CN118064436A - Chimeric promoter for enhancing gene expression - Google Patents
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Abstract
The present disclosure relates to chimeric promoter polynucleotides. 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 is in the biomedical field, and in particular relates to a polynucleotide of a chimeric 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
Gene therapy (GENE THERAPY) refers to the introduction of exogenous normal genes into target cells to correct or compensate for diseases caused by gene defects or abnormalities, and finally achieves the therapeutic purpose, and in recent years, rAAV has become a hotspot in gene therapy research as a gene therapy vector. A high-efficiency promoter can continuously and high-intensity start the expression of a target gene, and reduce the dosage required for achieving the treatment effect, thereby greatly reducing the treatment cost. The invention aims to solve the problem by optimizing a promoter sequence to improve transcription or specific expression of a target gene so as to reduce the treatment cost by adopting rAAV as a delivery vector.
Disclosure of Invention
The present disclosure provides a polynucleotide, wherein the polynucleotide is SEQ ID NO:2, and a nucleic acid sequence shown in SEQ ID NO. 2.
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 GBA1 of β -glucocerebrosidase (GCase) 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 AAV vector, an adenovirus vector, or a lentiviral vector.
In another aspect, the present disclosure provides an adeno-associated virus (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 9, 8, 1,2, 3B, 4, 5,6, 7, 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 gaucher disease.
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.
FIG. 1 shows the results of in vitro transfection of plasmids containing different promoters.
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.
Polynucleotide
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.
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.
The term "vector" as used herein refers to a nucleic acid comprising, consisting essentially of, or consisting of an intact replicon such that the vector may be 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 replicate 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 214el 0、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. 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.
Examples
The following examples are merely illustrative and are not intended to limit the scope or content of the present invention in any way.
In vitro transfection
Prior to transfection 24h, the hepatocyte line Huh7 was placed in 24 well plates at a cell density of 1.5×10 5 cells/well. mu.L of cell culture medium was added to each well. The transfection used was PEI-based transfection reagent, 0.15. Mu.g of plasmid containing the different promoters, and 0.15. Mu.g of plasmid containing the luciferase reporter gene were co-transfected per well. After transfection of 48 h, 300 μl of fresh whole cell culture medium was added to each well and the cells were re-incubated 24 h. Collecting cell culture supernatant, and detecting GCase enzyme activity by adopting an enzymatic reaction; cell lysis supernatant cells were collected after lysis of cells with cell lysis buffer (Promega) and the fluorescence intensity was read using a Varioskan LUX reader using a Steady-Glo luciferase assay system (Promega). All GCase activity reports were normalized with luciferase intensity.
Statistical analysis
Statistical analysis of t-test was performed using Prism 7 (Graph Pad) software.
Examples
Example 1: chimeric liver-specific promoters
The transcription factor is used for improving the treatment effect of gene therapy on liver-induced diseases, and the chimeric liver-specific promoter fragment is obtained through reasonable design, and the specific nucleotide sequence is shown in Table 1.
TABLE 1 nucleotide sequences of the different elements
Example 2: in vitro transfection
The human glucocerebrosidase gene (GBA 1) was first cloned into AAV vectors containing TTRm promoter and chimeric liver-specific promoter, respectively, to obtain the PG170 and PG171 plasmids (see Table 2). The constructed plasmid was then transfected in vitro in Huh7 hepatocytes and the ability of the different promoters to initiate foreign proteins in hepatocytes was compared by detecting GCase enzyme activity. As shown in FIG. 1, the chimeric liver-specific promoter can enhance the expression level of the foreign protein GCase in hepatocytes, compared with TTRm promoter.
TABLE 2 plasmid information
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 SEQ ID NO:2, and a nucleic acid sequence shown in SEQ ID NO. 2.
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 adeno-associated virus (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 9, 8,1, 2, 3B, 4, 5, 6, 7, 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 gaucher's disease.
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