WO2022252615A1 - Oligonucléotide antisens ciblant le gène ensg00000203930 et son application - Google Patents
Oligonucléotide antisens ciblant le gène ensg00000203930 et son application Download PDFInfo
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- WO2022252615A1 WO2022252615A1 PCT/CN2022/070187 CN2022070187W WO2022252615A1 WO 2022252615 A1 WO2022252615 A1 WO 2022252615A1 CN 2022070187 W CN2022070187 W CN 2022070187W WO 2022252615 A1 WO2022252615 A1 WO 2022252615A1
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- sequence
- gene
- antisense oligonucleotide
- aso
- seq
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
- C12N15/1135—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against oncogenes or tumor suppressor genes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/11—Antisense
- C12N2310/113—Antisense targeting other non-coding nucleic acids, e.g. antagomirs
Definitions
- the invention belongs to the technical field of gene medicine, and in particular relates to an antisense oligonucleotide (ASO) targeting the ENSG00000203930 gene, a method for using the ASO to inhibit the expression of the ENSG00000203930 gene, and a method for treating diseases by administering a drug containing the ASO .
- ASO antisense oligonucleotide
- Antisense oligonucleotide (ASO) regulation of specific target gene expression is derived from RNA interference technology, which is a technology that effectively regulates specific gene expression based on the principle of complementary base pairing.
- RNA interference technology which is a technology that effectively regulates specific gene expression based on the principle of complementary base pairing.
- the ENSG00000203930 gene is a gene contained in the human genome, and its transcription product is a long non-coding RNA (LncRNA).
- LncRNA long non-coding RNA
- the human genome less than 2% of the genome transcripts encode proteins, while at least 75% of the genome is transcribed into transcripts with no coding potential, most of which are long non-coding RNAs (LncRNAs) of more than 200 bases .
- LncRNAs long non-coding RNAs
- Studies in recent years have suggested that lncRNAs are involved in the regulation of various aspects of the occurrence and development of various diseases, including cancer. Therefore, it is regarded as a potential drug target for the treatment of diseases including cancer.
- CpG is a class of oligonucleotides containing CpG motifs, and has entered various stages of clinical trials for the treatment of patients with brain metastases.
- Our study found that the long non-coding RNA products expressed by ENSG00000203930 gene drive tumor brain metastasis.
- lncRNA does not produce protein products
- the existing drug development methods targeting proteins including small molecule inhibitors and biomacromolecular antibodies, are not suitable for the development of molecularly targeted drugs targeting lncRNA. Therefore, ASO drugs (direct synthesis or vector expression) are an important way to realize the development of targeted lncRNA drugs.
- the invention discloses a method for inhibiting the expression of the long-chain non-coding RNA gene-ENSG00000203930 gene and its application. Provides a new approach for the treatment of cancer brain metastases.
- RNA MALAT1 promotes brain metastasis by inducing epithelial-mesenchymal transition in lung cancer. J Neurooncol 121,101-108,doi:10.1007/s11060-014-1613-0(2015).
- RNA HOTAIR enhances aggressive biological behavior and is associated with short disease-free survival in human non-small cell lung cancer. Biochem Bioph Res Co 436,319-324, doi: 10. 2013.05.101(2013).
- the technical problem to be solved by the present invention is to provide a transcript that clones and prepares the non-coding long-chain RNA expressed by the ENSG00000203930 gene in the human brain metastatic cancer cell MDA-MB-231-BM, and discloses the transcript by sequencing full antisense sequence.
- the technical problem to be solved by the present invention is to provide an antisense oligonucleotide targeting ENSG00000203930 gene.
- the final technical problem to be solved by the present invention is to provide the application of the above-mentioned antisense oligonucleotides targeting ENSG00000203930 gene in the preparation of drugs for treating brain tumor metastasis.
- ENSG00000203930 gene expression transcript the antisense nucleotide sequence of the ENSG00000203930 gene expression transcript is shown in SEQ ID NO.1.
- Antisense oligonucleotide targeting ENSG00000203930 gene its sequence is the antisense sequence of 15-30 consecutive nucleotide sequences in SEQ ID NO.: 1, or 15-30 consecutive nucleotide sequences in SEQ ID NO.: 1 An antisense sequence of nucleotide sequences having at least 85% identity to the sequence.
- sequence of the antisense oligonucleotide is as shown in any of SEQ ID NO.2 ⁇ 4, or a sequence having at least 85% identity with any of SEQ ID NO.2 ⁇ 4; as a preferred
- sequence of the antisense oligonucleotide is shown in any of SEQ ID NO.2 ⁇ 4.
- the 5' end and 3' end of the antisense oligonucleotide are respectively modified by 1 to 5 locked nucleic acids
- the locked nucleic acid is a structure in which the 2'-O and 4'-C positions are shortened Special bicyclic nucleotide derivatives that act to form oxymethylene bridges, sulfomethylene bridges, or aminomethylene bridges.
- nucleotides in the antisense oligonucleotides are phosphorothioate-modified nucleotides.
- the structure of the antisense oligonucleotide is shown in formula (I);
- a, b, and c respectively represent the nucleic acid numbers of X, N, and Y; a, b, and c are natural numbers, wherein, 1 ⁇ a ⁇ 5, 1 ⁇ c ⁇ 5; 10 ⁇ a+b+c ⁇ 30;
- nucleotides in the antisense oligonucleotide backbone are phosphorothioate-modified nucleotides
- the sequence of N is any sequence shown in SEQ ID NO.: 2-4, or a sequence having at least 85% identity with any sequence shown in SEQ ID NO.: 2-4.
- Base is base adenine, guanine, cytosine, thymine, uracil, thymine or derivatives of these bases.
- the present invention also discloses a synthetic experimental antisense oligonucleotide (ASO) sequence and related modification information of the structural formula (I).
- ASO comprises 16 consecutive nucleotides in the antisense sequence of the ENSG00000203930 gene transcript disclosed by the present invention, and its sequence is: CAAAGGCGCGGACTTA (SEQ ID NO.2); this experimental ASO is characterized in that its main chain contains sulfur Phosphoester modifications, also including locked nucleic acids.
- ASO is Gapmer, which is characterized in that the two ends of ASO are continuous nucleotides with locked nucleic acid enclosing the middle unlocked nucleic acid.
- the application of the above-mentioned antisense oligonucleotide targeting ENSG00000203930 gene in the preparation of cell ENSG00000203930 gene expression inhibitor is within the protection scope of the present invention.
- the present invention also provides a method for inhibiting the expression of ENSG00000203930 gene in cells as described above.
- experimental ASOs are formulated as lipid formulations.
- the dose of ASO is 50 nM, which can reduce the expression level of ENSG00000203930 gene in cells by about 50%.
- the application of the above-mentioned antisense oligonucleotides targeting ENSG00000203930 gene in the preparation of drugs for treating brain metastases falls within the protection scope of the present invention.
- the experimental ASO dose was 2 mg/kg, which can achieve significant therapeutic effects, including significantly prolonging the survival period and inhibiting weight loss.
- a pharmaceutical composition comprising the antisense oligonucleotide according to any one of claims 2 to 10 and its pharmaceutically acceptable carrier, diluent or excipient; or optionally combined with another therapeutic agent .
- the therapeutic agent is CpG or a CpG analogue.
- An expression vector which includes the sequence shown in any one of SEQ ID NO.: 2 to 4, or contains a sequence that is at least 85% identical to the sequence shown in any one of SEQ ID NO.: 2 to 4 sequence.
- the expression vector is a lentiviral vector, an adenoviral vector, or other non-viral plasmid vectors, most preferably a lentiviral vector.
- composition of ASO targeting ENSG00000203930 gene expression and pharmaceutically acceptable carrier method of inhibiting ENSG00000203930 gene expression using the ASO, and application of the drug (singlely or in combination) containing the ASO for treating diseases caused by the ENSG00000203930 gene .
- the application for treating brain metastases is disclosed.
- G represents nucleotides with guanine, cytosine, adenine, uracil and thymine as bases, respectively.
- G means that the nucleotide base is thymine, and the sugar backbone can be deoxyribose or ribose.
- nucleotide or “nucleotide” or “deoxynucleotide” may also refer to modified nucleotides, as described in further detail below, or alternative replacement moieties. It will be clear to those skilled in the art that guanine, cytosine, adenine, thymine, uracil and thymine may be substituted by other groups without substantially changing the composition of the nucleotides comprising such substituent groups. Base-pairing properties of oligonucleotides. For example, without limitation, inosine-based nucleotides can base pair with adenine-, cytosine-, or uracil-containing nucleotides. Thus, nucleotides comprising uracil, guanine or adenine in the nucleotide sequences of the present invention may be replaced by nucleotides comprising, for example, inosine.
- the ENSG00000203930 gene is located on human chromosome X, and as understood by those skilled in the art, the gene may have different named names and different transcripts produced by the processing of transcripts.
- Antisense oligonucleotides are single-stranded or double-stranded sequences of less than 30 nucleotides in length that reduce gene expression based on the principle of complementary base pairing, and their nucleotides can be modified or unmodified ribonucleotides or deoxyribonucleotides.
- ASO based on the core seed sequence, single-stranded or double-stranded, nucleotide modified or not, adjusted nucleotide length (usually not more than 30 nucleotides), can also achieve the knockdown target The effect of genes.
- Various ASOs formed from unmodified or modified nucleotides can be synthesized by standard methods known in the art, as discussed further below, for example by using an automated DNA synthesizer, such as available from, for example, BIOSEARCH Applied Biosystems Automatic DNA synthesizer.
- modifications include modifications to the ASO backbone such as but not limited to phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkylphosphines salts (including 3'-alkylene phosphates and chiral phosphonates), phosphonates, phosphates including 3'-aminophosphorimides and aminoalkylphosphoramidates, thiophosphoramidic acids salts, thioalkylphosphonates and sulfites, 2'-5' linked these and those) analogs with reversed polarity, pairs of adjacent nucleoside units linked 3'-5' to 5' - 3' or 2'-5' to 5'-2', various salts, mixed salts and free acid forms; nucleotide ribose modifications such as but not limited to the inclusion of one or more substituted sugar groups, ASO Add OH at the 2' position: F: O-, S
- ASO conjugate modification such as but not limited to lipid moieties. All positions in a given compound need not be uniformly modified.
- ASO can also function through DNA plasmid or viral vector expression. Chemical modifications can improve the stability and other druggability properties of ASOs. Therefore, ASO-related applications that partially or completely include other types of modifications or no modifications based on the ASO sequence of the ENSG00000203930 gene transcript disclosed herein relate to the disclosure of the present invention. Those skilled in the art will understand this.
- the doses of ASO and CpG used alone or in combination can be adjusted and optimized according to the actual administration target and the severity of the disease.
- Data obtained, for example, from cell culture assays and animal studies can be used to formulate a range of dosage for use in humans.
- the dosage of compositions featured in this invention lies generally within a range of circulating concentrations in normal cells including the ED50 with little or no toxicity. Such information can be used to more accurately obtain optimal effective dosages.
- the dosage may vary within this range depending on the dosage form employed and the route of administration.
- the present invention specifically relates to an ASO targeting the ENSG00000203930 gene and a drug or a pharmaceutical composition comprising the ASO to treat diseases caused by the expression of the ENSG00000203930 gene, such as but not limited to brain metastasis cancer.
- the drug containing the experimental ASO is administered by intracranial injection.
- the composition may be administered by any means known in the art, including but not limited to oral or parenteral routes, including intracranial (e.g., intracerebroventricular, parenchymal, Intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), nasal, rectal, and topical (including buccal and sublingual) administration.
- the antisense sequence based on gene transcripts can also be realized by constructing an expression vector expressing ASO.
- Expression vectors are generally DNA plasmids or viral vectors.
- the expression product is double-stranded double-stranded ribonucleic acid (DsRNA) type ASO.
- DsRNA double-stranded double-stranded ribonucleic acid
- Viral vectors for expressing ASO can use, but are not limited to, lentiviruses.
- four types of lentivirus-based shRNA vectors were designed and prepared.
- These four vectors are respectively the following sequences in the antisense sequence of the transcripts of non-coding long-chain RNAs expressed by the ENSG00000203930 gene disclosed in the present invention: ATATTTACAATGACTGCAAGT (experimental shRNA1), AAATGTTGGTCTTCTCACAGG (experimental shRNA2), TTTATTGTATGATGTGTAGGT (experimental shRNA3) and TTTATAACTTTCCATCCAGAT (experimental shRNA4).
- the administration of experimental shRNA1 and experimental shRNA2 vectors to express ASO can also effectively inhibit the expression of ENSG00000203930 gene in cells, and inhibit the progression of cancer brain metastases.
- ASO drugs are oligonucleotide drugs, and the compounds have sufficient functional groups, and thus can react with any of a variety of inorganic bases, inorganic acids and organic acids to form Salt.
- Acids commonly used to form acid addition salts are inorganic acids such as but not limited to hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc., and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid , p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, etc.
- salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, Bromide, Iodide, Acetate, Propionate, Caprate, Caprylate, Acrylate, Formate, Isobutyrate, Caprylate, Heptanoate, Propionate, Oxalate, Malonate, succinate, nitrite, sebacate, fumarate, maleate, butene-1,4-dicarboxylate, epoxy-1,6-dimethyl salts, benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, Sulfonate, Xylenesulfonate, Phenylacetate, Phenylpropionate, Phenylbutyrate, Citrate, Lactate,
- the present invention has the following advantages:
- the present invention discovers for the first time that the long-chain non-coding RNA gene-ENSG00000203930 gene expresses a specific transcript sequence as a therapeutic target for brain metastases, and discloses the antisense sequence of the transcript, and also designs an ASO based on the disclosed antisense sequence, through synthesis or ASO based on vector expression can significantly inhibit the expression of the ENSG00000203930 gene, and has a significant inhibitory effect on brain metastasis.
- the application of the method of inhibiting the expression of the long-chain non-coding RNA gene-ENSG00000203930 gene in the preparation of drugs for inhibiting or treating brain metastasis of cancer is proposed.
- Figure 1 Preparation of ENSG00000203930 gene expression in brain metastatic cancer cell MDA-MB-231-BM Verification of expression of long-chain non-coding RNA transcript vector.
- Figure 4 Mouse body weight curves after treatment of mice with brain metastases by experimental ASO and CpG alone or in combination compared with control ASO.
- Figure 5 Survival curves of mice after experimental ASO and CpG alone or in combination treatment of mice with brain metastases compared to control ASO.
- Experimental shRNA1-4 contains the antisense nucleotide sequence region of the long-chain non-coding RNA transcript expressed by the ENSG00000203930 gene.
- Figure 7 Compared with the control shRNA, the expression level of ENSG00000203930 gene in brain metastasis cancer cell MDA-MB-231-BM after implementing experimental shRNA1 and experimental shRNA2 expressing ASO through lentiviral vector.
- the brain metastasis cancer cell MDA-MB-231-BM implements the experimental shRNA1 and the experimental shRNA2 through the lentiviral vector to express ASO, and then injects the mice four weeks later to form nuclear magnetic resonance NMR images in the brain metastases of the mice.
- Fig. 9 Compared with the control shRNA, the effect of the brain metastasis cancer cell MDA-MB-231-BM on the body weight of the mice after the experimental shRNA1 and the experimental shRNA2 express ASO through the lentiviral vector.
- Fig. 10 Compared with the control shRNA, the effect of the brain metastasis cancer cell MDA-MB-231-BM implementing experimental shRNA1 and experimental shRNA2 expressing ASO through lentiviral vector on the survival of mice.
- mice used in this experiment were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd., certificate number: 202013227; all experimental mice in this article were raised in the SPF (specific pathogen free) laboratory of the Animal Experiment Center of Nanjing Normal University Inside. According to the feeding requirements, the feeding density of all experimental mice is less than or equal to 5 per cage, the room temperature is kept in the range of 20-25 degrees Celsius, the humidity is kept at around 50%, and the light is automatically controlled (12h light/12h dark). The feed and litter for mice were purchased from Qinglongshan Animal Breeding Farm in Jingjiangning District.
- shRNA vector for expression of ASO based on lentivirus plko.1
- the reagents required for the experiment should be sterilized with 70% alcohol and sterilized by ultraviolet light for 30 minutes.
- TE buffer a mixture of N-[1-2,3-Dioleyoxy,Propyl]-n,n,n-Trimethylammonium Chloride (DOTMA) and Dioleoyl photidye-thanolamine (DOPE) [1:1 (w/w)] .
- DOTMA Dioleoyl photidye-thanolamine
- ASO ASO is 1:1 (w/w).
- Dosage ASO final solubility 50nM. After the ASO liposomes were incubated at 37°C for 10 hours, the drug-free complete medium was replaced. After 48 hours, the effect on ENSG00000203930 gene expression was detected by RT-qPCR.
- 293T cells were used to prepare lentivirus, and lentivirus-infected cells were collected. After 10 hours, the virus-free complete medium was replaced. After 48 hours, the effect on ENSG00000203930 gene expression was detected by RT-qPCR.
- Brain metastasis mouse model direct brain injection of 100,000 MDA-MB-231-BM cells into the ventricles of mice to establish a brain metastasis mouse model.
- Brain metastasis mouse model Ventricular injection of 100,000 MDA-MB-231-BM cells into the mouse ventricle to establish a brain metastasis mouse model.
- MDA-MB-231-BM cells were pretreated with ASO-expressing lentivirus
- Trizol (1 + 100 ⁇ L Trizol to a 1.5 mL centrifuge tube, grind the tissue until it turns white, and then add 900 ⁇ L Trizol.
- RNA reverse transcription into cDNA system add the required reagents (the whole process needs to use RNAase-free tip), after mixing evenly, instantaneously centrifuge for 20 seconds, put it into the PCR instrument for reverse transcription reaction,
- the reaction program is: 50°C, 15min; 85°C, 5sec. After the reaction, the cDNA was stored at -20°C.
- Example 1 Expression of ENSG00000203930 Gene Transcription Long-chain Noncoding RNA Transcript Vector Preparation in Human Brain Metastatic Cancer Cell Line MDA-MB-231-BM and the Full Sequence of the Antisense Chain of the Transcript.
- ENSG00000203930 gene transcription long-chain non-coding RNA transcript vector transfected cells in MDA-MB-231-BM prepared in Fig. 1 can express.
- SEQ ID NO.1 is the full antisense sequence of ENSG00000203930 gene transcription long-chain non-coding RNA product identified in the present invention in MDA-MB-231-BM, including 1,257 bases, of which A is 30.23%, and G is 24.42%, T was 26.81%, and C was 18.54%.
- the synthesis experiment ASO was designed.
- Figure 2 shows that the sequence of the experimental ASO is CAAAGGCGCGGACTTA, which contains a modified nucleotide with a 5'-phosphorothioate group and a Gapmer that locks the nucleic acid.
- the synthetic ASO compound was identified by HPLC analysis and mass spectrometry, and its molecular weight was 5310.24Da.
- Example 3 Experiment ASO inhibits the gene expression of ENSG00000203930 in cells.
- Figure 3 shows that compared with the control ASO, the experimental ASO can significantly inhibit the expression of the ENSG00000203930 gene in cells, and 50 nM of the experimental ASO can reduce the expression of the ENSG00000203930 gene by about 50%.
- Example 4 Activity of Drugs Containing Experimental ASOs in Treating Brain Metastatic Cancer.
- the drug containing the experimental ASO (alone or in combination with CpG) was administered, wherein the dose of ASO was 2 mg/kg, and the dose of CpG was 2 mg/kg, and the activity of the drug containing the experimental ASO in the treatment of brain metastases was observed.
- Figure 4 shows that compared with the control, the experimental ASO treatment alone can significantly alleviate the weight loss of the model brain metastasis mice, and the effect is better than that of CpG; the administration of the experimental ASO can further enhance the effect of CpG in alleviating the weight loss of the model brain metastasis mice.
- Figure 5 shows that compared with the control, the experimental ASO treatment alone significantly prolongs the survival of the model brain metastases mice, and the effect is better than that of CpG; and the administration of the experimental ASO can further enhance the CpG in prolonging the survival of the model brain metastases mice.
- Embodiment 5 the preparation and activity of vector expression ASO
- experimental shRNA1-4 Based on the antisense complete sequence of the non-coding long-chain RNA transcript expressed by the ENSG00000203930 gene disclosed in the present invention, four experimental shRNAs expressing ASO based on lentiviral vectors (ie, experimental shRNA1-4) were prepared.
- Figure 6 shows that experimental shRNA-1 and experimental shRNA-2 contain the antisense sequence region of the transcript of the non-coding long-chain RNA expressed by the ENSG00000203930 gene.
- Figure 7 shows that compared with the control, the experimental shRNA-1 and experimental shRNA-2 expressed based on the lentiviral vector can significantly inhibit the expression of the ENSG00000203930 gene in cells, and reduce the expression of the ENSG00000203930 gene by about 80%.
- Figures 9-10 show that, compared with the control, brain metastases MDA-MB-231-BM cells were administered with experimental shRNA-1 and experimental shRNA-2 expressed by lentiviral vectors, and their ability to form brain metastatic lesions was significantly weakened (Figure 8 ); its ability to reduce mouse body weight was significantly weakened (Figure 9); its ability to cause mouse death was significantly weakened (Figure 10).
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Abstract
L'invention concerne une séquence complète de brin antisens d'un transcrit d'ARN non codant long d'un gène ENSG00203930. Une séquence oligonucléotidique antisens (ASO) est conçue et synthétisée sur la base de la séquence complète du brin antisens du transcrit de l'ARN long non codant du gène ENSG00000203930. L'expression du gène ENSG00000203930 peut être inhibée par un ASO synthétique ou à vecteur, qui a un effet inhibiteur sur les métastases cérébrales cancéreuses.
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