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WO2025142999A1 - Nouvel arn double brin à base de séquence d'arn de périostine et utilisation associée - Google Patents

Nouvel arn double brin à base de séquence d'arn de périostine et utilisation associée Download PDF

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Publication number
WO2025142999A1
WO2025142999A1 PCT/JP2024/045858 JP2024045858W WO2025142999A1 WO 2025142999 A1 WO2025142999 A1 WO 2025142999A1 JP 2024045858 W JP2024045858 W JP 2024045858W WO 2025142999 A1 WO2025142999 A1 WO 2025142999A1
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Prior art keywords
double
sequence
seq
stranded rna
periostin
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English (en)
Japanese (ja)
Inventor
菜穂子 ベイリー小林
徹彦 吉田
エリック ネルソン ベイリー
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Toagosei Co Ltd
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Toagosei Co Ltd
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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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms

Definitions

  • the present disclosure relates to double-stranded RNA and compositions containing the double-stranded RNA, and methods of using the same. Specifically, the present disclosure relates to double-stranded RNA used to suppress or inhibit tumor cell proliferation or metastasis, and compositions comprising the double-stranded RNA.
  • This application claims priority based on Japanese Patent Application No. 2023-219517, filed on December 26, 2023, the entire contents of which are incorporated herein by reference.
  • POSTN POSTN
  • PN extracellular matrix protein
  • periostin has been suggested to be involved in vascular restenosis pathology, inflammation, angiogenesis, age-related macular degeneration, and retinal degeneration.
  • periostin Under normal conditions, periostin is expressed in various tissues, such as the periosteum, periodontal ligament, heart, and skin. It has also been reported that the expression level of periostin increases in various diseases, and that the splicing variants present in the C-terminal domain of periostin change.
  • International Publication WO2019/146621 discloses a pharmaceutical composition that targets a splicing variant of periostin.
  • nucleic acid drugs particularly the signal peptide region of periostin.
  • Nucleic acid drugs can be mass-produced by organic synthesis, and it is easy to control the uniformity of quality.
  • the main objective of the present disclosure is to provide a technique for suppressing or inhibiting cell proliferation in which periostin expression is involved.
  • the main sequence of the sense strand may be a part of the base sequence encoding the signal peptide region of periostin. This allows the double-stranded RNA to function as an siRNA (small interfering RNA) targeting periostin. In addition, since the base sequence of the signal peptide region of periostin is present upstream of mRNA, the double-stranded RNA may be able to effectively suppress periostin expression when functioning as an siRNA.
  • the antisense strand may be composed of a main sequence complementary to the sense strand and an additional sequence consisting of 2 to 4 bases added to the 5' or 3' end of the complementary main sequence.
  • the additional sequence may be added to the 3' end of the complementary base sequence.
  • the additional sequence of the antisense strand is added to the 3' end of the complementary base sequence.
  • the configuration of the additional sequence in the antisense strand may be the same as the configuration of the additional sequence of the sense strand described above.
  • the base sequence of the additional sequence of the antisense strand is the same as the additional sequence of the sense strand to which it hybridizes, but it may be a different base sequence.
  • the antisense strand is composed of a base sequence of, for example, 21 to 27 bases, and may be composed of 21 to 25 bases, or 21 to 23 bases.
  • the antisense strand is composed of a base sequence of the same length as the sense strand, and all or part of the base sequence, excluding the additional sequence, is composed of a base sequence complementary to the main sequence of the sense strand.
  • the antisense strand is composed of a base sequence of the same length as the sense strand, and all of the base sequence, excluding the additional sequence, is composed of a base sequence complementary to the main sequence of the sense strand.
  • the sense strand and antisense strand constituting the double-stranded RNA disclosed herein can be produced according to a general chemical synthesis method. For example, they can be synthesized using a commercially available DNA/RNA automatic synthesizer. In addition, the sense strand and antisense strand can be synthesized in vitro or in vivo based on genetic engineering techniques. In addition, the synthesized sense strand and antisense strand are preferably purified, and can be purified, for example, by HPLC or the like.
  • the double-stranded RNA disclosed herein can be produced, for example, by annealing (hybridizing) a sense strand and an antisense strand.
  • the annealing method may be any conventional method.
  • annealing can be performed by mixing equal amounts of a sense strand and an antisense strand in a solvent, heating at 90°C for 1 to 5 minutes, and then cooling to 4°C to room temperature.
  • a solvent include distilled water, pure water, ultrapure water, and buffers (e.g., HEPES-KOH buffer at pH 7.4, PBS, etc.).
  • buffers e.g., HEPES-KOH buffer at pH 7.4, PBS, etc.
  • composition includes the above-mentioned double-stranded RNA.
  • the composition may include various medicamentally (pharmacologically) acceptable carriers depending on the form of use.
  • a carrier generally used in medicine as a diluent, excipient, etc. is preferable.
  • a carrier varies appropriately depending on the use and form of the composition.
  • water, physiological buffer solutions, various organic solvents, etc. are included.
  • such a carrier may be an aqueous solution of alcohol (ethanol, etc.) of an appropriate concentration, glycerol, a non-drying oil such as olive oil, or a liposome.
  • secondary components that can be contained in the pharmaceutical composition include various fillers, extenders, binders, moisturizers, surfactants, dyes, fragrances, etc.
  • the composition may include carriers used in conventionally known drug delivery systems (DDS).
  • DDS drug delivery systems
  • compositions disclosed herein are not particularly limited.
  • typical forms of the composition include liquids, suspensions, emulsions, aerosols, foams, granules, powders, tablets, capsules, and ointments.
  • the composition may be freeze-dried or granulated to be dissolved in physiological saline or an appropriate buffer solution (e.g., PBS) immediately before use to prepare a medicinal solution.
  • compositions using double-stranded RNA (main component) and various carriers (secondary components) as materials may be in accordance with conventionally known methods, and such formulation methods themselves do not characterize the present disclosure, so detailed explanations are omitted.
  • main component double-stranded RNA
  • secondary components secondary components
  • the composition disclosed herein inhibits the proliferation of at least one type of cell.
  • the cells whose proliferation is inhibited are cells involved in the expression of periostin, such as tumor cells (e.g., sarcoma, neuroblastoma, retinoblastoma, embryonal tumor, etc.), fibroblasts, epithelial cells, mesothelial cells, osteoblasts, etc.
  • tumor cells e.g., sarcoma, neuroblastoma, retinoblastoma, embryonal tumor, etc.
  • fibroblasts e.g., fibroblasts, epithelial cells, mesothelial cells, osteoblasts, etc.
  • the composition disclosed herein preferably inhibits the proliferation of abnormally proliferating cells such as tumor cells.
  • the double-stranded RNA and composition disclosed herein can be preferably used as an antitumor agent (anticancer agent) that suppresses the proliferation of tumor cells.
  • composition disclosed herein includes, in addition to the double-stranded RNA described above, a peptide fragment (cell-penetrating peptide, CPP) that has cell membrane permeability and can pass through the cell membrane from outside the cell to introduce a foreign substance into the cytoplasm.
  • the peptide fragment is directly or indirectly bound (linked) to the double-stranded RNA disclosed herein to construct a construct of the peptide fragment and the double-stranded RNA.
  • double-stranded RNA has a negative charge and cannot pass through the cell membrane.
  • linker is placed between the peptide fragment and the double-stranded RNA.
  • the type of linker is not particularly limited. Typically, it is a peptidic linker, a non-peptidic linker, or the like.
  • the method of binding the peptide fragment and the double-stranded RNA is not particularly limited, and can be carried out according to various scientific methods known in the art.
  • composition disclosed herein includes a peptide fragment and the double-stranded RNA of the present disclosure.
  • the double-stranded RNA does not have to be bound to the N-terminal or C-terminal side of the peptide fragment.
  • the double-stranded RNA and the peptide fragment may form a complex, for example, by electrical or molecular interaction.
  • Such a complex is easily introduced into eukaryotic cells, and therefore the double-stranded RNA may be efficiently introduced.
  • Nucleic acids such as double-stranded RNA are typically negatively charged. Therefore, the peptide fragment used preferably has a high proportion of basic amino acids and is positively charged.
  • the proportion of the peptide fragment in this case may be 5 to 100 times that of the double-stranded RNA in molar terms, and preferably 40 to 60 times.
  • the present disclosure may provide a method for inhibiting the proliferation of at least one type of cell using the composition disclosed herein, the method comprising the steps of preparing a composition disclosed herein and delivering the composition to a cell of interest.
  • the method of administration of the composition is not particularly limited, and may be similar to the method conventionally used for the treatment of animals.
  • the composition may be used in vivo in a manner and dosage appropriate to its form and purpose.
  • a liquid formulation it can be administered in a desired amount to the affected area (e.g., malignant tumor tissue, virus-infected tissue, inflammatory tissue, etc.) of a patient or an individual animal (i.e., a living body) by intravenous, intralymphatic, intramuscular, subcutaneous, intradermal, or intraperitoneal injection.
  • a solid form such as a tablet or a gel or aqueous jelly such as an ointment can be administered directly to a specific tissue (e.g., an affected area such as a tissue or organ containing tumor cells, inflammatory cells, etc.).
  • a solid form such as a tablet can be administered orally.
  • the amount of the composition to be supplied in vivo is not particularly limited.
  • the lower limit of the amount of double-stranded RNA per kg of an animal may be 0.01 mg or more, 0.05 mg or more, or 0.1 mg or more.
  • the upper limit of the amount of double-stranded RNA per kg of an animal may be, for example, 10 mg or less, 5 mg or less, or 1 mg or less.
  • the amount of the composition to be supplied in vitro is not particularly limited.
  • the lower limit of the double-stranded RNA concentration may be, for example, 1 nM or more, 5 nM or more, or 10 nM or more.
  • the upper limit of the double-stranded RNA concentration in such a culture medium may be, for example, 10 ⁇ M or less, 5 ⁇ M or less, 2 ⁇ M or less, 1 ⁇ M or less, or 100 nM or less.
  • compositions disclosed herein can be delivered to the inside of target cells by known transfection methods. Examples include chemical gene transfer methods using cationic molecules (such as commercially available transfection reagents), physical transfer methods such as microinjection and electroporation, and biological gene transfer methods using viruses. As described above, the compositions may also be delivered to the inside of cells using peptide fragments that have cell membrane permeability.
  • the sense strand of the double-stranded RNA of Sample 1 consists of a main sequence (part of the base sequence encoding the periostin signal peptide) of SEQ ID NO: 18 and an additional sequence of TT added to the 3' end of the main sequence.
  • the sense strand of the double-stranded RNA of Samples 2 to 4 consists of a main sequence (part of the base sequence encoding the periostin signal peptide) of SEQ ID NO: 19 to 21 and an additional sequence of TT added to the 3' end of the main sequence.
  • the sense strand of the double-stranded RNA of Sample 5 consists of a main sequence (a randomly artificially prepared sequence) of SEQ ID NO: 7 and an additional sequence of TT added to the 3' end of the main sequence.
  • the antisense strand of each example consists of a sequence complementary to the main sequence and an additional sequence of TT added to the 3' end of the sequence.
  • the SK-N-SH strain which is a human neuroblastoma cell, was used as the tumor cell.
  • the SK-N-SH cells were pre-cultured in a culture medium of 10% FBS (fetal bovine serum) + E-MEM (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., Cat No. 051-07615) + 1% MEM non-essential amino acid solution (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., Cat No. 139-15651). Note that 0.5% penicillin-streptomycin (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., Cat No. 168-23191) was added to the culture medium only during pre-culture, but was not added during the following culture and evaluation.
  • the SK-N-SH cells that had adhered to the culture plate were washed with PBS, and then a 0.25% trypsin/EDTA solution was added and incubated at 37°C for 2 minutes. After the incubation, the above culture medium was added to inactivate the trypsin. Then, the cells were precipitated by centrifugation at 150 ⁇ g for 5 minutes. After removing the supernatant generated by centrifugation, the above culture medium was added to the precipitate (cell pellet) to prepare a cell suspension of approximately 5 ⁇ 10 4 cells/mL. A commercially available 96-well plate was prepared, and the cell suspension was seeded in each well at 5 ⁇ 10 3 cells/100 ⁇ L/well, and incubated overnight at 37°C under 5% CO 2 .
  • Example 1 On the second day, 3 ⁇ L of siRNA solution prepared to 2 mM with PBS was mixed with 75 ⁇ L of Opti-MEM (trademark) to prepare solution A. Also, 4.5 ⁇ L of Lipofectamine (trademark) RNAiMAX was mixed with 75 ⁇ L of Opti-MEM (trademark) to prepare solution B. Next, equal amounts of solution A and solution B were mixed to prepare solution C, which was then incubated at room temperature for 5 minutes. The prepared solution C was added to the wells in which SK-N-SH cells were cultured, so that the final concentration of double-stranded RNA was 4 ⁇ M. The mixture was then incubated at 37° C. under 5% CO 2 for 3 days.
  • Cell proliferation was evaluated using Cell Counting Kit-8 (CCK-8, Dojin Kagaku Kenkyusho).
  • CCK-8 Cell Counting Kit-8
  • siRNA siRNA
  • the 96-well plate in which SK-N-SH cells had been cultured was removed, 10 ⁇ L of CCK-8 was added to each well, and the plate was incubated at 37° C. under 5% CO 2 for 1.5 hours.
  • the absorbance of each well was measured at 450 nm.
  • the absorbance was the average value of three wells.
  • a well containing only the culture medium and CCK-8 reagent was provided as a blank. The value obtained by subtracting the absorbance of the blank from the absorbance of sample 1 was used as the measured value of sample 1.
  • Samples 2 to 4 were prepared similarly to Sample 1, except that the double-stranded RNA in Sample 1 was changed to the double-stranded RNA in Samples 2 to 4 shown in Table 1.
  • Sample 5 was prepared similarly to Sample 1, except that the double-stranded RNA in Sample 1 was changed to the double-stranded RNA in Sample 5 shown in Table 1.
  • Comparative Example The comparative example was the same as sample 1, except that a PBS solution was used instead of the RNA solution in sample 1. That is, in the comparative example, no double-stranded RNA was introduced.
  • Untreated wells were prepared in the same manner as Sample 1, except that the RNA solution and Lipofectamine (trademark) RNAiMAX were not added.
  • the cell viability in each test example is expressed as a percentage when the measured value of the untreated well is set to 100%, and is shown in Figure 2.
  • the cell viability was significantly lower in Samples 1 to 4 than in the comparative example. From the above test results, it is considered that the double-stranded RNAs of Samples 1 to 4 have the function of inhibiting the proliferation of tumor cells (human neuroblastoma cells).
  • the base sequence of SEQ ID NO: 7 is a random sequence having an ATCG content almost equivalent to that of the base sequences of SEQ ID NO: 1 to 4.
  • Double-stranded RNAs for use in samples 1 to 4 shown in Table 1 were prepared. Each of the double-stranded RNAs shown in samples 1 to 4 was dissolved in PBS so that the RNA concentration was 2 mM, to prepare an RNA solution. The RNA was then further diluted 10-fold with PBS to prepare a low-concentration RNA solution with an RNA concentration of 200 ⁇ M. A test was performed in the same manner as in the cell proliferation test of human neuroblastoma cells, except that the low-concentration RNA solution was used.
  • the final concentration of double-stranded RNA added to the wells in which SK-N-SH cells were cultured was set to 0.4 ⁇ M.
  • the cell viability in each test example was expressed as a percentage when the measured value of the untreated well was taken as 100%.
  • Figure 3 is a graph comparing the cell viability when the final concentration of added double-stranded RNA was 4.0 ⁇ M and 0.4 ⁇ M. As shown in Figure 3, the cell viability of samples 1 to 4 decreased. Furthermore, the cell viability of samples 1 to 4 was significantly lower than that of the comparative example. This shows that the double-stranded RNA of samples 1 to 4 had the function of inhibiting the proliferation of tumor cells (neuroblastoma cells) even at low concentrations. Since the double-stranded RNA of samples 1 to 4 has a sufficient tumor cell proliferation inhibition function even at low concentrations, it is possible to avoid nonspecific expression inhibition and nonspecific cell proliferation inhibition, and clinical application is expected. Among them, the double-stranded RNA of samples 3 and 4 showed particularly excellent inhibition of proliferation of human neuroblastoma cells. Furthermore, the double-stranded RNA of sample 4 had the same or higher cell inhibition function even at one-tenth the concentration.
  • double-stranded RNA was prepared for each of samples 6 to 12 shown in Table 1.
  • the double-stranded RNA shown in samples 6 to 12 was dissolved in PBS so that the RNA concentration was 2 mM, and an RNA solution was prepared.
  • the RNA was then further diluted 10-fold with PBS to prepare a low-concentration RNA solution with an RNA concentration of 200 ⁇ M.
  • the test was performed in the same manner as the cell proliferation test for human neuroblastoma cells. That is, in the test for samples 6 to 12, the final concentration of double-stranded RNA added to the wells in which SK-N-SH cells were cultured was set to 0.4 ⁇ M.
  • the cell viability in each test example was expressed as a percentage when the measured value for the untreated well was taken as 100%.
  • sterilized ultrapure water was used instead of the sample (double-stranded RNA was not introduced in the comparative example).
  • Figure 5 shows the cell viability of human neuroblastoma cells after 3 days of transfection with the double-stranded RNAs shown in samples 6 to 12.
  • the double-stranded RNAs in samples 6 to 12 had the ability to inhibit the proliferation of tumor cells (neuroblastoma cells) even at low concentrations. Therefore, non-specific inhibition of expression and non-specific inhibition of cell proliferation can be avoided, and clinical application is highly anticipated.
  • the tests using the double-stranded RNAs shown in samples 6 to 12 were carried out independently on a different day from the tests using the double-stranded RNAs shown in samples 1 to 5 above.
  • ⁇ Cell proliferation test of human breast cancer cells The same procedure was used as in the cell proliferation test of human neuroblastoma cells, except that human breast cancer cells, MDA-MB-231 strain, were used as tumor cells.
  • the cell viability in each test example is shown as a percentage when the measured value in the untreated well is taken as 100%, and is shown in Figure 4.
  • the cell viability of samples 1 to 4 was reduced, and was significantly lower than that of the comparative example. From this, it is believed that the double-stranded RNA of samples 1 to 4 has the function of inhibiting the proliferation of tumor cells (breast cancer cells).
  • Item 1 A double-stranded RNA having a first strand and a second strand complementary to the first strand, the first strand having a main sequence consisting of 19 to 23 bases, the 5'-terminal base of which is guanine (G) or cytosine (C), and an additional sequence consisting of 2 to 4 bases added to the 3'-terminal side of the main sequence, the main sequence being determined from a base sequence encoding a signal peptide region of periostin.
  • G guanine
  • C cytosine
  • Item 2 The double-stranded RNA according to Item 1, wherein the second strand has a main sequence complementary to the first strand and an additional sequence consisting of 2 to 4 bases added to the 3' end of the complementary main sequence.
  • Item 3 The double-stranded RNA according to item 1 or 2, in which at least three of the five bases on the 3'-terminal side of the main sequence are adenine (A) and/or uracil (U).
  • A adenine
  • U uracil
  • the nucleotide sequence encoding the periostin signal peptide region is the following nucleotide sequence: CCCTTTTTACCCATGTTTT (SEQ ID NO: 1); CTTTTTACCCATGTTTTCT (SEQ ID NO:2); GCTGCTTATTGTTAACCCT (SEQ ID NO:3); CTTATTGTTAACCCTATAA (SEQ ID NO: 4); CCCATGTTTTCTCTACTAT (SEQ ID NO: 18); CCATGTTTTCTCTATT (SEQ ID NO: 19); CTCTACTATTGCTGCTTAT (SEQ ID NO:20); CTATTGCTGCTTATTGTTA (SEQ ID NO:21); CTGCTTATTGTTAACCCTA (SEQ ID NO:22); CCCTATAAACGCCAACAAT (SEQ ID NO: 23); and CTATAAACGCCAACAATCA (SEQ ID NO: 24); Item 4.
  • the double-stranded RNA according to any one of Items 1 to 3, comprising:
  • Item 5 The double-stranded RNA according to any one of Items 1 to 4, wherein the base sequence constituting the additional sequence is thymine-thymine (TT).
  • TT thymine-thymine
  • Item 8 The composition according to item 5 or 6, which contains a peptide fragment having cell membrane permeability that can pass through the cell membrane from the outside of the cell and introduce a foreign substance into the cytoplasm.
  • Item 9 A method for inhibiting proliferation of at least one type of cell, comprising: A step of preparing a composition according to any one of items 6 to 8; and providing said composition to said cell in vitro or in vivo.
  • Item 10 The method according to any one of Items 7 to 9, wherein the animal species of the cells is the same as that of the periostin.

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Abstract

Est divulgué un ARN double brin ayant un premier brin et un second brin complémentaire du premier, le premier brin ayant une séquence principale comprenant 19 à 23 bases dans lesquelles la base 5'-terminale est la guanine (G) ou la cytosine (C) et une séquence supplémentaire comprenant 2 à 4 bases ajoutées au côté 3'-terminal de la séquence principale, la séquence principale étant déterminée parmi des séquences de base codant pour une région peptidique de signal de la périostine.
PCT/JP2024/045858 2023-12-26 2024-12-25 Nouvel arn double brin à base de séquence d'arn de périostine et utilisation associée Pending WO2025142999A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013147140A1 (fr) * 2012-03-29 2013-10-03 国立大学法人九州大学 Molécule d'acide nucléique apte à inhiber l'expression du gène périostine, procédé d'inhibition de l'expression du gène périostine et utilisation de ladite molécule d'acide nucléique
JP2023013932A (ja) * 2021-07-14 2023-01-26 東亞合成株式会社 ＳＡＲＳ－ＣｏＶ－２ ＲＮＡ配列に基づく新規ｓｉＲＮＡ及びその利用
US20230203490A1 (en) * 2020-05-07 2023-06-29 Eleven Therapeutics Ltd. Utilizing rna interference against sars-cov-2

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013147140A1 (fr) * 2012-03-29 2013-10-03 国立大学法人九州大学 Molécule d'acide nucléique apte à inhiber l'expression du gène périostine, procédé d'inhibition de l'expression du gène périostine et utilisation de ladite molécule d'acide nucléique
US20230203490A1 (en) * 2020-05-07 2023-06-29 Eleven Therapeutics Ltd. Utilizing rna interference against sars-cov-2
JP2023013932A (ja) * 2021-07-14 2023-01-26 東亞合成株式会社 ＳＡＲＳ－ＣｏＶ－２ ＲＮＡ配列に基づく新規ｓｉＲＮＡ及びその利用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PANDEY, ANAND KUMAR ET AL.: "An in silico analysis of effective siRNAs against COVID-19 by targeting the leader sequence of SARS-CoV-2", ADV CELL GENE THER, vol. 4, 2021, pages e107, XP055892815, DOI: 10.1002/acg2.107 *

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