CN108159434A - A kind of genophore and its gene therapy medicament for treating glaucoma - Google Patents

Abstract

The present invention relates to a kind of gene therapy vectors, include dominant suppressive (dominant negative) mankind sterile apha and TIR motif containing 1 (dnSARM1), promoter, the β globin intrones for increasing gene expression, human growth hormone poly (A) tail sequences etc..The invention further relates to the drug comprising said gene therapy vector and combinations.Its advantage is shown：The gene therapy vector of the present invention can be used to treat or prevent the retinal ganglial cells lesion as caused by glaucoma.

Description

A kind of genophore and its gene therapy medicament for treating glaucoma

Technical field

The present invention relates to gene engineering technology field, specifically, being a kind of genophore and its for treating glaucoma Gene therapy medicament.

Background technology

Glaucoma (glaucoma) is one group using characteristic optic atrophy and defect of visual field as the disease of common trait, disease It is its Major Risk Factors that rationality intraocular pressure, which increases,.It has now realized that, glaucoma belongs to a kind of neurodegenerative disease, disease Reason be characterized in the apoptosis of retinal ganglial cells (retinal ganglion cell, RGC) and its denaturation of aixs cylinder and Incident visual function progressive is lost.RGC is responsible for the visual signal captured to brain output by retina, due to high eye RGC caused by pressure, a variety of inherent causes or nerve retrograde affection etc. is persistently denaturalized or apoptosis, can lead to papillo-neuropathy Become, visual field missing, and then develop into glaucoma.

Glaucoma pathomechanism is complicated, has the participation of the factors such as h and E, but its definite molecular mechanism is still not clear.Portion Point glaucoma patient shows as intraocular hypertension, and the symptomatic treatments means such as drop intraocular pressure can be taken in clinic, but can not reverse for a long time or Delay the development of glaucoma.

Studies have found that in glaucoma animal model pathology early stage, there is metabolin nicotinamide adenine in retina Dinucleotides (nicotinamide adenine dinucleotide, NAD+) is horizontal to be declined.NAD+ is the important of biochemical reaction Medium participates in redox reaction as coenzyme, can also be used as substrate and participates in molecular signal transmission.NAD+ is synthesized in the cell Dynamic equilibrium between consumption will directly affect metabolism, the biological various biologicals process such as circadian rhythm and aging. Increase with the age, internal NAD+ levels decline, and with structure of mitochondria and dysfunction, believe using NAD+ as the cell of auxiliary substrate Number transmit enzymatic activity be affected, it may be possible to NAD+ is unbalance participate in retina nerve degeneration main mechanism.It is another studies have found that, It can delay RGC lesions by supplementing NAD+ or enhancing NAD+ route of synthesis, so as to which clear and definite NAD+ levels are to cause touching for RGC lesions Hair factor.

Research in recent years is found, in nervous system, SARM1 is the key molecule that NAD+ levels is promoted to decline, and in disease By inhibiting SARM1 activity that can effectively keep NAD+ levels and delaying neuronal degeneration in model.With reference to the development of biotechnology, The gene therapy method for eye disease based on adeno-associated virus (adeno-associatedvirus, AAV) carrier by Extensive concern, safety and validity obtain preliminary identification and accreditation.

Therefore, the present invention combines AAV technologies, and the gene therapy developed a kind of special target RGC and express SARM1 (DN) carries Body.

Invention content

First purpose of the present invention is, for deficiency of the prior art, to provide a kind of genophore.

Second object of the present invention is to provide a kind of pharmaceutical composition.

Third object of the present invention is to provide a kind of application of genophore.

Fourth object of the present invention is to provide a kind of method for treating glaucoma.

To realize above-mentioned first purpose, the technical solution adopted by the present invention is that：A kind of gland relevant viral vector, it is described Gland relevant viral vector contains enhancer, specificity or non-specific promoter, the gene order for expressing SARM1 (DN) albumen, The sequence such as SEQ ID NO of SARM1 (DN) albumen:Shown in 2.

Preferably, the gene order of expression SARM1 (DN) albumen is selected from and SEQ ID NO:1 has at least 96%, 97%, 98%th, the nucleotide sequence of 99%, 100% homology.

It is highly preferred that the gene order of the SARM1 (DN) contains SEQ ID NO:1.

Most preferably, the nucleotide sequence of the SARM1 (DN) albumen is selected from SEQ ID NO:1.

In any of the above-described preference, enhancer CMV, selected from SEQ ID NO:4 have the core of at least 95% homology Nucleotide sequence.It is highly preferred that the CMV is selected from and SEQ ID NO:4 have at least 96%, 97%, 98%, 99%, 100% together The nucleotide sequence of source property.Most preferably, the nucleotide sequence of the cmv enhancer is selected from SEQ ID NO:4.

In any of the above-described preference, adeno-associated virus can be selected from AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV2-AAV3, AAVrh.10, AAVhu.14, AAV3a/3b, AAVrh32.33, AAVHSC15, AAV-HSC17, AAVhu.37, AAVrh.8, CHt-P6, AAV2.5, AAV6.2, AAV2i8, AAV-HSC15/17, AAVM41, AAV9.45, AAV6 (Y445F/Y731F), AAV2.5T, AAV-HAE1/2, AAV clone 32/83, AAVShH10, AAV2(Y->F), AAV8 (Y733F), AAV2.15, AAV2.4, AAVM41, AAVr3.45AAV2 or AAV5.Most preferably, gland phase It closes virus and is selected from AAV2.

In any of the above-described preference, adeno-associated virus is single-stranded AAV.

In any of the above-described preference, chimeric interon of the gland relevant viral vector also containing one section of shortening, institute The chimeric intron sequence stated is selected from and SEQ ID NO:5 have the nucleotide sequence of at least 90% homology.

In any of the above-described preference, the gland relevant viral vector contains the gene of cmv enhancer, SARM1 (DN) Sequence, β-globin intrones, hGHpA, L-ITR, R-ITR, Ampicillin, f1ori.

In any of the above-described preference, the gene order such as SEQ ID NO of SARM1 (DN) albumen are expressed:Shown in 1, L-ITR Sequence such as SEQ ID NO:Shown in 3, cmv enhancer sequence SEQ ID NO:Shown in 4, β-globin intron sequences such as SEQ ID NO:Shown in 5, hGHpA sequences such as SEQ ID NO:Shown in 7, R-ITR sequences such as SEQ ID NO:Shown in 8, Ampicillin sequences Such as SEQ ID NO:Shown in 9, f1ori sequences such as SEQ ID NO:Shown in 11.

In any of the above-described preference, the gland relevant viral vector sequence contains SEQ ID NO:10.

To realize above-mentioned second purpose, the technical solution adopted by the present invention is that：A kind of pharmaceutical composition for treating glaucoma Object, containing above-mentioned gland relevant viral vector and pharmaceutically acceptable carrier, pharmaceutical composition expression SARM1 (DN) egg In vain.

To realize above-mentioned third purpose, the technical solution adopted by the present invention is that：It is prepared by above-mentioned gland relevant viral vector Treat the application in the drug of glaucoma.

To realize above-mentioned 4th purpose, the technical solution adopted by the present invention is that：A kind of method of gene therapy glaucoma, By gland relevant viral vector intraocular injection, transplanting SARM1 activity.Preferably, the intraocular injection refers to that subretinal space is noted It penetrates or intravitreal.

The invention has the advantages that：

The gene therapy vector of the present invention is for treatment or prevention retinal ganglial cells lesion as caused by glaucoma.

Description of the drawings

Attached drawing 1：The Plasmid pattern figure of AAV_SARM1 (DN) carrier.

Attached drawing 2：The plasmid characteristic pattern of AAV_SARM1 (DN).

Attached drawing 3：C57BL/6J mouse intravitreal AAV_SARM1 (DN) inner nuclear layer retinas after two weeks, immunofluorescence Colored graph.

Attached drawing 4：C57BL/6J mouse intravitreal AAV_SARM1 (DN) or AAV-GFP, and injecting at the moment simultaneously Side's injection bead particulates cause glaucoma, the inner nuclear layer retina after 2 weeks, 4 weeks, 8 weeks, it is illustrated that are its immunofluorescence dyeing Figure.

Attached drawing 5：C57BL/6J mouse intravitreal AAV_SARM1 (DN) or AAV-GFP are simultaneously being injected at the moment simultaneously Side's injection bead particulates cause glaucoma, the inner nuclear layer retina after 2 weeks, 4 weeks, 8 weeks, it is illustrated that for after its immunofluorescence dyeing RGC is carried out to count and survival rate analysis result figure.

Specific embodiment

The present inventor by research, provide a kind of gland relevant viral vector and its for treat the related drugs of glaucoma, Pharmaceutical composition etc..

Pharmaceutical composition and medicine box

For the ease of clinical practice, pharmaceutical composition of the invention may be embodied in injection delivery device (such as pumping needle) In, in the injection delivery device, the pharmaceutical composition of single administration amount can be included.The injection administration Device can be contained in medicine box, to facilitate storage, use.It needs to place equipped with the small container of drug suspension during transport In dry ice.It should usually be stored in -80 DEG C of refrigerators.

In medicine box or kit of the present invention, operation instructions are may also include, so that those skilled in the art press It is used according to correct mode.

As used herein, the ingredient of " pharmaceutically acceptable " apply to people and/or mammal and without excessively bad Side reaction (such as toxicity), i.e., with rational benefit/risk than substance.Term " pharmaceutically acceptable carrier ", which refers to, to be used for The carrier of Therapeutic Administration, including various excipient and diluent.This belongs to finger some medicament carriers in this way：Themselves is not Active constituent is necessary, and does not have excessive toxicity after applying.

Suitable pharmaceutically acceptable carrier is well known to those of ordinary skill in the art.In Remington ' It can be found about pharmaceutically acceptable carrier in sPharmaceutical Sciences (Mack Pub.Co., N.J.1991) Absolutely prove.Pharmaceutically acceptable carrier can contain liquid in the composition, such as water, BBS (Balanced SaltSolution) phosphate buffer, ringer solution, physiological saline, balanced salt solution, glycerine or sorbierite etc..In addition, There is likely to be complementary substance in these carriers, as lubricant, glidant, wetting agent or emulsifier, pH buffer substance and Stabilizer etc..

Gene therapy vector

Gene therapy vector in the present invention is virus expression carrier, and according to the present invention, virus expression carrier is gland correlation Viral (AAV) carrier is such as formed selected from AAV chimeric derived from serotypes A AV1,2,3,4,5,6,7,8,9 and 10 or its Group in AAV carriers such as AAV2-AAV3, AAVrh.10, AAVhu.14, AAV3a/3b, AAVrh32.33, AAVHSC15, AAV-HSC17, AAVhu.37, AAVrh.8, CHt-P6, AAV2.5, AAV6.2, AAV2i8, AAV-HSC15/17, AAVM41, AAV9.45, AAV6 (Y445F/Y731F), AAV2.5T, AAV-HAE1/2, AAV clone32/83, AAVShH10, AAV2 (Y-> F), AAV8 (Y733F), AAV2.15, AAV2.4, AAVM41, AAVr3.45AAV2 or AAV5, this can be better adapted for feeling emerging Efficient transduction is carried out in the tissue of interest.Transfection when, AAV only cause in host slight immune response (if there is Words).In a preferred embodiment of the invention, gene therapy vector is 2 or 5 carrier of AAV serotypes.In further preferred reality It applies in mode, gene therapy vector is 2 carriers of AAV.

The AAV carriers of the present invention are single-stranded AAV, can produce recombinant viral vector according to standard technique.For example, recombination gland phase Closing viral vectors can propagate in 293 cell of people (it provides trans- E1A and E1B characteristics), to reach in 10^7~10^13 disease Titre in the range of malicious particle/mL.Before applying in vivo, viral vectors can pass through gel filtration method (such as agarose column) Desalination is carried out, and is purified by subsequent filtering.Potential illeffects in the main body of purifying reduction drug administration carrier.It is given The virus of medicine is substantially free of wild-type virus and replication competent type virus.Suitable method, such as dodecyl sulphate can be passed through Sodium-polyacrylamide gel electrophoresis (SDS-PAGE), then carries out silver staining, to prove the purity of virus.

For people AAV suitable dose in the range of about 1 × 10^10~1 × 10^14 virion.

Gene order

SEQ ID NO:Shown in 1 is SARM1 (DN) sequence after optimization,

SEQ ID NO:Shown in 2 is original people SARM1 (DN) amino acid sequence,

SEQ ID NO:Shown in 3 is Left ITR sequences,

SEQ ID NO:Shown in 4 is CMV sequences,

SEQ ID NO:Shown in 5 is human β-globin intron sequences,

SEQ ID NO:Shown in 6 is MCS sequences,

SEQ ID NO:Shown in 7 is hGHpA sequences,

SEQ ID NO:Shown in 8 is Right ITR sequences,

SEQ ID NO:Shown in 9 is Ampicillin Resistance sequences,

SEQ ID NO:Shown in 10 is full nucleotide sequence,

SEQ ID NO:Shown in 11 is f1ori (2670-2976) sequence,

SEQ ID NO:Shown in 12 is recombination sequence.

Gene therapy vector is intraocular injection administration, and subretinal space or intravitreal administration may be used.Under In conjunction with specific embodiments, the present invention is further explained in face.It should be understood that these embodiments are merely to illustrate the present invention rather than limit The scope of the present invention processed.

Test method without specific conditions in the following example, usually according to normal condition such as J. Pehanorm Brookers It writes, Molecular Cloning:A Laboratory guide, the third edition, Science Press, condition described in 2002 or according to proposed by manufacturer Condition.

Experimental animal

Normal C57BL/6J mouse are purchased from Shanghai Slac Experimental Animal Co., Ltd..Periodicity of illumination 12h illumination- 12h is dark, is freely eaten, free water, what all zooscopies were issued in strict accordance with State Scientific and Technological Commission《Experiment The care of animal regulations》It carries out.

Main agents, consumptive material

Physiological saline (Zhejiang Tianrui Pharmaceutical Co., Ltd.), injection needles head (U.S. Becton Dickinson And Company companies), HA (Roche), TUJ1 (Abcam), secondary antibody goat anti-rabbit igg (JacksonImmuno), blood of goats (Sigma) clearly, Triton X-100 (Triton X-100) (Sigma), paraformaldehyde (Sigma).

Key instrument

Ophthalmology experiment surgical operation microscope (Japanese Nikon companies)；Ophthalmology microinstrument (the limited public affairs of Suzhou Ming Ren medical instruments Department)；Microsyringe (Hamilton companies of the U.S.)；Laser Scanning Confocal Microscope (Leca company).

The structure of mouse glaucoma model

The injection that is prepared in advance capillary needle tubing, needle tubing top is oval, and interior to angle there are 20 degree, and prepares The good bead particulates suspension (1.6*10^beads/ul) for having removed surface epoxy group.It chooses 6-8 weeks male mice and carries out abdominal cavity Injecting anesthetic, side are placed on operation console, and modeling eye needs level upward and need to expand pupil in advance.Operation consent is magnetic by preprepared Microparticulate suspensions blow and beat mixing again, and draw 1.5ul magnetic particle suspensions in capillary needle tubing rapidly.Capillary needle tubing and corneal limbus In 45 degree of angles, and in opposite side eyeball is fixed with plastic cement microforceps at 90 degree therewith.It is careful to be pierced into capillary needle tubing, it needs to ensure Needle tubing does not enter front depths, and forbids touching iris and crystal in the process.In injection point to placing a magnetic pole at side angle Gong Yuan, Slowly injection 1.5ul magnetic particle suspensions, injection process need to ensure to complete in 15 to 30 seconds afterwards, need to ensure magnetic in injection process Pole position is constant.Rapid after the completion of injection to remove capillary needle tubing, rear position of magnetic pole remains unchanged, and maintains 30 to 60 seconds to ensure There is particle to be not attached in corneal limbus to survey.Canthus Gong Yuan moves magnetic pole around eyeball later, is that magnetic particle is dispersed in angle Film, iris angle simultaneously form magnetic particle ring.Mouse needs side to be placed on hot blanket to recover after modeling, and resuscitation process needs to keep Modeling eye is upward.

It is prepared by magnetic micro-beads aaerosol solution：Because magnetic micro-beads surface is covered with epoxy group, should first be removed before use, it will The 10*Tris that 1ml magnetic micro-beads are mixed into rapidly the 0.02M sodium hydroxides (NaOH, MW39.997g/mol) of the fresh configurations of 50ml delays In the mixed liquor of fliud flushing, shaken at room temperature mixing 24 hours is collected bead particulates in test tube bottom using magnetic force.Test tube keep flat with Ensure that all particles are all adsorbed by magnetic force.Mixing 4 hours at room temperature.It is carefully gone out supernatant liquid with pipettor, carefully will Magnetic bead group is mixed into 50ml 10X Tris solution, and mixing simultaneously makes all particle suspensions.Bead particulates are dense in sterile equilibrium liquid Contracting and suspension:Experiment uses ultra-pure water oscillation cleaning particle 3 times.In super-clean bench, 500mlBBS piping and druming mixing is added in 3 times.It adds in 250mlBBS blows and beats mixing, makes particle resuspension.Ensure that solution is uniform as possible, and quickly that 25ul suspensions immigration 0.5ml is sterile Guan Zhong.Obtained Nanoparticle Solution ultimate density is 1.6*10^6/ul.4 DEG C of preservations.

Intravitreal

Using glass system capillary needle, locate inserting needle rearward in view film edge, corneosclera boundary, noted using micro syringe It penetrates, when injection should be noted needle angle and depth, pay attention to avoiding damage to crystal or other eye inner tissues.

Tissue treatment

Animal first via PBS carry out total body perfusion, after continue with 4% paraformaldehyde (PFA) perfusion, rate of flooding 5mL/ Minute.Eyeball and optic nerve impregnate about 2 hours after taking out in 4%PFA solution.It need to be in 0.1M PBS before tissue staining tile 4 DEG C of storages；Before tissue freezing section need in 30% sucrose solution soaked overnight.

Embodiment 1：It the structure of adenovirus vector and isolates and purifies

As shown in Figure 1 and Figure 2, main element includes cmv enhancer and SARM1 (DN) to the structure of plasmid AAV_SARM1 (DN) Sequence.Cmv enhancer can enhance the expression of transgene.Followed by hGHpA (SEQ ID NO after target gene:7), Expression cassette both sides are inverted terminal repeat (TR), i.e., viral vectors includes L-ITR (SEQ ID NO:3), R-ITR (SEQ ID NO:8), viral vectors further includes Ampicillin (SEQ ID NO:And f1ori (SEQ ID NO 9):11).

Viral vectors is obtained by plasmid co-transfection method.AAV2 coat protein genes will be contained and AAV can be helped Helper plasmid and AAV_SARM1 (DN) plasmid of the gene of duplication and HEK 293T cell cotransfections preliminarily form recombination gland phase Close viral vectors.After iodine gram butanol preliminary purification, by the fast protein using 5ml-Hitrp Q Ago-Gels as filler Liquid chromatograph is further purified by ion-exchange chromatography, the use of instrument is Pharmacia AKTA FPLC system (Amersham Biosciences,Piscataway,NJ).Agarose Gel column is eluted with pH8.0, the NaCl of 215mM later, The recombinant viral vector of peak value is collected.The liquid of collection by inspissator (100K concentrater, Millipore after), recombinant viral vector is concentrated with the elution inspissator containing 0.014% polysorbas20.DNase I are used again DNA other than virion is digested, and the method for passing through real-time fluorescence quantitative PCR determines the titre of virus.Finally use silver nitrate Dyeing-SDS polyacrylamide gel electrophoresis methods ensure that vector particles are contaminated and are free of endotoxin, and dispense subzero 80 Degree storage.

The characteristic spectrum of viral vectors AAV_SARM1 (DN) is as shown in Figure 1, the start-stop site of each element is as shown in Figure 2.

Embodiment 2：Adenovirus infection detects

Experimental method：

Tissue treatment：Mouse intravitreal HA label AAV_SARM1 (DN) after two weeks, according to aforementioned tissues processing side Method carries out the pre-treatment of eyeball, and clamping eyeball bottom using microforceps afterwards is lifted up, and the conjunctiva of peribulbar is cut with scissors And musculature, it keeps eyeball tissue complete, cuts off cornea, iris and crystalline lens and make eyecup, and detach retina and train of thought Film composite.

Immunofluorescence dyeing：Retina is chosen, 1h is closed in 20% goat serum solution, rear primary antibody is incubated overnight, and resists Body is respectively TUJ1, HA；PBS clean three times, each 10min, rear secondary antibody is incubated 1h；PBS cleanings are sealed after ten minutes three times, every time Piece.Change and take pictures using confocal microscopy retinal structure.

As a result：Mouse injection of AAV _ SARM1 (DN) after two weeks, carries out retina immunofluorescence dyeing tile, it is seen that eyeground There are the AAV_SARM1 (DN) of a large amount of HA labels, and (TUJ1 immunofluorescence dyeings) is overlapped with RGC, display AAV_SARM1 (DN) Infectious effect it is excellent (Fig. 3).

Embodiment 3：RGC survival rates detect

Experimental method：8 week old mouse unilateral side camera vitrea bulbi injection of AAV _ SARM1 (DN) (experimental group), AAV-GFP is (right According to group), at the same injection eye carry out anterior chamber's bead particulates injection, respectively at 2 weeks, 4 weeks, 8 weeks according to preceding method processing eyeball and Retina carries out immunofluorescence dyeing.Change and take pictures using confocal microscopy retinal structure.Each eyeball is random It chooses 5 visuals field and counts RGC (engineer's scales：20um), RGC survival rates are calculated and.

As a result：Quantitative analysis proves RGC gradual apoptosis in 2W, 4W, 8W after optic nerve pincers wound, and quantity is reduced significantly (experimental group)；In contrast, injection of AAV _ SARM1 (DN) mouse RGC apoptosis is not notable, display AAV_SARM1 (DN) has RGC There is protective effect.

The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art Member, under the premise of the method for the present invention is not departed from, can also make several improvement and supplement, these are improved and supplement also should be regarded as Protection scope of the present invention.

SEQUENCE LISTING

<110>No.1 People's Hospital Shanghai City

<120>A kind of genophore and its gene therapy medicament for treating glaucoma

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<170> PatentIn version 3.3

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ccggcaacaa ttaatagact ggatggaggc ggataaagtt gcaggaccac ttctgcgctc 660

ggcccttccg gctggctggt ttattgctga taaatctgga gccggtgagc gtgggtctcg 720

cggtatcatt gcagcactgg ggccagatgg taagccctcc cgtatcgtag ttatctacac 780

gacggggagt caggcaacta tggatgaacg aaatagacag atcgctgaga taggtgcctc 840

actgattaag cattggta 858

<210> 10

<211> 4654

<212> DNA

<213>Artificial sequence

<400> 10

cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccgggcaaag cccgggcgtc 60

gggcgacctt tggtcgcccg gcctcagtga gcgagcgagc gcgcagagag ggagtggcca 120

actccatcac taggggttcc tgcggccgca cgcgtggaat tcgctagtta ttaatagtaa 180

tcaattacgg ggtcattagt tcatagccca tatatggagt tccgcgttac ataacttacg 240

gtaaatggcc cgcctggctg accgcccaac gacccccgcc cattgacgtc aataatgacg 300

tatgttccca tagtaacgtc aatagggact ttccattgac gtcaatgggt ggagtattta 360

cggtaaactg cccacttggc agtacatcaa gtgtatcata tgccaagtac gccccctatt 420

gacgtcaatg acggtaaatg gcccgcctgg cattatgccc agtacatgac cttatgggac 480

tttcctactt ggcagtacat ctacgtatta gtcatcgcta ttaccatggt gatgcggttt 540

tggcagtaca tcaatgggcg tggatagcgg tttgactcac ggggatttcc aagtctccac 600

cccattgacg tcaatgggag tttgttttgc accaaaatca acgggacttt ccaaaatgtc 660

gtaacaactc cgccccattg acgcaaatgg gcggtaggcg tgtacggtgg gaggtctata 720

taagcagagc tcgtttagtg aaccgtcaga tcgcctggag acgccatcca cgctgttttg 780

acctccatag aagacaccgg gaccgatcca gcctccgcgg attcgaatcc cggccgggaa 840

cggtgcattg gaacgcggat tccccgtgcc aagagtgacg taagtaccgc ctatagagtc 900

tataggccca caaaaaatgc tttcttcttt taatatactt ttttgtttat cttatttcta 960

atactttccc taatctcttt ctttcagggc aataatgata caatgtatca tgcctctttg 1020

caccattcta aagaataaca gtgataattt ctgggttaag gcaatagcaa tatttctgca 1080

tataaatatt tctgcatata aattgtaact gatgtaagag gtttcatatt gctaatagca 1140

gctacaatcc agctaccatt ctgcttttat tttatggttg ggataaggct ggattattct 1200

gagtccaagc taggcccttt tgctaatcat gttcatacct cttatcttcc tcccacagct 1260

cctgggcaac gtgctggtct gtgtgctggc ccatcacttt ggcaaagaat tgggattcga 1320

acatcgattg aattccccgg ggatcctcta gagtcgacct gcagaagctt gcctcgagca 1380

gcgctgctcg agagatctac gggtggcatc cctgtgaccc ctccccagtg cctctcctgg 1440

ccctggaagt tgccactcca gtgcccacca gccttgtcct aataaaatta agttgcatca 1500

ttttgtctga ctaggtgtcc ttctataata ttatggggtg gaggggggtg gtatggagca 1560

aggggcaagt tgggaagaca acctgtaggg cctgcggggt ctattgggaa ccaagctgga 1620

gtgcagtggc acaatcttgg ctcactgcaa tctccgcctc ctgggttcaa gcgattctcc 1680

tgcctcagcc tcccgagttg ttgggattcc aggcatgcat gaccaggctc agctaatttt 1740

tgtttttttg gtagagacgg ggtttcacca tattggccag gctggtctcc aactcctaat 1800

ctcaggtgat ctacccacct tggcctccca aattgctggg attacaggcg tgaaccactg 1860

ctcccttccc tgtccttctg attttgtagg taaccacgtg cggaccgagc ggccgcagga 1920

acccctagtg atggagttgg ccactccctc tctgcgcgct cgctcgctca ctgaggccgg 1980

gcgaccaaag gtcgcccgac gcccgggctt tgcccgggcg gcctcagtga gcgagcgagc 2040

gcgcagctgc ctgcaggggc gcctgatgcg gtattttctc cttacgcatc tgtgcggtat 2100

ttcacaccgc atacgtcaaa gcaaccatag tacgcgccct gtagcggcgc attaagcgcg 2160

gcgggtgtgg tggttacgcg cagcgtgacc gctacacttg ccagcgccct agcgcccgct 2220

cctttcgctt tcttcccttc ctttctcgcc acgttcgccg gctttccccg tcaagctcta 2280

aatcgggggc tccctttagg gttccgattt agtgctttac ggcacctcga ccccaaaaaa 2340

cttgatttgg gtgatggttc acgtagtggg ccatcgccct gatagacggt ttttcgccct 2400

ttgacgttgg agtccacgtt ctttaatagt ggactcttgt tccaaactgg aacaacactc 2460

aaccctatct cgggctattc ttttgattta taagggattt tgccgatttc ggcctattgg 2520

ttaaaaaatg agctgattta acaaaaattt aacgcgaatt ttaacaaaat attaacgttt 2580

acaattttat ggtgcactct cagtacaatc tgctctgatg ccgcatagtt aagccagccc 2640

cgacacccgc caacacccgc tgacgcgccc tgacgggctt gtctgctccc ggcatccgct 2700

tacagacaag ctgtgaccgt ctccgggagc tgcatgtgtc agaggttttc accgtcatca 2760

ccgaaacgcg cgagacgaaa gggcctcgtg atacgcctat ttttataggt taatgtcatg 2820

ataataatgg tttcttagac gtcaggtggc acttttcggg gaaatgtgcg cggaacccct 2880

atttgtttat ttttctaaat acattcaaat atgtatccgc tcatgagaca ataaccctga 2940

taaatgcttc aataatattg aaaaaggaag agtatgagta ttcaacattt ccgtgtcgcc 3000

cttattccct tttttgcggc attttgcctt cctgtttttg ctcacccaga aacgctggtg 3060

aaagtaaaag atgctgaaga tcagttgggt gcacgagtgg gttacatcga actggatctc 3120

aacagcggta agatccttga gagttttcgc cccgaagaac gttttccaat gatgagcact 3180

tttaaagttc tgctatgtgg cgcggtatta tcccgtattg acgccgggca agagcaactc 3240

ggtcgccgca tacactattc tcagaatgac ttggttgagt actcaccagt cacagaaaag 3300

catcttacgg atggcatgac agtaagagaa ttatgcagtg ctgccataac catgagtgat 3360

aacactgcgg ccaacttact tctgacaacg atcggaggac cgaaggagct aaccgctttt 3420

ttgcacaaca tgggggatca tgtaactcgc cttgatcgtt gggaaccgga gctgaatgaa 3480

gccataccaa acgacgagcg tgacaccacg atgcctgtag caatggcaac aacgttgcgc 3540

aaactattaa ctggcgaact acttactcta gcttcccggc aacaattaat agactggatg 3600

gaggcggata aagttgcagg accacttctg cgctcggccc ttccggctgg ctggtttatt 3660

gctgataaat ctggagccgg tgagcgtggg tctcgcggta tcattgcagc actggggcca 3720

gatggtaagc cctcccgtat cgtagttatc tacacgacgg ggagtcaggc aactatggat 3780

gaacgaaata gacagatcgc tgagataggt gcctcactga ttaagcattg gtaactgtca 3840

gaccaagttt actcatatat actttagatt gatttaaaac ttcattttta atttaaaagg 3900

atctaggtga agatcctttt tgataatctc atgaccaaaa tcccttaacg tgagttttcg 3960

ttccactgag cgtcagaccc cgtagaaaag atcaaaggat cttcttgaga tccttttttt 4020

ctgcgcgtaa tctgctgctt gcaaacaaaa aaaccaccgc taccagcggt ggtttgtttg 4080

ccggatcaag agctaccaac tctttttccg aaggtaactg gcttcagcag agcgcagata 4140

ccaaatactg tccttctagt gtagccgtag ttaggccacc acttcaagaa ctctgtagca 4200

ccgcctacat acctcgctct gctaatcctg ttaccagtgg ctgctgccag tggcgataag 4260

tcgtgtctta ccgggttgga ctcaagacga tagttaccgg ataaggcgca gcggtcgggc 4320

tgaacggggg gttcgtgcac acagcccagc ttggagcgaa cgacctacac cgaactgaga 4380

tacctacagc gtgagctatg agaaagcgcc acgcttcccg aagggagaaa ggcggacagg 4440

tatccggtaa gcggcagggt cggaacagga gagcgcacga gggagcttcc agggggaaac 4500

gcctggtatc tttatagtcc tgtcgggttt cgccacctct gacttgagcg tcgatttttg 4560

tgatgctcgt caggggggcg gagcctatgg aaaaacgcca gcaacgcggc ctttttacgg 4620

ttcctggcct tttgctggcc ttttgctcac atgt 4654

<210> 11

<211> 306

<212> DNA

<213>Artificial sequence

<400> 11

cccgctcctt tcgctttctt cccttccttt ctcgccacgt tcgccggctt tccccgtcaa 60

gctctaaatc gggggctccc tttagggttc cgatttagtg ctttacggca cctcgacccc 120

aaaaaacttg atttgggtga tggttcacgt agtgggccat cgccctgata gacggttttt 180

cgccctttga cgttggagtc cacgttcttt aatagtggac tcttgttcca aactggaaca 240

acactcaacc ctatctcggg ctattctttt gatttataag ggattttgcc gatttcggcc 300

tattgg 306

<210> 12

<211> 5110

<212> DNA

<213>Artificial sequence

<400> 12

cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccgggcaaag cccgggcgtc 60

gggcgacctt tggtcgcccg gcctcagtga gcgagcgagc gcgcagagag ggagtggcca 120

actccatcac taggggttcc tgcggccgca cgcgtggaat tcgctagtta ttaatagtaa 180

tcaattacgg ggtcattagt tcatagccca tatatggagt tccgcgttac ataacttacg 240

gtaaatggcc cgcctggctg accgcccaac gacccccgcc cattgacgtc aataatgacg 300

tatgttccca tagtaacgtc aatagggact ttccattgac gtcaatgggt ggagtattta 360

cggtaaactg cccacttggc agtacatcaa gtgtatcata tgccaagtac gccccctatt 420

gacgtcaatg acggtaaatg gcccgcctgg cattatgccc agtacatgac cttatgggac 480

tttcctactt ggcagtacat ctacgtatta gtcatcgcta ttaccatggt gatgcggttt 540

tggcagtaca tcaatgggcg tggatagcgg tttgactcac ggggatttcc aagtctccac 600

cccattgacg tcaatgggag tttgttttgc accaaaatca acgggacttt ccaaaatgtc 660

gtaacaactc cgccccattg acgcaaatgg gcggtaggcg tgtacggtgg gaggtctata 720

taagcagagc tcgtttagtg aaccgtcaga tcgcctggag acgccatcca cgctgttttg 780

acctccatag aagacaccgg gaccgatcca gcctccgcgg attcgaatcc cggccgggaa 840

cggtgcattg gaacgcggat tccccgtgcc aagagtgacg taagtaccgc ctatagagtc 900

tataggccca caaaaaatgc tttcttcttt taatatactt ttttgtttat cttatttcta 960

atactttccc taatctcttt ctttcagggc aataatgata caatgtatca tgcctctttg 1020

caccattcta aagaataaca gtgataattt ctgggttaag gcaatagcaa tatttctgca 1080

tataaatatt tctgcatata aattgtaact gatgtaagag gtttcatatt gctaatagca 1140

gctacaatcc agctaccatt ctgcttttat tttatggttg ggataaggct ggattattct 1200

gagtccaagc taggcccttt tgctaatcat gttcatacct cttatcttcc tcccacagct 1260

cctgggcaac gtgctggtct gtgtgctggc ccatcacttt ggcaaagaat tgggattcga 1320

acatcgattg aattccacca tgtaccccta cgacgtgcct gactacgccg tgcccagctg 1380

gaaggaggcc gaggtgcaga cctggctgca gcaaatcggc ttctccaagt actgcgagag 1440

cttcagagaa caacaagtgg acggcgacct gctgctccgg ctgacagagg aggagctgca 1500

gacagatctg gggatgaaga gcggcatcac aaggaaaagg ttcttcaggg agctgacaga 1560

gctgaagacc ttcgccaact acagcacctg cgacagaagc aacctggccg actggctcgg 1620

cagcctggac cctaggttca ggcagtacac ctacggactc gtgagctgcg gcctcgacag 1680

gagcctgctc cacagggtca gcgaacagca gctgctggaa gactgtggaa tccacctggg 1740

agtgcacaga gccaggatcc tcaccgccgc cagggaaatg ctccatagcc ccctgccctg 1800

caccggcgga aaaccttcag gcgactgact cgagcagcgc tgctcgagag atctacgggt 1860

ggcatccctg tgacccctcc ccagtgcctc tcctggccct ggaagttgcc actccagtgc 1920

ccaccagcct tgtcctaata aaattaagtt gcatcatttt gtctgactag gtgtccttct 1980

ataatattat ggggtggagg ggggtggtat ggagcaaggg gcaagttggg aagacaacct 2040

gtagggcctg cggggtctat tgggaaccaa gctggagtgc agtggcacaa tcttggctca 2100

ctgcaatctc cgcctcctgg gttcaagcga ttctcctgcc tcagcctccc gagttgttgg 2160

gattccaggc atgcatgacc aggctcagct aatttttgtt tttttggtag agacggggtt 2220

tcaccatatt ggccaggctg gtctccaact cctaatctca ggtgatctac ccaccttggc 2280

ctcccaaatt gctgggatta caggcgtgaa ccactgctcc cttccctgtc cttctgattt 2340

tgtaggtaac cacgtgcgga ccgagcggcc gcaggaaccc ctagtgatgg agttggccac 2400

tccctctctg cgcgctcgct cgctcactga ggccgggcga ccaaaggtcg cccgacgccc 2460

gggctttgcc cgggcggcct cagtgagcga gcgagcgcgc agctgcctgc aggggcgcct 2520

gatgcggtat tttctcctta cgcatctgtg cggtatttca caccgcatac gtcaaagcaa 2580

ccatagtacg cgccctgtag cggcgcatta agcgcggcgg gtgtggtggt tacgcgcagc 2640

gtgaccgcta cacttgccag cgccctagcg cccgctcctt tcgctttctt cccttccttt 2700

ctcgccacgt tcgccggctt tccccgtcaa gctctaaatc gggggctccc tttagggttc 2760

cgatttagtg ctttacggca cctcgacccc aaaaaacttg atttgggtga tggttcacgt 2820

agtgggccat cgccctgata gacggttttt cgccctttga cgttggagtc cacgttcttt 2880

aatagtggac tcttgttcca aactggaaca acactcaacc ctatctcggg ctattctttt 2940

gatttataag ggattttgcc gatttcggcc tattggttaa aaaatgagct gatttaacaa 3000

aaatttaacg cgaattttaa caaaatatta acgtttacaa ttttatggtg cactctcagt 3060

acaatctgct ctgatgccgc atagttaagc cagccccgac acccgccaac acccgctgac 3120

gcgccctgac gggcttgtct gctcccggca tccgcttaca gacaagctgt gaccgtctcc 3180

gggagctgca tgtgtcagag gttttcaccg tcatcaccga aacgcgcgag acgaaagggc 3240

ctcgtgatac gcctattttt ataggttaat gtcatgataa taatggtttc ttagacgtca 3300

ggtggcactt ttcggggaaa tgtgcgcgga acccctattt gtttattttt ctaaatacat 3360

tcaaatatgt atccgctcat gagacaataa ccctgataaa tgcttcaata atattgaaaa 3420

aggaagagta tgagtattca acatttccgt gtcgccctta ttcccttttt tgcggcattt 3480

tgccttcctg tttttgctca cccagaaacg ctggtgaaag taaaagatgc tgaagatcag 3540

ttgggtgcac gagtgggtta catcgaactg gatctcaaca gcggtaagat ccttgagagt 3600

tttcgccccg aagaacgttt tccaatgatg agcactttta aagttctgct atgtggcgcg 3660

gtattatccc gtattgacgc cgggcaagag caactcggtc gccgcataca ctattctcag 3720

aatgacttgg ttgagtactc accagtcaca gaaaagcatc ttacggatgg catgacagta 3780

agagaattat gcagtgctgc cataaccatg agtgataaca ctgcggccaa cttacttctg 3840

acaacgatcg gaggaccgaa ggagctaacc gcttttttgc acaacatggg ggatcatgta 3900

actcgccttg atcgttggga accggagctg aatgaagcca taccaaacga cgagcgtgac 3960

accacgatgc ctgtagcaat ggcaacaacg ttgcgcaaac tattaactgg cgaactactt 4020

actctagctt cccggcaaca attaatagac tggatggagg cggataaagt tgcaggacca 4080

cttctgcgct cggcccttcc ggctggctgg tttattgctg ataaatctgg agccggtgag 4140

cgtgggtctc gcggtatcat tgcagcactg gggccagatg gtaagccctc ccgtatcgta 4200

gttatctaca cgacggggag tcaggcaact atggatgaac gaaatagaca gatcgctgag 4260

ataggtgcct cactgattaa gcattggtaa ctgtcagacc aagtttactc atatatactt 4320

tagattgatt taaaacttca tttttaattt aaaaggatct aggtgaagat cctttttgat 4380

aatctcatga ccaaaatccc ttaacgtgag ttttcgttcc actgagcgtc agaccccgta 4440

gaaaagatca aaggatcttc ttgagatcct ttttttctgc gcgtaatctg ctgcttgcaa 4500

acaaaaaaac caccgctacc agcggtggtt tgtttgccgg atcaagagct accaactctt 4560

tttccgaagg taactggctt cagcagagcg cagataccaa atactgtcct tctagtgtag 4620

ccgtagttag gccaccactt caagaactct gtagcaccgc ctacatacct cgctctgcta 4680

atcctgttac cagtggctgc tgccagtggc gataagtcgt gtcttaccgg gttggactca 4740

agacgatagt taccggataa ggcgcagcgg tcgggctgaa cggggggttc gtgcacacag 4800

cccagcttgg agcgaacgac ctacaccgaa ctgagatacc tacagcgtga gctatgagaa 4860

agcgccacgc ttcccgaagg gagaaaggcg gacaggtatc cggtaagcgg cagggtcgga 4920

acaggagagc gcacgaggga gcttccaggg ggaaacgcct ggtatcttta tagtcctgtc 4980

gggtttcgcc acctctgact tgagcgtcga tttttgtgat gctcgtcagg ggggcggagc 5040

ctatggaaaa acgccagcaa cgcggccttt ttacggttcc tggccttttg ctggcctttt 5100

gctcacatgt 5110

Claims (10)

1. a kind of gland relevant viral vector, which is characterized in that the gland relevant viral vector contains enhancer, specificity or non- Specificity promoter, the gene order for expressing SARM1 (DN) albumen, the sequence such as SEQ ID NO of SARM1 (DN) albumen:2 institutes Show.

2. gland relevant viral vector according to claim 1, which is characterized in that the gene sequence of expression SARM1 (DN) albumen Row such as SEQ ID NO:Shown in 1.

3. gland relevant viral vector according to claim 1, which is characterized in that the enhancer enhancer is CMV.

4. gland relevant viral vector according to claim 1, which is characterized in that the adeno-associated virus is AAV2.

5. gland relevant viral vector according to claim 1, which is characterized in that the adeno-associated virus is single-stranded AAV.

6. gland relevant viral vector according to claim 1, which is characterized in that the gland relevant viral vector also contains The chimeric interon of one section of shortening, the chimeric intron sequence are selected from and SEQ ID NO:5 have at least 90% homology Nucleotide sequence.

7. gland relevant viral vector according to claim 1, which is characterized in that the gland relevant viral vector contains Cmv enhancer, the gene order of SARM1 (DN), β-globin intrones, hGHpA, L-ITR, R-ITR, Ampicillin, f1ori。

8. gland relevant viral vector according to claim 7, which is characterized in that the gene sequence of expression SARM1 (DN) albumen Row such as SEQ ID NO:Shown in 1, L-ITR sequences such as SEQ ID NO:Shown in 3, cmv enhancer sequence SEQ ID NO:Shown in 4, β-globin intron sequences such as SEQ ID NO:Shown in 5, hGHpA sequences such as SEQ ID NO:Shown in 7, R-ITR sequences such as SEQ ID NO:Shown in 8, Ampicillin sequences such as SEQ ID NO:Shown in 9, f1ori sequences such as SEQ ID NO:Shown in 11.

9. a kind of pharmaceutical composition for treating glaucoma, which is characterized in that the pharmaceutical composition contains such as claim 1-8 Any gland relevant viral vector and pharmaceutically acceptable carrier, pharmaceutical composition expression SARM1 (DN) egg In vain.

10. according to application of any gland relevant viral vectors of claim 1-8 in the drug for preparing treatment glaucoma.