TW201210611A - Treatment of Nicotinamide Phosphoribosyltransferase (NAMPT) related diseases by inhibition of natural antisense transcript to NAMPT - Google Patents

Abstract

The present invention relates to antisense oligonucleotides that modulate the expression of and/or function of Nicotinamide Phosphoribosyltransferase (NAMPT), in particular, by targeting natural antisense polynucleotides of Nicotinamide Phosphoribosyltransferase (NAMPT). The invention also relates to the identification of these antisense oligonucleotides and their use in treating diseases and disorders associated with the expression of NAMPT.

Description

201210611 VI. Description of the Invention: [Technical Field of the Invention] Embodiments of the invention include oligonucleotides that modulate the expression and/or function of NAMPT and related molecules. • The present application claims priority to U.S. Provisional Patent Application Serial No. 61/375,126, filed on Jan. 19, 2010, which is hereby incorporated by reference. [Prior Art] 0 DNA-RNA and RNA-RNA hybridization are important for many aspects of nucleic acid function including DNA replication, transcription and translation. Hybridization is also central to a variety of techniques for detecting specific nucleic acids or altering their performance. Antisense nucleotides disrupt gene expression, e.g., by hybridization to a target RNA, thereby interfering with RNA splicing, transcription, translation, and replication. Antisense DNA has the additional feature that the DNA-RNA hybrid acts as a substrate for ribonuclease digestion, i.e., an activity that is present in most cell types. The antisense molecule can be delivered to the cell in the same manner as the oligodeoxynucleotide, or it can be expressed as an RNA molecule from the endogenous gene. The FDA recently approved an antisense drug, VITRAVENETM (for the treatment of giant viral retinitis), reflecting the anti-sense sequence has therapeutic utility. - SUMMARY OF THE INVENTION The summary is provided to present a summary of the invention. The conditions are set out so that they do not have to explain or limit the scope or meaning of the scope of the patent application. In one embodiment, the invention provides for the up-regulation of a corresponding sense gene by inhibiting the action of a natural antisense transcript by using an antisense oligonucleotide that targets any region of natural antisense transcription 158213.doc 201210611 Methods. It is also contemplated herein that inhibition of a natural antisense transcript can be achieved by siRNA, ribonuclease, and small molecules, which are considered to be within the present invention. An embodiment provides a method of modulating the function and/or performance of a NAMPT polynucleotide in a biological system, including but not limited to a patient cell or tissue, in vivo or in vitro, the method comprising: The cell or tissue is contacted with an antisense oligonucleotide having a length of from about 5 to about 30 nucleotides, wherein the oligonucleotide comprises nucleotides 1 to 882 of SEQ ID NO: 2, or SEQ ID NO: 3 to 915, or 1 to 165 of SEQ ID NO: 4, or 1 to 533 of SEQ ID NO: 5, or 1 to 522 of SEQ ID NO: 6, or 1 to SEQ ID NO: 7 to 141, or 1 to 519 of SEQ ID NO: 8, or 1 to 374 of SEQ ID NO: 9, or 1 to 240 of SEQ ID NO: 10, or 1 to 353 of SEQ ID NO: 11, or SEQ ID NO : 12 to 1 to 534, or SEQ ID NO: 13 to 1 to 959, or SEQ ID NO: 14 to 1 to 127, or SEQ ID NO: 15 to 1 to 232, or SEQ ID NO: 16 to 1 to 3 The reverse complement of a polynucleotide of 5 to 30 contiguous nucleotides within 87 has at least 50% sequence identity, thereby modulating the biological system (including such patient cells or tissues) in vivo or ex vivo. The function and/or performance of a NAMPT polynucleotide. In one embodiment, the oligonucleotide targets a NAMPT polynucleotide present in a biological system (eg, the nucleotides set forth in SEQ ID NOS: 2 to 16, and any variants thereof, dual genes, Natural antisense sequences of the source, mutant, derivative, fragment and complementary sequence). Antisense nucleotides 158213.doc 201210611 Examples are shown in SEQ ID NOs: 17 to 31. Another embodiment provides a method of modulating the function and/or expression of purine nucleotides in a patient's cells or tissues in vivo or in vitro, the method comprising affixing the cells or tissues to 5 to 3 nucleosides in length An antisense nucleotide contact of an acid, wherein the oligonucleotide has at least 50% sequence identity to a reverse complement of the antisense sequence of the purine polynucleotide; thereby modulating the patient cell or in vivo or in vitro The function and/or performance of purine nucleotides in tissues. Another embodiment provides a method of modulating the function and/or expression of sputum polynucleic acid in a cell or tissue of a patient in vivo or in vitro, the method comprising affixing the cell or tissue to a length of 5 to 30 nucleotides The antisense oligonucleotide contacts 'where the nucleotide has at least 50% sequence identity with the antisense nucleocapsid nucleoside of the antisense polynucleotide; thereby regulating the patient cell or tissue in vivo or ex vivo The function and/or performance of a ruthenium polynucleotide. In another embodiment, the invention encompasses a method of modulating the function and/or expression of a ruthenium polynucleotide in a biological system, the method comprising the natural antisense transcript of the biological system and a targeting ΝΑΜΡΤ polynucleotide At least one antisense raised nucleotide contacts, thereby modulating the function and/or performance of the purine polynucleotide in the biological system. In another embodiment, the invention encompasses a method of modulating the function and/or expression of a purine polynucleotide in a biological system, the method comprising the biological system and a natural antisense transcript targeting a purine polynucleotide At least one antisense oligonucleotide in the region contacts, thereby modulating the function and/or performance of the 158213.doc 201210611 NAMPT polynucleotide in the biological system. In one embodiment, the invention comprises a method of increasing the function and/or expression of a NAMPT polynucleotide having SEQ ID NO. 1 in a biological system, the method comprising targeting the biological system to the NAMPT polynucleoside Contact with at least one antisense oligonucleotide of the acid natural antisense transcript, thereby increasing the function and/or expression of the NAMPT polynucleotide or its expression product. In another embodiment, the invention comprises a method of increasing the function and/or expression of a NAMPT polynucleotide having SEQ ID NO. 1 in a biological system, the method comprising targeting the biological system to the NAMPT polynucleus Contacting at least one antisense oligonucleotide of a natural antisense transcript of a gluconate, thereby increasing the function and/or expression of the NAMPT polynucleotide or its expression product, wherein the natural antisense transcript is selected from SEQ ID NOS. 2 to 16. In another embodiment, the invention comprises a method of increasing the function and/or expression of a NAMPT polynucleotide having SEQ ID NO. 1 in a biological system, the method comprising targeting the biological system to the NAMPT polynucleus Contacting at least one antisense oligonucleotide of a natural antisense transcript of a gluconate, thereby increasing the function and/or expression of the NAMPT polynucleotide or its expression product, wherein the natural antisense transcript is selected from SEQ ID NOS. 2 to 16 and wherein the antisense oligonucleotides are selected from at least one of SEQ ID NOS. 17 to 31. In one embodiment, the composition comprises one or more antisense oligonucleotides that bind to a sense and/or antisense NAMPT polynucleotide. In one embodiment, the oligonucleotide comprises one or more modified or substituted nucleotides. 158213.doc 201210611 In one embodiment, the raised nucleotide comprises one or more modified linkages. In yet another embodiment, the modified nucleotide comprises a modified base comprising a phosphorothioate, a decylphosphonate, a peptide nucleic acid, a 2'-fluorene-fluorenyl group, a fluorine or carbon, a methylene A base or other locked nucleic acid (LNA) molecule. The modified nucleotide is preferably a locked nucleic acid molecule, including α-L-LNA. In one embodiment, the oligonucleotide is administered to the patient subcutaneously, intramuscularly, intravenously or intraperitoneally.

In one embodiment the 'oligonucleotide is administered as a pharmaceutical composition. The treatment regimen comprises administering to the patient an antisense compound at least once; however, the treatment can be modified to include multiple administrations over a period of time. The treatment can be combined with one or more other types of therapies. In one embodiment, the oligonucleotide is encapsulated in a liposome or linked to a carrier molecule (e.g., cholesterol, butylated AT peptide). Other aspects are described below. [Embodiment] For the purpose of explanation, several aspects of the invention are described below with reference to example applications. It should be understood that (d) many specific details, relationships, and methods are fully understood. However, it will be readily appreciated by those skilled in the art that the present invention may be practiced without y or multiple specific details or otherwise. The present invention is not limited by the ordering of operations or events' because these operations may occur in different orders and/or concurrently with other operations or events. Moreover, not all illustrated m events are required to practice the methods of the present invention. All genes, gene names and gene products are intended to correspond to homologs of any species of the compositions and methods disclosed herein, 1582l3.doc 201210611. Thus, such terms include, but are not limited to, human and mouse genes and gene products. It is to be understood that the invention is intended to be illustrative only and not to be construed as limiting. Thus, for example, for the genes disclosed herein, which are related to mammalian nucleic acid and amino acid sequences, are intended to encompass homologous and/or orthologous genes and gene products from other animals, Such animals include, but are not limited to, one of his mammals, fish, amphibians, reptiles, and birds. In one embodiment, the gene or nucleic acid sequence is a human gene or nucleic acid sequence. Definitions The terms used herein are for the purpose of describing particular embodiments only and are not intended to limit the invention. The singular forms "a" and "the" In addition, the terms "including", "having", "having" or "comprising" or "comprising" are used in the context of the embodiments and/or claims. "About" or "approximately" means that within the acceptable tolerances for a particular value as determined by the skilled artisan, this will depend in part on how the value is measured or measured, i.e., the limits of the measurement system. For example, according to the practice in the art, "about" can mean within 1 or more standard deviations. Or "about" may mean a range of up to 2 〇〇/0, preferably up to 10%, more preferably up to 5% and more preferably up to 1% of the specified value. Alternatively, particularly with respect to biological systems or methods, the term may mean within a certain order of magnitude, preferably within 5 times, and more preferably within 2 times. In the context of the application and the scope of the patent application 158213.doc 201210611 When describing a particular value, the term "about" is intended to mean within the acceptable tolerance of the particular value, unless otherwise stated. The term "mRNA" as used herein means the currently known mRNA transcript of the target gene, and any other transcript that can be elucidated. An "antisense oligonucleotide" or "antisense compound" means an RNA or DNA molecule that binds to another RNA or DNA (target RNA, DNA). For example, if it is an RNA oligonucleotide, it binds to another RNA target by means of RNA-RNA interaction and changes the activity of the target RNA. Antisense Ο Oligonucleotides can upregulate or downregulate the performance and/or function of a particular polynucleotide. For therapeutic, diagnostic or other purposes, this definition is meant to include any suitable foreign RNA or DNA molecule. Such molecules include, for example, antisense RNA or DNA molecules, interfering RNA (RNAi), microRNAs, ligation: RNA molecules, siRNA, enzymatic RNA, therapeutic editing RNA, and agonists and antagonist RNA, antisense oligomerization Compounds, antisense oligonucleotides, external leader sequences (EGS) oligonucleotides, alternative splicers, primers, probes, and other oligomeric compounds that hybridize to at least a portion of a target nucleic acid. 〇 Thus, such compounds can be introduced in the form of single-stranded, double-stranded, partially single-stranded or cyclic polymeric compounds. In the context of the present invention, the term "oligonucleotide" refers to an oligomer or polymer of ribonucleic acid ' (RNA) or deoxyribonucleic acid (DNA) or a mimetic thereof. The term "oligonucleotide" also includes natural or/or modified monomers or linked linear or cyclic conjugates, including deoxyribonucleosides, ribonucleosides, substituted and --spin isomeric forms, peptide nucleic acids (ΡΝΑ), locked nucleic acids (LNA), phosphorothioates, decylphosphonates and the likes 158213.doc 201210611 analogs. Oligonucleotides can rely on a defined pattern of monomer-monomer interactions, such as Watson_Crick type base pairing, Hodgsteen or reverse Hoxton type "everse

Hoogsteen type) A chimeric pair or a similar pattern specifically binds to a polynucleotide of interest. Nutrients can be "chimeric" oligonucleotides, that is, composed of different regions. In the context of the present invention, a "chimeric" compound is an oligonucleotide containing two or more chemical regions, such as a DNA region, an RNA region, a PNA region, and the like. Each chemical region is composed of at least one monomer unit (in the case of an oligonucleotide compound, i.e., a nucleotide). Such oligonucleotides typically comprise at least one f region in which the oligonucleotide is modified to exhibit one or more desired properties of the desired nucleotide including, but not limited to, for example Increased resistance to nuclease degradation, increased cellular uptake, and/or enhanced affinity for the δ of the target nucleic acid. Thus, different regions of the raised nucleotides may have different properties. The chimeric oligonucleotides of the invention may be formed into two or more oligonucleotides, modified oligonucleotides, oligonucleosides as described above. And/or a mixed structure of oligonucleotide analogs. The nucleotides may be composed of a region linked to a "storage register", that is, the monomers are generally connected continuously as in natural DNA or via spacers. The spacers are intended to form a covalent "bridge" between the zones and, preferably, have a length of no more than about 100 carbon atoms. The spacers may have different functionalities' such as having positive or negative charges, with specific nucleic acid binding properties (intercalators, groove binders, toxins, phosphors, etc.), lipophilic, and inducing specific secondary structures (eg, for example Inducing an alpha helix containing alanine peptide). As used herein, "ΝΑΜΡΤ" and "in the acid-lowering phosphoribosyl 158213.doc -10· 201210611 enzyme" include all family members, mutants, dual genes, fragments, species, coding and non-coding sequences, sense and Antisense polynucleotide strands, etc. As used herein, the words 1110035O14Rik, DKFZp666B131, MGC117256, NAmPRTase, Nampt, proline amine ribosyltransferase, PBEF, PBEF1, pre-B cell community enhancer 1, pre-B cell enhancer, VF, Visfatin, VISFATIN They are considered the same in the literature and are used interchangeably in this application. The term "oligonucleotide specific for" or "oligonucleotide to" as used herein means having (1) capable of forming a stable complex with one of the target genes or (Π) capable of An oligonucleotide that forms a sequence of a stable duplex with a portion of an mRNA transcript of a gene of interest. The stability of the complexes and duplexes can be determined by theoretical calculations and/or in vitro assays. Exemplary assays for determining the stability of hybrid complexes and duplexes are described in the Examples below. The term "target nucleic acid" as used herein encompasses DNA, RNA transcribed from the DNA (including precursor mRNA and mRNA), and 〇 cDNA, coding, non-coding sequence, sense or antisense nucleoside obtained from the RNA. acid. The specific hybridization of a compound with its target nucleic acid interferes with the normal function of the nucleic acid. This regulation of the function of the target nucleic acid by a compound that specifically hybridizes to the target nucleic acid is generally referred to as "antisense". The functions of the DNA to be interfered with include, for example, replication and transcription. The function of the RNA to be interfered with includes all important functions such as RNA translocation to protein translation sites, protein translation from RNA, RNA splicing to produce one or more mRNA species, and catalytic activity in which RNA can participate or promote. The overall effect of this interference on the function of the target nucleic acid is 158213.doc -11 · 201210611 Modulate the performance of the encoded product or nucleotide. RNA interference "RNAi" is mediated by a double-stranded RNA (dsRNA) molecule with sequence-specific homology to its "target" nucleic acid sequence. In certain embodiments of the invention, the mediator is a 5 to 25 nucleotide "small interference" RNA double bond (siRNA). The siRNA is derived from a dsRNA which is referred to by (10) (10). The siRNA duplex product is recruited in a polyprotein siRNA complex called rISC (rnA-inducible resting complex). Without wishing to be bound by any particular theory, the RISC is then directed to the target nucleic acid (suitably mRNA), where the siRNA duplex interacts in a sequence-specific manner to catalyze cleavage in a catalytic manner. Small interfering RNAs which can be used in accordance with the present invention can be synthesized and used according to procedures well known in the art and familiar to those skilled in the art. The small interfering RNAs used in the methods of the invention suitably comprise from about 1 to about 50 nucleotides (nt). In an example of a non-limiting embodiment, the siRNAs can comprise from about 5 to about 40 nt, from about 5 to about 30 nt, from about 1 to about 30 nt, from about 15 to about 25 nt, or from about 20 to 25 A bit of bitter acid. Selection of appropriate oligonucleotides is facilitated by the use of computer programs that automatically align nucleic acid sequences and indicate regions of homology or homology. The nucleic acid sequences obtained are compared using, for example, by searching a database such as GenBank or by sequencing the Pcr product. Comparing nucleic acid sequences from a variety of species allows for the selection of nucleic acid sequences that display an appropriate degree of identity between species. In the case of unscheduled genes, a Southern blot is performed to allow for the determination of the degree of identity between the target species and the genes of other species. As is well known in the art, an approximate measure of consistency can be obtained by performing a Southern dot method at varying degrees of stringency. Such procedures allow 158213.doc 12 201210611 to select oligonucleotides that are highly complementary to the target nucleic acid sequence in the individual to be controlled and that exhibit a lower degree of complementarity to the corresponding nucleic acid sequences in other species. Those skilled in the art will recognize that there is considerable freedom in selecting the appropriate regions for the genes used in the present invention. "Enzymatic RNA" means an RNA molecule having enzymatic activity (Cech, (1988) J_JmeWcijn Mec/. dwoc. 260, 3030-3035). The enzymatic nucleic acid (ribonuclease) functions by first binding to the target RNA. This binding is carried out via the target binding portion of the enzymatic nucleic acid which remains in close proximity to the enzymatic portion of the molecule used to cleave the target RNA. Thus, the enzymatic nucleic acid is first recognized, and then the target RNA is bound via base pairing, and once bound to the correct position, the target RNA is cleaved in an enzymatic manner. "Bee RNA" means an RNA molecule that mimics the natural binding domain of a ligand. Thus, the decoy RNA competes with the natural binding target for binding to a particular ligand. For example, it has been shown that overexpression of HIV transcriptional activation (TAR) RNA acts as a "bait" and effectively binds to the HIV tat protein, thereby preventing its binding to the TAR sequence encoded in HIV RNA. This situation is intended to be a specific instance. Those skilled in the art will recognize that this example is only one example, and that other embodiments can be readily produced using techniques generally known in the art. The term "monomer" as used herein generally denotes the attachment of a phosphodiester bond or an analog thereof to form a monomer having a size ranging from a few (e.g., about 3 to 4) monomer units to about several hundred monomer units. A monomer of a nucleotide. As described more fully below, phosphodiester-linked analogs include: phosphorothioates, dithiophosphates, methylphosphonates, selenophosphates, phosphoxamate 158213.doc •13- 201210611 ( Phosphoramidate) and its analogues. The term "nucleotide" encompasses naturally occurring nucleotides as well as non-naturally occurring nucleotides. Those skilled in the art should be aware that various types of nucleotides previously considered "non-natural" have been discovered in nature. Therefore, "nuclear acid" includes not only molecules known to contain purine and pyrimidine heterocycles, but also heterocyclic analogs and tautomers thereof. Illustrative examples of other types of nucleotides are adenine, guanine, thymine, cytosine, uracil, guanidine, xanthine, diamino guanidine, 8-sided oxy-N6-methyl adenine, 7 - denitrazine, 7-deazaguanine, N4, N4-acetylidene, N6, N6-B-bridge-2,6-diaminopurine, 5-mercaptocytidine, 5 -(C3-C6)-alkynylcytosine, 5-fluorouracil, 5-bromouracil, pseudoisopyrimidine, 2-hydroxy-5-methyl-4-triazolopyridine, isocytosine, isoguanine And the "non-naturally occurring" nucleotides described in U.S. Patent No. 5,432,272. The term "nucleotide" is intended to cover each and every of such examples as well as analogs and tautomers thereof. Nucleotides of particular interest are nucleotides containing adenine, guanine, thymine, cytosine, and uracil, which are considered to be naturally occurring nucleotides associated with therapeutic and diagnostic applications in humans. . Nucleotides include natural 2'-deoxy and 2'-transglycosides, such as those described in Kornberg and Baker, DNA Replication, 2nd Edition (Freeman, San Francisco, 1992), and analogs thereof. Nucleotide-related "analogs" include synthetic nucleotides having modified base moieties and/or modified sugar moieties (see, for example, Scheit, Nucleotide Analogs, John Wiley, New York, 1980; Freier and Altmann, 158213). .doc • 14· 201210611 (1997) Nucl. Acid. Res., 25(22), 4429-4443 ; Toulme, JJ, (2001) Nature Biotechnology 19:17-18 ; Manoharan M., (1999) Biochemica et Biophysica Acta 1489: 117-139; Freier SM, (1997) Nucleic Acid Research, 25: 4429-4443, Uhlman, E., (2000) Drug Discovery & Development, 3: 203-213; Herdewin P., (2000) Antisense & Nucleic Acid Drug Z) ev., 10: 297-310 General Description); 2'-0, 3'-C-linked [3.2.0] Ο ο Bicyclic arabinose. Such analogs include synthetic nucleotides that are involved in enhancing binding properties, such as duplex or triplex stability, specificity, or the like. As used herein, "monomer" means the pairing of substantially complementary strands of a gastric-growth compound. A pairing mechanism involves hydrogen bonding between complementary nuclear or nucleotide nucleotides (nucleotides) of a strand of an oligomeric compound, which may be a Watson _ creek, a tiger cretin or a reverse tiger Kistin hydrogen bonding. For example, adenine and thymine are complementary nucleotides paired by the formation of hydrogen bonds. Hybridization can occur in different situations. When the binding of the antisense agent to the target nucleic acid interferes with the normal function of the target nucleic acid to produce regulation of function and/or activity, and under conditions requiring specific binding, ie, in vivo or therapeutic treatment Under physiological conditions, and under conditions of performing in vitro assays, there is a sufficient degree of complementarity to avoid antisense compounds and non-target nucleic acid sequences: when non-specifically binds, the compound is "specifically hybridizable." The phrase "stringent hybridization conditions" and "stringent conditions" refer to the conditions under which the compound of the present invention hybridizes to its target sequence' and to the least amount of other sequences 15S213.doc •15-201210611. Stringent conditions are sequence dependent and will vary from case to case' and in the context of the present invention, the "stringent conditions" at which an oligomeric compound hybridizes to a target sequence are determined by the nature and composition of the polymerized compound and its investigation. determine. In general, stringent hybridization conditions include a low concentration (0.1 5 M) of a salt having an inorganic cation such as Na+ or K+ (i.e., low ion strength), and a temperature higher than 20 °C to 25. (: lower than the oligomeric compound: the temperature of the Tm of the target sequence complex, and the presence of, for example, formamidine, dimercaptoamine, dimethyl sulfite or detergent sodium lauryl sulfate (sr>S) Denaturing agents. For example, for each 1% guanamine, the rate of hybridization is reduced by 1.1%. An example of high stringency hybridization conditions is 6. 丨χ sodium chloride _ sodium citrate buffer at 6 〇t SSC) / 0.1% (W / V) SDS lasts 30 minutes. As used herein, "complementary" refers to the ability to precisely pair between two nucleotides on one or two oligomeric strands. For example, if The nucleocapsid at a position of the sense compound is capable of hydrogen bonding with a nucleobase at a position of the target nucleic acid, wherein the target nucleic acid is a DNA, RNA or nucleotide molecule, and the oligonucleotide is between the oligonucleotide and the target nucleic acid. The hydrogen bonding position is regarded as a complementary position. When the nucleotides which are hydrogen-bondable to each other occupy a sufficient number of complementary positions i in each molecule, the oligomeric compound and other DNA, RNA or nucleotide molecules are complementary to each other. "Specific hybridization" and "complementary" are used to indicate a sufficient number of nucleotides There is a sufficient degree of exact pairing or complementation to enable stable and specific binding between the oligomeric compound and the target nucleic acid. It will be appreciated that in this technique the sequence of the polymerized compound does not require a target nucleic acid that specifically hybridizes to it. The sequence is 1〇0% complementary. In addition, the nucleotide can be raised in one or more regions, and the heterogeneous parent can make the inserted or adjacent segment not participate in the 158213.doc -16 - 201210611 event (eg, ring structure, Mismatch or hairpin structure. The oligomeric compound of the invention comprises at least about 70%, or at least about 75%, or at least about 80%, or at least about 85°/◦, or at least about 90°/., or at least About 95%, or at least about 99%, of the sequence complementarity to the target region within the target nucleic acid sequence to which it is targeted. For example, 18 of the 20 nucleotides of the antisense compound are complementary to the target region and are therefore specific Sexually hybridized antisense compounds represent 90% complementarity. In this example, the remaining non-complementary nucleotides may be singular or interspersed with complementary nucleotides in complementary nucleotides without the need for each other or with complementary nucleotides Adjacent. Because of the squat, with side An antisense compound having a length of 18 nucleotides of 4 (four) non-complementary nucleotides in two regions in which the target nucleic acid is completely complementary has 77.8% overall complementarity with the target nucleic acid, and thus is within the scope of the present invention. The percentage of complementarity of the antisense compound to the target nucleic acid region can generally be determined using the BLAST program (basic local alignment search tool) and the PowerBLAST program known in the art. The homology, sequence identity or percent complementarity can be used by For example, Gap program (Wisconsin Sequence Analysis Package, 8th edition, for Unix, Genetics Computer Group, University ◎

Research Park, Madison Wis.) was determined using a preset setting using Smith and Waterman's algorithm (Ji/v. ΜαΜ·, (1981) 2, 482-489). • The term "thermal melting point (Tm)" as used herein refers to a temperature at which 50% of the nucleotides complementary to the target sequence hybridize to the target sequence at a given ionic strength, pH, and nucleic acid concentration. Generally, stringent conditions are those in which the salt concentration is at least about 0.01 to 1.0 M Na ion concentration (or other salt) at pH 7.0 to 8.3, and for short-raised nucleotides (eg, 10 to 50 nucleosides 158213.doc) -17- 201210611 Acid) The temperature is at least about 3 destabilizing agents to achieve severe conditions. As used herein, "regulation" means less (inhibition). . The nucleotide sequence associated with the wild-type gene can also be encompassed by the addition of a gene expression such as formamide (stimulation) or the term "variant" when the polynucleotide sequence is used. This definition may also include, for example, "dual genes", "splicing", "species" or "polymorphic" variants. A splicing variant may be significantly responsive to a reference molecule, but will generally have a greater or lesser number of polynucleic acids due to alternative splicing of exons during mRNA processing. The corresponding polypeptide may have other functional domains or no domain. A species variant is a polynucleotide sequence in which one species is different from another species. Variants of wild type gene products have particular utility in the present invention. A variant may be produced by at least one mutation in a nucleic acid sequence and may produce a altered mRNA or structure or work that may or may not be (4) polymorphic. Any common mutation that specifies that a natural or recombinant gene may have no variants with one or more dual native forms is generally attributed to the natural deletion, addition or substitution of nucleotides. In a given sequence, these types of changes can each occur individually or in combination with other changes one or more times. The resulting polypeptides generally have significant amino acid identity with each other. Polymorphism A variant of a polynucleotide sequence that is a specific gene between individuals of a given species. Polymorphic variants may also encompass "single nucleotide polymorphisms" or single base mutations in which the nucleotide sequence has a base change. The presence of SNp may indicate, for example, the propensity of a particular population to develop a disease condition, i.e., susceptibility and resistance. 158213.doc -18· 201210611 Derivatized polynucleotides include nucleic acids that undergo chemical modification, such as replacement of hydrogen with an alkyl group, a thiol group, or an amine group. For example, a derivatized nutrient derivative may comprise a non-naturally occurring moiety, such as a modified sugar moiety or an intersaccharide linkage. Examples include phosphorothioates and other sulfur-containing species known in the art. The derivatized nucleic acid may also contain a label 'including a radioactive nucleotide, an enzyme, a refractory agent, a chemiluminescent agent, a chromogen, a substrate, a cofactor, an inhibitor, a magnetic particle, and the like.

A "derived" polypeptide or peptide is, for example, a polypeptide or peptide modified by glycosylation, pegylation, sulphation, sulfation, reduction/alkylation, deuteration, chemical coupling or mild formalin treatment. . Derivatives may also be modified to contain direct or indirect fingerprinting, including but not limited to, radioisotope labels, fluorescent labels, and enzyme labels. The term "animal" or "patient" as used herein is intended to include (4) human sheep, elk, deer, mule deer, sau, mammal, monkey, horse, cow, ox, goat, dog, juvenile, rat, Mice, birds, chickens, reptiles, fish, insects and arachnids. "Mammal" covers warm-blooded mammals (such as humans and manufactured animals) who are usually treated with medical care. Examples __, canines, equines, bovines and humans, and only humans. "Treatment" encompasses the treatment of a disease condition in a mammal, and includes: (4) an anti-disease condition at the midline of the mammal, particularly in the mammalian condition of the disease but not yet diagnosed as having the condition, such as preventing its development; and /_ Reducing the suppression of disease and disease, the disease condition subsides until the desired two... The m treatment required for the disease also includes the improvement of the disease I58213.doc -19- 201210611 (eg, relieve pain or discomfort), where the improvement may or It may not directly affect the disease (eg cause, spread, performance, etc.). "Cancer" as used herein refers to all types of cancer or neoplasms or malignancies found in mammals, including but not limited to: leukemia, lymphoma, melanoma, carcinoma and sarcoma. Cancer itself manifests itself as a "tumor" or tissue that contains malignant cancer cells. Examples of tumors include sarcomas and carcinomas such as, but not limited to, fibrosarcoma, spot sarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, vascular sarcoma, endothelium, lymphangiosarcoma, lymphatic endothelial sarcoma , synovial tumor, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, #巢癌, prostate cancer, squamous cell carcinoma, basal cell carcinoma, gland Cancer, sweat gland cancer, sebaceous gland cancer, papillary carcinoma ' papillary adenocarcinoma, cystadenocarcinoma, myeloid carcinoma, bronchial carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, squamous cell tumor, embryonal carcinoma, Wimm's tumor tumor, cervical cancer, sputum tumor, lung cancer, small cell lung cancer, bladder cancer epithelial cancer, glioma, astrocytoma, test cell tumor, Gu Yin e tumor to s membranous tumor, pine Adenoma, hemangioblastoma, acoustic neuroma's recruitment of dendritic glioma, cerebrospinal mineraloma, melanoma, neuroblastoma and retinal palsy, sparse-T-, ·, · cell tumor . Other cancers that can be hunted by the disclosed compositions of the invention include, but are not limited to, for example, Hodgki's disease (Hodgki heart DiSeaSe), non-Hodgkin's lymphoma (N〇nH〇dgkin, s Lymphoma), multiple !·生月赵瘤, neuroblastoma, breast cancer, ovarian cancer, lung cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, small cell lung tumor, primary brain tumor, stomach cancer (st_ch __), knot 158213.doc -20- 201210611 Intestinal cancer, malignant pancreatic insulinoma, malignant carcinoid 'bladder cancer, gastric cancer, premalignant skin lesions, testicular cancer, lymphoma, squamous cell carcinoma, nerve Blastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, cervical cancer, endometrial cancer, adrenal cortical cancer, and prostate cancer. "Nervous disease or condition" as used herein refers to any disease or condition of the nervous system and/or the visual system. "Nervous diseases or conditions" include diseases or conditions involving the middle sacral nervous system (brain, brainstem and cerebellum), the peripheral nervous system (including the cranial phrenic nerve), and the autonomic nervous system (partly located in the central nervous system and the peripheral nervous system). 0 neurological diseases or conditions include (but are not limited to) acquired epilepsy aphasia; acute disseminated encephalomyelitis; adrenal leukodystrophy; age-related macular degeneration; corpus callosum dysplasia; agnostic disorder, Ecardi syndrome (Aieardi syndrome); Alexander disease; Alpers (disease); alternating hemiplegia, Alzheimer's disease; vascular madness Q; amyotrophic lateral sclerosis ; no brain; Angelman syndrome; hemangiomatosis; anoxia; aphasia; use of no; arachnoid cyst; arachnoiditis; Anor〇-hiari malformation (Anr〇nl_ Chiari malformation); arteriovenous Malformation; AsperSei* syndrome; telangiectasia dysmotility; attention deficit hyperactivity disorder; autism Autonomic dysfunction; back pain; Batten disease, Behcet's disease; Bell's palsy; benign primary tendon; benign local muscle atrophy; benign cranial Within ifj pressure, Binswanger's disease; risk 158213.doc -21 * 201210611 Cancer 布 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛Abscess; brain injury; brain tumor (including glioblastoma multiforme); vertebral tumor; Brown-Sequard syndrome; Canavan disease; carpal tunnel syndrome; burning pain Central pain syndrome; central cerebral spinal cord lysis; head disorder; cerebral aneurysm; cerebral arteriosclerosis; brain atrophy; cerebral giant disease; cerebral palsy; Chuck-Mali-Dos disease (Charc〇t_Marie_ Tooth disease); chemotherapy-induced neuropathy and neuralgia; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy; chronic pain; chronic regional pain syndrome; Coffin Lowry syndrome; coma, including persistent vegetative state; congenital bilateral flanks; cortical basal ganglia degeneration; cranial arteritis, craniosynostosis; Creutzfeldt_Jak〇b disease; Sexual injury disease; Cushing, s syndr〇me; giant cell inclusion disease; cell giant virus infection; dance eye-dance foot syndrome, Dandy Walk syndrome; Dawson disease De M〇rsieris syndrome; Dejerine_Klumke paisy; dementia, dermatomyositis; diabetic neuropathy; diffuse sclerosis; autonomic dysfunction; Dyslexia; dystonia; early infantile epilepsy; airborne sella syndrome

Syndr〇me); encephalitis; brain swelling; brain trigeminal neurovascular disease; epilepsy, Erb, s palsy; primary trembling; Fabry, S Disease); Fahr, s syndrome; 158213.doc -22- 201210611 syncope; familial spasm; hot seizure; Fisher syndrome; Friedreich's ataxia; frontotemporal dementia and other "tauopathy"; Gaucher's disease; Gerstmann's syndrome; giant cell arteritis; Cellular inclusion body disease; globular cell leukodystrophy; Guillain-Barre syndrome; HTLV-1 associated myelopathy; Hallerwoden-Spatz disease (Hallervorden-Spatz Head injury; headache; hemifacial spasm; hereditary spastic paraplegia; polyneuritis-type hereditary ataxia; herpes zoster; herpes zoster; Hirayama syndrome; HIV-related dementia And neuropathy (also AIDS) Performance); forebrain non-cracking malformation; Huntington's disease and other multi-crown glutamate repeats; water-free no brain malformation; hydrocephalus; hypercortisolism; hypoxia; Guided encephalomyelitis; inclusion body myositis; pigmentation disorder; infant phytanic acid accumulation disease; infantile refsum disease; infantile spasm; inflammatory myopathy; intracranial cyst; intracranial High pressure; Joubert syndrome; Keams-Sayre syndrome; Kennedy disease; Kinsboume syndrome; Klipper-Fair syndrome (Klippel) Feil syndrome); Krabbe disease; Kugelberg-Wel.ander disease; Kuru; Lafora disease; Lambert-Eaton severe Lambert-Eaton myasthenic syndrome; Lanta-Clivena 158213.doc -23- 201210611 Landau-Kleffner syndrome; dorsolateral medulla (Wallenberg) syndrome; learning difficulties Li's disease (Leigh's disease), even Lenn〇x_Gustaut syndrome, Lesch-Nyhan syndrome; brain white shell disease, Lewy body dementia; Cerebral palsy's atresia syndrome; L〇u Gehrig's disease (also known as motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease, Lem disease - neurological sequelae Lyme disease--neurological sequelae) 'Machado-Joseph disease; macrencephaly; megaiencephaly; Melkersson-Rosenthal syndrome; Menil Menieres disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; transient ischemic attack; Linear myopathy, Mobius syndrome; single limb muscle atrophy; motor neuron disease, moyamoya disease; mucopolysaccharidoses; multiple infarct dementia; multifocal Motor neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with orthostatic hypotension; muscular dystrophy; myasthenia gravis; Zhao Le lost diffuse sclerosis; infant myoclonic brain lesions Myoclonus; myopathy; congenital myotonia; narcolepsy; neurofibromatosis; antipsychotic malignant syndrome, neurological manifestations of AIDS; neurological sequelae of wolf therapy; neuromuscular rigidity; neurogenic wax Lipofuscin; neuronal migration, Niemann-Pick disease; O'Sullivan-McLi 158213.doc •24· 201210611 O'Sullivan-McLeod syndrome; occipital neuralgia; potential Spiral insufficiency sequence disorder; Ohtahara syndrome; 撖 桥 脑 脑 ; ;; 僵 肌 挛; optic neuritis; standing hypotension; overuse syndrome; paresthesia; neurodegenerative diseases or disorders ( Parkins〇nis disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dementia, multiple sclerosis and His diseases and conditions related to neuronal cell death); congenital myotonia; paraneoplastic disease; paroxysmal seizure; parry R〇mberg syndr〇nie; Pei-Mei Disease (Pelizaeus-Merzbacher disease); periodic paralysis; peripheral neuropathy; painful neuropathy and neuralgia; persistent vegetative state; diffuse developmental disorders; photorefractive reflex; phytanic acid accumulation disease; Pick's disease); nerve contusion; pituitary tumor; polymyositis; hole brain, post-polio syndrome; herpes zoster neuralgia; post-infectious encephalomyelitis' orthostatic low gold pressure; Praderweili syndrome (prader_Willi ◎ syndrome Primary spinal cord lateral sclerosis; prion disease; progressive facial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing gray matter atrophy; progressive nucleus itching; pseudocephaloma; Ramsay-Hunt syndrome (type I and type 11); Rasmussen's encephalitis; reflex sympathetic dystrophy syndrome; Lefsum's disease Refsum disease; repetitive motion sickness; repetitive stress injury; leg restlessness syndrome; retrovirus-associated spinal cord disease; Rett Syndrome; Raytheon syndrome syndrome; St. Patrick's disease (Saint vhus) Dance); Sandefoff 158213.doc -25- 201210611 Disease (Sandhoff disease); Schilder's disease (Schilder, s disease); Brain splitting; Visual septal hypoplasia; Infant cradle syndrome; Herpes zoster; Shy-Drager syndrome; Sjogren's syndrome; sleep apnea; Soto's syndrome; sputum; spina bifida; spinal cord injury; spinal cord tumor; spinal muscular atrophy; Stiff human syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subcortical arteriosclerotic encephalopathy; Sydenham chorea; fainting; syringomyelia Delayed exercise difficulty; Tay-Sachs disease; temporal arteritis; spinal cord syndrome; Thomsen disease; chest export syndrome Painful convulsions; Todd's paralysis; T〇urette syndrome; transient ischemic attack; infectious spongiform encephalopathy; transverse myelitis; traumatic brain injury; trembling; Neuralgia; tropical spastic paraplegia, tuberous sclerosis; vascular dementia (multiple infarct dementia); vasculitis, including temporal arteritis; 希希伯_林道病(v〇n Hippel-Lindau disease); Waulenberg syndrome (WaUenberg, s syndrome); Werdnig_H〇ffman disease 'west syndrome'; west whip; whiplash; Williams Syndrome; Wilder's disease (S disease); and Zeweger syndrome (ZeUweger syndr〇me). A "proliferative disease or condition" includes, but is not limited to, a hematopoietic neoplastic disorder involving a proliferative/neoplastic cell of hematopoietic origin caused by bone marrow, lymphoid or red jk spectroscopy or its precursor cells. These conditions include (but are not limited to) red 158213.doc •26· 201210611

Jk blastoma leukemia, acute promyelocytic leukemia (APML), chronic myelogenous leukemia (CML), lymphoid malignancies including, but not limited to, acute lymphoblastic leukemia (ALL) (which includes B lineage ALL and T Lineage ALL), chronic lymphocytic leukemia (CLL), young lymphocytic leukemia (PLL), hairy cell leukemia (HLL), and Waldenstrom's macroglobulinemia (WM). Other forms of malignant lymphoma include, but are not limited to, non-Hodgkin's lymphoma and its variants, peripheral tau cell lymphoma, adult tau cell leukemia/lymphoma (ATL), cutaneous T-cell lymphoma (CTCL), large Granulocyte lymphocytic leukemia (LGF), Hodgkin's disease, and Reed-Sternberg disease (Reed-Sternberg disease;). "Inflammation" refers to systemic inflammatory conditions and conditions associated with local migration and attraction of monocytes, leukocytes and/or neutrophils. Examples of inflammation include, but are not limited to, infection with pathogenic organisms (including gram-positive bacteria, gram_negative bacteria, viruses, fungi, and parasites (such as protozoa) And worms)), transplant rejection (including rejection of solid organs such as the kidneys, liver, heart, lungs or cornea, and rejection of bone marrow transplants, including graft versus host disease (GVHD)), or local chronic Or inflammation caused by acute autoimmune or allergic reactions. Autoimmune diseases include acute spheroid nephritis; rheumatoid or reactive arthritis; chronic glomerulonephritis; inflammatory bowel disease, such as Crohn's disease, ulcerative colitis, and necrosis Enterocolitis; hepatitis; sepsis; alcoholic liver disease; nonalcoholic steatosis; granulocyte transfusion related syndrome; inflammatory skin diseases such as contact dermatitis, atopic dermatitis, psoriasis; all 158213, doc -27- 201210611 Physical lupus erythematosus (SLE), autoimmune verrumitis, multiple sclerosis and some forms of diabetes, or any other autoimmune condition in which an individual's own immune system attacks cause pathological tissue damage. Allergic reactions include allergic asthma, chronic bronchitis, acute and delayed allergy. Systemic inflammatory conditions include reperfusion following sepsis, burns, or ischemic events (eg, thrombotic events in the heart, brain, intestine, or peripheral vascular structures, including myocardial infarction and stroke). Septicemia, ARDS, or multiple organ function Inflammation associated with disorder syndromes. Inflammatory cell recruitment also occurs in atherosclerotic plaques. Inflammatory cell recruitment also occurs in atherosclerotic plaques. Inflammation includes, but is not limited to, non-Hodgkin's lymphoma, Wegener's granulomat〇sis, Hashimotc/s thyroiditis, hepatocellular carcinoma, thymic atrophy, chronic pancreatitis , rheumatoid arthritis, reactive lymphoproliferative, osteoarthritis, ulcerative colitis, papillary carcinoma, Crohn's disease, ulcerative colitis, acute cholecystitis, chronic cholecystitis 'cirrhosis, chronic parotid gland Inflammation, peritonitis, acute otitis, chronic pancreatitis, chronic gastritis, adenomyosis, endometriosis, acute cervicitis, chronic cervicitis, lymphatic hyperplasia, multiple sclerosis, idiopathic thrombocytopenia Sexual purple I secondary to hypertrophy, original, psoriasis, emphysema, chronic pyelonephritis and chronic cystitis. Polynucleotide and oligonucleotide compositions and molecules are in one embodiment. In one embodiment, the target is a nucleic acid sequence comprising a base indoleamine phosphoribosyltransferase (NAMPT), including有 ρ 从 t t ( ( ( ( ( ( ( 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 NAMPT) An enzyme that converts nicotinamide to a nicotinamide mononucleotide by a nicotinamide single nucleotide transadenosylase in a mammalian biosynthetic pathway It is converted to nicotinamide adenine dinucleotide (NAD+). NAMPT is the rate-limiting factor in NAD+ biosynthesis. NAD+ and its phosphorylated and reduced form are redox reactions, which accept hydrides and coenzymes that supply hydrides. It has a central role in cell metabolism and energy production. NAD+ can also activate sirtuins (SIRT), which are histones and many transcriptional scorpions. Base enzymes. NAMPTs are localized in and function in the intracellular and extracellular compartments. Intracellular NAMP T produces NAD and thus has a cytoprotective benefit. NAMPT was originally identified as a gene product expressed in activated peripheral human lymphocytes and is associated with the maturation of B cell precursors, and is therefore referred to as pre-B cell potentiating factor. It is shown that in clinical and experimental sepsis, NAMPT is up-regulated during neutrophil activation and acts as an anti-apoptotic factor for neutrophils. In stimulated monocytes and in all-trans retinoic acid (ATRA) An increase in NAMPT content was observed during granule spheroid differentiation of induced myeloid leukemia cell line HL-60. NAMPT is a rate-limiting enzyme produced by NAD+, which is essential for SIRT1 activation and transcriptional regulation. The use of antisense raised nucleotides to prevent or treat diseases or conditions associated with NAMPT family members. Antisense nucleotides of the invention and/or stem cell regeneration obtained using and/or having antisense compounds can be utilized Exemplary nicotine-transamine phosphoribosyltransferase (NAMPT)-mediated diseases and disorders of cell/tissue therapy include: functions with NAMPT and / 158213.doc •29- 20121 0611 or a disease or condition associated with abnormal expression, cancer, a disease or condition characterized by cell proliferation or characterized by cell proliferation, apoptosis, a disease or condition associated with a mutation or abnormality in the expression or function of ΝΑΜρτ, cytopenia (eg cytopenia such as bone marrow or lymphocyte), neutropenia (such as severe congenital neutropenia, other forms of congenital and acquired neutropenia, chemotherapy induced Febrile neutropenia, etc.), leukemia, acute myeloid leukemia, cancer of bone marrow cell line, malignant disease associated with elevated NAMPT levels, congenital non-malignant disease or condition with hematopoiesis, attributed to Immunodeficiency, atherosclerosis, diseases or conditions associated with constant glucose abnormalities, diseases or conditions associated with abnormal insulin secretion, obesity, cardiovascular disease or condition, hepatocyte apoptosis, performance and/or activity change, a disease or condition associated with abnormal mitochondrial biogenesis, a disease, condition or condition associated with skeletal muscle; A disease, disorder, or condition associated with abnormal myogenesis; a disease, disorder, or condition associated with the FoXO gene family; a disease or condition associated with abnormality of the liver triglyceride; a disease associated with circadian rhythm activity, A disease or condition; a disease or condition associated with the immune system; a disease, disorder, or condition associated with epigenetic reprogramming after endotoxin tolerance; a viral infection, a disease associated with an abnormal antiviral response to interferon Or a condition, a chronic inflammatory disease or condition (eg, an inflammatory bowel disease, including Crohn's disease, ulcerative colitis, psoriasis, arthritis, etc., or a vascular disease or condition (eg, chronic ulceration, ischemia) Sexual wind, myocardial infarction, angina pectoris and vascular dementia, etc.), metabolic diseases or conditions, inflammation 158213.doc -30- 201210611 syndrome, aging, nonalcoholic fatty liver disease, and SIRT performance with deacetylase and / Or a disease or condition associated with an abnormal activity. In an embodiment of the invention, a treatment and/or makeup regimen and associated adjustment therapy are provided to an individual in need of skin treatment or at risk of developing a condition requiring skin treatment. The diagnosis can be made, for example, based on the individual's NAMPT status. The amount of NAMPT expression in a patient, such as a designated tissue of the skin, can be determined by methods known to those skilled in the art and described elsewhere herein, for example, by analyzing tissue using PCR-based or antibody-based detection methods. In one embodiment, sputum administration using one or more antisense oligonucleotides is administered to a patient in need thereof to prevent or treat any of the abnormalities associated with the performance, function, and activity of NAMPT in the normal control group. A disease or condition. In one embodiment, the oligonucleotide is specific for a polynucleotide of NAMPT, including but not limited to a non-coding region. NAMPT targets include variants of NAMPT; mutants of NAMPT, including SNPs; non-coding sequences of genomics; dual genes, fragments and analogs thereof. The oligodeoxynucleotide is preferably an antisense RNA molecule. According to an embodiment of the invention, the target nucleic acid molecule is not limited to the single 'NAMPT polynucleotide, but also extends to any isoforms of NAMPT, receptors, homologs, non-coding regions and analogs thereof. In one embodiment, the oligonucleotide targets a natural antisense sequence of a NAMPT target (a natural antisense sequence encoding a non-coding region), including but not limited to variants, dual genes, homologs, mutants Natural antisense sequences of derivatives, fragments, and their complementary sequences. The nucleotide raised is preferably an antisense RNA or a 158213.doc -31-201210611 DNA molecule. In one embodiment, the polymeric collection compounds of the present invention also include variants in which different bases are present at one or more nucleotide positions in the compound. For example, if the first nucleotide is adenine, a variant containing thymidine, guanosine, cytosine or other natural or non-natural nucleotides at this position can be produced. This can be done anywhere in the antisense compound. These compounds are then tested using the methods described herein to determine their ability to inhibit the performance of the target nucleic acid. In some embodiments, the homology, sequence identity or complementarity between the antisense compound and the target is from about 5% to about 6%. In some embodiments, the homology, sequence identity, or complementarity is from about 6% to about 7%. In some embodiments, homology, sequence identity or complementarity is from about 7% to about 80%. . In some embodiments, the homology 'sequence identity or complementarity is from about 80% to about 90%. In some embodiments, the homology, sequence identity, or complementarity is about 90%, about 92%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 1〇〇%. When the binding of the compound to the target nucleic acid interferes with the normal function of the target nucleic acid, resulting in reduced activity, and a sufficient degree of complementarity to avoid non-specific binding of the antisense compound to the non-target nucleic acid sequence under conditions requiring specific binding' Antisense compounds can specifically hybridize. Such conditions include, i.e., physiological conditions in the case of in vivo assay or therapeutic treatment, and conditions for performing assays in the case of in vitro assays. When a compound binds to a target DNA or RNA molecule to interfere with the normal function of the target DNA or RNA, resulting in reduced utility, and a sufficient degree of complementation to avoid the need for specific binding, That is, in the case of in vivo assay or therapeutic treatment and under physiological conditions in the case of in vitro assay, the antisense compound is non-specifically bound to the non-target sequence under the conditions of performing the assay, the antisense compound ( Whether it is DNA, RNA, chimera, substituted, etc., it can specifically hybridize.

In one embodiment, targeting NAMPT (including, but not limited to, antisense sequences identified and amplified using, for example, PCR, hybridization, etc., ie, one or more sequences as set forth in SEQ ID NO. 2 to 16 and Its analogs) can modulate the performance or function of NAMpT. In the examples, the performance or function was up-regulated compared to the control group. In one embodiment, the performance or function is down-regulated compared to the control group. In one embodiment, the oligonucleotide comprises a nucleic acid sequence as set forth in SEQ m N〇: 17 to 31, including antisense sequences identified and amplified using, for example, PCR, hybridization, and the like. Such oligonucleotides may comprise one or more modified nucleotides, shorter or longer fragments, modified linkages, and the like. Examples of modified bonds or internucleotide linkages include phosphorothioates, phosphorodithioates, or the like. In one embodiment, the nucleotide comprises a phosphorus derivative. The base derivative (or modified phosphate group) which can be attached to the sugar or sugar analog moiety of the modified oligonucleotide of the present invention may be a monophosphate, a diphosphate, a triphosphate, an alkyl phosphate Esters, alkyl phosphates, phosphorothioates and the like. The preparation of the above phosphate analogs and their incorporation into nucleotides, modified nuclear acid and nucleic acid are also known per se and need not be described herein. Those skilled in the art also utilize the specificity and sensitivity of antisense sequences for therapeutic use. Antisense oligonucleotides have been used as therapeutic moieties in the treatment of disease conditions in animals and humans. Antisense nucleotides have been safely and efficiently administered to 158213.doc •33-201210611 with humans and many clinical trials are currently underway. Thus, a shirt, a nucleoside acid can be a suitable therapeutic modality' that can be configured to be useful in the treatment of cells, tissues, and animals, particularly humans. In an embodiment of the invention, an antisense compound is recruited, particularly a nucleotide that binds to a target nucleic acid molecule and modulates the expression and/or function of the molecule encoded by the gene of interest. The function of the DNA to be disturbed includes, for example, replication and transcription. The function of the RNA to be disturbed includes all important functions, such as translocation of the rna to the protein translation site, translation of the protein from the RNA, splicing of the RNA to produce one or more mRNA species, and RNA may participate in or may promote catalytic activity. Depending on the function required, the function can be adjusted up or down. Antisense compounds include antisense oligomeric compounds, antisense oligonucleotides, external leader mEGS) nucleomonic acid, alternative splicing, primers, probes, and other polymeric compounds that hybridize to at least a portion of the target nucleic acid. Thus, such compounds can be introduced in the form of single-stranded, double-stranded, partially mono- or cyclic oligomeric compounds. In the context of the present invention, the drying of an antisense compound to a particular nucleic acid molecule can be a multi-step process. This method usually begins with (iv) the target nucleic acid that will regulate the function. The target nucleic acid can be, for example, a nucleic acid molecule that exhibits a specific cell or disease condition: a cellular gene (or mRNA transcribed from a gene), or from an infectious agent. In the present invention, the target nucleic acid encodes a secret amine trans-luciferase (NAMPT). The dry direction method also generally includes determining at least one target region, segment or site within the rod nucleic acid for performing the antisense interaction such that a desired effect, such as to modulate performance, is produced. Within the context of the present invention, the term 158213.doc -34 - 201210611 region is defined as having at least one identifiable structure, function, and knives in a target nucleic acid. The segment is within the region of the target nucleic acid. A "segment" is defined as a smaller or sub-portion of the zone within the target «. The "site" as used in the present invention is defined as the position within the target nucleic acid.

In an embodiment, the antisense oligonucleotide binds to the natural antisense sequence of nicotinamide to phosphoribosidase (ΝΑΜΡΤ) and modulates the expression and/or function of NAMpT (SEQ i). Examples of antisense sequences include seqidn〇·2 to 31°

In the present example, an antisense oligonucleotide binds to one or more segments of a base amide trans-luciferase (nAMPT) polynucleotide and modulates the expression and/or function of ΝΑΜρτ. The segments comprise at least 5 contiguous nucleotides of a purine sense or antisense polynucleotide. In one embodiment, the antisense oligonucleotide is specific for the natural antisense sequence of deuterium' wherein the combination of the oligonucleotide and the natural antisense sequence of NAmpt modulates the expression and/or function of purine. In one embodiment, the oligonucleotide compound comprises the sequence set forth in SEQ ID NOs: 17 to 31, i.e., an antisense sequence identified and amplified using, for example, PCR, hybridization, and the like. Such oligonucleotides may comprise one or more modified nucleotides, shorter or longer fragments, modified linkages, and the like. Examples of modified linkages or internucleotide linkages include phosphorothioates, dithiophosphates, or the like. In one embodiment, the nucleotide comprises a fill derivative. The phosphorus derivative (or modified phosphate group) which can be attached to the sugar or sugar analog moiety of the modified nucleotide of the present invention may be a monophosphate, a diphosphate, a tri-plate acid ester, an alkyl group. Phosphate esters, alkyl phosphates, phosphorothioates and their similar groups of l5S2B.doc-35-201210611. The preparation of the above-mentioned phosphate vinegar analogs and their incorporation into nucleotide acid, sister-modified nucleotides and oligonucleotides are also known per se and need not be described herein. The translation initiation scheme is known in the art. In the transcribed m let the molecule; in the corresponding face molecule is 55: ATG), so the translation initiation codon is also called "naco codon",

Start codon or "start codon". A few genes have a translation initiation codon with the RNA sequence 5 GUG, 5'-UUG or 5'-CUG; and it has been shown that 5 -AUA, Ό /^ττβ 或 or 5-CUG play a role in vivo. Therefore, the terms "transfer start codon" and "start codon" can cover many dense columns, but in each case the starting amino acid is usually methionine (in a nuclear organism) or Methionine (in the context of the present invention, the prokaryotic gene may have two or more alternative initiation codon types or tissues or under a specific set of conditions may be preferred: in the context of the present invention, "Start codon" in vivo = "start codon" means that regardless of the sequence of the codons, the start of the transcription of the mRNA encoded by the gene encoding nicotine amide transphosphate phosphoribosylase (ναμρ) "Terminator codon" can be -ΤΛΑ〇Α, 5,_UGA(^ ^DNA^ ^ ^ ^ ^ -Λ ^ The term "starting codon" and "translation starting secret" - or the base is covered in self-translating The beginning codon of Ren Hai or) about 25 to about 50 consecutive nucleotide words "stop codon area" and "transfer, political stop ... "similarly 'surgery (four) termination (four) sub-area" means 158213. Doc -36- 201210611 mRNA or base time covers the self-translating stop codon - direction (ie 5, or 3,) on about 25 A portion of about 5G consecutive cores (4), "starting codon region" (or "transition initiation codon region") and "terminating codon region" (or "transition termination codon region") are available for use in the present invention. The antisense compound is effectively targeted to all regions. It is known in the art that the open reading frame (ORF) or "coding region" of the region between the translation initiation codon and the translation stop codon is also an effective target. In the context of the present invention, the target region is the intragenic region encompassing the translation initiation codon or the translation stop codon of the open reading frame (GRF) of the gene. Refers to the 5, non-translated region (5.utr) of the translation initiation codon from the translation initiation codon 5, and thus includes the acidity between the cap 5 and the translation initiation codon ( Or the corresponding nucleotide acid in the gene. Another target region includes 3 in the direction of the translation stop codon in _A, the partial ❸ in the direction, the non-translated region Q (3'UTR), and Thus including the translation of the mRNA stop codon with the nucleotide between the 3, _ (or genetically) Corresponding nucleotides. mRNA25, the cap site comprises a Ν' methylated guanine nucleoside residue joined to the most terminal residue of mRNA 2 51 via a 5'-5' triphosphate linkage. The mRNAi5, cap region is considered to include 5. The cap structure itself, and 50 nucleotides adjacent to the cap site. Another target region of the invention is the 5' cap region. Although some eukaryotic mRNA transcripts will be translated directly, many contain a terminology One or more regions are excised from the transcript before the transcript is translated. The remaining (and therefore translated) regions are called "exons" and spliced 158213.doc -37· 201210611 together form a continuous mRNA sequence. In one embodiment, the targeted splice site (ie, intron-exon junction or exon_inclusion) is involved in a case where aberrant splicing is associated with a disease or an overproduction of a particular splicing product is associated with a disease. Sub-joints are especially useful. Another embodiment in which the abnormal fusion junction due to rearrangement or deletion is the target site. mRNA transcripts produced by splicing two (or more) mRNAs from different gene sources are referred to as "fusion transcripts". Introns can be efficiently targeted using antisense compounds that target, for example, DNA or precursor mRNA. In one embodiment, the antisense oligonucleotide binds to the coding and/or non-coding region of the polynucleotide of interest and modulates the expression and/or function of the target molecule. In one embodiment, the antisense oligonucleotide binds to a natural antisense polynucleotide and modulates the expression and/or function of the target molecule. In one embodiment, the antisense raised nucleotide binds to a sense polynucleotide and modulates the expression and/or function of the target molecule. Alternative RNA transcripts can be produced from the same genomic region of DNA. Such alternative transcripts are generally referred to as "variants." More specifically, "precursor mRNA variants, allogeneic" are transcripts produced by the same genome (10), which differ in their initiation or termination from other transcripts produced by the same genomic DNA and contain introns and Proton sequence. One or more exons or intron regions or portions thereof are excised during splicing, and the steroid mRNA variants produce smaller r mRNA variants. Therefore, the mRNA variant is a pre-warmed body mRNA variant, and each unique precursor mRNA variant must always produce a unique mRNA variant due to splicing. These mRNA variants are also referred to as "alternative splice variants". If 158213.doc -38· 201210611 is present in the splicing of the precursor mRNA variant, the precursor mRNA variant is identical to the mRNA variant. Variants can be produced by using alternative signals to initiate or terminate transcription. The precursor mRNA and mRNA may have more than one start codon or stop codon. A variant derived from the use of an alternative start codon precursor mRNA* mRNA is referred to as an "alternative initiation variant" of the precursor mRNA or mRNA. Their transcripts using alternative stop codons are referred to as "alternative termination variants" of the precursor mRNA or mRNA. A particular type of surrogate termination variant is a "polyA variant" in which a plurality of transcripts produced are replaced by a transcriptional machinery that alternatively selects a rpolyA termination signal, thereby terminating in a unique polyA position. Produced by the transcript of the point. Within the context of the present invention, the types of variants described herein are also examples of target nucleic acids. The position on the target nucleic acid to which the antisense compound hybridizes is defined as the portion of the target region targeted by the active antisense compound that is at least 5 nucleotides in length. Q Although certain sequences of some exemplary target segments are set forth herein, those skilled in the art will recognize that such sequences are used to illustrate and describe particular embodiments within the scope of the invention. Other target segments are readily identified by the average technician in accordance with the present invention. It is believed that a target segment of 5 to 100 nucleotides in length comprising at least 5 (f) consecutive nucleotides selected from a segment of the illustrative preferred target segment is also suitable for targeting. The target segment can comprise a DNA or RNA sequence comprising at least 5 contiguous nucleotides from the 5, _ terminus of an illustrative preferred target segment (remaining nucleoside 158213.doc -39 - 201210611 acid is a self-aligned target The upstream of the 5'-end of the segment begins and continues until the DNA or RNA contains a contiguous portion of the same DNA4 RNA of about 5 to about 1 nucleotide. Similarly, the preferred target segment is represented by a human or Chinese sequence comprising at least 5 contiguous nucleotides from the 3, _ terminus of an illustrative preferred target segment (the remaining nucleotide is Starting from the 3, _ end of the target segment, and continuing until the DNA or RNA contains the same 1)]8 or a contiguous segment of RNA) of about 5 to about 1 nucleotide. Those skilled in the art to provide the target segments shown herein will be able to identify other preferred target segments without undue experimentation. Once one or more target regions, segments or sites have been identified, an antisense compound that is sufficiently complementary to the target, i.e., sufficiently hybridized and of sufficient specificity, is selected to achieve the desired effect. In an embodiment of the invention, the anti-sense nucleoside I of the specific target is bound to a specific target of at least 5 nucleotides in length and can be synthesized such that each oligonucleotide is targeted to the overlapping sequence such that the synthesis The oligonucleotide covers the entire length of the target polynucleotide. Targets also include coding and non-coding areas. In one embodiment, the specific nucleic acid is preferably targeted using an antisense oligonucleotide. Targeting an antisense D to a particular nucleic acid is a multi-step process. This method usually begins by identifying the nucleic acid sequence that will regulate the function. The <target nucleic acid" can be, for example, a cellular gene (or mRNA transcribed from a gene) or a non-coding polynuclear, such as a non-coding, that is associated with a particular condition or disease condition. RNA can be classified as (1) messenger RNA (mRNA), which translates into protein, and (7) non-protein-encoding RNA (nCRNA). ncRNAs contain microRNAs, antisense transcripts, and other transcriptional units (τυ) that contain high-density stop codons and lack any broad open reading frame. Many ncRNAs appear to be 158213.doc 201210611 from the 3' untranslated region of the protein-coding locus (3·υτιι) to initiate the initiation site. ncRNAs are often rare, and at least half of the ncRNAs that have been sequenced by the FANT(R) M Association do not appear to be polyadenylated. For obvious reasons, most of the researchers focused on the polyadenylation mRNA processed and exported to the cytoplasm. Recently, it has been shown that the collection of non-polyadenylated nuclear RNA may be extremely large and that many of these transcripts are produced by so-called intergenic regions. The mechanism by which ncRNA modulates gene expression is base pairing with the target transcript. RNAs that act by base pairing can be grouped into (1) cis-encoding RNA, which encodes at the same genetic position, but acts on the strand opposite the RNA and thus appears to be completely complementary to its target; and (2 A trans-coded ruler, which encodes at a position corresponding to 111 <[8 different chromosomes, acts on the RNA and generally does not exhibit the full probability of pairing with its target. Without wishing to be bound by Wenli, the antisense oligonucleotides described herein can interfere with the expression of the corresponding sense messenger RNA by interfering with the antisense polynucleotide. However, this tone may be inconsistent (antisense knockout causes messenger 111^ eight increase) or may be one (antisense knockout causes concomitant messenger RNA reduction). In such cases, antisense raised nucleotides can target overlapping or non-overlapping portions of the antisense transcript, causing knockout or sequestration. Both the coding and non-coding antisense sequences can be targeted in the same manner, and any species can modulate the corresponding sense transcript in a consistent or inconsistent manner. The strategy for identifying novel nucleotides for use against a target can be based on any other means of knocking out antisense RNA transcripts with antisense oligonucleotides or modulating desired targets. Sincere 7: In the case of inconsistent regulation, knocking out antisense transcripts increases the performance of conventional (sense) genes. If the conventional (sense) gene coding is known or 158213.doc •41 · 201210611 疋 疋 疋 则 则 则 则 则 则 则 则 则 则 敲 敲 敲 敲 敲 敲 敲 敲 敲 敲 敲 敲 敲 敲 敲 敲 敲 可 可 可 可 可 可 可 可 可 可 可In general, in the case of consistent regulation, antisense and sense transcripts can be knocked out and thus a synergistic reduction in the expression of the conventional (sense) gene can be achieved. For example, if a knockout is achieved using an antisense oligonucleotide, this strategy can be applied to the antisense oligonucleotides of the dry sense transcript and (iv) the additional antisense oligo of the corresponding antisense transcript. Nucleotides' or simultaneously target a single energy symmetric antisense oligonucleotide that overlaps the sense and antisense transcripts. According to the present invention, antisense compounds include antisense oligonucleotides, ribonuclease outer leader (EGS) nucleotides, siRNA compounds, single strands = double stranded RNA interference (RNAi) compounds (such as Xiancai compounds) And other polymeric compounds that hybridize to at least a portion of the target nucleic acid and modulate their function. Thus, it may be DNA, RNA, class, class or a mixture thereof, or may be a mimic of one or more of them. Such compounds may be single-stranded, double-stranded, circular or hairpin oligomeric compounds and may contain structural elements such as internal or terminal protrusions, mismatches or rings. Linear antisense compounds are typically prepared, but may be joined or otherwise prepared into a ring and/or a branched shape. : A compound can include a construct such as a hybrid to form a complete or partial double ::: two strands or having sufficient self-complementarity to allow for a single strand; The two strands can be internally connected such that: free 3' or 5, the end, or can be joined to form a continuous inflammatory structure or "3 end ... with a hole to produce a single strand characteristic extension. The double-k compound may optionally include a protrusion at the end including a link to the end, a selected citric acid position, a sugar position, and a nucleus 158213.doc -42·201210611 group. Alternatively, the two strands can be joined via a non-nucleic acid moiety or a linker group. When formed by only _ strands, the dsRNA can be in the form of self-complementary hair (4) molecules that fold in half to form a duplex. Thus, the dsRNA can be in the form of a full or partial double strand. The specific regulation of gene expression can be achieved by the development of a stable gene expression in a transgenic cell line, but in some real cases, the gene expression or function is up-regulated. #由两: Or a single strand of a self-complementary hairpin type molecule in the form of a double-stranded pair, the two strands (or the single-stranded duplex forming region) are bases in Waldorf-gram A complementary RNA strand paired by Rick. Upon introduction into the system, the compounds of the invention may elicit one or more enzymes or structural proteins to function to affect cleavage or other modification of the target nucleic acid, or may function via a population-based mechanism. In general, nucleic acids (including nucleotides) can be described as "DNA-like" (ie, generally having one or more 2,-deoxy sugars, and generally having T instead of purine bases) or "RNA-like" (i.e., generally having one or more 2'-hydroxy sugars or 2'-modified sugars, and generally having an anthracene rather than a τ test group). Nucleic acid helices can employ more than one type of structure, most commonly A and B. In general, the nucleotide having a B-like structure is "DNA-like", and the oligonucleotide having an octagonal structure is "RNA-like". In some (funny) embodiments, the antisense compound can contain an A-shaped region and a b-shaped region. In one embodiment, the desired oligonucleotide or antisense compound comprises at least one of the following: antisense RNA, antisense DNA, chimeric antisense nucleotides, antisense recruitment comprising modified linkages Nucleotide, interfering RNA (RNAi), short interfering RNA (siRNA); micro-interfering RNA (miRNA); small temporal RNA (stRNA); 158213.doc -43- 201210611 or short hairpin RNA (shRNA); small RNA induction Gene activation (RNAa); small activating RNA (saRNA), or a combination thereof. dsRNA also activates gene expression, a mechanism called "small RNA-induced gene activation" or RNAa. The dsRNA targeting the gene promoter induces efficient transcriptional activation of related genes. RNAa has been demonstrated in human cells using synthetic dsRNA called "small activating RNA" (saRNA). It is currently unknown whether RNAa is retained in other organisms. Small double-stranded RNA (dsRNA) such as small interfering RNA (siRNA) and microRNA (miRNA) has been found to be a trigger for an evolutionarily conserved mechanism called RNA interference (RNAi). RNAi always causes gene quiescence by remodeling chromatin thereby inhibiting transcription, degrading complementary mRNA or blocking protein translation. However, in the case of a detailed intervening in the Examples section that follows, the display of nucleotides increases the expression and/or function of the nicotinamide-transferase-ribosylase (NAMPT) polynucleotide and its encoded product. It can also act as a small activating RNA (saRNA). Without wishing to be bound by theory, in the phenomenon known as dsRNA-induced transcriptional activation (RNAa), the target gene expression will be induced by targeting the sequence 'saRNA in the gene promoter. In another embodiment, the "better target segment" identified herein can be used to screen for other compounds that modulate the expression of a nicotine indoleamine phosphoribosyltransferase (NAMPT) polynucleotide. A "modulator" is a compound that reduces or increases the performance of a nucleic acid molecule encoding NAMPT and comprises at least one 5 nucleotide portion that is complementary to the preferred target segment. The screening method comprises the steps of contacting a preferred target segment of a nucleic acid molecule encoding a NAMPT-derived or natural antisense polynucleotide with one or more candidate modulators, and selecting one or more of 158213.doc-44- 201210611 Reduce or increase candidate modulators of the performance of nucleic acid molecules encoding NAMPT polynucleotides (eg, SEQ ID NOS: 17 to 31). Once the candidate modulator is shown to be capable of modulating (eg, reducing or increasing) the performance of a nucleic acid molecule encoding a NAMPT polynucleotide, the modulator can be used in other investigations of the function of the NAMPT polynucleotide or as the present invention. Research, diagnosis or therapeutic agent. Targeting a natural antisense sequence preferably modulates the function of the target gene. For example, the NAMPT gene (e.g., accession number NM_005746). In one embodiment, the target is an antisense polynucleotide of the NAMPT gene. In one embodiment, the antisense oligonucleotide targets a sense and/or natural antisense sequence of a NAMPT polynucleotide (eg, accession number NM_005746), variants thereof, dual genes, isoforms, and Sources, mutants, derivatives, fragments and complementary sequences. The oligonucleotide is preferably an antisense molecule and the target includes the coding and non-coding regions of the antisense and/or sense NAMPT polynucleotide. Preferred target segments of the invention may also be combined with the respective complementary antisense compounds of the invention to form stable double-stranded (duplex) oligonucleotides. These double-stranded oligonucleotide moieties have been shown in the art to modulate target expression via an antisense machine and to modulate translation and RNA processing. In addition, the double-stranded portion can undergo chemical modification. For example, the double-stranded portions have been shown to inhibit the target by triggering a classically hybridization of the antisense strands of the duplex with the target thereby triggering the enzymatic reduction of the target. In one embodiment, the antisense oligonucleotide targets a nicotine indoleamine phosphoribosyltransferase (NAMPT) polynucleotide (eg, accession number NM_005746), variants thereof, dual genes, isoforms, and Sources, mutants, derivatives, fragments and complementary sequences. The oligonucleotide is preferably an antisense molecule. 158213.doc -45- 201210611 According to an embodiment of the invention, the target nucleic acid molecule is not limited to NAMPT alone, but also to any of its polynucleotide variants and to produce, act, influence, or cause or be associated with NAMPT performance products. Any polynucleotide and/or any isoforms thereof. In one embodiment, the oligonucleotide targets a natural antisense sequence of a NAMPT polynucleotide, such as the polynucleotides set forth in SEQ ID NOs: 2 to 16, and any variants thereof, dual genes, Sources, mutants, derivatives, fragments and complementary sequences. Examples of antisense oligonucleotides are set forth in SEQ ID NOS: 17 to 31. In one embodiment, the oligonucleotide complements or binds to a nucleic acid sequence of a NAMPT antisense sequence, including, but not limited to, a non-coding sense and/or antisense sequence associated with a NAMPT polynucleotide; And modulating the performance and/or function of the NAMPT molecule. In one embodiment, the oligonucleotide complements or binds to the nucleic acid sequence of the NAMPT natural antisense sequence as set forth in SEQ ID NOs: 2 to 16, and modulates the expression and/or function of the NAMPT molecule. In one embodiment, the oligonucleotide comprises a sequence of at least 5 contiguous nucleotides of SEQ ID NOs: 17 to 31 and modulates the expression and/or function of the NAMPT molecule. Polynucleotide targets include NAMPT, including members of its family; variants of NAMPT; mutants of NAMPT, including SNPs; non-coding sequences of NAMPT; dual genes of NAMPT; fragments of species variants and the like. The priming acid is preferably an antisense molecule. In one embodiment, the oligonucleotide targeting the NAMPT polynucleotide comprises I58213.doc -46 - 201210611 comprising: antisense RNA, interfering RNA (RNAi), short interfering RNA (siRNA); micro interfering RNA (miRNA) Small time-series RNA (stRNA); or short hairpin RNA (shRNA); small RNA-induced gene activity (RNAa); or small activating RNA (saRNA). In one embodiment, targeting a nicotine indole to phosphoribosyltransferase (NAMPT) polynucleotide (e.g., SEQ ID NOs: 2 to 31) modulates the performance or function of such targets. In one embodiment, the performance or function is up-regulated compared to the control group. In one embodiment, the performance or function is down-regulated compared to the control group. In one embodiment, the antisense compound comprises the sequences set forth in SEQ ID NOs: 17 to 31. Such oligonucleotides may comprise one or more modified nucleotides, shorter or longer fragments, modified linkages, and the like. In one embodiment, SEQ ID NOS: 17 to 31 comprise one or more LNA nucleotides. Table 1 shows exemplary antisense oligonucleotides suitable for use in the methods of the invention. Table 1 :

Serial number antisense sequence name sequence SE〇IDNO:17 CUR-1724 SEQEDNO:18 CUR-1725 G*C*C*C*A*T*T*T*G*A*G*T*C*T*A *T*G*T*G*T*T SEQ ID NO: 19 CUR-1726 〇*0*0*Τ*0*Τ*0*Τ*0*0*Α*Α*0*0*0* Τ*0*Τ*0*Τ SEQIDNO:20 CUR-1727 g* D****c*c*a*t*a*c*c*t*a*c*t*t*c*a*c *c*a*g SEQIDNO:21 CUR-1728 G*C*C*C*T*A*G*GsiiT*C*T*T*T*Ci|!Ai|tT*A*G*C*A *C SEQIDNO: 22 CUR-1729 (^*γ*(^*Τ*Α*ί!Ι*Α*Τ*0*(^*Τ*Α*(Ι!*Α*Α*(^*(ΙΙ *Τ*(3*(Ι!*0 SEQIDNO:23 CUR-1730 C*A*T*G*C*C*A*C*C*A*C*G*T*C*C*A*G *C*T*A SE〇IDNO:24 CUR-1731 T*C*C*A*C*T*A*C*C*A*C*C*A*C*C*A*C*C* A*T*C SE〇EDNO:25 CUR-1732 G* Tintin*c*A*G*C*C*A*T*G*C*C*T*C*C*A*G*T SE〇 IDNO:26 CUR-1733 A*G*G*A*G*G*G*A*C*A*A*G*A*G*G*G*G*A*T*G*G*A SEQIDNO:27 CUR-1734 A*G*A*T*G*G*G*C*A*G*T*A*G*G*G*A*G*G*C*T*C SEQIDNO:28 CUR-1735 g* t*g*g*c*g*t*g*a*c*t*t*c*a*g*g*a*g*g*a SEQIDNO:29 CUR-1736 G*t*T*G *C*C*A*A*C*T*C*G*T*T*T*C*C*C*A*G*G SEQIDNO:30 CUR-1737 C*A*G*G*G* T*C*A*G*G*A*G*G*A*T*C*A*G*G*A SEQIDNO:31 CUR-1505 Control sequence C*c*T*C*T*C*C *A*C*G*C*G*C*A*G*T*A *C*A*T*T 158213.doc •47· 201210611 The modulation of the desired target nucleic acid can be carried out by several methods known in the art, for example, antisense oligonucleotides, siRNA, and the like. An enzymatic nucleic acid molecule (e.g., ribonuclease) is a nucleic acid molecule capable of catalyzing one or more of a variety of reactions' including the ability to repeatedly cleave other individual nucleic acid molecules in a nucleotide base sequence specific manner. These enzymatic nucleic acid molecules can be used, e.g., almost dry to any RNA transcript. Due to its sequence specificity, trans-lytic enzymatic nucleic acid molecules have been shown to be promising agents for human diseases. Enzymatic nucleic acid molecules can be designed to cleave specific rna targets within the background of cellular RNA. This cleavage event renders 11111>^ non-functional and eliminates protein expression from the RNA. In this way, the synthesis of proteins associated with disease conditions is selectively inhibited. In general, an enzymatic nucleic acid having an RNA cleavage activity acts by first binding to a target RNA. The binding proceeds via a target binding moiety of the enzymatic nucleic acid which remains in close proximity to the enzymatic moiety of the molecule used to cleave the target rna. Thus, the enzymatic nucleic acid is first recognized, and then binds to the target RNA via a complementary pairing, and I binds to the correct position, i.e., acts to cleave the target Rna in an enzymatic manner. Strategic cleavage of this target RNA will disrupt its ability to directly synthesize the encoded protein. After the S-enzymatic nucleic acid binds and cleaves its RNA target, it detaches from the other RNA to search for another target and can repeatedly bind and cleave the new target. Several methods such as phosphodiesters have been catalyzed by several methods such as the in vitro selection (evolution) strategy (〇rgel, (1979) Proc. R s〇c L〇nd〇n, B 2〇5, 43勹. Novel nucleic acid catalysts for cleavage and ligation of linkages and guanamine linkages. 158213.doc -48- 201210611 The development of catalytically active ribonuclease will significantly facilitate the use of RNA for cleavage of RNA for the purpose of regulating gene expression. Any strategy of the enzyme. Hammerhead ribonuclease acts, for example, at a catalytic rate (kcat) of about 1 miI T1 in the presence of a saturated (1 mM) concentration of Mg2+ cofactor. Artificial "RNA ligase" ribonuclease has been shown. The corresponding self-modification reaction is catalyzed at a rate of about 100 min·1. In addition, certain modified hammerhead ribonucleases having a binding arm composed of DNA are known to be close to 1 〇〇 min-i. The rate catalyzes the cleavage of RNA. Finally, the replacement of specific residues in the catalytic core of the hammerhead with certain nucleotide analogs results in a modified ribonuclease showing a catalytic rate improvement of up to 1 fold. These findings indicate ribose The acidase can be significantly greater than the catalytic rate promoted by most natural self-cleaving ribonucleases in vitro to promote chemical conversion. The structure of certain self-cleaving ribonucleases can then be optimized for maximum catalytic activity, or can be prepared for RNA-packed diacetate cleavage shows a significantly faster rate of new RNA motifs. 1987 (Uhlenbeck, Ο. C. (1987) Nature, 328: 596-600) first demonstrates an RNA catalyst that conforms to the "hammerhead" model. The RNA is cleavable by intermolecular cleavage. The RNA catalyst is recovered and reacted with various rnA molecules, indicating that it is indeed catalytic. The k-RNA based on the "hammerhead" motif has been used to carry out the appropriate bases in the catalytic RNA. Alter to maintain the necessary base pairing with the target sequence to cleave the specific target sequence. This allows the use of a catalytic ruler to cleave the target sequence and indicates that the catalytic RNA designed according to the "Clock" model can cleave specific receptors in vivo. RNA interference (RNAi) has become an effective tool for regulating gene expression in mammalian and mammalian cells 158213.doc -49· 201210611. RNA itself or in the form of DNA transmits small interfering RNA (siRNA), using a coding sequence that expresses a plastid or virus and a small hairpin RNA that is processed into siRNA. This system is capable of efficiently transporting precursor siRNA into the cytoplasm where it is The precursor siRNA is active and allows gene expression using a regulated and tissue-specific promoter. In one embodiment, the oligonucleotide or antisense compound comprises a ribonucleic acid (RNA) and/or (DNA) polymer. Or a polymer, or a mimetic, chimera, analog or homolog thereof. The term includes oligonucleotides consisting of naturally occurring nucleotides, sugars, and covalent internucleoside (backbone) linkages, as well as oligonucleotides having functionally similar non-naturally occurring portions. Such modified or substituted oligonucleotides are generally more desirable relative to the native form due to desirable properties such as enhanced cellular uptake, enhanced affinity for the target nucleic acid, and enhanced stability in the presence of nucleases. According to the invention, an oligonucleotide or "antisense compound" includes an antisense oligonucleotide (eg, RNA, DNA, mimetic, chimera, analog or homolog thereof), ribonuclease, external leader sequence ( EGS) oligonucleotides, siRNA compounds, single or double stranded RNA interference (RNAi) compounds (such as siRNA compounds), saRNA, aRNA, and other oligomeric compounds that hybridize to at least a portion of a target nucleic acid and modulate its function. Thus, it may be DNA, RNA, DNA-like, RNA-like or a mixture thereof, or may be a mimetic of one or more of them. Such compounds may be single-stranded, double-stranded, circular or hair-folding oligomeric compounds and may contain structural elements such as internal or terminal protrusions, mismatches or rings. Linear antisense compounds are typically prepared, but may be joined or otherwise prepared in a ring and/or branched form in the manner of 158213.doc • 50-201210611. Antisense compounds can include constructs, such as two strands that hybridize to form a fully or partially double-stranded compound, or a single plate that has sufficient self-complementarity to allow hybridization and form a fully or partially double-stranded compound. The two strands can be internally joined to leave a free 3' or 5, end, or can be joined to form a continuous hairpin structure or loop. The hairpin structure can have protrusions at the 5, or 3, end, resulting in an extension of the single strand feature. The double-stranded compound may include protrusions at the end, as appropriate. Other modifications may include attachment to a terminal, a selected nucleocyanate position, a sugar position, or a binding bond between the nucleus. Alternatively, the two strands can be joined via a non-nucleic acid moiety or a linker group. When only the - individual strands are formed, Xiao's secret money can be folded into the self-complementary cleavage type of the double-stranded body. Therefore, heart (10) eight can be in full or partial double-strand form. Specific regulation of gene expression can be obtained by stable performance of dsRNA hairpins in transgenic cell lines. When two strands or a single strand of a self-complementary hairpin type molecule in the form of a double-stranded pair is formed in itself, the two strands (or the single-stranded duplex forming region) are complementary to the base pairing RNA1. Following introduction into the system, the compounds of the invention may elicit—or multiple enzymes or structural proteins to act to affect cleavage or other repair of the target nucleic acid, or may function via a population-based mechanism. In general, 'nucleic acids (including nucleophilic acids) can be described as "DNA-like" (that is, generally have one or more extensive deoxygenated sugars, and generally have a τ instead of a nucleus) or "RNA-like" (also That is, there are generally - or more 2,-trans-glycosides or 2,-modified sugars, and generally have U instead of; The nucleic acid helix may be of a type or more, most commonly a B-shaped structure. In general, the nucleus acid having a B-like structure is 158213.doc 51 201210611 "DNA-like", and the oligo(tetra) acid having an A-shaped structure is "like rna". In some (same) embodiments, the antisense compound can comprise an A-shaped region and a B-shaped region. The antisense compound of the invention can comprise an antisense portion of from about 5 to about 8 nucleotides in length (ie, about 5 to about 8G nucleus. (4) The length of one part of the antisense strand or the antisense compound "Tow, and X s, the single antisense compound of the present invention contains 3 5 to about 8G nucleotides, and The double-stranded antisense compound of the present invention (such as dsRNA) comprises a sense strand and an antisense strand or a portion of 5 to about nucleotides long. 1022 34 46 58 70 As will be understood by those skilled in the art, it includes a length of 5 Η, 12 , 13, 14, 15 23 35 47 59 24 36 48 60 25 37 49 61 26 38 50 62 27 39 51 63 16 28 40 52 64 17 29 41 53 65 18 30 42 54 66 6, 7, 19 ' 20 31 4355 67 32 44 56 68 , 9 21 33 45 57 69

71, 72, 73, 74, 75, 76, 77, 78, 79 or 80 nucleotides or an antisense portion of any of the ranges. In a broad embodiment, the antisense compound of the invention has an antisense portion of from 1 to 5 nucleotides in length. As will be appreciated by those skilled in the art, including having lengths of 10, η, 12, 13, 14, 15, 16, 17, 18, 19, 2〇, 2ι, 22, 23, 24, 25, 26, 27, 28, 29, 3 〇, 31 m, 35 36, 37, 38, 39, 4 〇, 41, 42, 43 H, 牝, or % nucleus (4) or the antisense part of the material range thereof. In some embodiments, the length of the oligonucleotide is 15 nucleic acids. 0 P 158213.doc 52-201210611 In one embodiment, the antisense or oligonucleotide compound of the invention has a length of 12 or 13 to 3G The antisense part of the nuclear acid. As will be understood by the average technician, it has a length of 12, 13, ", 15, 16, 17, 18, 19, 20, 21, 22 ' 23 ' 24, 25, 26, 27, 28, 29 or 30 An antisense compound of nucleotide acid or any range of antisense portions thereof. In the examples, the polyamounting compound of the present invention also includes variants in which different bases are present at one or more nucleotide positions in the compound. For example, if the first nucleotide is adenosine, a variant containing thymidine, guanosine or cytosine at this position can be produced. This can be done anywhere in the antisense or dsRNA compound. These compounds are then tested using the methods described herein to determine their ability to inhibit the performance of the target nucleic acid. In some embodiments, the homology, sequence identity or complementarity between the antisense compound and the target is from about 4% to about. In some embodiments, the homology, sequence identity, or complementarity is from about 6% to about 7%. In some ❹ embodiments, 'homology, sequence identity or complementarity is from about 70% to about 80%. In some embodiments, the homology, sequence identity, or complementarity is about 80. /〇 to about 90%. In some embodiments, the homology, sequence identity, or complementarity is about 90%, about 92%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 1〇〇%. In one embodiment, antisense nucleotides such as the nucleic acid molecules set forth in SEQ ID NOS: 17 to 31 comprise one or more substitutions or modifications. In one embodiment, the nucleotide is substituted with a locked nucleic acid (LNA). In one embodiment, the nucleotide and the antisense nucleic acid molecules encoding the NAMPT and/or 158213.doc-53-201210611 or non-coding sequences are as described in SEQ ID NO: 1 and 16. One or more regions of the nucleic acid molecule of the sequence are shown. Oligonucleotides also target the overlapping regions of SEQ ID NOS: 1 to 16. Some preferred oligonucleotides of the invention are chimeric nucleotides. In the context of the present invention, "chimeric oligonucleotide" or "chimeric" is an oligonucleotide comprising two or more chemically distinct regions, each region being composed of at least one nucleotide. Such raised nucleotides typically contain at least one region of a modified nucleotide that confers one or more beneficial properties, such as increased nuclease resistance, enhanced cellular uptake, enhanced binding affinity to the target, and as sufficient cleavage RNA: DNA or RNA: the region of the substrate of the enzyme of the RNA hybrid. For example, 'RNase Η is an endonuclease that cleaves the RNA strand of RNA:DNA duplex. Therefore, 'activated ribonuclease Η causes rna target cleavage', thereby greatly improving the efficiency of antisense regulation of gene expression. Thus, when chimeric oligonucleotides are used, shorter nucleotides typically yield comparable results compared to phosphorothioate deoxynucleotides that hybridize to the same target region. Cleavage of the RNA target can typically be detected by gel electrophoresis and, if desired, by related nucleic acid hybridization techniques known in the art. In one embodiment, the chimeric nucleotide comprises at least one region modified to enhance binding affinity of the target, and a region that normally acts as a substrate for ribonuclease. The affinity of the nucleotide for its target, in this case the nucleic acid encoding ras, which is the temperature at which the nucleotide is raised and the target dissociation, is typically determined by measuring the Tm of the nucleotide/target pair. The dissociation was measured spectrophotometrically. The higher the Tm, the greater the affinity of the oligonucleotide for the target. The present invention can be formed into a composite structure of two or more oligonucleotides as described above, a modified 158213.doc-54-201210611 oligonucleotide, a nucleoside and/or an oligonucleotide mimetic Chimeric antisense compounds. Such compounds are also referred to as hybrids or interstitial polymers in the art. Representative U.S. patents which teach the preparation of such hybrid structures include, but are not limited to, U.S. Patent Nos. 5,013,830; 5,149,797; 5,220,007; 5,256,775; 5,366,878; 5,403,711; 5, 491, 133; 5, 565, 355; 5, 623, 065; 5, 652, 355; 5, 652, 356; and 5,700, 922; each of which is incorporated herein by reference. In one embodiment, the region of the modified nucleotide comprises at least one nucleotide modified at the T position of the sugar, preferably 2,-decyl, 2,-0-alkyl-oxime-fired A base or a 21-fluoro-modified nucleotide. In another embodiment, the rna modification comprises a 2'-fluoro, 2'-amino group and a 2Ό-fluorenyl modification on the ribose of the pyrimidine, abasic residue or RNA 3, terminal reverse base. Such modifications are typically incorporated into the oligonucleotide and have been shown to have a higher Tm (ie, higher target binding affinity) for the specified target compared to the 2'-deoxyoligonucleotide. ). The effect of this affinity enhancement is to greatly enhance the iRNAi oligonucleotide inhibition of gene expression. The ribonuclease 细胞 is a cell endonuclease that cleaves the RNA strand of the RNA:DNA duplex; therefore, activation of this enzyme causes cleavage of the RNA target, and thus the RNAi inhibition efficiency can be greatly enhanced. Cleavage of RNA targets can usually be demonstrated by gel electrophoresis. In one embodiment, the chimeric nucleotides are also modified to enhance nuclease resistance. The cell contains a variety of exonuclease and endonuclease which degrade the nucleic acid. A number of nucleotide and nucleoside modifications have been shown to result in a higher nuclease digestion resistance of 158213.doc -55 - 201210611 compared to native oligodeoxynucleotides. Nuclease resistance is typically measured by culturing the nucleus acid with a cell extract or an isolated nuclease solution, and is typically measured by gel electrophoresis over time to measure the amount of remaining intact nucleotide. The integrity of the oligonucleotides modified to enhance nuclease resistance is maintained for a longer period of time than unmodified oligonucleotides. A variety of nucleotide modifications have been shown to enhance or confer nuclease resistance. More preferably, it is an oligonucleotide containing at least one phosphorothioate modification. In some cases, a nucleotide modification that enhances the binding affinity of the target can also independently enhance nuclease resistance. Specific examples of some preferred oligonucleotides contemplated for use in the present invention include, for example, phosphorothioates, phosphotriesters, methyl phosphonates, short chain alkyl groups or cycloalkyl saccharide linkages or short bond heteroatoms. Or examples of modified primary bonds linked between heterocyclic sugars. Preferred are oligonucleotides having a phosphorothioate backbone and oligonucleotides having a hetero atom backbone, especially CH2--NH--0--CH2, CH2--N(CH3)--0- -CH2 [referred to as methylene (mercaptoimine) or MMI backbone], CH2--0--N(CH3)--CH2, CH2-N(CH3)--N(CH3)--CH2 And the Ο--N(CH3)--CH2--CH2 backbone, wherein the natural acid-filled diester backbone is represented by 0--P--0--CH2. De Mesmaeker et al. (1995) The amine amine backbone shown by Acc. Chem. Res. 28:366-374 is also preferred. Also preferred are oligonucleotides having an N-morpholinyl backbone structure (Summerton and Weller, U.S. Patent No. 5,034,506). In another embodiment, such as a peptide nucleic acid (PNA) backbone, the phosphodiester backbone of the oligonucleotide is replaced by a polyamine backbone that binds directly or indirectly to the polyamine backbone Aza nitrogen atom. The oligonucleotide may also comprise one or more substituted sugar moieties. Preferred nucleotides include one of the following in the 2' position: OH, SH, SCH3, F, OCN, OCH3, 158213.doc • 56- 201210611 0(CH2)nCH3, 0(CH2)nNH2 or 0 ( CH2)nCH3, wherein η is from 1 to about 10; Cl to CIO lower alkyl, alkoxyalkoxy, substituted lower carbon alkyl, aryl or aryl; Cl; Br; CN; CF3 OCF3; , S-- or N-alkyl; Ο-, S- or N-alkenyl; SOCH3; S02 CH3; 0N02; N02; N3; NH2; heterocycloalkyl; heterocycloalkylaryl; Alkylamino group; polyalkylamine group; substituted alkyl group; RNA cleavage group; conductor group; insertion group; group for improving the pharmacokinetic properties of the oligonucleotide; or modified oligo A group having the pharmacodynamic properties of a glycoside and other substituents having a similar nature to the oxime. Preferred modifications include 2'-methoxyethoxy [2i-0,CH2CH20CH3, also known as 2,-0-(2-decyloxyethyl)]. Other preferred modifications include 2'-methoxy (2'-0--CH3), 2·-propoxy (2,-OCH2CH2CH3) and 2, fluorine (2'-F). Similar modifications can also be made at other positions of the oligonucleotide, particularly at the 3' position of the sugar at the 3' end nucleotide and at the 5' position of the 5' end nucleotide. Oligonucleotides may also have a sugar mimetic, such as a cyclobutyl group, rather than a quinolate. Alternatively or additionally, the raised nucleotides may also include nucleobases (in the art)

Q is often referred to simply as "test base" to modify or replace. As used herein, "unmodified" or "natural" nucleotides include adenine (A), guanine (G), thymine (T), cytosine (C), and uracil (U). Modified nucleotides include nucleotides that are only occasionally or transiently found in natural nucleic acids, such as hypoxanthine, 6-methyladenine, 5-Me-pyrimidine, especially 5-mercapto-cytosine (also known as 5). -methyl-2'deoxycytosine and commonly referred to in the art as 5-Me-C), 5-hydroxydecylcytosine (HMC), glycosyl HMC, and long-acting disaccharide-based HMC, and synthetic nuclei Glycosylates, such as 2-aminoadenine, 2-(decylamino)adenine, 2-158213.doc •57-201210611 (saltyl) adenine, 2_(aminoalkylamino group Adenine or other hetero-substituted alkyl adenine, 2-thiouracil, 2-thio thymine, 5-bromouridine. Indole, 5-hydroxypurinyluracil, 8-nitroguanine, 7-deazaguanine, N6(6-aminohexyl)adenine and 2,6-diaminoguanidine. It may include "universal" bases known in the art, such as inosine. The 5-Me-C substitution has been shown to increase the nuclear fee duplex stability by Q 6 〇 c to i. 21 and is currently the preferred substituent substitution. Another modification of the oligonucleotides of the invention involves a moiety or conjugate that is chemically linked to the activity or cellular uptake of the oligonucleotide or the oligonucleotide. Such moieties include, but are not limited to, lipid moieties such as the cholesterol moiety, the fatty chain (eg, dodecyldiol or undecyl residue), the o-amine or polyethylene glycol chain or diamond Alkanoic acid. Oligonucleotides comprising a lipophilic moiety' and methods of preparing such a nucleus# acid are known in the art, for example, U.S. Patent Nos. 5,138, 〇45, 帛5,2ΐ8, ι〇5, and 5,459,255. . All positions in a given oligonucleotide are not necessarily uniformly modified, and indeed more than one of the foregoing modifications can be incorporated into a single raised nucleotide or even within a single nucleoside within an oligonucleotide. The invention also includes oligonucleotides as defined above as chimeric nucleotides. In another embodiment, the nucleic acid molecule of the invention is further than another portion of the compound including, but not limited to, non-initiated nuclear phytic acid, polyether, polyamine, polyamine, saccharide, carbohydrate, lipid or polyhydrocarbon compound Combine. Those skilled in the art will recognize that such molecules can be linked to several positions on the sugar, tester or phosphate group of one or more of any of the nucleotides (packet 3 nucleic acid molecules). 158213.doc -58- 201210611 The nucleotides used in accordance with the present invention are conveniently and generally prepared by well known solid phase synthesis techniques. Equipment for this synthesis is sold by several vendors including Appiied Bi〇 Systems. Any other means for this synthesis can also be utilized; the actual synthesis of the oligonucleotide is preferably within the capabilities of the average skilled person. It is also well known to use similar techniques to prepare other nucleotides, such as phosphorothioates and alkylated derivatives. It is also well known to use similar techniques and commercially available modified amidite and controlled microporous glass (CpG) products such as biotin, luciferin, acridine or psoralen modified amines and/or CPG ( Available from Glen Research, Sterling VA) to synthesize fluorescently labeled, biotinylated or otherwise modified oligonucleotides, such as cholesterol modified oligonucleotides. In accordance with the present invention, modifications, such as the use of LNA monomers to enhance efficacy, specificity, and duration of action and broaden the route of administration of nucleotides, including existing chemical changes such as MOE, ANA, FANA, PS, and the like, are used. This modification can be obtained by substituting one of the monomers in the current oligonucleotide with an lnA monomer. The LNA modified oligonucleotide may be similar in size to the parent compound or may be larger or preferably smaller. Preferably, the LNA modified oligonucleotides comprise less than about 70%, more preferably less than about 60%, optimally less than about 50% of the LNA monomer' and preferably have a size of between about 5 and 25 nucleotides. More preferably, between about 12 and 20 nucleotides. Preferably, the modified nucleotide backbone comprises, but is not limited to, a phosphorothioate, a palmitic phosphorothioate, a phosphorodithioate, a phosphate triester, an aminoalkyl sulphate, a thiol group. And other alkyl phosphonates (including 3' alkyl alkyl phosphonates and palmitic lactic acid esters), phosphonites, phosphonium esters (including 3,-aminophosphonamide 1582I3.doc-59 - 201210611 Ester and Aminoalkyl Phosphate Amine Vinegar), Thioline Amine Vinegar, Thioalkylphosphonate, Thioalkyl Triphosphate and Borane Filling with Normal 3'·5' Bonding a 2'-fluorene-linked analog of an acid ester, a borane-filled acid ester, and a borophosphoryl phosphate having a reverse polarity, wherein the adjacent nucleoside unit pair is 3'-5'-linked to 5'_3', or 2'_5 ' Connect to 5'-2'. Also included are various salts, mixed salts and free acid forms. Representative U.S. patents which teach the preparation of the above-described dish-containing bonds include, but are not limited to, U.S. Patent Nos. 3,687,808; 4,469,863; 4,476,301, 5,023,243; 5,177,196; 5,188,897, 5,264,423; 5,276,019 Nos. 5, 286, pp. 5, 286, pp. 5, 321, pp. 5, 399, 496; 5, 453, 496; 5, 455, 675; 5, 466, 677; 5, 476, 925; 5, 519, 126; 5, 541, 306; 5, 550, 111, 5, 563, 253 No. 5, 571, 799; 5, 587, 361; and 5, 625, 050, each of which is incorporated herein by reference. Preferred modified oligonucleotide backbones that do not include a ruthenium atom have a linkage between a short chain alkyl group or a cycloalkyl group, a mixed hetero atom, and an alkyl or cycloalkyl internucleoside linkage, or one or A primary bond formed by a plurality of short-chain heteroatoms or heterocyclic nucleoside linkages. These main chains comprise their main chains with N-morpholinyl linkages (partially formed by the nuclear bitter sugar moiety); oxime-burning backbone; sulfide, subhard and stone-wind primary bonds; Sulfhydryl backbone; fluorenyl sulfhydryl and thioindolyl backbone, containing olefin backbone; amine sulfonate backbone; ethyleneimine and fluorenyl sulfhydryl backbone; sulfonic acid Ester and sulfonamide backbone; guanamine backbone; and 1582I3.doc • 60· 201210611 Other backbones with a mixture of N, 〇, S and CH2 moieties. Representative U.S. patents which teach the preparation of such nucleosides include, but are not limited to, U.S. Patent Nos. 5,034,506; 5,166,315; 5,185,444; 5,214,134; 5,216,141; 5,235,033; Nos. 5,264,562; 5,264,564; 5,405,938; 5,434,257; 5,466,677; 5,470,967; 5,489,677; 5,541,307; 5,561,225; 5,596,086; 5,602,240; 5,610,289; 5,602,240 No. 5, 608, 046; Nos. 5, 610, 289; 5, 618, 704; 5, 623, 070; 5, 663, 312; 5, 633, 360; 5, 677, 437; and 5, 677, 439, each of which is incorporated herein by reference. In other preferred oligonucleotide mimetics, the sugar of the nucleotide unit is replaced with a novel group, i.e., the backbone. The basic unit is maintained to hybridize to the appropriate nucleic acid target compound. One such polymeric compound, i.e., an oligonucleotide mimetic that has been shown to have excellent hybridization properties, is referred to as a peptide nucleic acid (ρΝΑ). In the ruthenium compound, the sugar main chain of the nucleotide is replaced by a main chain containing a guanamine, and an aminoethylglycine main chain of δ. The nucleobase remains and binds directly or indirectly to the aza nitrogen atom of the indole moiety of the backbone. Representative U.S. patents which teach the preparation of a ruthenium compound include, but are not limited to, U.S. Patent Nos. 5,539,082; 5,714,331; and 5,719,262 each incorporated herein by reference. Other teachings of bismuth compounds can be found in

Nielsen et al., (1991) Science 254, 1497-1500. In one embodiment of the present invention, a nucleotide of 158213.doc-61 - 201210611 having a phosphorothioate backbone and a nucleoside having a hetero atom backbone, particularly -CH2-NH-0-CH2- , -CH2-N(CH3)-0-CH2- (referred to as methylene (methylimido) or MMI backbone), -CH2-0-N(CH3)-CH2-, -CH2N(CH3) -N(CH3)CH2- and -0-N(CH3)-CH2-CH2-, wherein the natural phosphodiester backbone is represented by -0-P-0-CH2 of U.S. Patent No. 5,489,677, the disclosure of which is incorporated herein by reference. The indoleamine backbone of U.S. Patent No. 5,602,240, incorporated herein by reference. Also preferred are oligonucleotides having the N-morpholinyl backbone structure of U.S. Patent No. 5,034,506, which is incorporated herein by reference. The modified nucleotide may also contain one or more substituted sugar moieties. Preferred oligonucleotides comprise one of the following in the 2' position: OH; F; 0-alkyl, S-alkyl or N-alkyl; 0-alkenyl, S-alkenyl or N-alkenyl Or alkynyl, S-alkynyl or N-alkynyl; or decyl-fluorenyl-alkyl, wherein the alkyl, alkenyl and alkynyl groups may be substituted or unsubstituted Cl to Cio alkyl or C2 to Cio dilute base and fast base. Particularly preferred are 〇(CH2)nOmCH3, 0(CH2)n0CH3, 0(CH2)nNH2, 0(CH2)nCH3, 0(CH2)n0NH2 and 0(CH2)n0N(CH3)2, wherein n and m can be 1 to about 10. Other preferred nucleotides include one of the following in the 2' position: Ci to C1Q lower alkyl, substituted lower alkyl, alkaryl, aralkyl, 0-alkylaryl or hydrazine- Aralkyl, SH, SCH3, OCN, Cl, Br, CN, CF3, OCF3, SOCH3, S02CH3, 0N02, N02, N3, NH2, heterocycloalkyl, heterocycloalkylaryl, aminoalkylamino, Pharmacodynamic properties of a polyalkylamino group, a substituted decyl group, an RNA cleavage group, a reporter group, an intercalation group, a pharmacokinetic property of a modified oligonucleotide, or a modified oligonucleotide a group, and other substituents having similar properties. Preferred modifications include 21-decyloxyethoxy (2'-0-158213.doc-62-201210611 CH2CH20CH3, also known as 2'-0-(2-methoxyethyl) or 2'-MOE) , that is, an alkoxyalkoxy group. Other preferred modifications include a 2'-dimethylaminooxyethoxy group as described herein below, that is, a 0(CH2)20N(CH3)2 group, also known as 2'-DMAOE; '-Dimethylaminoethoxyethoxy (also known in the art as 2·-0-dimethylaminoethoxyethyl or 2·-'DMAEOE), ie 2'-0 -CH2-0-CH2-N(CH2)2. Other preferred modifications include 2'-methoxy (2'-OCH3), 2'-aminopropoxy (2'-OCH2CH2CH2NH2) and 2'-fluoro (2'-F). It can also be carried out at other positions of the oligonucleotide, especially at the 3' end nucleotide or the 2'-5' ligation type oligonucleotide, at the 3' position of the sugar or at the 5' position of the 5' end nucleotide. Similar modification. Oligonucleotides may also have a sugar mimetic, such as a cyclobutyl moiety, rather than a pentofuranosyl sugar. Representative U.S. patents which teach the preparation of such modified sugar structures include, but are not limited to, U.S. Patent Nos. 4,981,957; 5,118,800; 5,319,080; 5,359,044; 5,393,878; 5,446,137; No. 5, 466, 785; No. 5, 519, pp; No. 5, 576, 811; ; <5,670,633; and 5,700,920, each of which is incorporated herein by reference. Nucleotides may also be modified or substituted with nucleobases (often referred to in the art as "test bases"). As used herein, "unmodified" or "natural" nucleotides include the purine bases adenine (A) and black mites (G), and the chlorpyrifos thymine (T), cytosine (C), and urine. Pyrimidine (U). Modified nucleus 158213.doc -63- 201210611 The acid contains other synthetic and natural nucleotides, such as 5-methylcytosine (5-me-C), 5-hydroxydecyl cytosine, astragalus, hypoxanthine , 2-amino adenine, adenine, and guanine, 6-methyl and other leuco derivatives, adenine and bird σ 令 令 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 Sulphur urine, bite, 2-thiothymidine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azouracil, cytosine And thymidine, 5-urine bite (sudden urine 10 bite), 4-thiourea D bite, 8-halogenated adenine 11 and guanine, 8-aminoadenine and guanine, 8 -thiol adenine and guanine, 8-thioalkyl adenine and guanine, 8-hydroxyadenine and guanine and other 8-substituted adenines and birds 吟 吟, 5- _ base ( Especially 5-indifferent) urinary guanidine and cytosine, 5-trifluoromethyluracil and cytosine and other 5-substituted uracil and cytosine, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azadenine, 7-deazaguanine and 7- Adenine nitrogen and 3 to 11 nitrogen votes Yin and birds 3 - deazaadenine. In addition, the nucleotides include those described in U.S. Patent No. 3,687,808; "The Concise Encyclopedia of Polymer Science And Engineering", pp. 858-859, Kroschwitz, JI, John Wiley & Sons, 1990 The nucleotides disclosed therein; Englisch et al., "Angewandle Chemie, International Edition", 1991, 30, pp. 613, and their nucleotides; and Sanghvi, YS, Chapter 15, "Antisense Research and Applications, pp. 289-302, Croike, ST and Lebleu, B. ed., CRC Press, 1993. Certain of these nucleotides are particularly useful for enhancing the binding affinity of the oligomeric compounds of the present invention. These nucleotides include a 5-substituted pyrimidine 158213.doc-64-201210611 bite, a 6-nitrogen bite, and a N-2, N-6, and 0-6 substituted guanidine containing a 2-aminopropyl gland. Indole, 5-propynyl uracil and 5-propynyl cytosine. 5-methylcytosine substitutions have been shown to increase the stability of nucleic acid duplexes. (: to 1.2 C (Sanghvi, YS, Crooke, ST and Lebleu B. ed., "Antisense Research and Applications", CRC Press, Boca Raton, 1993 'pp. 276-278)' and even more specifically and 2, - The currently preferred base substitution when the methoxymethoxy saccharide modification is combined. A representative U.S. patent that teaches the preparation of the modified nucleotides described above, as well as other modified nucleotides, includes, but is not limited to, U.S. Patent Nos. 3,687,8,8, and 4,845,205; 5,130,302; 5,134,066, 5,175,273; 5,367,066; 5,432,272; 5,457,187; 5,459,255 No. 5, 484, 908; No. 5, 502, 177; No. 5, 525, 711; No. 5, 552, 540; No. 5, 587, 469; No. 5, 596, 091; No. 5, 614, 617; No. 5, 750, 692; The method is incorporated herein. Another modification of the oligonucleotide of the present invention involves chemically linking to the activity, cell distribution or cellular uptake of one or more of the oligonucleotides. Or a combination. These moieties include, but are not limited to, lipid moieties such as cholesterol moieties, cholic acid, thioethers (eg, hexyl-S-trityl mercaptan), thiocholesterol, aliphatic chains (eg, twelve a diol or a decyl residue, a scale (for example, di-hexadecyl-racemic-glycerol or 1,2-hexadecyl-racemic-glyceryl-3H-phosphine Acid diethylammonium), polyamine or polyethylene glycol chain, or adamantane B 158213.doc -65- 201210611 acid, palmity moiety, or octadecylamine or hexylamino-carbonyl-hydroxycholesterol moiety. Representative U.S. patents for the preparation of such oligonucleotide conjugates include, but are not limited to, U.S. Patent Nos. 4,828,979; 4,948,882; 5,218,105; 5,525,465; 5,541,313; 730; 5,552,538; 5,578,717; 5.580.731; 5,580,731; 5,591,584; 5,109,124; 5,118,802; 5,138,045; 5,414,077 ; 5, 486, 603; 5, 512, 439; 5, 578, 718; 5, 608, 046; 4, 605, 044; 4, 667, 025; 4, 762, 779; 4, 789, 737; 4, 824, 941; 4, 835, 263; 4, 876, 335; 4, 904, 582; 4, 958, 013, 5.082.830; 5, 112, 963 No. 5,214,136; No. 5,082,830; No. 5,112,963; No. 5,214,136; No. 5,245,022; No. 5,254,469; No. 5,258,506; No. 5,262,536; No. 5,272,250; No. 5,292,873; Nos. 5,371,241; 5, 391, 723; 5, 416, 203; 5, 451, 463; 5, 510, 475; 5, 512, 667, 5, 514, 785; 5, 565, 552; 5, 567, 810; 5, 574, 142; No. 5,587, 371; 5,595, 726; 5, 597, 696; 5, 599, 923; 5, 599, 928 and 5, 688, 941, each of which is incorporated herein by reference. 158213.doc -66- 201210611 μ## Gift: The compounds of the invention can also be used in the field of drug discovery and target verification. The present invention encompasses the use of such compounds in drug discovery and the preferred target segments identified herein in an attempt to demonstrate nicotinic guanamine to ribosyl glucoside (NAMPT) polynucleotides and disease conditions, phenotypes or conditions There is a relationship between them. Such methods comprise detecting or modulating a τρτ polynucleotide comprising contacting a sample, tissue, cell or organism with a compound of the invention; measuring the nucleic acid or protein content of the NAMPT polynucleotide for a certain period of time after treatment and 'or a relevant phenotype or chemical endpoint; and compare the measured values to untreated samples or samples treated with other compounds of the invention, as appropriate. These methods can also be performed in parallel or in combination with other experiments to determine the function of an unknown gene for a target validation method, or to determine the effectiveness of a particular gene product as a target for treating or preventing a particular disease, condition or phenotype. Assessing gene expression up-regulation or inhibition: The transfer of an exogenous nucleic acid into a host cell or organism can be performed by directly detecting the presence of nucleic acids in the cell or organism (4). Such detection can be obtained by several methods well known in the art. For example, t, the presence of exogenous nucleic acid can be detected by Southern blot or by polymerase chain reaction (PCR) using primers that specifically amplify nucleic acid-related nucleotide sequences. . The performance of exogenous nucleic acids can also be measured using conventional methods including gene expression analysis. For example, Northern blotting and reverse transcription PCR (RT_PCR) can be used to detect and quantify mRNA produced by exogenous nucleic acids. The expression of RNA from an exogenous nucleic acid can also be detected by measuring enzymatic activity or reporter protein activity. For example, antisense modulating activity can be indirectly measured as a decrease or increase in the performance of a target nucleic acid indicative of an exogenous nucleic acid producing effector RNA as 158213.doc-67·201210611. Based on sequence conservation, the primers can be designed to amplify the coding region of the target gene. Initially, model control genes can be constructed using coding regions from the highest of each gene, but any coding or non-coding region can be used. Each control gene was combined by inserting each of the coding regions between the reporter coding region and its poly (A) signal. These plastids will produce mRNA with a reporter gene in the upstream part of the gene and a potential RNAi target in the 3, non-coding region. The efficacy of individual antisense oligonucleotides will be verified by adjusting the reporter gene. Reporter genes suitable for use in the methods of the invention include acetamyl hydroxy acid synthase (AHAS), test acylase (ap), beta galactosidase (LacZ), beta glucuronidase (GUS), and oxytetracycline Acetyltransferase (CAT), green fluorescent protein (GFP), red fluorescent protein (RFp), yellow fluorescent protein (YFP), cyan fluorescent protein (CFP), horseradish peroxidase (HRP), firefly Photozyme (Luc), nopaline synthase (N〇s), octopus synthase (OCS) and its derivatives. Give ampicillin, bleomycin, chloramphenicol, gentamycin, hygromycin, kanamycin, lincomycin A variety of selectable markers for resistance to methotrexate, phosphinothricin, puromycin, and tetracycline (tetracycline) are available. Methods for determining the regulation of a reporter gene are well known in the art and include, but are not limited to, fluorescence methods (e.g., fluorescence spectroscopy, fluorescence activated cell sorting (FACS), crab light microscopy), antibiotics. Resistance assay. 158213.doc • 68 - 201210611 NAMPT protein & mRNA expression can be assayed using methods known to those skilled in the art and described elsewhere herein. For example, an immunoassay such as eusa can be used to measure protein content. The beta NAmpt ELISA assay kit is commercially available, for example, from R & D Systems (Minneapolis, MN).

In the Examples, NAMPT expression (e.g., mRNA or protein) in a sample (e.g., in vivo cells or tissues) treated with the antisense oligonucleotide of the present invention is evaluated in comparison to the NAMPT expression in a control sample. For example, the performance of a protein or nucleic acid can be compared to a simulated or untreated sample using methods known to those skilled in the art. Alternatively, the assay can be compared to a sample treated with a control antisense oligonucleotide (e.g., an antisense oligonucleotide having altered or different sequences), depending on the desired information. In another embodiment, the difference in performance of the NAMPT protein or nucleic acid in the treated and untreated samples can be compared to the difference in performance between different nucleic acids in the treated and untreated samples, including any standards deemed appropriate by the investigator, such as housekeeping genes. . For comparison with the control group, the observed difference can be expressed as, for example, a ratio or a fractional form. In an embodiment, the amount of NAMPT mRNA or protein in the sample treated with the antisense oligonucleotide of the present invention is increased or decreased by about 1.25 to about 1 Å relative to the untreated sample or the sample treated with the control nucleic acid. Multiple or more than 10 times. In embodiments, the amount of mRNA or protein is increased or decreased by at least about 125 times, at least about 13 times, at least about 1.4 times, at least 5 times, at least about 16 times, at least m 7 times, at least about 1.8 times, at least About 2 times, at least about 25 times, at least about 3 times, at least about 3.5 times, at least about 4 times, at least about 45 times, at least about $ times, at least about 5. 5 times, at least about 6 times, at least about 6 5 times, at least about 7 times, at least about 158213.doc -69 · 201210611 7 · 5 times, at least about 8 times, at least s ς汾 ς汾 at least about 9.5 ^ 玍 约 about 8.5 times, at least about 9 times or at least About 10 times or more than 1 time. Kits, Research Reagents, Diagnosis, and Treatment The compounds of the present invention are chopped, treated, and (4) and can be used as components of research reagents and kits. In addition, the general use of the antisense, which can inhibit the expression of the gene with strong specificity, may be used to elucidate the function of a specific gene or distinguish the biological path. The function of various members. For use in kits and diagnostics and in various biological systems, the compounds of the invention, alone or in combination with other compounds or therapeutic agents, are useful as part of the genes expressed in the cells and tissues of the m-months for differential and/or combinatorial analysis. Or the pattern of expression of the entire complementary sequence. The term "biological system" or "system" as used herein is defined to mean any organism, cell, cell culture or tissue that exhibits or is capable of exhibiting the product of the nicotinic acid phosphatase (nampt) gene. Such systems include, but are not limited to, humans, transgenic animals, cells, cell culture tissue, xenografts, grafts, and combinations thereof. As a non-limiting example, the expression pattern in a cell or tissue treated with one or more antisense compounds is compared to a control cell or tissue not treated with an antisense compound, and when such patterns are associated with, for example, the gene of interest When the disease's association, signaling pathway, cell localization, performance, size, structure, or function is correlated, the patterns produced by different gene expression analyses are generated. Such analysis can be performed on stimulated or unstimulated cells and in the presence or absence of other compounds that affect the performance pattern. Examples of gene expression analysis methods known in the art include DNA arrays 158213.doc-70-201210611 columns or microarrays, SAGE (continuous analysis of gene expression), READS (restriction enzyme amplification of digested cDNA), TOGA (overall) Gene expression analysis), protein array and proteomic research, expression sequence tag (EST) sequencing, deletion of RNA fingerprinting (SuRF), deletion and selection, differential presentation (DD), comparative genomic hybridization, FISH ( Fluorescence in situ hybridization) technique and mass spectrometry method. The compounds of the invention are useful in research and diagnostics because such compounds hybridize to a nucleic acid encoding a nicotine indoleamine phosphoribosyltransferase (NAMPT). For example, oligonucleotides that hybridize at such efficiencies and under such conditions, as disclosed herein, as effective NAMPT modulators, are effective primers or probes, respectively, under conditions conducive to gene proliferation or detection. Such primers and probes are suitable for use in methods that require specific detection of nucleic acid molecules encoding NAMPT and are useful for detecting or amplifying such nucleic acid molecules for use in other NAMPT studies. Hybridization of antisense oligonucleotides of the invention, particularly primers and probes, with nucleic acids encoding NAMPT can be detected by methods known in the art. Such methods may include binding of the enzyme to the raised nucleotide, radiolabeling of the oligonucleotide, or any other suitable detection method. Kits that use these detection methods to test the NAMPT content of the sample can also be prepared. Those skilled in the art of therapeutic use also utilize the specificity and sensitivity of the antisense sequence. Antisense compounds have been used as therapeutic moieties in the treatment of disease conditions in animals including humans. Antisense oligonucleotide drugs have been safely and effectively administered to humans, and many clinical trials are currently underway. It is therefore determined that the antisense compound can be in a therapeutic form that can be configured to be useful in the treatment of cells, tissues, and animals, particularly humans. 158213.doc -71- 201210611 For treatment, an animal (preferably a human) suspected of having a disease or condition treated by modulation of the expression of a NAMPT polynucleotide is treated by administering an antisense compound of the invention . For example, in one non-limiting embodiment, the method comprises the step of administering to a subject in need of treatment a therapeutically effective amount of a NAMPT modulator. The namPT modulator of the present invention is effective for modulating the activity of NAMPT or regulating the performance of NAMPT protein. In one embodiment, the activity or performance of NAMPT in the animal is inhibited by about 10% compared to the control group. The activity or performance of NAMPT in animals is preferably inhibited by about 30%. The activity or performance of NAMPT in animals is more preferably inhibited by 5% or more. Thus, the polymeric compound modulates the performance of nicotine indoleamine phosphoribosyltransferase (NAMPT) mRNA by at least 10%, at least 50%, at least 25%, at least 30%, at least 40%, at least 50 compared to the control group. %, at least 60%, at least 70%, at least 75%, at least 80°/. At least 85%, at least 90%, at least 95%, at least 98%, at least 99% or at least 100%. In one embodiment, the activity or performance of nicotinamide transphosphatase (NAMPT) in the animal is increased by about 10% compared to the control. The activity or performance of NAMPT in animals is preferably increased by about 30%. The activity or performance of NAMPT in animals is preferably increased by 50% or more. Thus, the oligomeric compound modulates the performance of NAMPT mRNA by at least 1%, at least 50%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, compared to the control group. At least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 1%. For example, the performance of nicotine guanamine to phosphoribosyl 158213.doc-72-201210611 enzyme (NAMPT) can be measured in serum, liquid, adipose tissue, liver or any other body fluid, tissue or organ of an animal. Increase or decrease. The cells contained in the fluid, tissue or organ to be analyzed preferably contain a nucleic acid molecule encoding a NAMPT peptide and/or a NAMPT protein itself. The compounds of the present invention can be utilized in the form of a pharmaceutical composition by adding an effective amount of the compound to a suitable pharmaceutically acceptable diluent or carrier. The use of the compounds of the invention and the methods of the invention may also be suitable for prevention. Conjugates Another modification of an oligonucleotide of the invention involves the chemical ligation of one or more of the oligonucleotides to a portion or combination that enhances the activity, cellular distribution or cellular uptake of the oligonucleotide. Such moieties or combinations may include binding groups that are covalently bonded to a functional group such as a primary hydroxyl group or a secondary hydroxyl group. The binding group of the present invention includes an embedding group, a reporter molecule, a polyamine, a polyamine, a polyethylene glycol, a polyether, a group for enhancing the pharmacodynamic properties of the polymer, and a drug power for enhancing the oligomer. The nature of the group. Typical binding groups include cholesterol, lipids, phospholipids, biotin, morphazine, folic acid, phenanthridine, anthraquinone, acridine, luciferin, rhodamine, coumarin, and dyes. In the context of the present invention, groups that enhance pharmacodynamic properties include groups that improve uptake, enhance resistance to degradation, and/or enhance sequence-specific hybridization to a target nucleic acid. In the context of the present invention, groups which enhance the pharmacokinetic properties include groups which modify the uptake, distribution, metabolism or excretion of the compounds of the invention. A representative binding group is disclosed in International Patent Application No. PCT/US92/09196, filed on Oct. 23, 1992, and U.S. Patent No. 6,287,860, the disclosure of which is incorporated herein by reference. Binding moieties include, but are not limited to, lipid moieties such as steroidal moieties, cholic acid, thioethers (eg, hexyl-5-triphenyl 158213.doc-73-201210611 methyl mercaptan), thiocholesterol, aliphatic bonds (eg, dodecadiol or -j-alkyl residue), phospholipids (eg, di-hexadecyl-racemic-glycerol or 1,2-di-hexadecanoyl-racemic-glycerol) a radical 3-3-H-phosphonic acid triethyl bond), a polyamine or polyethylene glycol chain, or an adamantane acetic acid, a palmity moiety, or an octadecylamine or a hexylamino-carbonyl-hydroxycholesterol moiety. The oligonucleotide of the present invention may also be bound to an active drug such as aspirin, warfarin, phenylbutazone, ibuprofen, supprofen, ketoprofen ( Ketoprofen), (S)-(+)-pranoprofen ((S)-(+)-pranoprofen), carprofen, carnitine, 2,3,5-di broken The present formic acid, fiufenamic acid, folinic acid, benzoxine, chlorpyrazine, and second gas. Indomethacin, barbiturate, cephalosporin, sulfonamides, antidiabetic agents, antibacterial agents or antibiotics. Representative U.S. patents which teach the preparation of such oligonucleotide conjugates include, but are not limited to, U.S. Patent Nos. 4,828,979; 4,948,882; 5,218,105; 5,525,465; 5,541,313; .730, '5,552,538; 5,578,717; 5.580.731; 5,580,731; 5,591,584; 5,109,124; 5,118,802; 5,138,045; Nos. 5, 414, 037; 5, 486, 603; 5, 512, 439; 5, 578, 718; 5, 608, 046; 4, 587, 044; 4, 605, 735; 4, 667, 025; 4, 762, 779; 4, 789, 737; 4, 824, 941; 4, 835, 263; Doc -74· 201210611

U.S. Patent No. 5, 119, 924, No. 5, No. 5, No. 5, No. 5, No. 5, No. 5, No. 5, No. 5, No. 5, No. 5, No. 5, No. 5, No.

U.S. Patent Nos. 4,958,013; 5, 214, 136; 5, 214, 136; 5, 214, pp; 5, 214, 136; 5, 258, 506; 5, 214, 136; No. 5, 391, 723; No. 5, 510, 475; No. 5, 565, 552; No. 5,585, 481; No. 5,597, 696; Compounds of the invention may also be mixed, encapsulated, bound or otherwise Other molecules, molecular structures or mixtures are associated, for example, in the form of liposomes, receptor targeting molecules, oral, rectal, topical or other formulations to facilitate uptake, distribution and/or absorption. Representative U.S. patents which teach the preparation of such formulations which promote ingestion, distribution and/or absorption include, but are not limited to, U.S. Patent Nos. 5,108,921, 5,354,844; 5,416,016; 5,459,127; 5,521, No. 5, No. 5, No. 5, No. 5, No. 5, No. 5, No. 5, No. 5, No. 5, No. 5, 256, 221; 5, 356, 633; 5, 395, 619; 5, 416, 016; 5, 417, 978; 5, 462, 854; 158, 213. doc - 75 - 201210611 5, 469, 854; 5, 512, 295; 5, 527, 528; 5, 534, 259; 5, 543, 152 No. 5,556, 948; 5, 580, 575; and 5, 595, 756, each of which is incorporated herein by reference. Although antisense oligonucleotides need not be administered in the context of a vector to modulate target expression and/or function, embodiments of the invention pertain to expression vector constructs for expressing antisense nucleotides, including Promoter, hybridization initiation gene sequence, and has strong constitutive promoter activity or promoter activity that can be induced if desired. In one embodiment, the practice of the invention involves administering at least one of the above antisense oligonucleotides and a suitable nucleic acid delivery system. In one embodiment, the system includes a non-viral vector operably linked to the polynucleotide. Examples of such non-viral vectors include individual nucleotides (e.g., any one or more of SEQ ID NOS: 17 to 31) or a combination of suitable protein, polysaccharide or lipid formulations. Further suitable nucleic acid delivery systems include viral vectors, typically from adenovirus, adeno-associated virus (AAV), helper virus-dependent adenovirus, retrovirus or hemagglutinatin virus of japan_lip〇s〇. a sequence of at least one of the HVJ) complexes. The viral vector preferably comprises a strong eukaryotic promoter operably linked to a polynucleotide (e.g., a cellular giant virus (CMV) promoter). Further preferred vectors include viral vectors, fusion proteins and chemical conjugates. Retroviral vectors include Moloney murine! eukemia viruses and HIV-based viruses. A preferred base 158213.doc -76- 201210611 The viral vector for HIV comprises at least two vectors, wherein the (iv) and ρ〇ι genes are from the HIV genome and the env gene line is from another virus. DNA virus carrier: good. Such vectors include poxvirus vectors such as cloning virus or fowl pox vector, herpes virus vectors such as herpes simplex! Virus (hsv) vector, adenoviral vector; and adeno-associated virus vector. The antisense compound of the present invention encompasses any salt of Sg such as a pharmaceutically acceptable salt, ester or hydrazine, or any of the biologically active metabolites or residues thereof which are capable of providing (directly or indirectly) when administered to an animal including humans. Other Compounds 0 The term "pharmaceutically acceptable salts" refers to physiologically and pharmaceutically acceptable salts of the compounds of the present invention: that is, the desired biological activity of the parent compound is retained and does not confer unsuitable toxicology. The salt of action. For oligonucleotides, pharmaceutically acceptable salts and preferred examples of their use are further described in U.S. Patent No. 6,287,86, the disclosure of which is incorporated herein by reference. The invention also includes pharmaceutical compositions and formulations comprising the antisense compounds of the invention. The pharmaceutical compositions of the present invention can be administered in a number of ways depending on whether local or systemic treatment and the area to be treated are required. Administration may be topical (including ophthalmic and mucosal (including vaginal and rectal transmission), lung (eg by inhalation or insufflation of powder or aerosol, including intratracheal, intranasal, epidermal and transdermal by nebulizer) Oral or parenteral administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial 'eg intrathecal or intraventricular administration. For treatment of the central nervous system The tissue can be administered to the cerebrospinal fluid by, for example, injection 158213.doc • 77-201210611 or infusion. The administration of antisense RNA to cerebrospinal fluid is described, for example, in U.S. Patent Application Publication No. 2007/0117772, In the method for slowing familial ALS disease progression, the document is incorporated herein by reference in its entirety. When the antisense nucleotide of the present invention is intended to be administered to cells in the central nervous system, one or more The agent that promotes the targeting of antisense oligonucleotides across the blood-brain barrier can be administered together, for example, in the entorhinal cortex or hippocampus. By moving neurons into muscle tissue The delivery of a neurotrophic factor with an adenoviral vector is described, for example, in "Adenoviral-vector-mediated gene transfer into medullary motor neurons", which is incorporated herein by reference. Adenovirus vectors for the transfer of foreign genes into cells of the central nervous system particularly in brain, such as the striatum, the hypothalamus, the hippocampus, or the substantia nigra, are known in the art and are described, for example, in U.S. Patent No. 6,756,523. This document is incorporated herein by reference. Administration can be carried out rapidly, for example by injection, or by slow infusion or administration of a sustained release formulation over a period of time. It can also be linked or associated with an agent that provides the desired pharmaceutical or pharmacodynamic properties. For example, an antisense oligonucleotide can be any substance known in the art to promote penetration or transport across the blood-brain barrier (such as The antibody to the transferrin receptor is coupled and administered by intravenous injection. Antisense compounds can be used, for example, to make antisense compounds Increased and/or increased viral vector ligation of antisense compounds across the blood-brain barrier. Permeable blood-brain disorders 158213.doc -78- 201210611 Wall-breaking can also be achieved by, for example, infusion: sugar, including ( But not limited to) meso-erythritol, xylitol, D(+)galactose, D(+) lactose, D(+) xylose, galactitol, inositol, L(-) fructose, D(a) Mannitol, D(+)glucose, D(+)arabinose, D(mono)arabinose, cellobiose, D(+)maltose, D(+) raffinose, L(+)rhamnose, D(+ )disaccharide, D(-) 'ribose, adonitol, D(+) arabitol, L(-) arabitol, D(+) fucose, L(-) fucose, D ( -) tosuose, L (+) to threose and L (-) to threose; or amino acids, including (but not limited to) glutamic acid, lysine, arginine, scorpion Amine, aspartic acid, cysteine, glutamic acid, glycine, histidine, leucine, guanidine, phenylalanine, valine, serine, threonine, tyramine Acid, proline and taurine. Methods and materials for enhancing blood-brain barrier penetration are described in, for example, U.S. Patent No. 4,866,042, "Method for the delivery of genetic material across the blood brain barrier"; No. 6,294,520, "Material for passage through the blood-brain barrier"; No. 6,936,589, "Parenteral delivery systems", all of which are incorporated herein by reference in its entirety. The subject antisense compound can be mixed, encapsulated, bound or otherwise associated with other molecules, molecular structures or mixtures of the compounds in the form of, for example, liposomes, receptor targeting molecules, oral, rectal, topical or other formulations. Promote uptake, distribution and/or absorption. For example, cationic lipids can be included in the formulation to facilitate oligonucleotide uptake. One composition which exhibits uptake is LIPOFECTIN (available from GIBCO-BRL, Bethesda, MD). 158213.doc -79- 201210611 The nucleotides with at least one 2'-0-methoxyethyl modification are particularly suitable for oral administration. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. Coated covers, gloves and the like are also suitable. Pharmaceutical formulations of the invention, preferably in unit dosage form, may be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of bringing into association the active ingredient with a pharmaceutical carrier or excipient. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with a liquid carrier or a finely divided solid carrier or both, and, if necessary, shaping the product. The compositions of the present invention may be formulated into any of a number of possible dosage forms such as, but not limited to, lozenges, capsules, gel capsules, liquid syrups, soft gels, suppositories, and enemas. The compositions of the present invention may also be formulated as a suspension in an aqueous, non-aqueous or mixed medium. The aqueous feed liquid may further contain a substance which increases the viscosity of the suspension, such as "cellulosin, sorbitol and/or dextran. The suspension may also contain a steady (four). Pharmaceutical compositions of the invention include, but are not limited to, solutions, emulsions, beads, and formulations containing liposomes. The pharmaceutical compositions and formulations of the present invention may comprise - or a plurality of penetration enhancers, carriers, excipients or other active or inactive ingredients. Formula = II 小 A small droplet-shaped heterogeneous system usually exceeding the diameter of °·1. In addition to the dispersed phase, the emulsion may have other components and active agents which may be present in the form of a liquid phase, an oil phase, or as a separate phase in the form of 158213.doc -80-201210611. Microemulsions are included as an embodiment of the invention. Emulsions and their use are well known in the art and are further described in U.S. Patent No. 6,287,860. Formulations of the invention include liposome formulations. The term "liposome" as used in the present invention means a vesicle composed of two borne lipids arranged in a spherical double layer or a double layer. Liposomes are monolayer or multilamellar vesicles having a membrane formed from a lipophilic material and an aqueous interior containing the composition to be delivered. The cationic liposome is a positively charged liposome, which interacts with a negatively charged DNA molecule to form a stable complex. A pH-sensitive or negatively charged liposome will retain DNA rather than form a complex with it. Both cationic and non-cationic liposomes have been used to deliver DNA into cells. Liposomes also include "sterically stabilized" liposomes, as used herein, which refers to liposomes comprising one or more specific lipids. When incorporated into liposomes, these particular lipids produce liposomes with enhanced cycle life relative to liposomes lacking such particular lipids. An example of a sterically stabilized liposome is one in which a portion of the vesicle-forming lipid portion of the liposome comprises one or more glycolipids or those liposomes that are derivatized with one or more hydrophilic polymers such as polyethylene glycol (PEG) moieties. Liposomes and their use are further described in U.S. Patent No. 6,287,860. The pharmaceutical formulations and compositions of the present invention may also include a surfactant. The use of surfactants in pharmaceuticals, formulations and emulsions is well known in the art. Surfactants and their use are further described in U.S. Patent No. 6,287,860, incorporated herein by reference. In an embodiment, the present invention utilizes various permeation enhancers to effect efficient delivery of the nucleus, particularly the oligonucleotides, 158213.doc-81.201210611. In addition to facilitating the diffusion of non-lipophilic drugs across the cell membrane, penetration enhancers also enhance the penetration of lipophilic drugs! Biopenetration enhancers can be classified into one of five broad categories, namely surfactants, fatty acids, Bile salts, chelating agents and non-chelating non-surfactants. Penetration enhancers and their use are further described in U.S. Patent No. 6,287,860, incorporated herein by reference. Those skilled in the art will recognize that formulations are typically designed according to their intended use, i.e., the route of administration. Used for bureau. Preferred formulations of the present invention include those formulations in which the nucleotides of the present invention are mixed with topical delivery agents such as quercetin, liposomes, fatty acids, fatty acid esters, steroids, chelating agents, and surfactants. Preferred lipids and sorghum plastids include neutral lipids and liposomes (eg, dioleoyl-phospholipid oxime D〇PE ethanolamine, dimyristoyl phosphatidylcholine DMPC 'distearate phosphatidylcholine choline ), negative lipids and liposomes (such as dimyristylphospholipid glycerol DMPG) and cationic lipids and liposomes (eg diterpenoid tetramethylaminopropyl D〇TAp and dioleyl) Phospholipid 醯ethanolamine DOTMA). For topical or other administration, the oligonucleotides of the invention may be encapsulated within or may form a complex with the compound, particularly with cationic liposomes. Alternatively, the raised nucleotides can be complexed with lipids, especially with cationic menthosides. Preferred fatty acids and their esters, pharmaceutically acceptable salts and their use are further described in U.S. Patent No. 6,287,86. Compositions and formulations for oral administration include powders or granules, micronized microparticles, suspensions or solutions in water or non-aqueous medium, and gels 158213.doc •82· 201210611 Capsules, gel capsules, worries , β + Su Shi η _, (four). Adding _, flavoring agent, dilute (four), emulsifier, dispersing aid or binder may be a combination of the oligonucleotides of the present invention and the reinforced agent, the surfactant, and the chelate, Ingredients of the agent. Preferred surfactants include fatty acids and/or their salts, bile acids and/or salts thereof. Preferred phosphonate acids and salts and their use are described in U.S. Patent No. 6,287, the disclosure of which is incorporated herein by reference.

It is a combination of penetration enhancers, such as a fatty acid/salt combined with a bile acid/salt. Particularly preferred combinations are the sodium salts of lauric acid, citric acid and udca. Other anti-reflection enhancers include polyoxyethylene _9_lauryl ether, polyoxyethylene bismuth __: the oligonucleotide of the present invention may comprise spray-dried particles or composites to form micron or nanoparticle particles. Pass the mouth. Oligo(tetra) acid complexes and their use are further described in U.S. Patent No. 6,287,86, the disclosure of which is incorporated herein by reference. Compositions and formulations for parenteral, intrathecal or intraventricular administration may also include buffers, diluents, and other suitable additives such as, but not limited to, penetration enhancers, carrier compounds, and other pharmaceuticals. A sterile aqueous solution of apharmaceutically acceptable carrier or excipient). Certain embodiments of the invention provide pharmaceutical compositions comprising one or more polymeric compounds and one or more other chemotherapeutic agents that act by a non-antisense mechanism. Examples of such chemotherapeutic agents include, but are not limited to, cancer chemotherapeutic drugs such as daun〇rubicin, daunomycin, dactinomyCin, cranberry (d〇) X〇rubicin), epirubicin, idarubicin, esopubicin 158213.doc -83· 201210611 (esorubicin), bleomycin, mafosfamide , ifosfamide, cytosine arabinoside, bischloroethyl-nitrosurea, busulfan, mitomycin C), actinomycin D, mithramycin, prednisone, hydroxyprogesterone, testosterone, tamoxifen, Dakaba. Dacarbazine, procarbazine, hexamethylmelamine, pentamethyl melamine, mitoxantrone, amsacrine, chlorambucil , methylcyclohexylnitrosourea, nitrogen mustards, melphalan, cyclophosphamide, 6-drainage, 6-thioguanine, glucosamine, 5-azacytidine, transbasic urea, deoxycoformycin, 4-hydroxyperoxy-phosphoniumamine, 5-fluorouracil (5-FU), 5-fluorodeoxyuridine (5- FUdR), amidoxime (MTX), colchicine, taxol, vincristine, vinblastine, etoposide (VP-16), top three Trimetrexate, irinotecan, topotecan, gemcitabine, teniposide, cisplatin, and diethylstilbestrol (DES). When used with a compound of the invention, the chemotherapeutic agents can be administered individually (e.g., 5-FU and oligonucleotide), sequentially (e.g., 5-FU and oligonucleotides for a period of time, followed by MTX and oligonucleosides). 158213.doc -84- 201210611 acid) or in combination with one or more other such chemotherapeutic agents (eg, 5_FU, Μτχ & nucleotides, or 5-FU, radiation therapy, and oligonucleotides). These include, but are not limited to, non-steroidal anti-inflammatory drugs and anti-inflammatory drugs for corticosteroids and include, but are not limited to, ribivirin, vidarabine, acyclovir, and ganciclovir ( Antiviral agents of gancicl(vir) can also be combined with the compositions of the invention. Combinations of antisense compounds and other non-antisense drugs are also within the scope of the invention. Two or more combinations of the compounds may be used together or sequentially. In another related embodiment, the compositions of the present invention may contain one or more antisense compounds (especially oligonucleotides) that are dry to the first nucleic acid, and one or more other antisense compounds that target the second nucleic acid target. . For example, the first target can be a specific antisense sequence of amidoxime phosphoribosyltransferase (NAMPT) and the first target can be a region from another nucleotide sequence. Alternatively, the compositions of the invention may contain two or more antisense compounds that target different regions of the same nicotine guanamine transphosphoryrosidase (NAMPT) nucleic acid target. Many examples of antisense compounds are described herein, and others may be selected from suitable compounds known in the art. Two or more combinations of the compounds may be used together or sequentially. Administration: The formulation of the Xianxin therapeutic composition and its subsequent administration (administration) are within the abilities of those skilled in the art. Administration depends on the severity and response of the condition to be treated, wherein the course of treatment lasts from several days to several months until the cure is achieved or the disease condition is alleviated. The optimal dosing schedule can be calculated from measurements of drug accumulation in the tract. The average skilled person can easily determine the optimal dose, method of administration and repetition rate. The optimal dose will vary depending on the relative potency of the individual oligonucleotides and can generally be based on an EC50 estimate found to be effective in both in vitro and in vivo animals. In general, the dose is 10 mg per kilogram of body weight, and may be administered once or more per A, weekly, monthly or yearly, or even every 2 to 20 years. As a general practitioner, the repetition rate of administration can be estimated based on the measured residence time and concentration of the drug in the body fluid or tissue. After successful treatment, the patient may need to undergo maintenance therapy to prevent the recurrence of the disease, in which the nucleotides are administered at a maintenance dose ranging from 1 Kg to 10 mg per kilogram of body weight, administered once or more per day. Once every 2 to 2 years. In one embodiment, the patient is treated with a drug at a dose of at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5 mg, at least about 6 mg per kilogram of body weight, At least about 7 mg, at least about 8 mg, at least about 9 mg, at least about 1 mg, at least about 15 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 35 mg, at least about 40 mg At least about 45 mg, at least about 5 mg, at least about 6 mg, to >, about 70 mg, at least about 80 mg, at least about 9 mg, or at least about 1 mg. Certain injectable doses of antisense oligonucleotides are described, for example, in U.S. Patent No. 7,563,884, "Antisense modulati 〇n 〇f ρτρΐΒ εχρΓ_〇η", which is incorporated herein by reference in its entirety. While the various embodiments of the invention have been described, it is understood that Many variations of the disclosed embodiments can be made in accordance with the disclosure herein without departing from the spirit and scope of the invention. Therefore, the breadth and scope of the present invention should not be limited to any of the above embodiments. 158213.doc -86 - 201210611. All documents mentioned herein are in the form of data. All publications and patent documents cited in this application are hereby incorporated by reference in their entirety for all purposes in the the the the the the To the extent that this document cites references to various references, the applicant does not admit that any particular reference is made to it. "Previous techniques ^ Embodiments of the compositions and methods of the invention are illustrated in the following examples.

EXAMPLES The following non-limiting examples are illustrative of selected embodiments of the invention. It is to be understood that the proportions of the component elements and variations of the alternatives are readily apparent to those skilled in the art and are within the scope of the embodiments of the invention. Example 1: Designing an antisense nucleic acid molecule for nicotine indoleamine phosphoribosyltransferase (nampt) and antisense nucleotide specificity of purine nucleotides. The term "p... "Specific nucleotides" or "targeting oligonucleotides" means having (1) capable of forming a stable complex with a part of a target gene or (a stable part of the mRNA transcript of the target gene) Oligonucleotide of the sequence of the duplex. Promote appropriate nucleotide collection by using a computer program (such as IDT AntiSense Design, IDT OligoAnalyzer) that automatically identifies the subsequence of 19 to 25 nucleotides of each specified sequence. Alternatively, the subsequences will form a hybrid at the desired melting temperature (typically 50% (: to 60. under the squat to the target polynucleotide sequence) and will not form a self-dimer or other complex secondary junction 158213. Doc-87-201210611. Further facilitating the selection of appropriate oligonucleotides by using a computer program that automatically aligns nucleic acid sequences and indicates regions of homology or homology. Such programs are used, for example, by searching such as GenBank The library or the nucleic acid sequences obtained are sequenced by sequencing the pCR product. Comparing the nucleic acid sequences from the various genes and the intergenic regions of the specified genome allows selection of nucleic acid sequences that display an appropriate degree of specificity to the gene of interest. Such procedures allow for the selection of nucleotides that exhibit a high degree of complementarity with the target nucleic acid sequence and a lower degree of complementarity with other nucleic acid sequences in the specified genome. Those skilled in the art will recognize that it is selected for use in the present invention. There is considerable freedom in the proper region of the gene. When the binding of the antisense compound to the target nucleic acid interferes with the normal function of the target nucleic acid, resulting in a regulatory function and/or activity, and in the case where specific binding is required, ie in vivo Under physiological conditions in the case of internal or therapeutic treatment, and under conditions of performing in vitro assays, there is a sufficient degree of complementarity to avoid non-specific binding of the antisense compound to the non-target nucleic acid sequence. The compound is "specifically hybridizable". The hybridization properties of the nucleotides described herein may be As determined by one or more in vitro assays known in the art. For example, the properties of the nucleoside oxime described herein can be determined using a melting curve assay by determining between a target natural antisense sequence and a potential drug molecule. Binding strength is obtained. The binding strength between the target natural antisense sequence and the potential drug molecule (molecular) can be estimated using any established method for measuring the strength of the intermolecular interaction, such as a saliency curve assay. 1582l3.doc -88- 201210611 The melting curve test determines the temperature at which a natural antisense sequence/molecular complex is rapidly converted from a double strand to a single strand configuration. This temperature is generally accepted as a reliable measure of the strength of the interaction between two molecules. A cDNA replica of a sense RNA molecule or a synthetic DNA or RNA nucleotide corresponding to the binding site of the molecule performs a melting curve assay. Multiple kits containing all the necessary reagents to perform this assay are available (eg, Applied Biosystems Inc., MeltDoctor kit). Such kits include suitable buffer solutions containing a double-stranded DNA (dsDNA) binding dye such as ABI HRM dye, SYBR Green, SYTO, and the like. The nature of the dsDNA dye is such that it emits little fluorescence when in free form, but emits intense fluorescence when bound to dsDNA. To perform the assay, the cDNA or corresponding nucleotides are mixed with molecules of the specified concentration in a particular manufacturer's protocol. The mixture is heated to 95 ° C to dissociate all of the preformed dsDNA complexes, then slowly cooled to room temperature or other lower temperatures specified by the manufacturer to bond the DNA molecules. The newly formed composite was then slowly heated to 95 ° C while continuously collecting data on the amount of fluorescence produced by the reaction. The intensity of the fluorescence is inversely proportional to the amount of dsDNA present in the reaction. Data can be collected using a real-time PCR instrument compatible with the kit (eg ABI’s StepOne Plus Instant PCR System or lightTyper instrument, Roche Diagnostics, Lewes, UK). A plot of fluorescence versus negative derivative of temperature (-d(fluorescence)/dT) on the y-axis versus temperature (X-axis) using a suitable software (eg lightTyper (Roche) or SDS Dissociation Curve (ABI)) To build a melting peak. This data was analyzed to identify the temperature at which the dsDNA complex rapidly transitions to a single molecule. This temperature is called 158213.doc -89- 201210611

Tm is proportional to the strength of the interaction between the two molecules. The Tm usually exceeds 40 °C. Example 2: Modulation of NAMPT Polynucleotides All antisense oligonucleotides used in Example 2 were designed as described in Example 1. The manufacturer (IDT Inc., Coralville, IA) was instructed to manufacture the designed thiophosphate oligo-oligonucleotides and to provide the designed phosphorothioate analogs shown in Table 1. An asterisk mark between the nucleotides indicates the presence of a thiophthalate linkage. The nucleotides required for the experiments in Example 2 can be synthesized using any suitable prior art method, such as the method used for IDT: on a solid support such as 5 micron controlled microporous glass beads (CPG), using phosphorous Phosphoramidite monomer (normal nucleotide acid with all active groups protected by a protecting group such as trityl on sugar, benzoquinone on A and c, and G on G N-2-isobutyl). The protecting group prevents an inappropriate reaction during the synthesis of the oligonucleotide. The protecting group is removed at the end of the synthesis process. The initial nucleotide is attached to the solid support via 3, carbon, and the synthesis is carried out in the 3, to 5, direction. Adding a new base to the growing oligonucleotide strand is carried out in 4 steps: 1) using tri-acetic acid from the fixed nucleotide 5, removing the protecting group by oxygen; 2) using the tetrazole to immobilize the nucleotide Below the sequence - the nuclear acid is coupled together; the reaction is carried out via the aminotetrazolium phosphate intermediate; 3) the unreacted free nucleotides and reaction by-products are washed off and the unreacted fixed nucleotides are capped. In order to prevent its participation in the next round of synthesis; by using acetic anhydride and N-mercaptoimidazole for free 5, the base is brewed to achieve capping; 4) stabilizing the bond between the nucleotides to produce phosphoric acid The ester bond uses iodine and water, or the Beaucage reagent is used if a thiolate bond is required (3H-1, 2-cracked-branched f 1 τ 7T _ alcohol · 3 - Ming - 158213.doc -90· 201210611 I, ι-dioxide) oxidizes phosphorus. The embedded backbone can be constructed by alternating two oxidants. The 4-step cycle described above is repeated for each nucleotide in the sequence. When the complete sequence was synthesized, nucleotides were cleaved from the solid support and the protecting group was removed using ammonium hydroxide at elevated temperature. The protecting group is washed away by desalting and the remaining oligonucleotides are lyophilized. Treatment of HepG2 cells with antisense nucleosides To perform the experiment designed in Example 2, HepG2 cells from ATCC (Catalog No. HB-8065) were grown in growth medium (MEM/EBSS (at MEM/EBSS) at 37 ° C and 5% CO 2 . Hyclone catalog number SH30024 or Mediatech catalog number MT-10-010-CV) +10°/〇FBS (Mediatech catalog number MT35-011-CV) + penicillin/streptomycin (Mediatech catalog number MT3 0 -002-CI)) grows. One day before the experiment, the cells were recoated in a 6-well culture dish at a density of 0.5 x 10 4 ml per ml, and incubated overnight at 37 ° C and 5% CO 2 . On the day of the experiment, the medium in the 6-well plate was changed to fresh growth medium. The nucleotides transported by the manufacturer in lyophilized form were diluted to a concentration of 20 μΜ using deionized water with ribonuclease/deoxyribonuclease. 2 μL of this solution was incubated with 400 μM OptiMEM medium (Gibco Cat. No. 31985-070) and 4 μL Lipofectamine 2000 (Invitrogenl Cat. No. 11668019) for 20 minutes at room temperature, followed by dropwise application. One well of a 6-well culture dish with HepG2 cells. A similar mixture including 2 μΐ water instead of the nucleotide solution was used to simulate the transfection control group. After incubation for 3 hours to 18 hours at 37 ° C and 5% CO 2 , the medium was changed to fresh growth medium. 48 hours after the addition of the antisense oligonucleotide, the medium 158213.doc -91 · 201210611 was removed and the SV total RNA isolation system from Promega (catalog number Z3 105) or the RNeasy total RNA isolation kit from Qiagen was used (catalog No. 74181) Extract RNA from cells following the manufacturer's instructions. 600 ng of extracted RNA was added to the reverse transcription reaction performed using the Verso cDNA kit from Thermo Scientific (catalog number AB1453B) or the high capacity cDNA reverse transcription kit (catalog number 43 688 13) as described in the manufacturer's protocol. Using the cDNA from this reverse transcription reaction, the ABI Taqman gene expression mixture (catalog number 4369510) and the ABI-designed bow tweezers/probes were used by real-time PCR (Applied Biosystems Taqman Gene Expression Assay: Hs00237184_ml (NAMPT), Applied Biosystems Inc., Foster City CA) monitors gene expression. The following PCR cycles were used: 50 ° C for 2 minutes, 95 ° C for 10 minutes, 40 cycles (95 ° C for 15 seconds, 60 ° C for 1 minute), using a StepOne Plus Instant PCR Machine (Applied Biosystems). The fold change in gene expression after treatment with antisense oligonucleotides was calculated based on the difference in 18S-corrected dCt values between the treated and mock transfected samples. Pound 耒, * Immediate PCR results showed that the polymer designed as the NAMPT antisense sequence BE778214 did not increase the NAMPT content in HepG2 cells (Fig. 1). Treatment of MCF-7 cells with antisense nucleotides To perform the experiment designed in Example 2, MCF-7 cells from ATCC (catalog number HTB-22) were grown in growth medium at 37 ° C and 5% CO 2 ( MEM/EBSS (Hyclone catalog number SH30024 or Mediatech catalog number MT-10-010-CV) +10% FBS (Mediatech catalog number MT35-011-CV) + penicillin/streptomycin (Mediatech catalog number MT30-002-CI) ) growing in. On the day before the experiment, the cells were recoated at a density of 0·5χ1〇5 per ml 158213.doc 92- 201210611 in a 6-well culture dish at 37 ° C and 5 ° /. Cultivate overnight under C02. On the day of the experiment, the medium in the 6-well culture dish was changed to fresh growth medium. Oligonucleotides transported by the manufacturer in lyophilized form were diluted to a concentration of 20 μΜ using deoxyribonuclease/deoxyribonuclease deionized water. 2 μL of this solution was incubated with 400 μM OptiMEM medium (Gibco Cat. No. 31985-070) and 4 μL serotonin 200 0 (lnvitrogenl Cat. No. 11668019) for 20 minutes at room temperature, followed by dropwise application to MCF- 7 cells in a well of a 6-well culture plate. A similar mixture including 2 μΐ water instead of the oligonucleotide solution was used to simulate the transfection control group. After incubation for 3 to 18 hours at 37 ° C and 5% CO 2 , the medium was changed to fresh growth medium. 48 hours after the addition of antisense nucleotides, the medium was removed and the SV Total RNA Isolation System from Promega (Cat. No. Z3105) or the RNeasy Total RNA Isolation Kit from Qiagen (Cat. No. 74181) followed the manufacturer's instructions. Extract RNA from cells. 600 ng of extracted RNA was added to the reverse transcription reaction performed using the Verso cDNA kit from Thermo Scientific (catalog number AB1453B) or the high capacity cDNA reverse transcription kit (catalog number 43 68813) as described in the manufacturer's protocol. Using the cDNA from this reverse transcription reaction, the ABI Taqman gene expression mixture (catalog number 4369510) and the ABI designed primer/probe were used by real-time PCR (Applied Biosystems Taqman Gene Expression Assay: Hs00237184_ml, Applied

Biosystems Inc., Foster City CA) monitors gene expression. The following PCR cycles were used: 2 minutes at 50 °C, 10 minutes at 95 °C, 40 cycles (15 seconds at 95 °C, 1 minute at 60 °C), using the Step One Plus Instant PCR Machine (Applied Biosystems) . The fold change in gene performance after treatment with antisense oligonucleotides was calculated based on the difference in 18S-corrected dCt values between 158213.doc -93 and 201210611 of the treated and mock transfected samples. The results of the real-time PCR showed that the oligonucleotides designed as NAMPT antisense sequences BE778214 and skoblyby.aAp07 did not increase the NAMPT content in MCF-4 cells (Fig. 2). Treatment of DXJ145 cells with antisense nucleotides DU145 cells from ATCC (catalog number HB-81) were grown in growth medium (MEM/EBSS (Hyclone catalog number SH30024 or Mediatech catalog number MT) at 37 ° C and 5% CO 2 -10-010-CV) +10% FBS (Mediatech Cat. No. MT3 5-011-CV) + Penicillin/Streptomycin (Mediatech Cat. No. MT30-002-CI)). One day before the experiment, the cells were recoated in a 6-well culture dish at a density of 0.5 x 105 per ml, and cultured at 37 ° C and 5% CO 2 . On the day of the experiment, the medium in the 6-well culture dish was changed to fresh growth medium. All antisense oligonucleotides were diluted to a concentration of 2 〇 μΜ. 2 μL of this solution was incubated with 400 μΐ Opti-MEM medium (Gibco Cat. No. 31985-070) and 4 μL serotonin 2000 (Invitrogenl Cat. No. 11668019) for 20 minutes at room temperature and applied to HepG2 cells. Hole in a hole in the culture plate. A similar mixture comprising 2 μΐ water instead of the oligonucleotide solution was used for the untranslated control group. After incubation for 3 hours to 18 hours at 37 ° C and 5% CO 2 , the medium was changed to fresh growth medium. 48 hours after the addition of antisense nucleotides, the medium was removed and the SV total RNA isolation system from Promega (catalog number Z3 105) or the RNeasy total RNA isolation kit from Qiagen (catalog number 74181) was followed by the manufacturer. Describe the extraction of RNA from cells. Add 6 ng of RNA to 158213.doc -94 - 201210611 as described in the manufacturer's protocol using the Verso cDNA kit from Thermo Scientific (catalog number AB1453B) or the high capacity cDNA reverse transcriptome (catalog number 4368813) In the reverse transcription reaction. The cDNA from this reverse transcription reaction was used, and the Applied Biosystems Taqman Gene Expression Assay was designed by using the primers/probes designed by ABI in the immediate use of the 81 Ding & 911^11 Gene Expression Mixture (Cat. No. 43 69510) and ABI. Hs00237184_ml, Applied Biosystems Inc., Foster City CA) monitors gene expression. The following PCR cycles were used: 50 ° C for 2 minutes, 95 ° C for 10 minutes, 40 cycles (95 ° C for 15 seconds, 60 ° C for 1 minute), using a StepOne Plus real-time PCR machine (Applied Biosystems). The fold change in gene expression after treatment with antisense nucleotides was calculated based on the difference in the 18S·corrected dCt values between the treated and mock transfected samples. The results of real-time PCR showed that the oligonucleotide designed as the NAMPT antisense sequence skoblyby.aApr07 did not increase the NAMPT content in DU145 cells (Fig. 3). HEK 293 cells were treated with antisense oligonucleotides at 37. (: and 5% C02 HEK 293 cells from ATCC (Catalog No. CRL-1573) in growth medium (MEM/EBSS (Hyclone catalog number SH30024 or Mediatech catalog number MT-10-010-CV) + 1% FBS (Mediatech catalog number MT35-011-CV) + penicillin/streptomycin (Mediatech catalog number MT30-002-CI)) was grown. On the day before the experiment', the cells were recoated in 6 wells at a density of 0.5χ105 per ml. Incubate in the dish 'and in 37. (: and 5% C02. On the day of the experiment, replace the medium in the 6-well plate with fresh growth medium. Dilute all antisense oligonucleotides to 158213.doc -95- 201210611 Concentration 20 μΜ. Incubate 2 μL of this solution with 400 μM Opti-MEM medium (Gibco Cat. No. 31985-070) and 4 μListamine 2000 (Invitrogen Catalog No. 11668019) for 20 minutes at room temperature, and Apply to each well of a 6-well culture dish with HEK 293 cells. A similar mixture including 2 μΐ water instead of oligonucleotide solution was used in the untranslated control group. Incubate at 37 ° C and 5% CO 2 After 3 to 18 hours, the medium was changed to fresh growth medium. After the addition of antisense nucleotides 48 The medium was removed and the RNA was extracted from the cells using the SV Total RNA Isolation System from Promega (Cat. No. Z3 105) or the RNeasy Total RNA Isolation Kit from Qiagen (Cat. No. 74181) following the manufacturer's instructions. 600 ng RNA Add to the reverse transcription reaction performed using the Verso cDNA kit from Thermo Scientific (catalog number AB1453B) or the high-capacity cDNA reverse transcription kit (catalog number 4368813) as described in the manufacturer's protocol. Use cDNA from this reverse transcription reaction Gene expression was monitored by immediate PCR using the ABI Taqman Gene Expression Mix (Cat. No. 4369510) and ABI designed primer/probe (Applied Biosystems Taqman Gene Expression Assay: Hs00237184_ml, Applied Biosystems Inc., Foster City CA). PCR cycle: 50 ° C for 2 minutes, 95 ° C for 10 minutes, 40 cycles (95 ° C for 15 seconds, 60 ° C for 1 minute), using Mx4000 thermal cycler (stratagene) or StepOne Plus real-time PCR machine (Applied Bi〇SyStems). The fold change in gene expression after treatment with antisense oligonucleotides was calculated based on the difference in 18S-corrected dCt values between the treated and mock transfected samples. The results of real-time PCR showed that the content of NAMPT mRNA in HEK 293 cells was significantly increased 48 hours after treatment with an antisense oligonucleotide of NAMPT antisense sequence 158213.doc •96-201210611 skoblyby_aApr〇7 (Fig. 4). The stirred control oligonucleotide (CUR_1505) did not increase the NAMPT content in HEK 293 cells. While the invention has been described and described with respect to the embodiments the embodiments In addition, although specific features of the invention may be disclosed in relation to only one of several embodiments, such features may be combined with one or more other features of other embodiments, which may be desired for any specified or particular application. advantageous. The Abstract of the Invention will allow the reader to quickly ascertain the nature of the technical disclosure. The conditions are set forth as not to explain or limit the scope or meaning of the following claims. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a diagram showing the results of real-time PCR, which shows the fold change of NAMPT mRNA after treatment of HepG2 cells with a phosphorothioate-introduced nucleotide introduced by lipofectamine 2000 as compared with a control group. + standard deviation. The bands indicated as CUR-1724, CUR-1725, CUR-1726 and CUR-1727 correspond to the samples treated with SEQ ID NO.. 17 to 20, respectively. Figure 2 is a graph of the results of real-time PCR showing the fold change + standard deviation of NAMPT mRNA after MCF-7 cells were treated with phosphorothioate-introduced nucleotides introduced with lipofectamine 2000 as compared to the control group. The bands denoted CUR-1728, CUR-1729, CUR-1730, CUR-1731 and CUR-1732 correspond to the samples treated with SEQ ID NOS: 21 to 25, respectively. 158213.doc -97- 201210611 Figure 3 is a graph of the results of real-time PCR showing changes in NAMPT mRNA after treatment of DU145 cells with phosphorothioate nucleotides introduced with lipofectamine 2000 compared to the control group. Multiple + standard deviation. The bands denoted CUR-1733, CUR-1734, CUR-1735 and CUR-1736 correspond to the samples treated with SEQ ID NOS: 26 to 29, respectively. Figure 4 is a graph showing the results of real-time PCR showing the fold change + standard deviation of NAMPT mRNA after HEK 293 cells were treated with phosphorothioate-inducing nucleotides introduced with lipofectamine 2000 as compared with the control group. The bands denoted as CUR-173 7 and CUR-15 05 correspond to the samples treated with SEQ ID NO: 3 0 to 31, respectively.

BRIEF DESCRIPTION OF THE SEQUENCE LISTING: SEQ ID NO: 1 : Homo serotonin guanamine transphosphatase (NAMPT) transcript variant 3 mRNA (NCBI accession number: NM_005746); SEQ ID NO: 2: natural NAMPT antisense sequence ( SEQ ID NO: 3 • Natural NAMPT antisense sequence (skoblyby.aApr07); SEQ ID NO: 4: native NAMPT antisense sequence (sernorby.aAuglO-unspliced); SEQ ID NO: 5: natural NAMPT anti Sequence (wyflubu.aAugl 0-unspliced); SEQ ID NO: 6: native NAMPT antisense sequence (swysmorbu.aAuglO-unspliced); SEQ ID NO: 7: native NAMPT antisense sequence (zuflubu.aAuglO-unspliced) SEQ ID NO: 8: native NAMPT antisense sequence (ployblyby.aAug10-unspliced); SEQ ID NO: 9: native NAMPT antisense sequence (skablyby.aAug10-unspliced); SEQ ID NO: 10: native NAMPT Antisense sequence (skublyby.aAug 1 0-unspliced); SEQ ID NO: 11: natural NAMPT antisense sequence (swarsmorbu.aAuglO-unspliced); SEQ ID 158213.doc -98- 201210611 NO: 12: natural NAMPT anti- Sequence (CD639886); SEQ ID NO: 13: natural NAMPT antisense sequence (BM451023); SEQ ID NO: 14: natural NAMPT counter Sequence (R22881); SEQ ID NO: 15: natural NAMPT antisense sequence (DW442985); SEQ ID NO: 16: natural NAMPT antisense sequence (BM717984); SEQ ID NO: 17 to 31: an antisense oligonucleotide. * indicates thioate vinegar linkage; SEQ ID NO: 3 1 : control oligonucleotide (CUR-1505).

158213.doc -99- 201210611 〇

Sequence Listing <110> US Occidental Limited Company

<120> Treatment of NAMPT-associated diseases by inhibition of natural antisense transcripts of glutamine transluciferase (NAMPT) <130> NAMPT <140> 100129854 <141> 2011-08-19 < 150>61/375,126 <151> 2010-08-19 <160> 31 <170> patentin version 3.5 <210> 1 <211> 4593 <212> DNA <213> Homo sapiens< 400 > 1 gctgccgcgc cccgcccttt ctcggccccc ggagggtgac ggggtgaagg cgggggaacc gaggtgggga gtccgccaga gctcccagac tgcgagcacg cgagccgccg cagccgtcac ccgcgccgcg tcacggctcc cgggcccgcc ctcctctgac ccctcccctc tctccgtttc cccctctccc cctcctccgc cgaccgagca gtgacttaag caacggagcg cggtgaagct catttttctc cttcctcgca gccgcgccag ggagctcgcg gcgcgcggcc cctgtcctcc ggcccgagat gaatcctgcg gcagaagccg agttcaacat cctcctggcc accgactcct acaaggttac tcactataaa caatatccac ccaacacaag caaagtttat tcctactttg aatgccgtga aaagaagaca gaaaactcca aattaaggaa ggtgaaatat Gaggaaacag tattttatgg gttgcagtac attcttaata agtacttaaa aggtaaagta gtaaccaaag agaaaatcca ggaagccaaa gatgtctaca aagaacattt ccaagatgat gtct ttaatg aaaagggatg gaactacatt cttgagaagt atgatgggca tcttccaata gaaataaaag ctgttcctga gggctttgtc attcccagag gaaatgttct cttcacggtg gaaaacacag atccagagtg ttactggctt acaaattgga ttgagactat tcttgttcag tcctggtatc caatcacagt ggccacaaat tctagagagc agaagaaaat attggccaaa tatttgttag aaacttctgg taacttagat ggtctggaat acaagttaca tgattttggc tacagaggag tctcttccca agagactgct ggcataggag catctgctca cttggttaac ttcaaaggaa cagatacagt agcaggactt gctctaatta aaaaatatta tggaacgaaa gatcctgttc caggctattc tgttccagca gcagaacaca gtaccataac agcttggggg aaagaccatg aaaaagatgc ttttgaacat attgtaacac agttttcatc agtgcctgta tctgtggtca gcgatagcta tgacatttat aatgcgtgtg agaaaatatg gggtgaagat ctaagacatt 158213- sequence Listing, doc 60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 201210611 taatagtatc aagaagtaca caggcaccac taataatcag acctgattct ggaaaccctc 1260 ttgacactgt gttaaaggtt ttggagattt taggtaagaa gtttcctgtt Actgagaact 1320 caaagggtta caagttgctg ccaccttatc ttagagttat tcaaggggat ggagtagata 1380 ttaata cctt acaagagatt gtagaaggca tgaaacaaaa aatgtggagt attgaaaata 1440 ttgccttcgg ttctggtgga ggtttgctac agaagttgac aagagatctc ttgaattgtt 1500 ccttcaagtg tagctatgtt gtaactaatg gccttgggat taacgtcttc aaggacccag 1560 ttgctgatcc caacaaaagg tccaaaaagg gccgattatc tttacatagg acgccagcag 1620 ggaattttgt tacactggag gaaggaaaag gagaccttga ggaatatggt caggatcttc 1680 tccatactgt cttcaagaat ggcaaggtga caaaaagcta ttcatttgat gaaataagaa 1740 aaaatgcaca gctgaatatt gaactggaag cagcacatca ttaggcttta tgactgggtg 1800 tgtgttgtgt gtatgtaata cataatgttt attgtacaga tgtgtggggt ttgtgtttta 1860 tgatacatta cagccaaatt atttgttggt ttatggacat actgcccttt catttttttt 1920 cttttccagt gtttaggtga tctcaaatta ggaaatgcat ttaaccatgt aaaagatgag 1980 tgctaaagta agctttttag ggccctttgc caataggtag tcattcaatc tggtattgat 2040 cttttcacaa ataacagaac tgagaaactt ttatatataa ctgatgatca cataaaacag 2100 atttgcataa aattaccatg attgctttat gtttatattt aacttgtatt tttgtacaaa 2160 caagattgtg taagatatat ttgaagtttc agtgatttaa cagtctttcc aacttttcat 2220 gatttttatg a gcacagact ttcaagaaaa tacttgaaaa taaattacat 2280 ccattaatca gcaaataaaa catggcctta acaaagttgt ttgtgttatt gtacaatttg 2340 aaaattatgt cgggacatac cctatagaat tactaacctt actgcccctt gtagaatatg 2400 tattaatcat tctacattaa agaaaataat ggttcttact ggaatgtcta ggcactgtac 2460 agttattata tatcttggtt gttgtattgt accagtgaaa tgccaaattt gaaaggcctg 2520 tactgcaatt ttatatgtca gagattgcct gtggctctaa tatgcacctc aagattttaa 2580 ggagataatg tttttagaga gaatttctgc ttccactata gaatatatac ataaatgtaa 2640 aatacttaca aaagtggaag tgccttttgt tagtgtattt taaagtaatt acacttctga atttattttt 2700 catattctat agttggtatg acttaaatga attactggag tgggtagtga gtgtacttaa 2760 atgtttcaat tctgttatat tttttattaa gtttttaaaa aattaaattg gatattaaat 2820 tgtatggaca tcatttatta attttaaact gaatgccctc aataagtaat actgaagcac 2880 attcttaaat gaagataaat tatctccaat gaaaagcatg acatgtgttt caatagaaga 2940 atcttaagtt ggctaaattc aaagtgcttg acatcaaaat gttctagagt gattagctac 3000 tagattctga atcatacatc acatctgact agagaccagt ttctttcgaa tgattctttt 3060 atgtatgtag atctgtt Ctt ctgaggcagc ggttggccaa ctatagccca aaggccaaat 3120 -2- 158213-sequence table.doc 201210611

ttggacttct ttttataaat gcagattgtc tatggctgct ttcccactac tccagcctaa 3180 ggtaaacagc tgcaatagaa gccaaatgag aatcgcaaag cccaaaatgt ttattaacct 3240 gccctttaca caaaattaca caaaaagttt cctgatctct gttctaagaa aaggagtgtg 3BOO ccttgcattt aaaaggaaat gttggtttct agggaaggga ggaggctaaa taattgatac 3360 ggaattttcc tcttttgtct tcttttttct cacttaagaa tccgatactg gaagactgat 3420 ttagaaaagt ttttaacatg acattaaatg tgaaatttta aaaattgaaa agccataaat 3480 catctgtttt aaatagttac atgagaaaat gatcactaga ataacctaat tagaagtgtt 3540 atcttcatta aatgtttttt gtaagtggta ttagaaagaa tatgtttttc agatggttct 3600 ttaaacatgt agtgagaaca ataagcatta ttcactttta gtaagtcttc tgtaatccat 3660 gatataaaat aattttaaaa tgatttttta atgtatttga gtaaagatga gtagtattaa 3720 gaaaaacaca catttcttca caaaatgtgc taaggggcgt gtaaagaatc aaaagaaact 3780 attaccaata atagttttga taatcaccca taattttgtg tttaaacatt gaaattatag 3840 tacagacagt attctctgtg ttctgtgaat ttcagcagct tcagaataga gtttaattta 3900 gaaatttgca gtgaaaaaag ctatctcttt gttcacaacc ataaatcagg agatggagat 3960 taattc tatt ggctcttagt cacttggaac tgattaattc tgactttctg tcactaagca 4020 cttggtattt ggccatctcc attctgagca ccaaacggtt aacacgaatg tccactagaa 4080 ctctgctgtg tgtcaccctt aaatcagtct aaatcttcca gacaaaagca aatggcattt 4140 atggatttaa gtcattagat tttcaactga cattaattaa tccctcttga ttgattatat 4200 catcaagtat ttatatctta aataggaggt aggatttctg tgttaagact cttatttgta 4260 ccctataatt aaagtaaaat gttttttatg agtatccctt gttttccctt cttaaattgt 4320 tatcaaacaa tttttataat gaaatctatc ttggaaaatt agaaagaaaa atggcaaggt 4380 atttattgtt ctgtttgcca taatttagaa ctcacactta agtattttgt agttttacat 4440 tcctttttaa cccattcagt ggagaatgtc agcttttctc ccaagttgta tgttaagtct 4500 attctaatat gtactcaaca tcaagttata aacatgtaat aaacatggaa ataaagttta 4560 gctctattag tgaagtgtta aaaaaaaaaa aaa 4593 < 210 > 2 < 211 > 882 < 212 > DNA < 213 > Homo sapiens < 400 > 2 gaaaattatt gtaaacgcat ttaaacaaat tattatttct attttgagac ggagtctcgc 60 tctgtcgccc aggctggagt gcagtggctg gatctcggct cactgcaagc tccgcctccc 120 tggttcacgc catcctcctg cctcacacct gtaa tcccag cactttggga ggctgaggcg 180 158213 · Sequence Listing .doc 201210611 ggctgatcac ttgagcccag gattttgaga ccggcctggg caacatggtg aagacccatc 240 tctgcaaaaa atacagaagt tggctggacg tggtggcatg tgcctgtagt cccagcttct BOO ctgaaaggag actgacgtgg gaggattgcc tgagcccggg gaggttgtag catgtagagg 360 acctgagaaa ctgtttttca taggtcacaa caacatgaca aataataaca catagactca 420 aatgggcccc ctcacttgat tcaaagccct ggattattat accatcctac caaatagcaa 480 tcaggcactg ccaattgggc atgcagctcc ttgtctccct ccctcagagt gctatgaaag 540 acctagggct catatatttg ttcaggcaaa gtgagtgtat ctgtgccact cctgttgcca 600 cacacccttg cagacagcct cgggtgcacc tttatatttc aaagttggct cagatactcc 660 aatctgacct gatttgactc agttaaaaaa cactgctgaa gtaaggtatg gaactcacct 720 actgggaacc ctgaagtggg cttacatttc ctttatattc tctagatcgc aatacaacgt 780 gtccaagcca tgtgaaaagg agtttaaatt tactggcttt tttatcaact gcagcttgga 840 acccaagtta tccgggaagg caccaaaagg gtccagtcca ga 882 < 210 > 3 <211> 915 <212> DNA <213> Homo sapiens <400> 3 ccgcctggga ccttccgtcc tacccagtcc tg gccggttt tctgggtcct cctgaagtca 60 cgccacccgg ctagggggcg aggagcctcc tactgcccat cttcccgtcc accacgcgca 120 gttactcacc tttgtctccg gcctggatta aggatccagc ctttcgcctc catccctctt 180 gtccctcctg atcctcctga ccctgtcttt aagatcccag gagctgcggt gaggagtgag 240 gctgaggggc ccctttcatc tgatgcagcg actccgcttt cctccggcgg ctctgtctat 300 ggctgagctc tttgatcctt tgagagatgg tttgactttt cccgagcaaa gagcctgcgt 360 tgaaaagcgg gggtggaatt cagtcctcac agataatgag gggacaagac ctaattgaac 420 cgagtattgc cgggaaggaa aaggcaacgg gccaagcctt tgacagggtg cgacactgac 480 ttttatcatc gttatagtct ttaaatcctg ggaaacgagt tggcaacccc aaaataaaga 540 agtgtaatga cgtctgatga cttcacccaa atacagacca ttccaagaaa gacttgcgca 600 gttctcatgc gtggttgcgt ttttgcataa aactaagatt ccctttgtcc gcatgtttaa 660 tagcttaaaa ataaattgag gtttttatcg gataaaagta gccaggaaaa agtgatacag 720 tgaaaacgat tacaggatat ttatagactt gtctttcaag ttattagaag tctcattcta 780 tctgggggca gtgatggtgg tggtggtagt ggaacttgtg aattgagatt catagtggaa 840 cttgtgaatt gagattcatc tcgaaactgg aggcatggct gagacttcta a Taaagacaa 900 cctcagtcaa cacta 915 4- 158213 · Sequence Listing.doc 201210611 <210> 4 <211> 165 ' <212> DNA <213> Homo sapiens <400> 4 catgtacagt tttgggctga ttctcaacta tacagatgca catacaggct gggaatggtg 60 gctcacacct gtaatctcag cactttagga ggcctgagtc aaggagttcg aggccaaaca 120 gttgagactg tttcccagac tgggaaacag tgagaccccc atctc 165 < 210 > 5 < 211 > 533 < 212 > DNA < 213 > Homo sapiens < 400 > 5 ctgtgtatac acgtaagtgc taaagtgcct gaaaggcacc tgggaacagt acttaactga 60 caccaaggta agagactgtc agttcagctg agctaagggg aaaacggcaa ttaggtgtgt 120 cagctgagat tgctatgtgt aaggtcctcc cccttctccc tgcagacttt tcttctattt 180 cttttttcct ttccacatga aagcccctat gtcccaacac caaatgtctt agctgaagga 240 attcccactt ctcttaagca aggcagtttg gaagaggtag tggaagaaac ctcatctctg 300 ttattacaag agatctattc cggacgcctc atattggaac tctaaataca ccatcaccgc 360 agaaatactg tttgatttgg aagtgagaag tattatgtac aacaatcttt ggaaaactac 420 tataatttgg gtactgacct tactctatct ccaccaaact ctttcgaaca gaaaaaaact 480 tgtgtttcat agctgtag At accatctgag attcgtatac atcaaaatgt cag 533

≪ 210 > 6 < 211 > 522 < 212 > DNA < 213 > Homo sapiens < 400 > 6 aaagatttat ctgtagcttg cgatgctgtt tggtacgata gcgttcaccc acacaagaac 60 ttctttcaaa attgggagtg catcctctca aaccctgctt tggttttatc aactgatttt 120 actgatattc gaagtccttt gttgtcattt caacgatgtt cacagcatct ttgccagcag 180 tagatttcat ctcaagaaac cactttctgt atccacccat atgaagcaaa tcctcatctg 240 ttcaagttta atcatgagac tgcagcaatt cagtcagatc ttcaggctcc accacttcta 300 gttatctagc tatttctacc acatttgtag ttacttcctc cactgaagtc ttgaagtcaa 360 atcaagactc agttatctgt gaaggttgga atcaatttct tccaaactcc tgttaatgct 420 gacattttaa cgtcctccca tgaagcatga tgttcttaaa tggcatctag aatggtgaac 480 cctttcagct acagacttaa gaatatattt cttctttttt tt 522 158213- sequence Listing .doc 201210611 < 210 > 7 <211> 141 <212> DNA <213> Homo sapiens <400> 7 agagagagaa gcagctgcct aatgggcaca cacaacagaa aggaatgaac tgaaagacag 60 cagaatttgg tactgctaat atctcaatgt ggtatgttcc aaaagtcaat gacttaacat 120 gactacttta cttgtacaat g 141 <210> 8 <211> 519 <;2 12 > DNA < 213 > Homo sapiens < 400 > 8 tgaacataaa tcatttttcc tgtttagctt tgatctcaag ttcaggaaag ccaatgctgt 60 ctttgggtac acagtctcaa tctcagtaaa acttggctct atcctcaaga atcttcatag 120 cttagtacaa gaatcctaag atgaatatat ttccattgat gattctgaat gaatgtgctg 180 tttccttgcc aatggtagca tacttgcaac tctataaaaa tagcccctaa tgcagcacac 240 agacaacctt ggaggtaaat ctttatagta acaagtgatc tgagagttta agtcaagcag 300 gagacttgga gctgttttcc ttaagtacaa cagatagtga tatactaaaa ggtacaggga 360 agactcatca aaagctagaa gtatatgtca gggcttatta aggttagaat ccagggactg 420 atcccacttt aataaaattt aagaagtagc taagcaagat agctaataca gaatctgcag 480 caatgaaatt tatgtcaatt cactaaaatg caaaaacaa 519 < 210 > 9 < 211 > 374 < 212 > DNA < 213 > Homo sapiens < 4〇 〇> 9 caatgtaaat aactccaact tctttagtgg gactaagtag tgagatagaa gaaaagcaca 60 cacgatgaag taaaacttga aaaatggtgt ggatcttata gcacaagttt gtaagtctga 120 ttcatagttt tatttctcca cagtttgacc cttactgttc aggtacttaa tgatgcattc 180 tttatcagat ttaaaattac tagaaggcaa gttattttct ttttctgaga aga Cgaagag 240 tcaaaagcaa aatggaaatg tctctaagct atttaactct gtatcttggt ctaaaagtat 300 actgaaaatg ttctttgtac aaatacagct ccagttctgg acaataatta aatatttata 360 attttaaagc ttca 374 <210> 10 <211> 240 6- 158213 - Sequence Listing.doc 201210611 <212> DNA <213> Homo sapiens <; 400 > 10 ttttttgaaa aaaagctgcc ttgaattcct aatcaccata tataaatttc acagctcttt 60 gaaacttcta taaaatcaac ttctgtccct cctggatttc aaaatactac ttatctttgt 120 cttcttttat aatacccaat aggtcaccaa catttattaa atgaatggtt aaaaatatgc 180 tgaattctag ataaccagct tacagatgac cctttgagaa gcaacctaca ccggacagca 240 < 210 > 11 < 211 > 353 < 212 > DNA < 213 & gt Homo sapiens <400> 11 tgtgaactca gacatgatcg tgggagttgc ttcggccatg aaatgtgtac cgagatggtg 60

tgtttccctt cccagcagca gctttaagag cttgtgcatg gtttggcatt ctctcttttc 120 cttctgccac cgagactgca gtattccaga tatgagccaa tcctctcact taaatcctga 180 aatgtggaca acatggaatc aagtcagagc caactggttc cggacacggg tatgaaagag 240 aaataaatct tttctgttgt aagccacaga gattgtggga ttgttgccac agtatgacct 300 ggttaacctt gacaggtaca gggctccaca cacactgttt tctttcttct cct 353 < 210 > 12 < 211 > 534 < 212 > DNA <213> Homo sapiens <220><221> mi sc-f eatu re <222> (519)..(519) <223> n is a, c, g or t <220><;221> misc-feature <222> (524)..(524) <223> n is a, c, g or t <220><221> misc_feature <222> (528)..( 528) <223> n is a, c, g or t <220><221> misc.feature <222> (531)..(532) <223> n is a, c, g or t <220><221> mi sc a feature < 222 > (534) _ (534) < 223 > n is a, c, g or t 158213 - Sequence Listing. doc 201210611 <400> Gggggctagg gggcgaggag cctcctactg cccatcttcc cgtccaccac gcgcagttac 60 tcac ctttgt ctccggcctg gattaaggat ccagcctttc gcctccatcc ctcttgtccc 120 tcctgatcct cctgaccctg tctttaagat cccaggagct gcggtgagga gtgaggctga 180 ggggcccctt tcatctgatg cagcgactcc gctttcctcc ggcggctctg tctatggctg 240 agctctttga tcctttgaga gatggtttga cttttcccga gcaaagagcc tgcgttgaaa 300 agcgggggtg gaattcagtc ctcacagata atgaggggac aagacctaat tgaaccgagt 360 attgccggga aggaaaaggc aacgggccaa gcctttgaca gggtgcgaaa ctgactttta 420 tcatcgttat agtctttaaa tcctgggaaa cgagttggca accccaaaat aaagaagtgt 480 aatgacgtct Gatgacttca cccaaataca gaccattcnc aganaganga nnan 534 <210> 13 <211> 959 <212> DNA <213> Homo sapiens <220><221><222><22B><220><221>;<222><223><220><221><222><223><220><221><222><223><220><221><;222><223>·>>>> 0123 2222 2222 <220><221><222><223><220><221> misc-feature (579). .(582) n is a, c g or t misc_feature (584)..(584) n is a, c, g or t mi sc-feature (588).. (588) n is a, c, g or t misc_feature (591).. (592 n is a, c, g or t misc—feature (607)..(607) n is a ' c ' g or t misc_feature (621)·, (623) n is a, c, g or t misc Feature C6S0) · (650) n is a, c, g or t mis cofeature 158213 - Sequence Listing.doc 201210611 <222> (653).-(653) <223> n is a, c, g or t <220><221> mi sc-f eat u re <222> (690).-(691) <223> shouting, c, g or t <220><221> mi Sc a feature <222> (750)..(750) <223> n is a, c, g or t <400> 13

tttcactttt cccgagcaaa gagcctgcgt tgaaaagcgg gggtggaatt cagtcttcac 60 agataatgag gggacaagac ctaattgaac cgagtattgc cgggaaggaa aaggcaacgg 120 gccaagcctt tgacagggtg cgaaactgac ttttatcatc gttatagtct ttaaatcctg 180 ggaaacgagt tggcaacccc 40 atacagacca aaaataaaga agtgtaatga cgtctgatga cttcacccaa of ttccaagaaa gacttgcgca gttctcatgc gtggttgcgt ttttgcataa 300 aactaagatt ccctttgtcc gcatgtttaa tagcttaaaa ataaattgag gtttttatcg 360 gataaaagta gccaggaaaa agtgatacag tgaaaacgat tacaggatat ttatagactt 420 gtctttcaag ttattagaag tctcattcta tctgggggca gtgatggtgg tggtggtagt 480 ggaacttgtg aattgagatt catagtggaa cttgtgaatt gagattcatc tcgaaactgg 540 aggcatggct gagacttcta ataaagacaa cctcagtcnn nnanaaanaa nnaaaaaaa: a 600 aaaaaanaaa aaaaaaaaaa nnnagaaaaa aaaaaaaaaa accccccaan ccncccaaaa 660 acccaccaac ccccctaacc accacccacn ncccacccca cccaaaccca aaaccccccc 720 ccaccaaacc caaccccccc ccccaccacn aaaaaacaca ccgccggggc cgccccccct 780 aaaaaaatcc cccccggggg gggccccaac ttttcccggc cccccttttt ttttttgtga 840 acaacacgcg ccccc Ctaag gtcggtgcgc cctcaaaaaa caacaacccc gccccgcccc 900 ccccttttat tttaaaaccc ccccgcttta tgagaaaata atccttcctc tggggcgga 959 <210> 14 <211> 127 <212><213> DNA Homo sapiens <220><221> nvi sc-feature <222> (104), (104) <Z23> n is a, c, g or t < 220 < 221 > rnisc_feature < 222 > (120) _ (120) < 223 > n is a, c ' g or t -9- 158213 - Sequence Listing.doc 201210611 <400> 14 ggaggcagcg gggcagcccc ggcgcgtgac ccgggcgct acctaagttc gagttcccgg 60 cacgcgacgg gagggcgggg ctggagggag cgttcccagc tttnccagtg ccacgaggan 120 ccggttc 127 <210> 15 <211> 232 <212> DNA < 213 > Homo sapiens < 400 > 15 ggccattacg gccggggggg accttccgct cctacccact ccgtgcccgg gtctctgggt 60 cctcctgcaa ctcgcgccac ccggcctatg gggcgaggag cctcctactg cccatcttcc 120 cgtccaccac gcgcagttac tcacctttgt ctccggcctg tattgcggat ccagcctttc 180 gcctccttcc ctcttgtccc tcctgatcct cctgaccctg tctttaagat cc 232 < 210 > 16 < 211 > 387 <212> DNA <213> Human < 400 > 16 ggcactcaga ctggtgaact ttactatttc tttttcttac ctttccctaa cctatatgct 60 gttttcacat cctccatata agactggttt tcttgaggaa gctgaacatg aaaggctata 120 tgtctgattc catttatttg aaattctgga aagggcaaag ttataatgaa agagagcaga 180 tcagtggttg tcagagactg ggattatgag aagcagaatg actgcaagca ggtctgagga 240 aacttcttgg ggtgatgaga atgatatatg tggttatacg actgtataca tttgtcaaaa 300 ttcactgaat tctaagctta aagttggtga atagcatata aattagatct taataaaact 360 gaactaaaaa aaaaaaaaaa Aaaggac 387 <210> 17 <211> 20 <212> DNA <213> Artificial sequence <220><223> antisense oligonucleotide <400> 17 atcctcccac gtcagtctcc 20 <210><211> 21 <212> DNA <213>Artificial sequence <220><223> Antisense nucleotide 158213 - Sequence Listing. doc -10- 201210611 <400> 18 gcccatttga gtctatgtgt t <210> 19 <211> 20 <212> DNA <213>Artificial sequence<220><223> Antisense nucleotides <400> 19 ggctgtctgc aagggtgtgt <210> 20 <211><212> DNA <213> artificial sequence

<220><223>Antisense oligonucleotide <400> 20 gttccatacc tacttcacca g <210> 21 <211> 21 <212> DNA <213> Artificial sequence <220><223> Antisense oligonucleotide <400> 21 gccctaggtc tttcatagca c <210> 22 <211> 21 <212> DNA <213> artificial shore column <220><223> antisense oligonucleoside Acid <400> 22 ctctacatgc tacaacctcc c <210> 23 <211> 20 <212> DNA <213>Artificial sequence <220><223> Antisense oligonucleotide <400> 23 catgccacca Cgtccagcta 158213 - Sequence Listing. doc 21201210611 <210> 24 <211> 21 <212> DNA <213> Artificial Sequence <220><22B> Antisense Oligonucleotide <400> 24 tccactacca ccaccaccat c <210> 25 <211> 20 <212> DNA <213> Artificial sequence <220><223> Antisense oligonucleotide <400> 25 gtctcagcca tgcctccagt <210> 26 <211> 21 <212> DNA <213> artificial sequence <220><223> antisense oligonucleoside Acid <400> 26 aggagggaca agagggatgg a 20 21 <210> 27 <211> 20 <212> DNA <213> artificial sequence <220><223> antisense oligonucleotide <400> 27 agatgggcag taggaggctc 20 <210> 28 <211> 20 <212> DNA <213> artificial sequence <220><223> antisense oligonucleotide <400> 28 gtggcgtgac ttcaggagga 20 <210&gt 29 -12- 158213 · Sequence Listing.doc 201210611 <211> 21 <212> DNA <213>Artificial Sequence<220><223> Antisense Nucleotide<400> 29 gttgccaact cgtttcccag g <210> 30 <211> 20 <212> DNA <213> Artificial Sequence <220>

<223> Antisense Oligonucleotide <400> 30 cagggtcagg aggatcagga <210> 31 <211> 21 <212> DNA <213>Artificial Sequence <220><223> Control Sequence<400> 31 cctctccacg cgcagtacat t

158213 - Sequence Listing. doc

Claims (1)

201210611 VII. Scope of application for patents: 1. A method for the function and/or performance of a guanamine-transfer ribosyl ribosylase (NAMPT) polynucleotide in an in vitro regulated biological system, the method comprising: At least one antisense oligonucleotide having a length of 5 to 30 nucleotides in contact with the natural antisense of the at least one oligonucleotide and the nicotinamide transaminase (NAMPT) polynucleotide The reverse complement of the sequence has at least 50% sequence identity; thereby modulating the function and/or performance of the nicotine indoleamine phosphoribosyltransferase (NAMPT) polynucleotide. 2. A method of modulating the function and/or expression of a nicotine guanamine-transphosphoryl ribosylase (NAMPT) polynucleotide in a biological system according to claim 1, the method comprising: bringing the biological system to at least one length In contact with 5 to 30 nucleotide antisense oligonucleotides, wherein the at least one nucleotide and the natural antisense transcript comprising SEQ ID NO: 2, nucleotides 1 to 882, or SEQ ID NO: 3 to 915, or 1 to 165 of SEQ ID NO: 4, or 1 to 533 of SEQ ID NO: 5, or 1 to 522 of SEQ ID NO: 6, or 1 to 141 of SEQ ID NO: 7, Or SEQ ID NO: 8 to 1 519, or SEO 〇 ID NO: 9 to 1 to 374, or SEQ ID NO: 1 to 1 to 240, or SEQ ID NO: 1 to 1 to 353, or SEQ ID NO: 12 to 534, or SEQ ID NO: 13 to 1 to 959, or SEQ ID NO: 14 to 1 to 127, or SEQ ID NO: 15 to 1 to 232, or SEQ ID NO: 16 to 1 to 387 The reverse complement of a polynucleotide of 5 to 30 contiguous nucleotides has at least 50% sequence identity; thereby modulating the function of the chiral amine ribosyl ribosylase (NAMPT) polynucleotide and / or performance. 3. A method for the in vitro regulation of the function and/or expression of a guanine-transphosphoryl ribose 158213.doc 201210611 nucleotide (NAMPT) polynucleotide in a patient cell or tissue, the method comprising: causing the cells or The tissue is contacted with at least an antisense oligonucleotide having a length of 5 to 3 nucleotides, wherein the nucleotide is opposite to the nicotine indole phosphoribosyltransferase (NAMPT) polynucleotide The oligodeoxynucleotide has at least 50% sequence identity; thereby, in vitro, modulating the function and/or performance of the nampt nucleotide in the cells or tissues of a patient. 4. A method of modulating the function and/or expression of a nicotine guanamine transphosphoryrosidase (NAMPT) polynucleotide in a patient cell or tissue according to claim 3, the method comprising: causing the cell or tissue to be at least one An antisense nucleotide contact of 5 to 30 nucleotides in length, wherein the at least one oligonucleotide and the natural antisense transcript comprising nucleotides 1 to 882 of SEQ ID NO: 2, or SEQ ID NO : 3 to 1 to 915, or SEQ ID NO: 4 to 1 to 165, or SEQ ID NO: 5 to 1 to 533, or SEQ ID NO: 6 to 1 to 522, or SEQ ID NO: 7 to 1 to 141 Or 1 to 519 of SEQ ID NO: 8, or 1 to 374 of SEQ ID NO: 9, or 1 to 240 of SEQ ID NO: 10, or 1 to 353 of SEQ ID NO: 11, or SEQ ID NO: 12 to 1 534, or SEQ ID NO: 13 to 1 to 959, or SEQ ID NO: 14 to 1 to 127, or SEQ ID NO: 15 to 1 to 232, or SEQ ID NO: 16 to 1 to 3 87 The reverse complement of the 5 to 30 contiguous nucleotides of the polynucleotide has at least 50% sequence identity; thereby modulating the function of the awake amine repelling ribosyltransferase (NAMPT) polynucleotide And / or performance. 5. A method for the in vitro regulation of the function and/or expression of a nicotine guanamine-transphosphoryl ribosylase (NAMPT) polynucleotide in a biological system, the method comprising: 158213.doc 201210611 The at least one antisense nucleus of the region of the natural antisense oligonucleotide of the nicotine guanamine-transphosphoryl ribosyltransferase (NAMPT) polynucleotide is contacted, thereby modulating the chiral amine transesterase The function and/or performance of a base enzyme (NAMPT) polynucleotide. 6. The method of claim 5, wherein the function and/or performance of the nicotine indoleamine phosphoribosyltransferase (NAMPT) is increased in vitro relative to the control group. 7. The method of claim 5, wherein the at least one antisense nucleotide targets a natural antisense D sequence of a nicotine indoleamine phosphoribosyltransferase (NAMPT) polynucleotide. 8. The method of claim 5, wherein the at least one antisense nucleotide targets a nucleic acid sequence comprising a coding and/or non-coding nucleic acid sequence of a nicotine indoleamine phosphoribosyltransferase (NAMPT) polynucleotide . 9. The method of claim 5, wherein the at least one antisense oligonucleotide targets overlapping and/or non-overlapping sequences of a nicotine indoleamine phosphoribosyltransferase (NAMPT) polynucleotide. The method of claim 5, wherein the at least one antisense oligonucleotide comprises one or more modifications selected from the group consisting of at least one modified sugar moiety 'to J modified internucleoside linkages, At least one modified nucleotide and combinations thereof. The method of claim 10, wherein the one or more modifications comprise at least one modified sugar moiety selected from the group consisting of: 2, 〇 〇 曱 methoxyethyl modified sugar moiety 71 2 oxime modified sugar moiety, 2'-0-alkyl-modified sugar moiety, bicyclic sugar moiety, and combinations thereof. 12. The method of claim 1, wherein the one or more modifications comprise at least one of 158213.doc 201210611 modified internucleoside linkages selected from the group consisting of phosphorothioate, 2, methoxyl (MOE), 2-fluoro, alkyl phosphonate, dithiophosphate, alkyl thiophosphonate, ph〇sph〇ramidate, urethane, carbonate, Phosphate triester, acetamidate, carboxynonyl ester, and combinations thereof. 13. The method of claim 1 , wherein the one or more modifications comprise at least one modified nucleotide selected from the group consisting of a peptide nucleic acid (pNA), a locked nucleic acid (LNA), an adenine nucleic acid (FANA), Analogs, derivatives and combinations. 14. The method of claim 1, wherein the at least one oligonucleotide comprises at least one oligonucleotide sequence as set forth in SEQ ID NO: Π to 31. 15. A method of in vitro modulating the function and/or expression of a nicotine guanamine-transfer ribosyl ribosylase (NAMPT) gene in a mammalian cell or tissue, the method comprising: affixing the cell or tissue to at least one length Antisense to a nicotinicinamine-transphosphoryltransferase (ΝΑΜρτ) polynucleotide by contacting at least one siRNA nucleotide with a short interfering RNA (siRNA) oligonucleotide of 5 to 3 nucleotides Polynucleotide specific, wherein the at least one siRNA raised nucleotide and at least about 5 antisense and/or sense nucleic acid molecules of the nicotinicinamine phosphoribosyltransferase (ΝΑΜρτ) polynucleotide Complementary sequences of contiguous nucleic acids have at least 50% sequence identity; and in vitro modulate the function and/or expression of nicotinamide transphosphatase (NAMPT) in mammalian cells or tissues. The method of claim 15, wherein the oligonucleotide is at least about complementary to the antisense and/or sense nucleic acid molecule having the nicotinicinamine phosphoribosyltransferase (NAMPT) polynucleotide. The sequence of 5 contiguous nucleic acids has a sequence identity of at least 8〇 158213.doc 201210611. 17. A method for in vitro regulation of the function and/or expression of amylin ribosyl ribosylase (NAMPT) in a mammalian cell K-woven, the method comprising: causing the cells or tissues to be at least Antisense nucleoside acid exposure of about 5 to 30 nucleotides of 'the at least one antisense nucleotide to the sense and/or natural to the nicotinamide transphosphatase (NAMPT) polynucleotide The non-coding and/or coding sequence of the antisense version is distinctive, and the at least one antisense oligonucleotide has at least 50% sequence identity to at least one of the nucleic acid sequences set forth in SEQ ID N:: And the in vitro regulation of the function and/or expression of the nicotine indoleamine phosphoribosyltransferase (NAMPT) in mammalian cells or tissues. 18. The use of an antisense nucleotide for the manufacture of a medicament for modulating the function and/or performance of a serotonin ribosyltransferase (NAMPT) polynucleotide in a biological system. Wherein the nucleotide is 5 to 30 nucleotides in length and is at least 50% identical to the reverse complement of the natural antisense sequence of the nicotinic indoleamine phosphoribosyltransferase (NAMPT) polynucleotide. Sex. 19. The use of claim 18, wherein the oligonucleotide is associated with a natural antisense transcript nucleotide 1 to 882 comprising SEq id NO: 2, or 1 to 915 of SEQ ID NO: 3, or SEQ ID NO : 1 to 165, or 1 to 533 of SEQ ID NO: 5, or 1 to 522 of SEQ ID NO: 6, or 1 to 141 of SEQ ID NO: 7, or 1 to 519 of SEQ ID NO: 8. Or 1 to 374 of SEQ ID NO. 9 or 1 to 240 of SEQ ID NO: 10, or 1 to 353 of SEQ ID NO: 11, or 1 to 534 of SEQ ID NO: 12, or SEQ ID NO : 13 158213.doc _5. 201210611 1 to 959, or SEQ ID NO: 14 to 1 to 127, or SEQ ID NO: 15 to 1 to 232, or SEQ ID NO: 16 to 1 to 387 within 5 to 30 The reverse complement of the contiguous nucleotide polynucleotide has at least 50% sequence identity. 20. Use of an antisense raised nucleotide for the manufacture of a medicament for modulating the function and/or expression of a nicotinamide transphosphatase (NAMPT) polynucleotide in a cell or tissue of a patient Wherein the oligonucleotide is 5 to 30 nucleotides in length and has at least 50% sequence identity to the antisense oligonucleotide of the nicotine indoleamine phosphoribosyltransferase (NAMPT) polynucleotide . 21. The use of claim 20, wherein the oligonucleotide and the natural antisense transcript nucleotides 1 to 882 comprising SEQ ID NO: 2, or 1 to 915 of SEQ ID NO: 3, or SEQ ID NO : 1 to 165, or 1 to 533 of SEQ ID NO: 5, or 1 to 522 of SEQ ID NO: 6, or 1 to 141 of SEQ ID NO: 7, or 1 to 519 of SEQ ID NO: 8. Or SEQ ID NO: 9 to 1 74, or 1 to 240 of SEQ ID NO: 10, or 1 to 353 of SEQ ID NO: 11, or 1 to 534 of SEQ ID NO: 12, or SEQ ID NO : 1 to 959 of 13, or 1 to 127 of SEQ ID NO., or 1 to 232 of SEQ ID NO: 15, or 5 to 30 contiguous nucleotides of 1 to 387 of SEQ ID NO: 16 The reverse complement of the polynucleotide has at least 50% sequence identity. 22. The use of an antisense oligonucleotide for the manufacture of a medicament for modulating the function and/or expression of a nicotinamide phosphatase (NAMPT) polynucleotide in a biological system, wherein The oligonucleotide targets the 158213.doc 201210611 region of the natural antisense raised nucleotide of the nicotine indoleamine phosphoribosyltransferase (NAMPT) polynucleotide. 23. The use of claim 22, wherein the function and/or performance of the test for amidoxime phosphoribosylase (NAMPT) is increased in vivo relative to a control group, wherein the use of claim 22, wherein Antisense oligonucleotides target the natural antisense sequence of the chitosan-transferase ribosylase (NAMPT) polynucleotide. 25. The use of claim 22, wherein the antisense oligonucleotide targets a nucleic acid sequence comprising a coding and/or non-coding nucleic acid sequence of a final amidoxime phosphoribosyltransferase (NAMPT) polynucleotide. ® 26. The use of claim 22, wherein the antisense oligonucleotide is dried to the overlapping and/or non-overlapping sequence of the final amidoxime phosphoribosylase (NAMPT) polynucleotide. The use of claim 22, wherein the antisense oligonucleotide comprises one or more modifications selected from the group consisting of at least one modified sugar moiety, at least one modified internucleoside linkage, at least one modified core Glycosylates and combinations thereof. 28. The use of claim 27, wherein the one or more modifications comprise at least one modified sugar moiety selected from the group consisting of: 2, _〇_methoxyethyl modified sugar moiety, 2'-decyloxy modification A sugar moiety, a 2,_〇-alkyl modified sugar moiety, a bicyclic sugar moiety, and combinations thereof. 29. The use of claim 27, wherein the one or more modifications comprise at least one modified internucleoside linkage selected from the group consisting of: phosphorothioate, 2,-methoxyethyl (MOE), 2 -1, tartaric acid vinegar, dithio acid vinegar 'alkyl thiophosphine I ruthenium, phosphonium amide, urethane, carbonate, phosphate triester, acetaminophen, carboxymethyl Base esters and combinations thereof. 30. The use of Umbrella, Gantu, Zhongshui, or a plurality of modifications as claimed in claim 27 includes at least one of 158213.doc 201210611 Modified nucleotides selected from the group consisting of peptide nucleic acids (PNA), locked nucleic acids (LNA) ), arabinic acid (FANA), analogs, derivatives and combinations thereof. 31. The use of claim 18, wherein the oligonucleotide comprises at least one nucleotide sequence as set forth in SEQ ID NOs: I7 to 1!. 32. Use of a short interfering RNA (siRNA) oligonucleotide for the production of a function and/or expression of a nicotine guanamine transphosphatase (NAMPT) gene in a mammalian cell or tissue An agent wherein the siRNA oligonucleotide is 5 to 30 nucleotides in length and specific for an antisense polynucleotide of a nicotinic guanamine transphosphoposyltransferase (NAMPT) polynucleotide; 5 siRNA vouchers having at least 5 互补 with the antisense of the serotonin ribosyl ribosylase (NAMPT) polynucleotide and/or the complement of at least about 5 contiguous nucleic acids of the sense nucleic acid molecule % sequence consistency. 33. The use of claim 32, wherein the oligonucleotide is at least about complementary to the antisense and/or sense nucleic acid molecule having a final nucleotide phosphatase ribosyltransferase (NAMPT) polynucleotide The sequence of 5 contiguous nucleic acids has at least 8% sequence identity. 34. Use of an antisense oligonucleotide for the manufacture of a medicament for modulating the function and/or expression of nicotinamide transphosphatase (NAMPT) in a mammalian cell or tissue, wherein Antisense oligonucleotides are about 5 to 30 nucleotides in length and are non-coding and/or non-coding and/or natural antisense strands of nicotinamide transphosphatase (Nampt) polynucleic acid. The coding sequence is specific in that the antisense oligonucleotide has at least 50% sequence identity to at least one of the nucleic acid sequences set forth in SEQ ID NOS: 1 to 16. 158213.doc 1 5. A synthetic modified nucleotide comprising at least one modification, wherein the at least one modification in 201210611 is selected from the group consisting of: at least one modified sugar moiety; at least one modified internucleotide linkage At least one modified nucleotide and a combination thereof; wherein the oligonucleotide hybridizes to the nicotinic guanamine transphosphatase (NAMPT) gene in vivo or in vitro as compared to a normal control group An antisense compound of the nicotinicinamine-transphosphoryl ribosylase (NAMPT) gene and/or an antisense compound which exhibits a nucleoside and a nucleoside with a nucleoside transphosphoryrosylase (NAmpt) a sequence of at least about 5 contiguous nucleic acids complementary to the antisense and/or sense nucleic acid molecules of the nucleoside, its homologs, homologs, isoforms, variants, derivatives, mutants, fragments or combinations having at least about 5 contiguous nucleic acids 5〇% sequence consistency. 36. The oligonucleoside of claim 35, wherein the oligonucleotide is 5 to 30 nucleotides in length and is inverted from 5 to 30 contiguous nucleotides within the natural antisense transcript of the NAMPT gene The complementary sequence has at least 50% sequence identity. 37. The nucleotide of claim 36, wherein the at least one modification comprises an internucleotide linkage selected from the group consisting of: a thiolate, a decyl phosphonate, a dithiolate Alkyl thiophosphonates, phosphonium amides, urethanes, carbonates, phosphates, acetamides, carboxymethyl esters, and combinations thereof. 3. The oligonucleotide of claim 36, wherein the raised nucleotide comprises at least one phosphorothioate internucleotide linkage. 3. The oligonucleotide of claim 36, wherein the nucleotide comprises a backbone of a phosphorothioate internucleotide linkage. 40. The oligonucleotide of claim 36, wherein the raised nucleotide comprises at least one 158213.doc 201210611 modified nucleotide selected from the group consisting of: a peptide nucleic acid, a locked nucleic acid (LNA), Analogs, derivatives and combinations. 41. The oligonucleotide of claim 36, wherein the nucleotide comprises a plurality of modifications, wherein the modifications comprise modified nucleotides selected from the group consisting of phosphorothioates, alkyl phosphonates, Phosphorothioate, alkyl thiophosphonate, phosphonium amide, urethane, carbonate, phosphotriester, acetamide, carboxydecyl ester, and combinations thereof. 42. The nucleic acid of claim 36, wherein the oligonucleotide comprises a plurality of modifications, wherein the modifications comprise modified nucleotides selected from the group consisting of peptide nucleic acids, locked nucleic acids (LNA), analogs thereof , derivatives and combinations. 43. The oligonucleotide of claim 36, wherein the oligonucleotide comprises at least one modified sugar moiety selected from the group consisting of: 2|-〇-methoxyethyl modified sugar moiety, 2'. Modified sugar moieties, 2|_〇-alkyl modified sugar moieties, bicyclic sugar moieties, and combinations thereof. 44. The nucleotide of claim 36, wherein the oligonucleotide comprises a plurality of modifications wherein the modifications comprise a modified sugar moiety selected from the group consisting of: 2, _〇_methoxyethyl modified sugar moiety 2'-mercapto-modified sugar moiety, 2,_〇_院-modified sugar moiety, bicyclic sugar moiety, and combinations thereof. 45. The nucleotide of claim 36, wherein the nucleotide is at least about 5 to 30 nucleotides in length and is antisense to the nicotinicin phosphatase (ΝΑΜρτ) polynucleotide And/or a sense strand hybrid, wherein the raised nucleotide and at least the antisense and/or sense encoding and/or non-coding nucleic acid sequence of the nicotine indoleamine phosphoribosyltransferase (NAMPT) polynucleotide The complementary sequence of about 5 contiguous nucleic acids has at least about 60% sequence identity. 158213.doc -10·201210611 46. The oligonucleotide of claim 36, wherein the nucleotide and the nicotine indole phosphoryl ribosylase (NAMPT) polynucleotide are antisense and/or A complementary sequence of at least about 5 contiguous nucleic acids of a sense encoding and/or non-coding nucleic acid sequence has at least about 80% sequence identity. 47. The nucleotide of claim 36, wherein the oligo-nuclear acid is in vivo or in vitro with at least one nicotine indoleamine phosphoribosyltransferase (NAMPT) polynucleoside compared to a normal control group. The acid hybridizes and modulates the performance and/or function of the at least one nicotine guanamine transphosphatase (NAMPT) polynucleotide. 〇 48. The nucleotide of claim 36, wherein the oligonucleotide comprises the sequence set forth in SEQ ID NOs: 17 to 31. 49. A pharmaceutical composition comprising one or more oligonucleotides as claimed in one or more nicotine guanamine transphosphatase (ΝΑΜρτ) polynucleotides and pharmaceutically acceptable Accepted excipients. 50. The composition of claim 49, wherein the oligonucleotides have at least about 40% sequence identity compared to any of the nucleotide sequences set forth in SEQ ID NO: 17 to 31. 51. The composition of claim 49, wherein the raised nucleotides comprise a nucleotide sequence as set forth in SEQ m NO: 17 to 31. 52. The composition of claim 51, wherein the nucleotide nucleotides as set forth in SEQ ID NOS: 17 to 31 comprise one or more modifications or substitutions. 53. The composition of claim 52, wherein the one or more modifications are selected from the group consisting of: thio & acid esters, decyl phosphonates, peptide nucleic acids, locked nucleic acid (LNA) molecules, and combinations thereof. 54. Use of an antisense oligonucleotide for the manufacture of a nucleoside phosphatase (NAMPT) polynucleotide and/or 158213.doc 201210611 and/or at least one nicotinic acid phosphatase (NAMPT) polynucleotide and/or At least one agent encoding a disease associated with the product, wherein the antisense oligonucleotide binds to the at least one natural antisense sequence of a serotonin ribosyltransferase (NAMPT) polynucleotide and modulates the at least one The performance of the base amide transphosphoribozyme (NAMPT) polynucleotide. 55. The use of claim 54 wherein the disease associated with the at least one nicotine indole phosphoribosyltransferase (NAMPT) polynucleotide is selected from the group consisting of: a disease associated with abnormal function and/or performance of NAMPT or A condition, a cancer, a disease or condition characterized by cell proliferation or characterized by cell proliferation, apoptosis, a disease or condition associated with a mutation or abnormality in NAMPT expression or function, or a cytopenia (eg, bone marrow or lymphocyte system, etc.) Hematocytopenia), neutropenia (such as severe congenital neutropenia, other forms of congenital and acquired neutrophil reduction, chemotherapy-induced febrile neutrophils) Reduction, etc.), leukemia, acute myeloid leukemia (AML) 'Cell cancer in bone marrow cell line, malignant disease associated with elevated NAMPT levels, congenital non-malignant disease or condition with hematopoiesis, attributed to ΝΑΜρτ and/ Or immunodeficiency with altered activity, atherosclerosis, a disease or condition associated with a constant glucose abnormality, a disease or condition associated with abnormal insulin secretion, Fat disease, a cardiovascular disease or disorder, hepatocyte> weeks death, and hydrocarbons occur mitochondrial disease associated or heterologous hanging disorders, diseases associated with the skeletal muscle, which! : diseases, disorders, or diseases associated with abnormal cell production _ /, οχ 豕 diseases, disorders, or conditions associated with steroids; diseases or conditions associated with abnormal liver glycerol; and circadian rhythm 158213.doc -12 - 201210611 Diseases, disorders or conditions associated with the immune system; diseases or conditions associated with the immune system, diseases, conditions or conditions associated with epigenetic reprogramming after endotoxin tolerance; viral infections, and interferons A disease or condition associated with an abnormal antiviral response, a chronic inflammatory disease or condition (eg, inflammatory bowel disease, including Crohn's disease, ulcerative colitis, psoriasis, arthritis), or a disease or condition ( For example, chronic ulcers, ischemic stroke, myocardial infarction, angina pectoris and vascular dementia, etc.), metabolic diseases or conditions, inflammation, aging, nonalcoholic fatty liver disease, and the performance of SIRT with sirtuins and / or a disease or condition associated with abnormal activity. 56. A method of inducing apoptosis in a biological system in vitro, the method comprising administering to the system a 5 to 3 nucleotides in length and inverting from a natural antisense transcript of a ΝΑΜρτ polynucleotide An oligonucleotide that is at least 50% identical to 5 to 3 contiguous nucleotides in the complementary sequence. 57. The method of claim 56, wherein the natural antisense transcript has a 9 ID NO: 2 to 16. 58. The method of claim 56, wherein the biological system is a patient cell or tissue. 59. A method of inducing apoptosis in a biological system in vitro, the method comprising administering to the system a nucleotide of about 5 to 3 nucleotides in length, wherein the nucleotide is targeted by a target The gene is upregulated to a natural antisense transcript of the gene of interest, and wherein the oligonucleotide is at least 5% identical to the reverse complement of the natural antisense transcript of the upregulated gene. 60. Use of an oligonucleotide for the manufacture of an agent for inducing apoptosis in a biological system 158213.doc • 13-201210611, wherein the nucleotide is 5 to 30 nucleotides in length The acid is at least 50% identical to 5 to 3 contiguous nucleotides in the reverse complement of the native antisense transcript of the NAMPT polynucleotide. 61. The use of claim 60, wherein the natural antisense transcript has a redundant ID NO: 2 to 16. 62. The use of claim 60, wherein the biological system is a patient cell or tissue. 63. Use of an oligonucleotide for the manufacture of an agent for inducing apoptosis in a biological system, wherein the oligonucleotide is about 5 to 3 nucleotides in length and is targeted by The gene is up-regulated to the natural antisense transcript of the gene of interest, and wherein the oligonucleotide is at least 5% identical to the reverse complement of the native antisense transcript of the up-regulated gene. 64_ A method for identifying and selecting at least one natural antisense transcript for a ΝΑΜρτ gene. Sex as a method for oligonucleotides of a selected target polynucleotide administered in vivo, the method comprising: identifying at least An oligonucleotide comprising at least 5 contiguous nucleotides at least partially complementary to an antisense polynucleotide of the selected polynucleotide of interest; measuring antisense oligonucleotides under stringent hybridization conditions a thermal melting point of the hybrid of the target polynucleotide or the antisense polynucleotide of the selected polynucleotide of interest; and selecting at least one oligonucleoside for in vivo administration based on the obtained reagent acid. 158213.doc -14-