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WO2024210835A1 - Méthode de traitement du psoriasis - Google Patents

Méthode de traitement du psoriasis Download PDF

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Publication number
WO2024210835A1
WO2024210835A1 PCT/SG2024/050219 SG2024050219W WO2024210835A1 WO 2024210835 A1 WO2024210835 A1 WO 2024210835A1 SG 2024050219 W SG2024050219 W SG 2024050219W WO 2024210835 A1 WO2024210835 A1 WO 2024210835A1
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mir
mirna
sequence
ezh2
mimic
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Gowtham Subramanian
Prabha SAMPATH
Shan QUAH
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Agency for Science Technology and Research Singapore
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Agency for Science Technology and Research Singapore
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • 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
    • 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
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]
    • C12N2310/141—MicroRNAs, miRNAs

Definitions

  • the present disclosure relates to the field of biotechnology.
  • the present invention refers to non-coding nucleic acids capable of modulating gene expression. More particularly, the present disclosure relates to the modulation of Enhancer of Zeste homolog 2 (EZH2) by microRNA 101 (miR-101).
  • EZH2 Enhancer of Zeste homolog 2
  • miR-101 microRNA 101
  • Psoriatic patients are treated symptomatically only with topical or intravenous steroids that are unable to provide long term relief, where patients have frequent flare-ups. There is thus an unmet need for managing psoriasis effectively.
  • the present disclosure provides a method of treating psoriasis, wherein the method comprises administering a therapeutically effective amount of a microRNA (miRNA) comprising a sequence as set forth in SEQ ID NO: 2 to a subject suffering from psoriasis.
  • miRNA microRNA
  • the miRNA comprises a sequence as set forth in SEQ ID NO: 3. In another example, the miRNA comprises a sequence as set forth in SEQ ID NO: 4. In another example, the miRNA comprises a sequence as set forth in SEQ ID NO: 5.
  • the therapeutically effective amount of miRNA is a mimic of a wild-type miR-101-3p.
  • administering decreases EZH2 expression in the subject.
  • decrease in EZH2 expression decreases psoriatic lesions in the subject suffering from psoriasis.
  • the present disclosure provides a miR-101-3p mimic, wherein the miR-101- 3p mimic does not comprise a sequence as set forth in SEQ ID NO: 5.
  • Fig. 1A is a heatmap showing miRNA microarray data from biopsies of healthy skin and lesional skin from psoriasis patients. Hierarchical clustering shows the distinct expression patterns of microRNAs in lesional skin compared to healthy skin. The heatmap shows that the number of upregulated miRNAs and the number of downregulated miRNAs in lesional skin compared to healthy skin are 42 and 26 respectively.
  • Fig. IB is a subset heatmap showing the top 10 upregulated miRNAs and top 10 downregulated miRNAs in lesional skin compared to healthy skin.
  • Fig. 1 B shows that microRNA 101 -3p (miR-101 -3p) is downregulated in lesional skin.
  • IL-17 mediated downregulation of miR-101-3p upregulates EZH2 and promotes epidermal hyperplasia.
  • Fig. 2A shows the binding site for miR-101-3p on the wild-type (WT) sequence of EZH2 3’-UTR (boxed up).
  • WT wild-type
  • EZH2 3’-UTR boxed up
  • the seed sequence of EZH2 (boxed up) was mutated to disrupt the binding site for miR-101 -3p, where miR-101-3p binds to EZH2 via the boxed up portion.
  • Fig. 2B shows that luciferase reporter constructs containing wild-type EZH2 3’-UTR had significantly reduced luciferase reporter activity. In contrast, luciferase reporter constructs containing mutant EZH2 3’-UTR where the miR-101-3p mimic binding site was mutated showed no change in reporter activity, demonstrating the binding region of miR-101-3p mimic to EZH2.
  • Fig. 2C is a confocal image showing in situ hybridization for mature miR-101 -3p and immunohistochemical staining for EZH2 in biopsies of lesional skin from psoriasis patients and healthy skin samples.
  • DAPI blue
  • Fig. 2C shows that miR-101-3p is found in decreased amounts in lesional skin compared to healthy skin.
  • EZH2 is found in high amounts in lesional skin compared to healthy skin.
  • Scale bar is 20 pm.
  • FIG. 2D is a western blot showing the differences in protein expression levels of EZH2 in total cell extracts from N/TERT-1 cells transfected with control mimic, miR-101-3p mimic, or miR-144 mimic. GAPDH was used as a loading control.
  • Fig. 2D is a representative western blot of three independent experiments. Fig. 2D shows that the protein expression level of EZH2 is lower in N/TERT-1 cells transfected with miR-101-3p mimic compared to control mimic or miR-144 mimic.
  • Fig. 2E shows the relative transcript abundance of miR-101 -3p in confluent N/TERT-1 cultures treated with IFNy’ 1L-17A/F, or TNFa for 24 h as determined by qRT-PCR.
  • Fig. 2E shows that the relative transcript abundance of miR-101-3p is lowest in N/TERT-1 cells treated with IL-17A/F compared to N/TERT-1 cells treated with control, IFN ⁇ or TNFa.
  • Fig. 2F is a western blot showing the levels of EZH2 expression in N/TERT-1 cultures treated with IFNyj IL-17A/F or TNFa.
  • Fig. 2F shows that the levels of EZH2 expression is highest in N/TERT- 1 cultures treated with IL-17A/F compared to control, IFN ⁇ . or TNFa.
  • Fig. 2G is a graphical model depicting the regulatory pathway of IL- 17.
  • miR- 101-3p causes de-repression of EZH2 which promotes epidermal differentiation and homeostasis.
  • increased IL-17 activity downregulates miR-101-3p which is necessary for de-repression of EZH2.
  • Increased amounts of EZH2 increases EZH2-mediated H3K27 trimethylation which leads to keratinocyte proliferation and epidermal hyperplasia.
  • Psoriasis is a chronic, systemic autoimmune disease. Persistent inflammation, uncontrolled keratinocyte proliferation and aberrant differentiation are the major hallmarks of psoriasis. Subjects suffering from psoriasis commonly display symptoms of lesions. Lesions can be discrete, oval erythematous papules or plaques covered with thick, silvery scales. Lesions can also be accompanied by itching and are localized on external skin, such as the knees, elbows, trunk, or scalp. While psoriasis is rarely life-threatening, the lesions resulting from psoriasis can be detrimental to a subject’s quality of life.
  • Excessive keratinocyte proliferation is a characteristic feature of psoriatic skin lesions.
  • This hyperproliferative phenotype is caused by epigenetic factors - particularly EZH2 (Enhancer of Zeste homolog 2) and EZH2 -mediated trimethylation of lysine 27 on histone H3 (H3K27me3).
  • EZH2 and H3K27me3 which are overexpressed in carcinoma are also upregulated in psoriatic lesions.
  • non-coding RNA refers to RNA molecules that are not translated into a protein but can have functional roles in transcription and translation.
  • examples of non-coding RNAs can be, but are not limited to, microRNAs (miRNAs), small interfering RNAs (siRNAs), piwi-interacting RNAs (piRNAs), transfer RNAs (tRNAs), or ribosomal RNAs (rRNAs).
  • the non-coding RNA is a miRNA.
  • miRNA refers to small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides and are involved in RNA silencing and post-transcriptional regulation of gene expression, where they can suppress translation of their target transcripts.
  • miRNA can he, but are not limited to, miR-101 , miR-199, miR-31 , miR-125b, miR-21 , or miR-203.
  • the miRNA is miR-101.
  • the miRNA is miR-101-3p.
  • keratinocyte differentiation is epigenetic ally regulated by miRNA.
  • miR-101 As described herein, analysis of differentially expressed miRNAs in lesional skin from psoriasis patients identified miR-101 to be a miRNA that was consistently downregulated in psoriatic lesions compared to healthy skin. An inverse correlation between the expression of miR-101 and EZH2 was observed in psoriatic lesional skin.
  • the disclosure provides herein a method of treating psoriasis, wherein the method comprises administering a therapeutically effective amount of a microRNA (miRNA) comprising a sequence as set forth in SEQ ID NO: 2 to a subject suffering from psoriasis.
  • a microRNA comprising a sequence as set forth in SEQ ID NO: 3.
  • the miRNA comprises a sequence as set forth in SEQ ID NO: 4.
  • the miRNA comprises a sequence as set forth in SEQ ID NO: 5.
  • a miRNA comprising a sequence as set forth in SEQ ID NO: 2 in the manufacture of a medicament for treating psoriasis.
  • the miRNA comprises a sequence as set forth in SEQ ID NO: 3.
  • the miRNA comprises a sequence as set forth in SEQ ID NO: 4.
  • the miRNA comprises a sequence as set forth in SEQ ID NO: 5.
  • a miRNA comprising a sequence as set forth in SEQ ID NO: 2 for use in treating psoriasis.
  • the miRNA comprises a sequence as set forth in SEQ ID NO: 3.
  • the miRNA comprises a sequence as set forth in SEQ ID NO: 4.
  • the miRNA comprises a sequence as set forth in SEQ ID NO: 5.
  • a miRNA comprising a sequence as set forth in SEQ ID NO: 2 for use in therapy.
  • a miRNA comprising a sequence as set forth in SEQ ID NO: 2 for use in medicine.
  • the miRNA comprises a sequence as set forth in SEQ ID NO: 3.
  • the miRNA comprises a sequence as set forth in SEQ ID NO: 4.
  • the miRNA comprises a sequence as set forth in SEQ ID NO: 5.
  • the miRNA should be capable of binding to the target protein EZH2.
  • the miRNA as used herein is a mimic of a wild-type miR-101.
  • the miR-101 mimic as used herein is a mimic of miR-101-3p.
  • the term “mimic” refers to a synthetic RNA construct which has substantially the same sequence as an endogenous RNA and performs substantially the same function.
  • the term ‘’substantially the same sequence” in the context of the miR-101 mimic as used herein refers to a mimic which has a nucleotide sequence that is similar to or identical to the wildtype miR-101.
  • the miR-101 mimic is a mimic of wild-type miR-101-3p.
  • the miR-101 mimic has one or more nucleotide differences with the sequence of wild-type miR-101-3p.
  • the sequence of the miR-101-3p mimic has no nucleotide differences with the sequence of wild-type miR-101-3p.
  • the miR-101-3p mimic is identical to the wild-type miR-101-3p.
  • the miRNA as described herein comprises a sequence as set forth in SEQ ID NO: 2, where the miRNA has 13 nucleotide differences or less compared to the sequence of wild-type miR-101-3p.
  • the miRNA as described herein comprises a sequence as set forth in SEQ ID NO: 3, where the miRNA has 9 nucleotide differences or less compared to the sequence of wild-type miR-101-3p.
  • the miRNA as described herein comprises a sequence as set forth in SEQ ID NO: 4, where the miRNA has 6 nucleotide differences or less compared to the sequence of wild-type miR-101-3p.
  • the miRNA as described herein comprises a sequence as set forth in SEQ ID NO: 5, where the miRNA has no nucleotide differences compared to the sequence of wild-type miR-101-3p.
  • the miR-101 mimic has a sequence that has substantially the same sequence as wild-type miR-101-3p.
  • the miR-101-3p mimic is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%, identical to SEQ ID NO: 1.
  • the miR-101 -3p mimic does not comprise a sequence as set forth in SEQ ID NO: 5.
  • nucleotide difference refers to a modification of a nucleotide sequence compared to a reference sequence, where examples of modification can be, but are not limited to, base substitutions, base deletions, base additions, base methylation, base acetylation, locked nucleic acids (LNAs), phosphorothioate backbone modifications, and any other modifications known to a skilled person.
  • modification can be, but are not limited to, base substitutions, base deletions, base additions, base methylation, base acetylation, locked nucleic acids (LNAs), phosphorothioate backbone modifications, and any other modifications known to a skilled person.
  • LNAs locked nucleic acids
  • the miR-101-3p mimic comprises a sequence as set forth in SEQ ID NO: 2, where the miR-101-3p mimic as described herein has 13 nucleotide differences or less compared to the sequence of wild-type miR-101 -3p.
  • the miR-101 -3p mimic as described herein comprises a sequence as set forth in SEQ ID NO: 3, where the miR-101-3p mimic has 9 nucleotide differences or less compared to the sequence of wild-type miR-101-3p.
  • the miR- 101 -3p mimic as described herein comprises a sequence as set forth in SEQ ID NO: 4, where the miR- 101-3p mimic has 6 nucleotide differences or less compared to the sequence of wild-type miR-101-3p.
  • the miR-101-3p mimic as described herein comprises a sequence as set forth in SEQ ID NO: 5, where the miR-101-3p mimic has no nucleotide differences compared to the sequence of wild-type miR-101-3p.
  • a miR-101-3p mimic can bind to EZH2, and it is also understood by a skilled person that a miR-101-3p mimic has substantially the same sequence as an endogenous wild-type miR-101-3p, where the similarity in sequence between a miR-101-3p mimic and a wild-type miR-101 -3p can be located on a binding region.
  • binding region refers to a region on a first nucleotide sequence which binds to a region on a second nucleotide sequence by complementary base pairing.
  • the binding of a first nucleotide sequence to a second nucleotide sequence at such regions are sufficient for binding of the entirety of the first nucleotide sequence to a second nucleotide sequence, even if other regions on the first and second nucleotide sequence are not complementary to each other.
  • the miR-101-3p mimic as used herein binds to EZH2 via the binding region.
  • the sequence as set forth in SEQ ID NO: 6 is the binding region of miR-101-3p.
  • the binding region is called a seed sequence.
  • the miRNA should be formulated and administered suitably.
  • the miRNA as described herein can be packaged with or within a carrier selected from a pharmaceutically acceptable excipient, a transfection agent, a liposome, a conjugate, a nanoparticle, an exosome, a saline solution, or any other suitable carrier which will be known to a skilled person.
  • a carrier selected from a pharmaceutically acceptable excipient, a transfection agent, a liposome, a conjugate, a nanoparticle, an exosome, a saline solution, or any other suitable carrier which will be known to a skilled person.
  • the miRNA formulation can further comprise preservatives, buffers, stabilizing agents, or any other suitable additive for formulating the miRNA to be suitable for topical administration.
  • suitable additives can be, but are not limited to, animal and vegetable fats, oils, waxes, paraffins, emulsifiers, emollients, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or any other suitable additive known to a skilled person for formulating a topical composition.
  • the miRNA is formulated as a cream, an ointment, a spray, a paste, a powder, a foam, a lotion, a gel, a solution, a patch, a composition, a formulation, a suspension, a solution, an emulsion, or any other forms suitable for topical administration which are known in the art.
  • the miRNA formulation can further comprise additives or diluents such as a binder, a solubilizing agent, a suspension aid, an emulsifying agent, a stabilizing agent, a pH adjusting acid, base, or buffers, or any other suitable additive or diluents for formulating the miRNA to be suitable for systemic administration.
  • the miRNA is formulated as an infusion, an injection, a composition, a formulation, a suspension, a solution, or any other forms suitable for systemic administration which are known in the art.
  • the miRNA as described herein is provided as a kit. Such kits can further comprise carriers, additives, or instructions for use of the miRNA as described herein.
  • the amount of miRNA to be administered can be calculated by a skilled person.
  • the calculation of the amount of miRNA to be administered can be performed with factors such as, but are not limited to, age, weight, severity of psoriatic lesions and disease, the mode of administration, and any other factors known by a skilled person to be important for calculating the amount of miRNA to be administered to increase the level of miRNA in a subject.
  • the amount of miRNA to be administered is between 0.1 to 1 pM/kg of body weight, 1 to 100 pm/kg of body weight, 100 pm to 1 mM/kg of body weight, 1 mM to 10 mM/kg of body weight, 10 mM to 100 mM/kg of body weight, or 100 mM to 1 M/kg of body weight.
  • the miRNA can be administered systemically.
  • systemic administration can be, but are not limited to, intravenous, intraperitoneal, intramuscular, subcutaneous, or any other mode of systemic administration known in the art.
  • administration of the miRNA as described herein results in an increase in the level of miR-101-3p in a subject, where the increase in the level of miR-101-3p is sufficient to decrease expression of EZH2 in the subject.
  • administration of the therapeutically effective amount of miRNA as described herein decreases EZH2 expression in a subject.
  • the term “decreased EZH2 expression” in the context of miR-101 -3p administration to a subject refers to a reduction in the level of EZH2 protein or mRNA in a subject compared to before the subject was administered miR-101-3p.
  • Decreased EZH2 expression can be measured by any methods known in the art, which can be, but are not limited to, qRT-PCR, western blotting, in situ hybridization, confocal imaging, luciferase assay, heat mapping, and any other methods known in the art.
  • the decrease in EZH2 expression decreases psoriatic lesions in a subject suffering from psoriasis.
  • the term “decreased psoriatic lesions” in the context of miR- 101-3p administration to a subject refers to a reduction in the severity of psoriatic lesions compared to before the subject was administered miR-101-3p.
  • Methods of ascertaining a decrease in severity are known in the art, which can be, but are not limited to, a clinical examination, a biopsy, an observation of morphology of plaque type, and any other methods known in the art, where a decrease in severity is demonstrated by, for example, a reduction in the extent of lesions on the external skin surface, a decrease in itching, and any other reduction in symptoms of psoriasis that can be easily determined by a skilled person.
  • Example 1 miR-101-3p is significantly downregulated in psoriasis
  • Example 2 IL-17 mediated downregulation of miR-101-3p upregulates EZH2 and promotes epidermal hyperplasia.
  • miR-101-3p was predicted to have a binding site in the 3’ UTR of the EZH2 transcript (Fig. 2A). 3 ’-UTR was cloned into a luciferase reporter construct and co-transfection of miR-101-3p mimics with EZH2 wild-type 3’-UTRs significantly reduced luciferase reporter activity. In contrast, when the miR-101-3p binding site was mutated, no change in reporter activity was observed, demonstrating that miR-101-3p binds to a region on EZH2 (shown boxed up in Fig.
  • IL-17 is a major regulator of miR-101-3p expression, where qRT-PCR shows a significant reduction in miR-101-3p expression in response to IL-17 treatment compared to the control, but not with TFN-y or TNF-a treatment (Fig. 2E).
  • IL-17 is an upstream regulator of miR- 101-3p
  • Total cell extracts were also collected and subjected to Western blot analysis. A significant increase in EZH2 expression in response to IL- 17 treatment was observed compared to the control (Fig. 2F).
  • IL-17 mediates modulation of miR-101-3p expression, which in turn elicits sustained expression of EZH2, that leads to enhanced keratinocyte proliferation and epidermal hyperplasia in psoriasis (Fig. 2G).
  • Table 2 Figure legend of table 1 [0063] Table 3: Patient samples

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Abstract

La présente invention concerne l'utilisation d'une quantité thérapeutiquement efficace de microARN-101-3p (miR-101-3p) pour traiter un sujet souffrant de psoriasis par l'intermédiaire de la modulation de l'expression de l'activateur de l'homologue 2 de Zeste (EZH2).
PCT/SG2024/050219 2023-04-05 2024-04-03 Méthode de traitement du psoriasis Pending WO2024210835A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008142567A2 (fr) * 2007-05-18 2008-11-27 Karolinska Institutet Innovations Ab Molécules de micro arn associées à des troubles inflammatoires de la peau
WO2017163132A2 (fr) * 2016-03-24 2017-09-28 Stemlab, Sa Utilisation d'exosomes dérivés de sang de cordon pour la réparation tissulaire
WO2021063734A1 (fr) * 2019-09-30 2021-04-08 Eberhard Karls Universitaet Tuebingen Medizinische Fakultaet Inhibiteurs de cdk4/6 pour le traitement du psoriasis
WO2021063737A1 (fr) * 2019-09-30 2021-04-08 Eberhard Karls Universitaet Tuebingen Medizinische Fakultaet Agent pour le traitement du psoriasis

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008142567A2 (fr) * 2007-05-18 2008-11-27 Karolinska Institutet Innovations Ab Molécules de micro arn associées à des troubles inflammatoires de la peau
WO2017163132A2 (fr) * 2016-03-24 2017-09-28 Stemlab, Sa Utilisation d'exosomes dérivés de sang de cordon pour la réparation tissulaire
WO2021063734A1 (fr) * 2019-09-30 2021-04-08 Eberhard Karls Universitaet Tuebingen Medizinische Fakultaet Inhibiteurs de cdk4/6 pour le traitement du psoriasis
WO2021063737A1 (fr) * 2019-09-30 2021-04-08 Eberhard Karls Universitaet Tuebingen Medizinische Fakultaet Agent pour le traitement du psoriasis

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
JIN QIFANG, HE WENFENG, CHEN LEIFENG, YANG YANG, SHI KE, YOU ZHIPENG: "MicroRNA‑101‑3p inhibits proliferation in retinoblastoma cells by targeting EZH2 and HDAC9", EXPERIMENTAL AND THERAPEUTIC MEDICINE, SPANDIDOS PUBLICATIONS, GR, GR , pages 1663 - 1670, XP093225069, ISSN: 1792-0981, DOI: 10.3892/etm.2018.6405 *
LI BO, XIE DALONG, ZHANG HUI: "MicroRNA-101-3p advances cisplatin sensitivity in bladder urothelial carcinoma through targeted silencing EZH2", JOURNAL OF CANCER, IVYSPRING INTERNATIONAL PUBLISHER, AU, vol. 10, no. 12, 1 January 2019 (2019-01-01), AU , pages 2628 - 2634, XP093225064, ISSN: 1837-9664, DOI: 10.7150/jca.33117 *
WANG HONGRUI, MENG YAKE, CUI QUANJUN, QIN FUJUN, YANG HAISONG, CHEN YU, CHENG YAJUN, SHI JIANGANG, GUO YONGFEI: "MiR-101 Targets the EZH2/Wnt/β-Catenin the Pathway to Promote the Osteogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells", SCIENTIFIC REPORTS, NATURE PUBLISHING GROUP, US, vol. 6, no. 1, US , XP093225090, ISSN: 2045-2322, DOI: 10.1038/srep36988 *

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