CN117947035A - Promoter for enhancing gene expression - Google Patents
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Abstract
The present disclosure relates to a novel promoter polynucleotide. In addition, the present disclosure also relates to nucleic acid constructs, vectors, viral particles and compositions comprising the polynucleotides described in the present disclosure for driving transcriptional expression of genes, and the use in the preparation of gene therapies for the treatment of related diseases.
Description
Technical Field
The present disclosure relates to biomedical fields, and in particular to polynucleotides of a novel promoter. In addition, the present disclosure also relates to nucleic acid constructs, vectors, viral particles and compositions comprising the polynucleotides described in the present disclosure for driving transcriptional expression of genes, and the use in the preparation of gene therapies for the treatment of related diseases.
Background
Hepatolenticular degeneration (WD) is a rare autosomal recessive genetic disease that affects mainly the liver, nervous system and other tissues. The root cause of the disease is mutation of the ATP7B gene located on chromosome 13, leading to abnormal ATP7B protein function. The ATP7B gene codes for a P-type copper transport ATPase which is mainly expressed in liver cells and is used for transmembrane transport of copper ions. Abnormal ATP7B protein function results in hepatocytes reducing copper excretion into bile, resulting in copper ion accumulation in the liver and other tissues. Under abnormal copper metabolism, ceruloplasmin cannot bind enough copper ions, resulting in additional symptoms such as hemolytic anemia. ATP7B has a basic P-type atpase structure, including a complex cytoplasmic N-terminal tail with six independently folded copper ion responsive elements (CREs) of about 70 amino acids in length, and a copper ion transmembrane channel formed by eight transmembrane domains.
Gene therapy is a leading biomedical field aimed at treating a range of genetic and chronic diseases by modulating, repairing or replacing defective genes in patients. Since the 90 s of the 20 th century, gene therapy has made significant progress and has been successful in several clinical trials. The core idea of this therapeutic approach is to repair or replace the affected genes with exogenous DNA or RNA, thereby correcting intracellular genetic defects. Thus, researchers often choose exogenous promoters synthesized from other organisms or artificially to ensure that the gene of interest is expressed efficiently in vivo. Compared with exogenous promoters, endogenous promoters are derived from upstream of the target genes, have better biocompatibility, have more obvious synergistic effect with the target genes, and can retain endogenous tissue specificity, physiology, molecular regulation and the like when the target genes are expressed by using the endogenous promoters. In order to fully utilize the advantages of the endogenous promoter, the present disclosure develops different forms of ATP7B endogenous promoters, and experiments prove that the preferred promoters can drive the expression of ATP7B genes with high efficiency, and can be used in gene therapy vectors to treat hepatolenticular degeneration. The present disclosure provides a potential solution, which can fully exert the advantages of endogenous promoters, aims to efficiently drive gene expression on the basis of retaining the functions of endogenous tissue specificity, physiological regulation, molecular regulation and the like, and brings new possibilities for the treatment mode of genetic diseases.
Disclosure of Invention
The present disclosure provides a polynucleotide, wherein the polynucleotide comprises a sequence selected from the group consisting of SEQ ID NO：5、SEQ ID NO：7、SEQ ID NO：6、SEQ ID NO：1、SEQ ID NO：9、SEQ ID NO：2、SEQ ID NO：4、SEQ ID NO：3、SEQ ID NO：12、SEQ ID NO：13、SEQ ID NO：8、 or SEQ ID NO:11, and a nucleic acid sequence of the group consisting of the nucleic acid sequences of the group consisting of 11.
The present disclosure provides a nucleic acid construct comprising:
1) A polynucleotide sequence of interest;
2) A transcriptional regulatory element operably linked to a polynucleotide sequence of interest, wherein said transcriptional regulatory element comprises a polynucleotide as described above and said transcriptional regulatory element is located upstream of said polynucleotide sequence of interest.
In some embodiments, wherein the polynucleotide sequence of interest is a nucleic acid sequence encoding ATP7B or a variant thereof.
In another aspect, the present disclosure provides a vector comprising a polynucleotide as described above or a nucleic acid construct as described above.
In some embodiments, wherein the vector is a viral vector, preferably the viral vector is an adeno-associated viral (AAV) vector, an adenovirus vector, or a lentiviral vector.
In another aspect, the present disclosure provides an AAV particle comprising a vector and a capsid protein as described above.
In some embodiments, wherein the AAV is selected from the group consisting of serotypes 1,2, 3B, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, rh10, or hu37 and any one AAV serotype isolated from human and non-human mammals or variants thereof.
In another aspect, the present disclosure provides a pharmaceutical composition comprising a vector as described above, or an AAV particle as described above, and a pharmaceutically acceptable excipient.
In another aspect, the present disclosure provides the use of a polynucleotide as described above, a nucleic acid construct as described above, a vector as described above, an AAV particle as described above, or a pharmaceutical composition as described above, in the manufacture of a medicament for treating or preventing a disease in a subject.
In some embodiments, an effective amount of a vector as described above, an AAV particle as described above, or a pharmaceutical composition as described above is administered to a subject.
In some embodiments, wherein the disease is an ATP 7B-related disease, preferably the disease is hepatolenticular degeneration.
In some embodiments, wherein the subject is a mammal, preferably the subject is a human.
Drawings
The present disclosure may be more fully understood with reference to the following drawings.
Figure 1 shows the copper transport capacity exhibited by different ATP7B endogenous promoters after driving expression of the ATP7B gene, with some promoters having significant advantages over negative controls. A higher relative firefly luciferase activity/Renilla luciferase activity ratio indicates a higher copper ion accumulation in the cell, corresponding to a lower copper transport capacity. The data presented in the graph are expressed as mean ± Standard Error (SEM), each group sample size (n) is 3, the inter-group variance mark ns represents p >0.05, p <0.01, p <0.001.
Detailed Description
The following description of the present disclosure is intended only to illustrate various embodiments of the present disclosure. Therefore, the particular modifications discussed should not be construed as limiting the scope of the present disclosure. It will be apparent to those skilled in the art that various equivalents, changes, and modifications can be made without departing from the scope of the disclosure, and it is to be understood that such equivalent embodiments are intended to be included herein. All references cited herein, including publications, patents, and patent applications, are incorporated by reference in their entirety.
Unless otherwise the skilled artisan generally understand the same meaning.
The terms "nucleotide" and "polynucleotide" are used interchangeably herein to refer to a polymeric form of nucleotides of any length, either ribonucleotides or deoxyribonucleotides. Thus, the term includes, but is not limited to, single-stranded, double-stranded or multi-stranded DNA or RNA, genomic DNA, cDNA, DNA-RNA hybrids, or polymers comprising, consisting essentially of, or consisting of purine and pyrimidine bases or other natural, chemically or biochemically modified, non-natural or derivatized nucleotide bases. In some embodiments, the polynucleotide comprises a sequence selected from the group consisting of SEQ ID NOs: 1-13.
The term "promoter" as used herein means a control sequence, which is a region of a polynucleotide sequence that controls the initiation and rate of transcription of a coding sequence, such as a gene or a transgene. Promoters may be constitutive, inducible, repressible, or tissue specific. In some embodiments, the promoter is a truncated endogenous promoter comprising a sequence selected from SEQ ID NO：5、SEQ ID NO：7、SEQ ID NO：6、SEQ ID NO：1、SEQ ID NO：9、SEQ ID NO：2、SEQ ID NO：4、SEQ ID NO：3、SEQ ID NO：12、SEQ ID NO：13、SEQ ID NO：8、 or SEQ ID NO:11, and a nucleic acid sequence of the group consisting of seq id no.
The term "vector" as used herein refers to a nucleic acid comprising, consisting essentially of, or consisting of an intact replicon or Inverted Terminal Repeat (ITR) such that the vector may be preserved and/or replicated when placed into a cell by, for example, transfection, infection, or transformation procedures. It will be appreciated in the art that once inside the cell, the vector may be stored and/or replicated as an extrachromosomal (episomal) element, or may be integrated into the host cell chromosome. The vector may comprise nucleic acid derived from a retrovirus, adenovirus, herpes virus, baculovirus, modified baculovirus, papilloma virus, AAV viral vector, lentiviral vector, adenovirus vector, alphaviral vector, etc., preferably the vector described herein is selected from AAV vector, adenovirus vector, or lentiviral vector.
The term "adeno-associated virus" or "AAV" as used herein refers to a member of the class of viruses associated with that name and belonging to the genus parvoviridae-dependent parvovirus. Adeno-associated virus is a single stranded DNA virus that grows only in cells, with some functions provided by co-infected helper viruses. All AAV serotypes apparently exhibit very similar replication characteristics mediated by homologous rep genes; and all carry three related capsid proteins. At least 13 sequentially numbered naturally occurring AAV serotypes are known in the art. Non-limiting exemplary serotypes for use in the methods disclosed herein include any of these 13 serotypes, e.g., AAV2, AAV8, AAV9, or variant serotypes such as AAV-DJ and AAV php.b. AAV particles comprise, consist essentially of, or consist of three major viral proteins VP1, VP2, and VP 3. In embodiments, the AAV comprises an AAV capsid protein selected from the group consisting of AAVPHP.B、AAVrh74、AAV 110、AAV 204、AAV 214、AAV 214A、AAV 214e、AAV 214e8、AAV 214e9、AAV 214el0、AAV ITB102_45 and AAV 214 AB. In embodiments, AAV refers to any of serotypes AAV1, AAV2, AAV3B, AAV, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12 or AAV13, AAVrh10, AAVhu37, or AAV serotypes isolated from humans and non-human mammals, or variants thereof. In embodiments, the AAV particle comprises a polypeptide selected from the group consisting of AAV1、AAV2、AAV2G9、AAV3、AAV3a、AAV3b、AAV3-3、AAV4、AAV4-4、AAV5、AAV6、AAV6.1、AAV6.2、AAV6.1.2、AAV7、AAV7.2、AAV8、AAV9、AAV9.11、AAV9.13、AAV9.16、AAV9.24、AAV9.45、AAV9.47、AAV9.61、AAV9.68、AAV9.84、AAV9.9、AAV10、AAV11、AAV12、AAV16.3、AAV24.1、AAV27.3、AAV42.12、AAV42-1b、AAV42-2、AAV42-3a、AAV42-3b、AAV42-4、AAV42-5a、AAV42-5b、AAV42-6b、AAV42-8、AAV42-10、AAV42-11、AAV42-12、AAV42-13、AAV42-15、AAV42-aa、AAV43-1、AAV43-12、AAV43-20、AAV43-21、AAV43-23、AAV43-25、AAV43-5、AAV44.1、AAV44.2、AAV44.5、AAV223.1、AAV223.2、AAV223.4、AAV223.5、AAV223.6、AAV223.7、AAV1-7/rh.48、AAV1-8/rh.49、AAV2-15/rh.62、AAV2-3/rh.61、AAV2-4/rh.50、AAV2-5/rh.51、AAV3.1/hu.6、AAV3.1/hu.9、AAV3-9/rh.52、AAV3-11/rh.53、AAV4-8/r11.64、AAV4-9/rh.54、AAV4-19/rh.55、AAV5-3/rh.57、AAV5-22/rh.58、AAV7.3/hu.7、AAV16.8/hu.10、AAV16.12/hu.11、AAV29.3/bb.1、AAV29.5/bb.2、AAV106.1/hu.37、AAV114.3/hu.40、AAV127.2/hu.41、AAV127.5/hu.42、AAV128.3/hu.44、AAV130.4/hu.48、AAV145.1/hu.53、AAV145.5/hu.54、AAV145.6/hu.55、AAV161.10/hu.60、AAV161.6/hu.61、AAV33.12/hu.17、AAV33.4/hu.15、AAV33.8/hu.16、AAV52/hu.19、AAV52.1/hu.20、AAV58.2/hu.25、AAVA3.3、AAVA3.4、AAVA3.5、AAVA3.7、AAVC1、AAVC2、AAVC5、AAV-DJ、AAV-DJ8、AAVF3、AAVF5、AAVH2、AAVrh.72、AAVhu.8、AAVrh.68、AAVrh.70、AAVpi.1、AAVpi.3、AAVpi.2、AAVrh.60、AAVrh.44、AAVrh.65、AAVrh.55、AAVrh.47、AAVrh.69、AAVrh.45、AAVrh.59、AAVhu.12、AAVH6、AAVLK03、AAVH-1/hu.1、AAVH-5/hu.3、AAVLG-10/rh.40、AAVLG-4/rh.38、AAVLG-9/hu.39、AAVN721-8/rh.43、AAVCh.5、AAVCh.5R1、AAVcy.2、AAVcy.3、AAVcy.4、AAVcy.5、AAVCy.5R1、AAVCy.5R2、AAVCy.5R3、AAVCy.5R4、AAVcy.6、AAVhu.1、AAVhu.2、AAVhu.3、AAVhu.4、AAVhu.5、AAVhu.6、AAVhu.7、AAVhu.9、AAVhu.10、AAVhu.11、AAVhu.13、AAVhu.15、AAVhu.16、AAVhu.17、AAVhu.18、AAVhu.20、AAVhu.21、AAVhu.22、AAVhu.23.2、AAVhu.24、AAVhu.25、AAVhu.27、AAVhu.28、AAVhu.29、AAVhu.29R、AAVhu.31、AAVhu.32、AAVhu.34、AAVhu.35、AAVhu.37、AAVhu.39、AAVhu.40、AAVhu.41、AAVhu.42、AAVhu.43、AAVhu.44、AAVhu.44R1、AAVhu.44R2、AAVhu.44R3、AAVhu.45、AAVhu.46、AAVhu.47、AAVhu.48、AAVhu.48R1、AAVhu.48R2、AAVhu.48R3、AAVhu.49、AAVhu.51、AAVhu.52、AAVhu.54、AAVhu.55、AAVhu.56、AAVhu.57、AAVhu.58、AAVhu.60、AAVhu.61、AAVhu.63、AAVhu.64、AAVhu.66、AAVhu.67、AAVhu.14/9、AAVhu.t 19、AAVrh.2、AAVrh.2R、AAVrh.8、AAVrh.8R、AAVrh.10、AAVrh.12、AAVrh.13、AAVrh.13R、AAVrh.14、AAVrh.17、AAVrh.18、AAVrh.19、AAVrh.20、AAVrh.21、AAVrh.22、AAVrh.23、AAVrh.24、AAVrh.25、AAVrh.31、AAVrh.32、AAVrh.33、AAVrh.34、AAVrh.35、AAVrh.36、AAVrh.37、AAVrh.37R2、AAVrh.38、AAVrh.39、AAVrh.40、AAVrh.46、AAVrh.48、AAVrh.48.1、AAVrh.48.1.2、AAVrh.48.2、AAVrh.49、AAVrh.51、AAVrh.52、AAVrh.53、AAVrh.54、AAVrh.56、AAVrh.57、AAVrh.58、AAVrh.61、AAVrh.64、AAVrh.64R1、AAVrh.64R2、AAVrh.67、AAVrh.73、AAVrh.74、AAVrh8R、AAVrh8R A586R mutant, AAVrh8R R533A mutant, AAAV, BAAV, goat AAV, bovine AAV、AAVhE1.1、AAVhEr1.5、AAVhER1.14、AAVhEr1.8、AAVhEr1.16、AAVhEr1.18、AAVhEr1.35、AAVhEr1.7、AAVhEr1.36、AAVhEr2.29、AAVhEr2.4、AAVhEr2.16、AAVhEr2.30、AAVhEr2.31、AAVhEr2.36、AAVhER1.23、AAVhEr3.1、AAV2.5T、AAV-PAEC、AAV-LK01、AAV-LK02、AAV-LK03、AAV-LK04、AAV-LK05、AAV-LK06、AAV-LK07、AAV-LK08、AAV-LK09、AAV-LK10、AAV-LK11、AAV-LK12、AAV-LK13、AAV-LK14、AAV-LK15、AAV-LK16、AAV-LK17、AAV-LK18、AAV-LK19、AAV-PAEC2、AAV-PAEC4、AAV-PAEC6、AAV-PAEC7、AAV-PAEC8、AAV-PAEC11、AAV-PAEC12、AAV-2-pre-miRNA-101、AAV-8h、AAV-8b、AAV-h、AAV-b、AAV SM 10-2、AAV Shuffle 100-1、AAV Shuffle 100-3、AAV Shuffle 100-7、AAV Shuffle 10-2、AAV Shuffle 10-6、AAV Shuffle 10-8、AAV Shuffle 100-2、AAV SM 10-1、AAV SM 10-8、AAV SM 100-3、AAV SM 100-10、BNP61 AAV、BNP62 AAV、BNP63 AAV、AAVrh.50、AAVrh.43、AAVrh.62、AAVrh.48、AAVhu.19、AAVhu.11、AAVhu.53、AAV4-8/rh.64、AAVLG-9/hu.39、AAV54.5/hu.23、AAV54.2/hu.22、AAV54.7/hu.24、AAV54.1/hu.21、AAV54.4R/hu.27、AAV46.2/hu.28、AAV46.6/hu.29、AAV128.1/hu.43、 true type AAV (ttAAV), UPENN AAV, japanese AAV10 serotype 、AAV CBr-7.1、AAV CBr-7.10、AAV CBr-7.2、AAV CBr-7.3、AAV CBr-7.4、AAV CBr-7.5、AAV CBr-7.7、AAV CBr-7.8、AAV CBr-B7.3、AAV CBr-B7.4、AAV CBr-E1、AAV CBr-E2、AAV CBr-E3、AAV CBr-E4、AAV CBr-E5、AAV CBr-e5、AAV CBr-E6、AAV CBr-E7、AAV CBr-E8、AAV CHt-1、AAV CHt-2、AAV CHt-3、AAV CHt-6.1、AAV CHt-6.10、AAV CHt-6.5、AAV CHt-6.6、AAV CHt-6.7、AAV CHt-6.8、AAV CHt-P1、AAV CHt-P2、AAV CHt-P5、AAV CHt-P6、AAV CHt-P8、AAV CHt-P9、AAV CKd-1、AAV CKd-10、AAV CKd-2、AAV CKd-3、AAV CKd-4、AAV CKd-6、AAV CKd-7、AAV CKd-8、AAV CKd-B1、AAV CKd-B2、AAV CKd-B3、AAV CKd-B4、AAV CKd-B5、AAV CKd-B6、AAV CKd-B7、AAV CKd-B8、AAV CKd-H1、AAV CKd-H2、AAV CKd-H3、AAV CKd-H4、AAV CKd-H5、AAV CKd-H6、AAV CKd-N3、AAV CKd-N4、AAV CKd-N9、AAV CLg-F1、AAV CLg-F2、AAV CLg-F3、AAV CLg-F4、AAV CLg-F5、AAV CLg-F6、AAV CLg-F7、AAV CLg-F8、AAV CLv-1、AAV CLv1-1、AAV Clv1-10、AAV CLv1-2、AAV CLv-12、AAV CLv1-3、AAV CLv-13、AAV CLv1-4、AAV Clv1-7、AAV Clv1-8、AAV Clv1-9、AAV CLv-2、AAV CLv-3、AAV CLv-4、AAV CLv-6、AAV CLv-8、AAV CLv-D1、AAV CLv-D2、AAV CLv-D3、AAV CLv-D4、AAV CLv-D5、AAV CLv-D6、AAV CLv-D7、AAV CLv-D8、AAV CLv-E1、AAV CLv-K1、AAV CLv-K3、AAV CLv-K6、AAV CLv-L4、AAV CLv-L5、AAV CLv-L6、AAV CLv-M1、AAV CLv-M11、AAV CLv-M2、AAV CLv-M5、AAV CLv-M6、AAV CLv-M7、AAV CLv-M8、AAV CLv-M9、AAV CLv-R1、AAV CLv-R2、AAV CLv-R3、AAV CLv-R4、AAV CLv-R5、AAV CLv-R6、AAV CLv-R7、AAV CLv-R8、AAV CLv-R9、AAV CSp-1、AAV CSp-10、AAV CSp-11、AAV CSp-2、AAV CSp-3、AAV CSp-4、AAV CSp-6、AAV CSp-7、AAV CSp-8、AAV CSp-8.10、AAV CSp-8.2、AAV CSp-8.4、AAV CSp-8.5、AAV CSp-8.6、AAV CSp-8.7、AAV CSp-8.8、AAV CSp-8.9、AAV CSp-9、AAV.hu.48R3、AAV.VR-355、AAV3B、AAV4、AAV5、AAVF1/HSC1、AAVF11/HSC11、AAVF12/HSC12、AAVF13/HSC13、AAVF14/HSC14、AAVF15/HSC15、AAVF16/HSC16、AAVF17/HSC17、AAVF2/HSC2、AAVF3/HSC3、AAVF4/HSC4、AAVF5/HSC5、AAVF6/HSC6、AAVF7/HSC7、AAVF8/HSC8、AAVF9/HSC9、AAV-PHP.B（PHP.B）、AAV-PHP.A（PHP.A）、G2B-26、G2B-13、TH1.1-32、TH1.1-35、AAVPHP.B2、AAVPHP.B3、AAVPHP.N/PHP.B-DGT、AAVPHP.B-EST、AAVPHP.B-GGT、AAVPHP.B-ATP、AAVPHP.B-ATT-T、AAVPHP.B-DGT-T、AAVPHP.B-GGT-T、AAVPHP.B-SGS、AAVPHP.B-AQP、AAVPHP.B-QQP、AAVPHP.B-SNP（3）、AAVPHP.B-SNP、AAVPHP.B-QGT、AAVPHP.B-NQT、AAVPHP.B-EGS、AAVPHP.B-SGN、AAVPHP.B-EGT、AAVPHP.B-DST、AAVPHP.B-DST、AAVPHP.B-STP、AAVPHP.B-PQP、AAVPHP.B-SQP、AAVPHP.B-QLP、AAVPHP.B-TMP、AAVPHP.B-TTP、AAVPHP.S/G2A12、AAVG2A15/G2A3、AAVG2B4、AAVG2B5, and variants thereof.
As used herein, the term "subject" includes any human or non-human animal. The term "non-human animal" includes all vertebrates, e.g., mammals and non-mammals, e.g., non-human primates, sheep, dogs, cats, horses, cows, chickens, rats, mice, amphibians, reptiles, and the like. The terms "patient" or "subject" are used interchangeably unless otherwise indicated. In the present disclosure, the preferred subject is a human.
As used herein, the term "treating" refers to administering to a subject an effective amount of a polynucleotide, nucleic acid construct, vector, AAV particle, or pharmaceutical composition according to the disclosure, such that the subject has a reduction in at least one symptom of the disease or an improvement in the disease, e.g., a beneficial or desired clinical outcome. For the purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptoms, diminishment of extent of disease, stabilization of the disease state (i.e., not worsening), delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. Treatment may refer to an extension of survival compared to the expected survival without treatment. Thus, those skilled in the art recognize that treatment may improve a disease condition, but may not be a complete cure for the disease. As used herein, the term "treatment" includes prophylaxis. Or the treatment is "effective" in cases where the progression of the disease is reduced or stopped. "treatment" may also mean an extension of survival compared to the expected survival in the absence of treatment. In some embodiments, the patient in need of treatment includes a condition that has been diagnosed with an ATP 7B-related disorder. In some embodiments, the patient in need of treatment includes a condition that has been diagnosed with hepatolenticular degeneration, and may develop such a condition due to genetic susceptibility or other factors.
As used herein, the term "effective amount" means an amount sufficient to achieve the desired effect. In the case of use in therapy or prophylaxis, the effective amount will depend on the type and severity of the condition in question and the characteristics of the individual subject, such as general health, age, sex, weight and tolerance to the pharmaceutical composition. In gene therapy, for example, in some embodiments, an effective amount is an amount sufficient to modulate some or all of the functions of the gene of interest. In other embodiments, an effective amount of an AAV viral particle is an amount sufficient to modulate expression of a gene in a subject. One skilled in the art will be able to determine the appropriate amount based on these and other factors.
Double luciferase detection method
The reporter plasmid pGL4×MRE-LUC was used in the experiments to assess the copper transport capacity of the different ATP7B endogenous promoters after driving transcriptional expression of the ATP7B gene. The reporter plasmid contains 4 Metal Response Elements (MREs), and the MREs is derived from a mouse metallothionein-1 promoter, and is cloned in series to the upstream of a simple E1B promoter to jointly drive the gene expression of firefly luciferase, so as to construct the reporter plasmid pGL4 xMRE-LUC. In the experiments, HEK293T cells were transfected simultaneously with pGL4 xmre-LUC and ATP7B expression vectors comprising different endogenous promoters, while empty plasmids were used as negative controls. At the time of transfection, all cells were transfected with a considerable amount of pCMV-RL plasmid to use the expression of renilla luciferase as a transfection reference. After 24 hours of transfection, the cells were cultured for an additional 24 hours in a complete medium environment containing 75 μm copper sulfate, while a baseline control group without copper sulfate treatment was included. Finally, firefly luciferase activity and Renilla luciferase activity were measured using TRANSDETECT ® double-luciferin reporting kit from Beijing full gold Biotechnology Co. Relative fluorescence intensity units were calculated by normalizing firefly luciferase activity to Renilla luciferase activity.
Statistical analysis
Statistical analysis was performed using Prism 8 (Graph Pad) software. Inter-group variance analysis was performed by one-way variance analysis. The significance differences and sample sizes are well-marked in the diagrams or legends.
Examples
The following examples are merely illustrative and are not intended to limit the scope or content of the present disclosure in any way.
Example 1: analysis of transcription factor binding sites in 5000 bp upstream to 100 bp downstream of the ATP7B transcription initiation site was performed to determine the design of different ATP7B endogenous promoters
A transcription factor is a protein molecule that specifically binds to a specific sequence upstream and downstream of a gene of interest to ensure that the gene of interest is expressed at a specific intensity at a specific time and space. Transcription factors control chromosomal organization and transcription by recognizing specific DNA sequences, i.e., transcription factor binding sites, to form a complex system to direct genomic expression.
In the experiment, 33 transcription factors known to be positively correlated with enhanced transcriptional activity were selected, and predictive analysis was performed on these transcription factor binding sites in 5000 bp upstream to 100 bp downstream of the ATP7B transcription start site. As shown in Table 1, the results indicate that the binding sites of these transcription factors are mainly enriched in the region 1000 bp upstream to 3500 bp upstream of the ATP7B transcription initiation site.
TABLE 1 transcription factor binding sites positively correlated with the neutralization enhancing activity of 5000 bp upstream to 100 bp downstream of the ATP7B transcription initiation site
Note that: negative values represent the number of bases from the transcription start site of the transcription factor binding site, positive values represent the number of bases from the transcription start site of the transcription factor binding site, and positive values represent the number of bases from the transcription start site of the transcription factor binding site, representing a complex of the two transcription factors
Example 2: different ATP7B endogenous promoters can drive ATP7B gene to be transcribed and expressed, and the promoter has obvious copper transport capacity
13 Truncated promoters of different lengths were designed, taking into account the distribution of the enrichment region of the transcription factor binding site upstream and downstream of the ATP7B transcription start site and the sequence of the Metal Response Element (MREs), as shown in Table 2. Using pcDNA3.1 as a plasmid vector backbone, the full-length wild-type ATP7B sequence (Genebank NM-000053.4) was cloned downstream of 13 promoters. As described above, the copper transport capacity was tested using the dual luciferase assay, with a lower ratio of relative firefly luciferase activity to anemone luciferase activity representing higher copper transport capacity. As shown in FIG. 1, promoter-2, promoter-3, promoter-4, promoter-5, promoter-6, promoter-7, promoter-8, promoter-9, promoter-11, promoter-12 and promoter-13 are capable of driving transcriptional expression of ATP7B gene and exhibit good copper transporting ability, wherein promoter-1, promoter-2, promoter-4, promoter-5, promoter-6, promoter-7 and promoter-9 exhibit optimal transcriptional activity.
TABLE 2 sequences of different ATP7B promoters
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Incorporated by reference
The entire contents of each patent and scientific document referred to herein is incorporated by reference for all purposes.
Equivalency of
The present disclosure may be embodied in other specific forms without departing from its spirit or essential characteristics. The above embodiments should therefore be regarded as illustrative in all respects, rather than limiting on the invention described herein. The scope of the disclosure is, therefore, indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are intended to be embraced therein.
Claims (10)
1. A polynucleotide, wherein the polynucleotide is selected from the group consisting of SEQ ID NO：5、SEQ ID NO：7、SEQ ID NO：6、SEQ ID NO：1、SEQ ID NO：9、SEQ ID NO：2、SEQ ID NO：4、SEQ ID NO：3、SEQ ID NO：12、SEQ ID NO：13、SEQ ID NO：8、 or SEQ ID NO:11, and a nucleic acid sequence of the group consisting of 11.
2. A nucleic acid construct comprising:
1) A polynucleotide sequence of interest;
2) A transcriptional regulatory element operably linked to a polynucleotide sequence of interest, wherein the transcriptional regulatory element comprises the polynucleotide of claim 1 and the transcriptional regulatory element is upstream of the polynucleotide sequence of interest.
3. A vector comprising the polynucleotide of claim 1 or the nucleic acid construct of claim 2.
4. The vector of claim 3, wherein the vector is a viral vector.
5. The vector of claim 4, wherein the viral vector is an adeno-associated viral (AAV) vector, an adenovirus vector, or a lentiviral vector.
6. An AAV particle comprising the vector of any one of claims 3-5 and a capsid protein.
7. The AAV particle of claim 6, wherein the AAV is selected from the group consisting of serotypes 1,2, 3B, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, rh10, or hu37, and any one AAV serotype isolated from human and non-human mammals or variants thereof.
8. A pharmaceutical composition comprising the vector of any one of claims 3 to 5, or the AAV particle of any one of claims 6 or 7, and a pharmaceutically acceptable excipient.
9. Use of a polynucleotide according to claim 1, a nucleic acid construct according to claim 2, a vector according to any one of claims 3 to 5, an AAV particle according to claim 6 or 7, or a pharmaceutical composition according to claim 8 in the manufacture of a medicament for treating or preventing a disease in a subject.
10. The use of claim 9, wherein the disease is an ATP 7B-related disease.
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