg / kg body weight, of siRNA formed into an siRNA conjugate with a pharmaceutically acceptable conjugate molecule. The above amounts can be preferred in administering the siRNA, pharmaceutical composition, and / or siRNA conjugate of the disclosure. The amount of double-stranded oligonucleotide in one or more of the provided oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions provided by the methods of the disclosure to inhibit expression of the SOD1 gene in a cell is readily determined by one of skill in the art depending on the desired effect to be obtained. For example, in some embodiments, the oligonucleotide is an siRNA, the oligonucleotide conjugate is an siRNA conjugate, and the amount of siRNA in the provided siRNA conjugate is an amount sufficient to reduce expression of the SOD1 gene and result in an extracellular concentration of 1 pM to 1 mM, or 0.01 nM to 100 nM, or 0.05 nM to 50 nM, or to about 5 nM at the surface of the target cell. The amount required to achieve this local concentration will vary depending on various factors including the method of delivery, the site of delivery, the number of cell layers between the site of delivery and the target cell or tissue, whether the delivery is local or systemic, etc. The concentration at the site of delivery can be significantly higher than the concentration at the surface of the target cell or tissue. Cell The disclosure provides a cell that expresses SOD1 mRNA, the cell comprising one or more of the provided single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, and pharmaceutically acceptable salts and pharmaceutical compositions thereof. Kit The disclosure provides a kit comprising one or more of the provided single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, and pharmaceutically acceptable salts and pharmaceutical compositions thereof. In some embodiments, the kits described herein can provide one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions described herein in a container. In some embodiments, the kits described herein can include a container that provides a pharmaceutically acceptable excipient. In some embodiments, the kits can also include other ingredients such as stabilizers or preservatives, etc. In some embodiments, the kits described herein include at least one other therapeutic agent in a container other than the container of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions described herein. In some embodiments, the kits can include instructions for admixing one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions with a pharmaceutically acceptable carrier and / or excipient or other ingredients, if any. In the kits of the present disclosure, the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions, and / or pharmaceutically acceptable excipients can be provided in any form, such as liquid form, dry form, or lyophilized form. In some embodiments, the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions, and optional pharmaceutically acceptable excipients are substantially pure and / or sterile. In some embodiments, sterile water can be provided in the kits of the present disclosure. The present disclosure will be further described by way of Examples, but the present disclosure is not in any way limited thereto. Without wishing to be limited, the present application is further described in detail in the following embodiments and examples of exemplary embodiments of double-stranded oligonucleotides in the pharmaceutical compositions, oligonucleotides and / or oligonucleotide conjugates of the present disclosure, which are illustrative embodiments of small interfering RNA (siRNA). In this case, the double-stranded oligonucleotides, the pharmaceutical compositions comprising the double-stranded oligonucleotides and the oligonucleotide conjugates of the present disclosure are respectively siRNA, the pharmaceutical compositions comprising siRNA and the siRNA conjugates. In the context of the present disclosure, for ease of description, the siRNA, the pharmaceutical compositions comprising the siRNA and the siRNA conjugates in these embodiments are also referred to as siRNA of the present disclosure, the pharmaceutical compositions of the present disclosure and the siRNA conjugates of the present disclosure. This does not mean that the double-stranded oligonucleotides of the present disclosure can only be siRNA, on the contrary, the double-stranded oligonucleotides can be other variants disclosed herein or known to those skilled in the art, such as small activating RNA (saRNA) and the like. It is envisaged that, based on the detailed description of siRNA, the pharmaceutical compositions comprising siRNA and siRNA conjugates, other double-stranded oligonucleotides will similarly play a role when used alone, or when forming the pharmaceutical compositions and / or oligonucleotide conjugates described in the present disclosure. Examples Unless otherwise specified, the reagents and culture used in the following examples are commercially available, and the nucleic acid electrophoresis, real-time PCR and other operations are performed according to the methods described in Molecular Cloning (Cold Spring Harbor Laboratory (1989)). Synthesis of siRNA provided by the present disclosure According to the preparation method described in steps 13-2 to 13-4 in Preparation Example 13 of CN110959011A, the following siRNAs a1-siRNAa12 in Table 2 were prepared, the only difference being that the nucleotide monomers were connected one by one in the order of nucleotide arrangement of each siRNA in Table 2 from the 3' end to the 5' end direction to synthesize the siRNA, and the sense strand and the antisense strand of the siRNA contained in each siRNA are shown in Table 2; after the synthesis was completed, for siRNAa1-siRNAa11, 3K (MWCO) ultrafiltration tube centrifugal ultrafiltration desalination purification was used to obtain the mixture of methylamine salt and ammonium salt of siRNAa1-siRNAa11; for siRNAa12, the synthesized product was first ion-purified by strong anion exchange filler self-packed column, and then desalted and purified by HiPrep 26 / 13 Desalting desalting pre-packed column to obtain the sodium salt of siRNAa12. After each siRNA was diluted to a concentration of 0.2 mg / mL using ultrapure water (Milli-Q ultrapure water instrument, resistivity 18.2 MΩ*cm (25℃)), the molecular weight was detected using a liquid chromatograph-mass spectrometer (LC-MS, Liquid Chromatography-Mass Spectrometry, purchased from Waters Company, model: LCT Premier). Among them, the theoretical value of the sense strand of siRNAa2 is 6402.461, and the measured value is 6400.85. The theoretical value of the sense strand of siRNAa12 is 6402.46, and the measured value is 6400.8; the theoretical value of the antisense strand is 6774.38, and the measured value is 6773.2. The measured value is consistent with the theoretical value, which indicates that the synthesized siRNAa1-siRNAa12 is the target designed double-stranded nucleic acid sequence. Table 2 Nucleotide sequence in siRNA Among them, the capital letters C, G, U, A and T represent the base composition of the nucleotide; the lowercase letter m represents that the nucleotide adjacent to the left of the letter m is a 2'-methoxy modified nucleotide; the lowercase letter f represents that the nucleotide adjacent to the left of the letter f is a 2'-fluorine modified nucleotide; the lowercase letter s represents that the two nucleotides between the left and right of the letter are phosphothioate groups; The lowercase letter d represents that the nucleotide to the right of the letter is a deoxyribonucleotide; ia represents a reverse dealkylated deoxyribonucleotide; VP represents that the nucleotide represented by the capital letter adjacent to the right of the letter combination is a 5'-VP modified nucleotide. Preparation of siRNA conjugates provided by the present disclosure According to the preparation method described in CN110959011A Preparation Example 13, the following conjugates 1-2 in Table 3 were prepared, and the only difference was that the sense strand and the antisense strand of the siRNA contained in each siRNA conjugate were as shown in Table 3; For the nucleic acid sense strand and antisense strand sequences of the siRNA numbered as conjugates 1-2 in the following Table 3 in the nucleic acid sequence, the nucleotide phosphoramidite monomers were connected one by one, respectively, to synthesize the sense strand and the antisense strand of the siRNA. After the synthesis was completed, 3K (MWCO) ultrafiltration tube was used for centrifugal ultrafiltration desalination purification. The siRNA conjugate was diluted to a concentration of 0.2 mg / mL (calculated as siRNA) using ultrapure water (Milli-Q ultrapure water instrument, resistivity 18.2 MΩ*cm (25 °C)), and then the molecular weight was detected by liquid chromatography-mass spectrometry (LC-MS, purchased from Waters Company, model: LCT Premier). The theoretical value of the molecular weight of the positive strand of conjugate 1 was 7746.675, and the measured value was 7745.64; the theoretical value of the molecular weight of the negative strand was 6698.38, and the measured value was 6693.1. The measured value was consistent with the theoretical value, indicating that the synthesized conjugate had the target designed double-stranded nucleic acid sequence. Each siRNA conjugate is a mixture of the methylamine salt and the ammonium salt of a compound having the structure shown in formula (403), wherein the P atom shown in formula (403) is covalently linked to the oxygen atom in the reverse dealkylated deoxynucleotide (ia) shown in formula (35) connected to the ribose ring by a methylene group at the 3' end of the positive strand of the siRNA represented by Nu, thereby covalently linked to the positive strand of the siRNA. And the siRNA contained in the siRNA conjugate has the siRNA sequence corresponding to conjugate 1-2 in Table 3, respectively. Table 3 siRNA sequence in siRNA conjugate Comparison of the synthesis of reference conjugate 1-2 of preparation example 1-2 Reference conjugate 1-2 in Table 3 was prepared by solid phase synthesis according to the same method as preparation example 13-14. The theoretical value of the positive strand of reference conjugate 1 is 7746.675, and the measured value is 7745.64. The theoretical value of the negative strand is 6740.444, and the measured value is 6739.60. Reference conjugate 1-2 is a mixture of the methylamine salt and the ammonium salt of a compound having the structure shown in formula (403), wherein the conjugate group is connected to the ribose 3' position of the 3' end nucleotide of the positive strand of the siRNA represented by Nu. Reference conjugate 1 and reference conjugate 2 respectively have very similar sequence composition and the same conjugate structure as conjugate 1 and conjugate 2, and the difference lies in the different modification schemes. Experimental example 1 Inhibition activity of siRNA of the present disclosure in vitro This experimental example investigates the activity of siRNA a1-a11 of the present disclosure in mouse liver primary cells that can normally express SOD1 gene. Mouse primary hepatocytes were obtained by extracting fresh liver tissue from C57BL / 6 mice (6 weeks old, purchased from Sibeifu (Beijing) Biotechnology Co., Ltd.) and adjusting the density of the mouse primary hepatocytes to 2x10 5 cells / mL to obtain a mouse primary hepatocyte suspension. Then, the mouse primary hepatocyte suspension was added to different culture wells of a 12-well plate, and the mouse primary hepatocytes were inoculated into the culture wells. The volume of the mouse primary hepatocyte suspension added was 0.5 mL / well, and the number of mouse primary hepatocytes was 1x10 5 cells / well. The siRNAs were respectively formulated into working solutions of siRNAs a1-a11 with a concentration of 20 μM using a PBS buffer. To 24 culture wells (all of which were culture wells containing mouse primary hepatocytes and Opti-MEM described above), 3 μL of the working solutions of siRNAs a1-a11 and PBS were respectively added, and each working solution was added to 2 culture wells. Then, 197 μL of DMEM was added to each culture well to obtain a transfection mixture with a final concentration of 50 nM. The groups to which siRNAs were added were respectively recorded as test group 1-test group 11, and the group to which PBS was added was recorded as a blank control group. After the test groups 1-11 and the blank control group described above were cultured in the culture wells for 4 h, the supernatant in each culture well was removed, and 1000 μL of Opti-MEM medium was added to each well. The 12-well plate was placed in a CO2 incubator and continued to be cultured at 37°C for 24 h. The total RNA in each well of cells was respectively extracted according to the method recorded in the UNIQ-10 column total RNA extraction kit (purchased from Sangon Biotech, model: Sangon Biotech). For each well of cells, 1 μg of total RNA was respectively extracted, and a reverse transcription kit (purchased from Genecopoeia, model: TSK301M) was used. Goldenstar TM Oligo(dT) 17 As a primer, a reverse transcription reaction system of 20 μL was configured according to the reverse transcription operation steps in the kit instructions, and the total RNA of each well of cells was subjected to reverse transcription. The reverse transcription conditions were as follows: for each reverse transcription reaction system, the reverse transcription reaction system was incubated at 50°C for 50 min, then incubated at 85°C for 5 min, and finally incubated at 4°C for 30 s. After the reaction was completed, 80 μL of DEPC water was added to the reverse transcription reaction system to obtain a solution containing cDNA. For each reverse transcription reaction system, 5 μL of the solution containing cDNA described above was taken as a template, and a PCR kit (purchased from Genecopoeia, model: TSK302M) was used. The reagents provided by SYBR qPCR SuperMix Plus kit (purchased from Coastal Protein Technology Co., Ltd., item number E096-01B) were configured to form a qPCR reaction system 20 μL, wherein the PCR primer sequences for amplifying the target gene SOD1 and the internal reference gene GAPDH were shown in Table 4, and the final concentration of each primer was 0.25 μM. Each qPCR reaction system was placed on an ABI StepOnePlus Real-Time PCR instrument, and amplification was performed using a three-step method, and the amplification program was 95°C pre-denaturation for 10 min, then 95°C denaturation for 30 s, 60°C annealing for 30 s, 72°C extension for 30 s, and the above denaturation, annealing and extension processes were repeated for 40 times, and then the product W1 containing the amplified target gene SOD1 and internal reference gene GAPDH was obtained. The product W1 was then sequentially incubated at 95°C for 15 s, 60°C for 1 min, and 95°C for 15 s, and the real-time fluorescence quantitative PCR instrument collected the melting curves of the target gene and the internal reference gene GAPDH in the product W1, respectively, to obtain the Ct values of the target gene SOD1 and the internal reference gene GAPDH. Table 4 primer sequence information The comparative Ct (ΔΔCt) method was used to perform relative quantitative calculation on the target gene SOD1 in each test group, and the calculation method was as follows: ΔCt (test group) = Ct (test group target gene) - Ct (test group internal reference gene) ΔCt (control group) = Ct (control group target gene) - Ct (control group internal reference gene) ΔΔCt (test group) = ΔCt (test group) - ΔCt (control group average) ΔΔCt (control group) = ΔCt (control group) - ΔCt (control group average) Wherein, ΔCt (control group average) is the arithmetic mean of ΔCt (control group) of each culture hole of the blank control group. Thus, each culture hole of the test group and the blank control group corresponds to a ΔΔCt value. The average value of the blank control group was taken as the reference to normalize the expression level of the mRNA of the test group, and the average value of the mRNA expression level of the blank control group was defined as 100%, Test group mRNA relative expression level = 2-ΔΔCt (test group) x 100% Test group mRNA inhibition rate = (1-test group mRNA relative expression level) x 100%. The experimental results are shown in Table 5 below. Table 5 inhibition rate of SOD1 mRNA in mouse liver primary cells As can be seen from the results in Table 5, at a concentration of 50 nM, the siRNAs of the present disclosure can all achieve effective inhibition of SOD1 mRNA in in vitro cell experiments, and in particular, the inhibition rates of siRNAs a1-a4 on SOD1 mRNA are all above 95%; the inhibition rates of siRNAs a1-a2 on SOD1 mRNA are both 99%. In vivo inhibition activity of the conjugates of the present disclosure This experimental example investigates the activity of conjugate 1-2 in mice in vivo. The prepared conjugate 1-2 was dissolved in PBS to prepare an injection solution at a concentration of 0.2 mg / mL. Twenty-five mice (strain: C57BL / 6j, level: SPF, gender: female, purchased from Sibeifu (Beijing) Biotechnology Co., Ltd.) were randomly divided into groups of 5, and were recorded as test group 1-2, comparative test group 1-2, and a blank control group. Each mouse in the test group 1-2 was administered with an injection solution of conjugate 1 or conjugate 2 at a dose of 5 mL / Kg of mouse body weight by subcutaneous injection in the abdomen, each mouse in the comparative test group 1-2 was administered with an injection solution of reference conjugate 1 or reference conjugate 2 at a dose of 5 mL / Kg of mouse body weight, and each mouse in the blank control group was administered with PBS solution at a dose of 5 mL / Kg. The mice were sacrificed on the 8th day after administration, and the liver tissues were collected and stored in RNAlater. The expression of SOD1 mRNA in the liver tissues of the mice was detected by the same method as in experimental example 1, and the inhibition rate was calculated. The results are summarized in Table 6. Table 6 Inhibition rate of SOD1 mRNA in mice As can be seen from the results in Table 6, in the mice administered with the conjugates of the present disclosure, good inhibition of SOD1 mRNA was observed, and the inhibition rate of conjugate 1-2 on SOD1 mRNA was maintained at above 64%, and in particular, the inhibition rate of conjugate 1 on SOD1 mRNA was above 78%, indicating that the conjugates provided by the present disclosure can effectively inhibit the level of SOD1 mRNA in mice. As described above, the difference between reference conjugate 1 and conjugate 1 is that the nucleotide sequences are basically the same, but the modification schemes are different; the difference between reference conjugate 2 and conjugate 2 is that the nucleotide sequences are basically the same, but the modification schemes are different. The inhibition rates of conjugate 1 and conjugate 2 provided by the present disclosure on SOD1 mRNA are at least 7.76% higher than those of the reference conjugates with the same sequence but different modifications, and even above 18%. Activity evaluation of siRNAs of the present disclosure on SOD1 mRNA in dorsal root ganglion (DRG) of rats in vivo The experiment example investigates the activity of the siRNAa12 of the present disclosure in rats in vivo. In the experiment, 24 male SD rats weighing about 250 g (grade: SPF, purchased from Sibeifu (Beijing) Biotechnology Co., Ltd.) were randomly divided into two groups, 12 rats in each group. The rats in the test group were given an injection of siRNAa12 (calculated by siRNA, concentration 18 mg / mL, volume 50 μL per rat) at a dose of 0.9 mg per rat by intrathecal injection; the rats in the blank control group were given an injection of artificial cerebrospinal fluid (ACSF, batch number: 1105A24; production unit: LEAGENE) by intrathecal injection. All rats were anesthetized 15 minutes before administration. After confirming anesthesia, a single intrathecal injection was performed at an angle of 70°-80° in the L5-L6 intervertebral space. The first administration day was recorded as D1. The animals were dissected twice (6 rats per group each time) on D15 and D29, and the cervical, thoracic and lumbar spinal cords were taken in sequence after euthanasia and stored in RNA later. The total RNA in each tissue sample was extracted according to the method recorded in the MagaBio plus total RNA purification kit II (purchased from Hangzhou Bioer Technology Co., Ltd., item number: BSC69L1E) instructions. The expression amount of SOD1 mRNA in the cervical, thoracic and lumbar spinal cords of rats was detected by the same method as in experiment example 1, and the expression amount of SOD1 mRNA in each tissue sample of the rats in the blank control group was normalized to 100% to calculate the inhibition rate of SOD1 mRNA expression in each tissue sample of the rats. The PCR primer sequences for amplifying the target gene SOD1 and the internal reference gene rat GAPDH are shown in Table 7. Table 7 Primer sequence information The results are summarized in Table 8. Table 8 Inhibition rate of SOD1 mRNA in rat DRG As can be seen from the results in Table 8, the siRNA provided by the present disclosure significantly inhibits the expression of SOD1 mRNA in different parts of the rat spinal cord; among them, in the lumbar spinal cord and thoracic spinal cord, the inhibition rate of SOD1 mRNA increases with time, and on the 29th day, the inhibition rate of SOD1 mRNA in the thoracic spinal cord is 81.0%, and the inhibition rate of SOD1 mRNA in the lumbar spinal cord can even reach 86.5%. It shows that the siRNA of the present disclosure has excellent long-acting inhibition on SOD1 mRNA in rats in vivo. The above describes some embodiments of the present disclosure in detail, but the present disclosure is not limited to the specific details in the above-described embodiments. Within the technical concept scope of the present disclosure, various simple modifications can be made to the technical solutions of the present disclosure, and these simple modifications all belong to the protection scope of the present disclosure. In addition, it should be noted that the various specific technical features described in the above-described embodiments can be combined in any appropriate manner without contradiction. In order to avoid unnecessary repetition, the present disclosure will not further describe various possible combination manners. In addition, various different embodiments of the present disclosure can also be combined in any manner, as long as it does not deviate from the idea of the present disclosure, it should also be considered as disclosed by the present disclosure.

Claims

1. A single-stranded oligonucleotide of 16-30 nucleotides in length having sufficient complementarity to SOD1 mRNA to mediate an RNAi effect; each nucleotide in the single-stranded oligonucleotide is a modified or unmodified nucleotide, wherein, In the single-stranded oligonucleotide, at least one nucleotide is a nucleotide X, and at least one nucleotide is a fluorine-modified nucleotide; and, in the direction from the 5' end to the 3' end, at least one nucleotide X is located after the 8th nucleotide of the single-stranded oligonucleotide and is spaced 4-7 nucleotides from the 8th nucleotide; And, in the direction from the 5' end to the 3' end, if the 14th nucleotide of the single-stranded oligonucleotide is a nucleotide X, and all nucleotides after the 15th nucleotide of the single-stranded oligonucleotide are modified nucleotides, then the 13th nucleotide of the single-stranded oligonucleotide is selected from one of an alkoxy-modified nucleotide, an alkyl-modified nucleotide, a substituted alkyl-modified nucleotide, an amine-modified nucleotide, a thermally unstable nucleotide, and a BNA. Each nucleotide X is a deoxynucleotide or an unmodified nucleotide.

2. The single stranded oligonucleotide of claim 1, wherein, The length of the single-stranded oligonucleotide is 17-28, 19-26, or 20-24 nucleotides; or the length of the single-stranded oligonucleotide is 19, 21, or 23 nucleotides.

3. The single stranded oligonucleotide of claim 1 or 2, wherein, The number of nucleotides X is 1-3.

4. The single stranded oligonucleotide of any one of claims 1-3, wherein, Each nucleotide X is located after the 8th nucleotide of the single-stranded oligonucleotide; and, in the direction from the 5' end to the 3' end, each nucleotide X is spaced 3, 5, 7, or 10 nucleotides from the 8th nucleotide of the single-stranded oligonucleotide; or one of the nucleotides X is spaced 5 nucleotides from the 8th nucleotide.

5. The single stranded oligonucleotide of claim 4, wherein, The single-stranded oligonucleotide contains only one nucleotide X, which is spaced 5 nucleotides from the 8th nucleotide of the single-stranded oligonucleotide in the direction from the 5' end to the 3' end; Or, the single-stranded oligonucleotide contains two nucleotides X, in which one nucleotide X is spaced 5 nucleotides from the 8th nucleotide of the single-stranded oligonucleotide, and the other nucleotide X is spaced 3, 7, or 10 nucleotides from the 8th nucleotide of the single-stranded oligonucleotide in the direction from the 5' end to the 3' end.

6. The single stranded oligonucleotide of any one of claims 1-5, wherein, The number of modified nucleotides accounts for more than 50%, more than 70%, or more than 85% of the total number of nucleotides in the single-stranded oligonucleotide; or the number of unmodified nucleotides in the single-stranded oligonucleotide is not more than 5, not more than 4, not more than 3, not more than 2, or not more than 1; or each of the total nucleotides in the single-stranded oligonucleotide is independently a modified nucleotide.

7. The single stranded oligonucleotide of any one of claims 1-6, wherein, The number of fluorine-modified nucleotides is 2-7.

8. The single stranded oligonucleotide of claim 7, wherein, In the direction from the 5' end to the 3' end, the fluorine-modified nucleotides refer to 2-5 of the 2nd, 5th, 6th, 7th, 12th, 16th, 18th, and 19th nucleotides of the single-stranded oligonucleotide.

9. The single stranded oligonucleotide of claim 8, wherein, In the direction from the 5' end to the 3' end, the fluorine-modified nucleotides refer to the 2nd and 6th nucleotides of the single-stranded oligonucleotide; or the 2nd, 6th, and 16th nucleotides; or the 2nd, 5th, 7th, 12th, and 16th nucleotides; or the 2nd, 7th, 12th, 16th, and 19th nucleotides; or the 2nd, 6th, 12th, 16th, and 19th nucleotides.

10. The single stranded oligonucleotide of claim 9, wherein, In the single-stranded oligonucleotide, each modified nucleotide other than the nucleotide X and the fluorine-modified nucleotide is independently selected from one of an alkoxy-modified nucleotide, a substituted alkoxy-modified nucleotide, an alkyl-modified nucleotide, a substituted alkyl-modified nucleotide, an amine-modified nucleotide, a thermally unstable nucleotide, and a BNA.

11. The single stranded oligonucleotide of claim 10, wherein, In the single-stranded oligonucleotide, there is no thermally unstable nucleotide, or the number of thermally unstable nucleotides is 1 or 2; or, each modified nucleotide other than the nucleotide X, the fluorine-modified nucleotide, and the thermally unstable nucleotide is selected from an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide.

12. The single stranded oligonucleotide of claim 11, wherein, The single-stranded oligonucleotide has a length of 19-23 nucleotides, and In the direction from the 5' end to the 3' end, the 14th nucleotide is the nucleotide X, 2 of the 5th-7th nucleotides and the 19th nucleotide, and the 2nd, 12th, and 16th nucleotides are fluorine-modified nucleotides, the 3rd nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, the 5th nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide when it is not a fluorine-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide; or, In the direction from the 5' end to the 3' end, the 12th and 14th nucleotides are the nucleotide X, the 2nd, 7th, and 16th nucleotides are fluorine-modified nucleotides, and the 3rd or 5th nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide; and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide; or, In the direction from the 5' end to the 3' end, the 14th and 16th nucleotides are the nucleotide X, the 2nd and 6th nucleotides are fluorine-modified nucleotides, the 13th nucleotide is a substituted alkoxy-modified nucleotide or a BNA, and the 3rd or 5th nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide; in the direction from the 3' end to the 5' end, one of the 1st-2nd nucleotides in the single-stranded oligonucleotide is a thermally unstable nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide; or, In the direction from the 5' end to the 3' end, one of the 16th-19th nucleotides and the 14th nucleotide is the nucleotide X, the 2nd and 6th nucleotides are fluorine-modified nucleotides, the 16th nucleotide is a fluorine-modified nucleotide when it is not the nucleotide X, the 13th nucleotide is a substituted alkoxy-modified nucleotide or a BNA, and the 3rd or 5th nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide; the 20th nucleotide is an alkoxy-modified nucleotide or a thermally unstable nucleotide; and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide.

13. The single stranded oligonucleotide of claim 12, wherein, The single-stranded oligonucleotide has a length of 21 nucleotides, and In the direction from the 5' end to the 3' end, the 14th nucleotide is the nucleotide X, the 2nd, 6th, and 16th nucleotides are fluorine-modified nucleotides, the 3rd or 5th nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide; or, the 14th nucleotide is a deoxynucleotide, the 2nd, 5th, 7th, 12th, and 16th nucleotides are fluorinated nucleotides, the 3rd nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide; or, the 14th nucleotide is a deoxynucleotide, the 2nd, 7th, 12th, 16th, and 19th nucleotides are fluorinated nucleotides, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide; or, the 14th nucleotide is a deoxynucleotide, the 2nd, 6th, 12th, 16th, and 19th nucleotides are fluorinated nucleotides, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide; or, the 12th and 14th nucleotides are deoxynucleotides, the 2nd, 7th, and 16th nucleotides are fluorinated nucleotides, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide; or, the 14th nucleotide is a deoxynucleotide, the 16th nucleotide is an unmodified nucleotide, the 2nd and 6th nucleotides are fluorinated nucleotides, the 13th nucleotide is a substituted alkoxy-modified nucleotide, the 2nd nucleotide of the single-stranded oligonucleotide is a thermally unstable nucleotide in the 3' to 5' direction, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide; or, the 14th nucleotide is a deoxynucleotide, the 19th nucleotide is an unmodified nucleotide, the 2nd, 6th, and 16th nucleotides are fluorinated nucleotides, the 13th nucleotide is a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide.

14. The single stranded oligonucleotide of any one of claims 10-13, wherein, each alkoxy-modified nucleotide is a methoxy-modified nucleotide; and / or each substituted alkoxy-modified nucleotide is a 2'-O-methoxyethyl-modified nucleotide; and / or each BNA is a LNA, ENA, or cET BNA; and / or each thermally unstable nucleotide is a GNA.

15. The single stranded oligonucleotide of any one of claims 1-14, wherein, each of at least 2 of the linking groups between adjacent nucleotides in the single-stranded oligonucleotide is independently a phosphoramidate group.

16. The single stranded oligonucleotide of claim 15, wherein, each of 1-4 of the linking groups between adjacent nucleotides in the first 5 nucleotides at the 5' end and / or 1-4 of the linking groups between adjacent nucleotides in the first 5 nucleotides at the 3' end of the single-stranded oligonucleotide is independently a phosphoramidate group; and / or if there is an unmodified nucleotide in the single-stranded oligonucleotide, each of 1 or 2 of the 2 linking groups between the unmodified nucleotide and an adjacent nucleotide is independently a phosphoramidate group; and / or Each of 2-6, or 4, of the linking groups between adjacent nucleotides in the single-stranded oligonucleotide is independently a phosphorothioate group with a modification group.

17. The single stranded oligonucleotide of claim 15 or 16, wherein, Each of the linking groups between adjacent nucleotides in the first 1-3 nucleotides at the 5' end and the first 1-3 nucleotides at the 3' end of the single-stranded oligonucleotide is independently a phosphorothioate group with a modification group; and / or if there are unmodified nucleotides in the single-stranded oligonucleotide, each of the 1 or 2 of the 2 linking groups between each of the unmodified nucleotides and an adjacent nucleotide is independently a phosphorothioate group with a modification group.

18. The single stranded oligonucleotide of any one of claims 15-17, wherein, Phosphonate groups having a modifying group are phosphorothioate groups having the structure of formula (28):

19. The single stranded oligonucleotide of any one of claims 1-18, wherein, The 5'-terminal nucleotide of the single-stranded oligonucleotide is a 5'-hydroxyl nucleotide, a 5'-phosphate nucleotide, or a 5'-phosphate analog modified nucleotide, the 5'-hydroxyl nucleotide has a structure shown as formula (29); the 5'-phosphate nucleotide has a structure shown as formula (30); and the 5'-phosphate analog modified nucleotide has one selected from structures shown as formula (31) to formula (34): wherein R is selected from one of H, OH, OCH3, and F; Base represents a nucleic acid base selected from A, U, C, G, or T.

20. The single stranded oligonucleotide of any one of claims 1-19, wherein, The single-stranded oligonucleotide has a length of 21 nucleotides, and in the direction from the 5' end to the 3' end, the 14th nucleotide is a deoxynucleotide, the 2nd, 5th, 7th, 12th, and 16th nucleotides are fluorine-modified nucleotides, the 3rd nucleotide is a methoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is a methoxy-modified nucleotide; the linking group between any two adjacent nucleotides in the first 1-3 nucleotides at the 5' end and the linking group between any two adjacent nucleotides in the first 1-3 nucleotides at the 3' end are phosphorothioate groups; the 5' terminal nucleotide is a 5'-hydroxyl nucleotide represented by formula (29) or a 5'-vinylphosphonate-modified nucleotide represented by formula (31).

21. The single stranded oligonucleotide of any one of claims 1-20, wherein, the single-stranded oligonucleotide is substantially, substantially, or completely reverse complementary to the SOD1 mRNA over a span of at least 16 nucleotides, over a span of 16-25 nucleotides, over a span of 18-23 nucleotides, or over a span of 19-21 nucleotides; and / or in the direction from the 5' end to the 3' end, the nucleotide sequence of the single-stranded oligonucleotide except for the 1st nucleotide is completely reverse complementary to the SOD1 mRNA; or, the entire nucleotide sequence of the single-stranded oligonucleotide is completely reverse complementary to the SOD1 mRNA.

22. The single stranded oligonucleotide of any one of claims 1-21, wherein, The single-stranded oligonucleotide contains a nucleotide sequence II, which is selected from one of the following i)-xi) represented sequences: i) the nucleotide sequence II is equal in length to the nucleotide sequence represented by SEQ ID NO: 2, and has no more than 3 base differences: 5'-Z2 UUACUUUCCUUCUGCUCG-3' (SEQ ID NO: 2), wherein Z2 is A or U, and the nucleotide sequence II contains a nucleotide Z'2 at a position corresponding to Z2, Z'2 being the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence; ii) the nucleotide sequence II is equal in length to the nucleotide sequence represented by SEQ ID NO: 4, and has no more than 3 base differences: 5'-Z4 CUUUCUUCAUUUCCACCU-3' (SEQ ID NO: 4), wherein Z4 is A or U, and the nucleotide sequence II contains a nucleotide Z'4 at a position corresponding to Z4, Z'4 being the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence; ​ wherein Z4 is A or U, and nucleotide sequence II comprises a nucleotide Z'4 at a position corresponding to Z4, Z'4 being the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence; iii) nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 6, and differs by no more than 3 bases: 5'-Z6UGAACAUGGAAUCCAUGC-3' (SEQ ID NO: 6), wherein Z6 is A or U, and nucleotide sequence II comprises a nucleotide Z'6 at a position corresponding to Z6, Z'6 being the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence; iv) nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 8, and differs by no more than 3 bases: 5'-Z8CUGGAUAGAGGAUUAAAG-3' (SEQ ID NO: 8), wherein Z8 is A or U, and nucleotide sequence II comprises a nucleotide Z'8 at a position corresponding to Z8, Z'8 being the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence; v) nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 10, and differs by no more than 3 bases: 5'-Z 10 UCAUUUCCACCUUUGCCC-3' (SEQ ID NO: 10), Among them, Z 10 For A or U, the position in nucleotide sequence II corresponds to Z. 10 nucleotide Z' 10 Z' 10 It is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence; vi) nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 12, and differs by no more than 3 bases: 5'-Z 12 ACAUGCCUCUCUUCAUCC-3' (SEQ ID NO: 12), wherein Z is A or U, the nucleotide sequence II comprises a nucleotide Z' at a position corresponding to Z 12 , and Z' is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence. 12 12 12 ​​​ vii) nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 14, and differs by no more than 3 bases: 5'-Z 14 CCAACAUGCCUCUCUUCA-3' (SEQ ID NO: 14), Among them, Z 14 For A or U, the position in nucleotide sequence II corresponds to Z. 14 nucleotide Z' 14 Z' 14 It is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence; viii) nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 16, and differs by no more than 3 bases: 5'-Z 16 CACCUUCACUGGUCCAUU-3' (SEQ ID NO: 16), Among them, Z 16 For A or U, the position in nucleotide sequence II corresponds to Z. 16 nucleotide Z' 16 Z' 16 It is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence; ix) nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 18, and differs by no more than 3 bases: 5'-Z 18 AUCCAUGCAGGCCUUCAG-3' (SEQ ID NO: 18), Among them, Z 18 For A or U, the position in nucleotide sequence II corresponds to Z. 18 nucleotide Z' 18 Z' 18 It is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence; x) nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 20, and differs by no more than 3 bases: 5'-Z 20 UUUCCACCUUUGCCCAAG-3' (SEQ ID NO: 20), wherein Z is A or U, the nucleotide sequence II comprises a nucleotide Z' at a position corresponding to Z 20 , and Z' is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence. 20 20 20 wherein Z is A or U, the nucleotide sequence II comprises a nucleotide Z' at a position corresponding to Z 20 , and Z' is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence. 20 20 20 wherein Z is A or U, the nucleotide sequence II comprises a nucle xi) nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 22, and differs by no more than 3 bases: 5'-Z 22 CUUUGCCCAAGUCAUCUG-3' (SEQ ID NO: 22), wherein Z is G or C, and the nucleotide sequence II comprises a nucleotide Z' at a position corresponding to Z 22 22 22 22 is the first nucleotide of the 5' end of the single-stranded oligonucleotide sequence.​​​ 23. The single stranded oligonucleotide of claim 22, wherein, nucleotide sequence II differs by no more than 1 base from the nucleotide sequence set forth in SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, or SEQ ID NO: 22; Alternatively, the nucleotide sequence II is identical to the nucleotide sequence shown in SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, or SEQ ID NO:

22.

24. The single stranded oligonucleotide of claim 22 or 23, wherein, The single-stranded oligonucleotide further comprises a nucleotide sequence IV, which is linked to the 3' end of the nucleotide sequence II, has a length of 1, 2, 3, or 4 nucleotides, each nucleotide in the nucleotide sequence IV is independently one of non-fluorinated modified nucleotides, the nucleotide sequence IV is substantially reverse-complementary or completely reverse-complementary to SOD1 mRNA, each of the non-fluorinated modified nucleotides is independently selected from one of 2'-methoxy modified nucleotides, 2'-alkyl modified nucleotides with an alkyl group having a carbon number of 1-3, 2'-amino modified nucleotides, 2'-substituted amino modified nucleotides, and heat-unstable nucleotides; Alternatively, the nucleotide sequence IV has a length of 2 nucleotides.

25. The single stranded oligonucleotide of any one of claims 22-24, wherein, The single-stranded oligonucleotide further comprises a nucleotide sequence V, each nucleotide in the nucleotide sequence V is independently a non-fluorinated modified nucleotide, the nucleotide sequence V has a length of 1-3 nucleotides, is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II, and constitutes a 3' overhang end of the antisense strand of a double-stranded oligonucleotide formed by the single-stranded oligonucleotide and a sense strand; Alternatively, the nucleotide sequence V has a length of 2 nucleotides, and in a direction from the 5' end to the 3' end, the nucleotide sequence V is two consecutive thymine deoxynucleotides, two consecutive uracil nucleotides, or is completely reverse-complementary to SOD1 mRNA; Alternatively, the single-stranded oligonucleotide is an antisense strand of any one of siRNA1-siRNA11 listed in Table 1; Alternatively, the single-stranded oligonucleotide is an antisense strand of any one of siRNAa1-siRNAa12 listed in Table 2; Alternatively, the single-stranded oligonucleotide is an antisense strand of any one of conjugate 1 or conjugate 2 listed in Table 3.

26. A double stranded oligonucleotide comprising a sense strand and an antisense strand, each nucleotide in the sense strand being a modified or unmodified nucleotide, the sense strand and antisense strand being at least partially reverse complementary forming a double stranded region, wherein, The antisense strand is a single-stranded oligonucleotide according to any one of claims 1-25.

27. The double-stranded oligonucleotide of claim 26, wherein, The sense strand has a length of 19-23 nucleotides; alternatively, the sense strand and the antisense strand have the same length, and each has a length of 19, 20, or 21 nucleotides; alternatively, the sense strand has a length of 19 nucleotides, and the antisense strand has a length of 20-24 nucleotides; alternatively, the sense strand has a length of 20 nucleotides, and the antisense strand has a length of 21-24 nucleotides; alternatively, the sense strand has a length of 21 nucleotides, and the antisense strand has a length of 22-24 nucleotides; Alternatively, the sense strand is 19 nucleotides in length and the antisense strand is 21 nucleotides in length; or the sense strand is 21 nucleotides in length and the antisense strand is 23 nucleotides in length.

28. The double-stranded oligonucleotide of claim 26 or 27, wherein, In the sense strand, 2-3 of the 11th-13th nucleotides from the 3' end to the 5' end are fluorine-modified nucleotides, the 1st and / or the last nucleotide is an alkoxy-modified nucleotide or an inverted abasic deoxynucleotide, and the nucleotides at the remaining positions are non-fluorine-modified nucleotides, each of which is independently selected from one of an alkoxy-modified nucleotide, an alkyl-modified nucleotide, an amine-modified nucleotide, and a thermally unstable nucleotide.

29. The double-stranded oligonucleotide of claim 28, wherein, In the sense strand, 2-3 of the 11th-13th nucleotides from the 3' end to the 5' end are fluorine-modified nucleotides, the 1st and / or the last nucleotide is an alkoxy-modified nucleotide or an inverted abasic deoxynucleotide, and the nucleotides at the remaining positions are non-fluorine-modified nucleotides, each of which is independently selected from one of an alkoxy-modified nucleotide, an alkyl-modified nucleotide, an amine-modified nucleotide, and a thermally unstable nucleotide.

30. The double-stranded oligonucleotide of claim 28 or 29, wherein, Each of the alkoxy-modified nucleotides is a methoxy-modified nucleotide.

31. The double-stranded oligonucleotide of any one of claims 26-30, wherein, In the sense strand, at least one of the linking groups between adjacent nucleotides is a phosphate group with a modification group, which is present at at least one of the following: between the adjacent nucleotides of the 1st-5th nucleotides from the 5' end and between the adjacent nucleotides of the 1st-5th nucleotides from the 3' end.

32. The double-stranded oligonucleotide of claim 31, wherein, Each of 1-4 of the linking groups between the adjacent nucleotides of the 1st-5th nucleotides from the 5' end and / or 1-4 of the linking groups between the adjacent nucleotides of the 1st-5th nucleotides from the 3' end of the sense strand is independently a phosphate group with a modification group; or the phosphate group with a modification group is a phosphorothioate group with a structure as shown in formula (28); Alternatively, the sense strand is the sense strand of any one of siRNA1-siRNA11 listed in Table 1; Alternatively, the sense strand is the sense strand of any one of siRNAa1-siRNAa12 listed in Table 2; Alternatively, the sense strand is the sense strand of any one of conjugate 1 or conjugate 2 listed in Table 3.

33. The double-stranded oligonucleotide of any one of claims 26-32, wherein, The sense strand comprises 19-21 nucleotides, and the antisense strand comprises 21-23 nucleotides; In the sense strand, 2-3 of the 11th-13th nucleotides from the 3' end to the 5' end are fluorine-modified nucleotides, the 1st and / or the last nucleotide is an alkoxy-modified nucleotide or an inverted abasic deoxynucleotide, and the nucleotides at the remaining positions are non-fluorine-modified nucleotides, each of which is independently selected from one of an alkoxy-modified nucleotide, an alkyl-modified nucleotide, an amine-modified nucleotide, and a thermally unstable nucleotide. Each of 1-4 of the linking groups between the adjacent nucleotides of the 1st-5th nucleotides from the 5' end and / or 1-4 of the linking groups between the adjacent nucleotides of the 1st-5th nucleotides from the 3' end of the sense strand is independently a phosphate group with a modification group; or the phosphate group with a modification group is a phosphorothioate group with a structure as shown in formula (28); 34. The double-stranded oligonucleotide of claim 33, wherein, The sense strand comprises 19-21 nucleotides, and the antisense strand comprises 21-23 nucleotides; In the sense strand, the 11th and 13th nucleotides from the 3' end to the 5' end are fluorine-modified nucleotides, the 1st nucleotide is an inverted abasic deoxynucleotide, and the nucleotides at the remaining positions are all alkoxy-modified nucleotides; the linking groups between adjacent nucleotides at the 1st-3rd nucleotides from the 5' end to the 3' end of the sense strand or the linking groups between adjacent nucleotides at the 1st-3rd nucleotides from the 3' end to the 5' end of the sense strand are phosphate groups with a modification group; In the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 2nd, 5th, 7th, 12th and 16th nucleotides are fluorine-modified nucleotides, the 3rd nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 2nd, 7th, 12th, 16th and 19th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 2nd, 6th, 12th, 16th and 19th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 12th and 14th nucleotides from the 5' end to the 3' end are deoxynucleotides, the 2nd, 7th and 16th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide, or, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 16th nucleotide is an unmodified nucleotide, the 2nd and 6th nucleotides are fluorine-modified nucleotides, the 13th nucleotide is a substituted alkoxy-modified nucleotide, the 2nd nucleotide from the 3' end to the 5' end is a thermally unstable nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 19th nucleotide is an unmodified nucleotide, the 2nd, 6th and 16th nucleotides are fluorine-modified nucleotides, the 13th nucleotide is a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide. the linking groups between the adjacent nucleotides in the 1st to 3rd nucleotides from the 5' terminal end of the antisense strand and the linking groups between the adjacent nucleotides in the 1st to 3rd nucleotides from the 3' terminal end are phosphates with a modification group, and if there are unmodified nucleotides, the linking group between each of the unmodified nucleotides and the adjacent nucleotide is a phosphate with a modification group; and the 5' terminal nucleotide of the antisense strand is a 5'-hydroxyl nucleotide represented by formula (29) or a 5'-vinyl phosphate modified nucleotide represented by formula (31).

35. The double-stranded oligonucleotide of claim 34, wherein, the sense strand comprises 19 nucleotides, and the antisense strand comprises 21 nucleotides; in the sense strand, the 11th and 13th nucleotides from the 3' terminal end to the 5' terminal end are fluorine-modified nucleotides, the 1st nucleotide is an inverted dealkylated deoxynucleotide, and the nucleotides at the remaining positions are methoxy-modified nucleotides; the linking groups between the adjacent nucleotides in the 1st to 3rd nucleotides from the 5' terminal end and the 3' terminal end of the sense strand are phosphorothioate groups; in the antisense strand, the 14th nucleotide from the 5' terminal end to the 3' terminal end is a deoxynucleotide, the 2nd, 5th, 7th, 12th and 16th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is a methoxy-modified nucleotide; the linking groups between the adjacent nucleotides in the 1st to 3rd nucleotides from the 5' terminal end and the 3' terminal end of the antisense strand are phosphorothioate groups; and the 5' terminal nucleotide of the antisense strand is a 5'-hydroxyl nucleotide represented by formula (29) or a 5'-vinyl phosphate modified nucleotide represented by formula (31).

36. The double-stranded oligonucleotide of any one of claims 26-35, wherein, the double-stranded region formed by the sense strand and the antisense strand comprises 16-23 base pairs; or the double-stranded region formed by the sense strand and the antisense strand comprises 18, 19, 20 or 21 base pairs; and / or the sense strand and the antisense strand are substantially reverse complementary or completely reverse complementary within the double-stranded region; and / or the number of base differences between the sense strand and the SOD1 mRNA is not more than 3, not more than 2 or not more than 1; or there is no base difference between the sense strand and the SOD1 mRNA.

37. The double-stranded oligonucleotide of claim 36, wherein, the double-stranded oligonucleotide is an siRNA.

38. The double-stranded oligonucleotide of claim 37, wherein, the sense strand contains a nucleotide sequence I, and the antisense strand contains a nucleotide sequence II; the nucleotide sequence I and the nucleotide sequence II are selected from one group consisting of the following i)-xi) represented sequences: i) the nucleotide sequence I is equal in length to the nucleotide sequence represented by SEQ ID NO: 1, and has no more than 3 base differences, and the nucleotide sequence II is equal in length to the nucleotide sequence represented by SEQ ID NO: 2, and has no more than 3 base differences: 5'-CGAGCAGAAGGAAAGUAAZ1-3' (SEQ ID NO: 1); 5'-Z2UUACUUUCCUUCUGCUCG-3' (SEQ ID NO: 2), wherein Z1 is U, A or an inverted abasic deoxy nucleotide, Z2 is A or U, nucleotide sequence I comprises a nucleotide Z'1 at a position corresponding to Z1, nucleotide sequence II comprises a nucleotide Z'2 at a position corresponding to Z2, and Z'2 is the first nucleotide at the 5' end of the antisense strand; ii) nucleotide sequence I is identical in length to the nucleotide sequence set forth in SEQ ID NO: 3 and differs by no more than 3 bases, and nucleotide sequence II is identical in length to the nucleotide sequence set forth in SEQ ID NO: 4 and differs by no more than 3 bases: 5'-AGGUGGAAAUGAAGAAAGZ3-3' (SEQ ID NO: 3); 5'-Z4CUUUCUUCAUUUCCACCU-3' (SEQ ID NO: 4), wherein Z3 is U, A or an inverted abasic deoxy nucleotide, Z4 is A or U, nucleotide sequence I comprises a nucleotide Z'3 at a position corresponding to Z3, nucleotide sequence II comprises a nucleotide Z'4 at a position corresponding to Z4, and Z'4 is the first nucleotide at the 5' end of the antisense strand; iii) nucleotide sequence I is identical in length to the nucleotide sequence set forth in SEQ ID NO: 5 and differs by no more than 3 bases, and nucleotide sequence II is identical in length to the nucleotide sequence set forth in SEQ ID NO: 6 and differs by no more than 3 bases: 5'-GCAUGGAUUCCAUGUUCAZ5-3' (SEQ ID NO: 5); 5'-Z6UGAACAUGGAAUCCAUGC-3' (SEQ ID NO: 6), wherein Z5 is U, A or an inverted abasic deoxy nucleotide, Z6 is A or U, nucleotide sequence I comprises a nucleotide Z'5 at a position corresponding to Z5, nucleotide sequence II comprises a nucleotide Z'6 at a position corresponding to Z6, and Z'6 is the first nucleotide at the 5' end of the antisense strand; iv) nucleotide sequence I is identical in length to the nucleotide sequence set forth in SEQ ID NO: 7 and differs by no more than 3 bases, and nucleotide sequence II is identical in length to the nucleotide sequence set forth in SEQ ID NO: 8 and differs by no more than 3 bases: 5'-CUUUAAUCCUCUAUCCAGZ7-3' (SEQ ID NO: 7); 5'-Z8CUGGAUAGAGGAUUAAAG-3' (SEQ ID NO: 8), wherein Z7 is U, A or an inverted abasic deoxy nucleotide, Z8 is A or U, nucleotide sequence I comprises a nucleotide Z'7 at a position corresponding to Z7, nucleotide sequence II comprises a nucleotide Z'8 at a position corresponding to Z8, and Z'8 is the first nucleotide at the 5' end of the antisense strand; v) nucleotide sequence I is identical in length to the nucleotide sequence set forth in SEQ ID NO: 9 and differs by no more than 3 bases, and nucleotide sequence II is identical in length to the nucleotide sequence set forth in SEQ ID NO: 10 and differs by no more than 3 bases: 5'-GGGCAAAGGUGGAAAUGAZ9-3' (SEQ ID NO: 9); 5'-Z 10 UCAUUUCCACCUUUGCCC-3' (SEQ ID NO: 10), wherein Z9is U, A, or an inverted abasic deoxynucleotide, Z 10 is A or U, and the nucleotide sequence I comprises a nucleotide Z'9at a position corresponding to Z9, and the nucleotide sequence II comprises a nucleotide Z'9at a position corresponding to Z 10 10 10 is the first nucleotide of the 5' end of the antisense strand;​​ vi) nucleotide sequence I is equal in length to the nucleotide sequence set forth in SEQ ID NO: 11 and differs from the nucleotide sequence set forth in SEQ ID NO: 11 by no more than 3 bases, and nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 12 and differs from the nucleotide sequence set forth in SEQ ID NO: 12 by no more than 3 bases: 5'-GGAUGAAGAGAGGCAUGUZ 11 -3'(SEQ ID NO:11); 5'-Z 12 ACAUGCCUCUCUUCAUCC-3' (SEQ ID NO: 12), Wherein, the Z 11 It is a U, A, or reverse debased deoxynucleotide, Z 12 For A or U, the nucleotide sequence I contains a position corresponding to Z. 11 nucleotide Z' 11 The nucleotide sequence II contains a position corresponding to Z. 12 nucleotide Z' 12 Z' 12 It is the first nucleotide at the 5' end of the antisense strand; vii) nucleotide sequence I is equal in length to the nucleotide sequence set forth in SEQ ID NO: 13 and differs from the nucleotide sequence set forth in SEQ ID NO: 13 by no more than 3 bases, and nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 14 and differs from the nucleotide sequence set forth in SEQ ID NO: 14 by no more than 3 bases: 5'-UGAAGAGAGGCAUGUUGGZ 13 -3'(SEQ ID NO: 13); 5'-Z 14 CCAACAUGCCUCUCUUCA-3' (SEQ ID NO: 14), wherein Z is 13 U, A or an inverted abasic deoxynucleotide, 14 A or U, the nucleotide sequence I comprising a nucleotide Z' at a position corresponding to Z 13 13 , the nucleotide sequence II comprising a nucleotide Z' at a position corresponding to Z 14 14 14 Z' is the first nucleotide of the 5' end of the antisense strand;​​​ viii) nucleotide sequence I is equal in length to the nucleotide sequence set forth in SEQ ID NO: 15 and differs from the nucleotide sequence set forth in SEQ ID NO: 15 by no more than 3 bases, and nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 16 and differs from the nucleotide sequence set forth in SEQ ID NO: 16 by no more than 3 bases: 5'-AAUGGACCAGUGAAGGUGZ 15 -3'(SEQ ID NO: 15); 5'-Z 16 CACCUUCACUGGUCCAUU-3' (SEQ ID NO: 16), wherein Z is 15 U, A or an inverted abasic deoxynucleotide, 16 A or U, the nucleotide sequence I comprising a nucleotide Z' at a position corresponding to Z 15 , the nucleotide sequence II comprising a nucleotide Z' at a position corresponding to Z 15 , the nucleotide sequence III comprising a nucleotide Z' at a position corresponding to Z 16 , the nucleotide sequence IV comprising a nucleotide Z' at a position corresponding to Z 16 , the nucleotide sequence V comprising a nucleotide Z' at a position corresponding to Z 16 Z' is the first nucleotide of the 5' end of the antisense strand; ix) nucleotide sequence I is equal in length to the nucleotide sequence set forth in SEQ ID NO: 17 and differs from the nucleotide sequence set forth in SEQ ID NO: 17 by no more than 3 bases, and nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 18 and differs from the nucleotide sequence set forth in SEQ ID NO: 18 by no more than 3 bases: 5'-CUGAAGGCCUGCAUGGAUZ 17 -3'(SEQ ID NO:17); 5'-Z 18 AUCCAUGCAGGCCUUCAG-3' (SEQ ID NO: 18), wherein Z is 17 U, A, or an inverted abasic deoxynucleotide, 18 A or U, the nucleotide sequence I comprising a nucleotide Z' at a position corresponding to Z 17 17 , the nucleotide sequence II comprising a nucleotide Z' at a position corresponding to Z 18 18 18 Z' is the first nucleotide of the 5' end of the antisense strand;​​​ x) nucleotide sequence I is equal in length to the nucleotide sequence set forth in SEQ ID NO: 19 and differs from the nucleotide sequence set forth in SEQ ID NO: 19 by no more than 3 bases, and nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 20 and differs from the nucleotide sequence set forth in SEQ ID NO: 20 by no more than 3 bases: 5'-CUUGGGCAAAGGUGGAAAZ 19 -3'(SEQ ID NO:19); 5'-Z 20 UUUCCACCUUUGCCCAAG-3' (SEQ ID NO: 20), Wherein, the Z 19 It is a U, A, or reverse debased deoxynucleotide, Z 20 For A or U, the nucleotide sequence I contains a position corresponding to Z. 19 nucleotide Z' 19 The nucleotide sequence II contains a position corresponding to Z. 20 nucleotide Z' 20 Z' 20 It is the first nucleotide at the 5' end of the antisense strand; xi) nucleotide sequence I is equal in length to the nucleotide sequence set forth in SEQ ID NO: 21 and differs from the nucleotide sequence set forth in SEQ ID NO: 21 by no more than 3 bases, and nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 22 and differs from the nucleotide sequence set forth in SEQ ID NO: 22 by no more than 3 bases: 5'-CAGAUGACUUGGGCAAAGZ 21 -3'(SEQ ID NO:21); 5'-Z 22 CUUUGCCCAAGUCAUCUG-3' (SEQ ID NO: 22), wherein Z 21 is G, C or an inverted abasic deoxynucleotide, Z 22 is G or C, the nucleotide sequence I comprising a nucleotide Z 21 corresponding to Z 21 , the nucleotide sequence II comprising a nucleotide Z 22 corresponding to Z 22 , Z 22 is the first nucleotide of the 5' end of the antisense strand.

39. The double-stranded oligonucleotide of claim 38, wherein, nucleotide sequence I differs from the nucleotide sequence set forth in SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, or SEQ ID NO: 21 by no more than 1 base, and nucleotide sequence II differs from the nucleotide sequence set forth in SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, or SEQ ID NO: 22 by no more than 1 base.

40. The double-stranded oligonucleotide of claim 39, wherein, the double-stranded oligonucleotide is as set forth in any one of siRNA1-siRNA11 set forth in Table 1.

41. An oligonucleotide conjugate comprising at least one oligonucleotide group and a delivery group conjugated to the oligonucleotide group, the oligonucleotide group being a group formed by removing one or more atoms or atom groups from the single-stranded oligonucleotide of any one of claims 1-25 or the double-stranded oligonucleotide of any one of claims 26-40.

42. The oligonucleotide conjugate of claim 41, wherein, the delivery group comprises a linker group and a pharmaceutically acceptable targeting group, and the oligonucleotide group, the linker group and the targeting group are covalently or non-covalently linked in sequence, each of the targeting groups is independently selected from a ligand group capable of binding to a cell surface receptor or a group capable of increasing compatibility with a tissue; or each of the targeting groups is selected from a ligand capable of binding to a mammalian hepatocyte surface asialoglycoprotein receptor; or the oligonucleotide conjugate comprises an oligonucleotide group that is an siRNA group formed by an siRNA listed in Table 1; or the oligonucleotide conjugate comprises an oligonucleotide group that is an siRNA group formed by an siRNAa1-siRNAa12 listed in Table 2; Alternatively, the oligonucleotide conjugate has the structure shown in Formula (403): in formula (403), Nu is an oligonucleotide group; or the oligonucleotide group is a double-stranded oligonucleotide group, a P atom is covalently linked to a 3' terminal nucleotide of a sense strand of the double-stranded oligonucleotide group; or the 3' terminal nucleotide of the sense strand of the double-stranded oligonucleotide group is a reverse deoxy-abasic nucleotide, a P atom is covalently linked to the double-stranded oligonucleotide group by replacing an oxygen atom in a hydroxyl group via a methylene group linked to a ribose ring in the reverse deoxy-abasic nucleotide of the 3' terminal of the sense strand of the double-stranded oligonucleotide group; or the oligonucleotide conjugate is one of conjugate 1 or conjugate 2 listed in Table 3.

43. A pharmaceutically acceptable salt of the single-stranded oligonucleotide of any one of claims 1-25, the double-stranded oligonucleotide of any one of claims 26-40 or the oligonucleotide conjugate of claim 41 or 42; or the pharmaceutically acceptable salt is a water-soluble salt of part or all of the single-stranded oligonucleotide, the double-stranded oligonucleotide or the oligonucleotide conjugate; or the water-soluble salt is one or more of an amine salt, an alkali metal salt or an alkaline earth metal salt; or the amine salt is one or more of an ammonium salt, a methylamine salt, a tertiary amine salt, a quaternary ammonium salt, the alkali metal salt is one or more of a potassium salt or a sodium salt, and the alkaline earth metal salt is one or more of a calcium salt or a magnesium salt; or the tertiary amine salt is a triethylamine salt, a triisopropylamine salt or a N,N-diisopropylethylamine salt; or the pharmaceutically acceptable salt is a sodium salt or a partial sodium salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide or the oligonucleotide conjugate.

44. A pharmaceutical composition comprising one or more of the single-stranded oligonucleotide of any one of claims 1-25, the double-stranded oligonucleotide of any one of claims 26-40, the oligonucleotide conjugate of claim 41 or 42, and the pharmaceutically acceptable salt of claim 43, and a pharmaceutically acceptable excipient; or, the pharmaceutically acceptable excipient is one or more of a solvent, a protective agent, an osmotic pressure regulator, and a pharmaceutically acceptable other carrier; or, the solvent is one of deionized water, water for injection, a pH buffer, physiological saline, ethanol, or an aqueous ethanol solution.

45. Use of one or more of the single-stranded oligonucleotide of any one of claims 1-25, the double-stranded oligonucleotide of any one of claims 26-40, the oligonucleotide conjugate of claim 41 or 42, the pharmaceutically acceptable salt of claim 43, and the pharmaceutical composition of claim 44 in the manufacture of a medicament for treating and / or preventing a disease or a symptom associated with SOD1 mRNA level.

46. The use of claim 45, wherein, The disease or symptom associated with SOD1 mRNA level is amyotrophic lateral sclerosis, lung cancer, or breast cancer.

47. A method of treating and / or preventing a disease or a symptom associated with SOD1 mRNA level, the method comprising administering to a subject in need thereof an effective amount of one or more of the single-stranded oligonucleotide of any one of claims 1-25, the double-stranded oligonucleotide of any one of claims 26-40, the oligonucleotide conjugate of claim 41 or 42, the pharmaceutically acceptable salt of claim 43, and the pharmaceutical composition of claim 44.

48. A method of modulating the expression level of SOD1 gene in a cell in vitro or in vivo, the method comprising contacting the cell in vivo or in vitro with an effective amount of one or more of the single-stranded oligonucleotide of any one of claims 1-25, the double-stranded oligonucleotide of any one of claims 26-40, the oligonucleotide conjugate of claim 41 or 42, the pharmaceutically acceptable salt of claim 43, and the pharmaceutical composition of claim 44.

49. One or more of the single-stranded oligonucleotide of any one of claims 1-25, the double-stranded oligonucleotide of any one of claims 26-40, the oligonucleotide conjugate of claim 41 or 42, the pharmaceutically acceptable salt of claim 43, and the pharmaceutical composition of claim 44 for use as a medicament.

50. A cell expressing SOD1 mRNA, the cell comprising one or more of the single-stranded oligonucleotide of any one of claims 1-25, the double-stranded oligonucleotide of any one of claims 26-40, the oligonucleotide conjugate of claim 41 or 42, the pharmaceutically acceptable salt of claim 43, and the pharmaceutical composition of claim 44.

51. A kit comprising one or more of the single stranded oligonucleotide of any one of claims 1-25, the double stranded oligonucleotide of any one of claims 26-40, the oligonucleotide conjugate of claim 41 or 42, the pharmaceutically acceptable salt of claim 43, and the pharmaceutical composition of claim 44.

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