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WO2016166600A1 - Administration de micro-arn à l'aide de microparticules de cellules souches mésenchymateuses - Google Patents

Administration de micro-arn à l'aide de microparticules de cellules souches mésenchymateuses Download PDF

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WO2016166600A1
WO2016166600A1 PCT/IB2016/000563 IB2016000563W WO2016166600A1 WO 2016166600 A1 WO2016166600 A1 WO 2016166600A1 IB 2016000563 W IB2016000563 W IB 2016000563W WO 2016166600 A1 WO2016166600 A1 WO 2016166600A1
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mir
cancer
bcl2
microrna
microparticle
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Agamemnon Epenetos
Marianna PROKOPI
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TROJANTEC TECHNOLOGIES Ltd
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TROJANTEC TECHNOLOGIES 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
    • C12N15/111—General methods applicable to biologically active non-coding nucleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6901—Conjugates being cells, cell fragments, viruses, ghosts, red blood cells or viral vectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5063—Compounds of unknown constitution, e.g. material from plants or animals
    • A61K9/5068—Cell membranes or bacterial membranes enclosing drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • C12N2330/00—Production
    • C12N2330/10—Production naturally occurring

Definitions

  • the present invention relates generally to the treatment of cancer and more specifically to the use of microparticles containing microRNA for the treatment of cancer.
  • Non-coding RNA is an RNA molecule that is not translated into a protein. Less-frequently used synonyms are non-protein-coding RNA (npcRNA), non- messenger RNA (nmRNA), functional RNA (fRNA) or simply RNA. The DNA sequence from which a functional non-coding RNA is transcribed is often called an RNA gene.
  • Non- coding RNA genes include highly abundant and functionally important RNAs such as transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), as well as RNAs such as snoRNAs, microRNAs, siRNAs, snRNAs, exRNAs, piRNAs and scaRNAs and the long ncRNAs that include examples such as Xist and HOTAIR.
  • tRNAs transfer RNAs
  • rRNAs ribosomal RNAs
  • RNAs such as snoRNAs, microRNAs, siRNAs, snRNAs, exRNAs, piRNAs and scaRNAs and the long ncRNAs that include examples such as Xist and HOTAIR.
  • tRNAs transfer RNAs
  • rRNAs ribosomal RNAs
  • RNAs such as snoRNAs, microRNAs, siRNAs, snRNAs, exRNAs, piRNAs and scaRNAs
  • ncRNAs are non functional, and are the product of spurious transcription.
  • Non-coding RNA have roles in several biological functions RNA splicing, DNA replication, gene regulation, genome defense, chromosome structure and also have a role in several diseases and disorders such as cancer, Autism, Alzheimer's disease and hearing loss.
  • Cancer is one of the leading diseases the human population is facing. Many types of cancer are still impossible to be cured with conventional therapies/drugs. This poor outcome of cancer therapy relates in part to insufficient drug or gene delivery to tumor sites; therefore, there is an urgent need to propose novel strategies for tumor targeting.
  • MicroRNAs miRNA
  • miRNA therapeutics The rationale for developing miRNA therapeutics is based on the premise that aberrantly expressed miRNAs play key roles in the development of human disease and that correcting these miRNA deficiencies by either antagonizing of restoring miRNA function may provide a therapeutic benefit.
  • This new class of gene regulators is transcribed from the genome and binds primarily in the '3 untranslated region of mRNA; targets negatively regulating protein production by inducing mRNA cleavage, increasing mRNA decay or repressing mRNA translation.
  • miRNAs play critical roles in the development and progression of several types of cancers. Indeed, several miRNAs are reported to act as tumor suppressors or oncogenes. Examples of miRNAs with oncogenic activity are miR-155 and miR-17-92; in contrast, miR-15a, miR-16 and miR-34 and let-7 families are tumor suppressor miRNAs. In all cases, gain or loss of a particular miRNA results in altered expression of an mRNA that is critical for cell maintenance, proliferation, apoptosis or differentiation. It has been shown that there is a relationship between a miRNA cluster, mir- 17-92, and the Myc oncogenic pathway.
  • let-7 miRNA has added an entirely new dimension to antitumor therapeutic approaches.
  • the invention provides for the delivery of stable miRNAs/miRNA inhibitors into cells as a therapeutic regimen.
  • the present invention is based on methods for treating cancer by administering a microparticle containing microRNA to a patient.
  • the present invention also provides methods for downregulating a cancer associated protein by contacting a tumor cell with a microparticle containing microRNA.
  • the present invention also provides kits comprising microparticles for use in the methods of the invention.
  • the present invention provides a method of treating cancer comprising administering a Wharton' s Jelly cell derived microparticle to a patient in need thereof, thereby treating the cancer.
  • the microparticle targets cancer cells.
  • the microparticle comprises exogenous microRNA.
  • the microRNA is miR-34, miR-192, miR-145, miR-143, miR-16-l require miR125b, miR-30, miR-128, miR-504, miR380, miR-33, miR-25, miR-449, miR-215, miR605, miR-29, miR-17-92, miR-21, let-7, miR-15/16, miR-200 or miR-34.
  • the administration of the microparticle downregulates a cancer associated protein.
  • the cancer associated protein is E2F 1, HBP 1, CDKN1A, NCOA3, ERa, PTEN, MECP2, HOXA5, VPS4B, MYCN, RAB 14, DPYSL2, TGFBR2, TSGl Ol, ARHGAP12, BACEl, PDCD4, PTEN, RECK, PPARa, TIMP3, FasL, TGFBR2, SERINB5, CDK2AP1 , TPM1, CDKN1B, KIT, PPP2R2A, p27kipl, CDKNIC, ERa, KIT, DDIT4, BNIP3L, ZEB2, TBKl, CREBZF, MYBLl, DKK2, NIRF, NF2, CASP3, TRIM71 , BACEl, DMTF l , C22orf5, BCL2, ARL2, CCNT2, TPPP3, VEGFA, R
  • the cancer is breast cancer, lung cancer, colorectal cancer, pancreatic cancer, head and neck cancer, brain cancer, melanoma, skin cancer, prostate cancer, thyroid cancer, kidney cancer or bladder cancer.
  • the method further comprises administering a chemotherapeutic agent or radiation.
  • the present invention provides for a method of downregulating a cancer associated protein comprising identifying the cancer associated protein in a tumor sample; generating a Wharton' s Jelly cell derived microparticle comprising microRNA; and contacting the tumor with the microparticle, thereby downregulating the cancer associated protein.
  • the cancer associated protein is E2F 1, HBP 1, CDKN1A, NCOA3, ERa, PTEN, MECP2, HOXA5, VPS4B, MYCN, RAB 14, DPYSL2, TGFBR2, TSGlOl , ARHGAP12, BACEl , PDCD4, PTEN, RECK, PPARa, TIMP3, FasL, TGFBR2, SERINB5, CDK2AP1, TPM1 , CDKN1B, KIT, PPP2R2A, p27kip l, CDKNIC, ERa, KIT, DDIT4, BNIP3L, ZEB2, TBKl, CREBZF, MYBLl, DKK2, NIRF, NF2, CASP3, TRIM71, BACEl, DMTF l, C22orf5, BCL2, ARL2, CCNT2, TPPP3, VEGFA, RARS, FGF2, ZNF622, DNAJB4, PURA, SHOC2,
  • the microparticle is transfected with exogenous microRNA.
  • the microRNA is miR-34, miR-192, miR-145, miR-143, miR- 16-1,, miR125b, miR-30, miR-128, miR-504, miR380, miR-33, miR-25, miR-449, miR-215, miR605, miR-29, miR-17-92, miR-21, let-7, miR-15/16, miR-200 or miR-34.
  • the cancer is breast cancer, lung cancer, colorectal cancer, pancreatic cancer, head and neck cancer, brain cancer, melanoma, skin cancer, prostate cancer, thyroid cancer, kidney cancer or bladder cancer.
  • the present invention provides a composition comprising a Wharton' s Jelly cell derived microparticle and exogenous microRNA.
  • the exogenous microRNA downregulates a cancer associated protein.
  • the microRNA is miR-34, miR-192, miR-145, miR-143, miR- 16-1,, miR125b, miR-30, miR-128, miR-504, miR380, miR-33, miR-25, miR-449, miR- 215, miR605, miR-29, miR-17-92, miR-21 , let-7, miR-15/16, miR-200 or miR-34.
  • the present invention provides a kit for the downregulation of a cancer associated protein comprising a Wharton's Jelly cell derived microparticle and instructions for use.
  • the microparticle is transfected with exogenous microRNA.
  • the microRNA is miR-34, miR-192, miR-145, miR-143, miR-16-l cramp miR125b, miR-30, miR-128, miR-504, miR380, miR- 33, miR-25, miR-449, miR-215, miR605, miR-29, miR-17-92, miR-21 , let-7, miR- 15/16, miR-200 or miR-34.
  • the cancer associated protein is E2F 1, HBP1, CDKN1A, NCOA3, ERa, PTEN, MECP2, HOXA5, VPS4B, MYCN, RAB 14, DPYSL2, TGFBR2, TSG101, ARHGAP 12, BACE1, PDCD4, PTEN, RECK, PPARa, TIMP3, FasL, TGFBR2, SERINB5, CDK2AP1, TPM1, CDKN1B, KIT, PPP2R2A, p27kip l, CDKN1C, ERa, KIT, DDIT4, BNIP3L, ZEB2, TBK1 , CREBZF, MYBL1 , DKK2, NIRF, NF2, CASP3, TRIM71 , BACE1, DMTF 1, C22orf5, BCL2, ARL2, CCNT2, TPPP3, VEGFA, RARS, FGF2, ZNF622, DNAJB4, PURA, SHOC2, LUZP1
  • Figures 1A-C show the activation and functions of the p53 tumor suppressor and their cellular effects.
  • Figure 1A Key proteins participating in the activation and posttranscriptional control of p53 in response to cellular stress are shown.
  • Figure IB Functions of p53 dependent on its role as a transcription factor are summarized here. Representative examples of p53 activated proteins and miRNAs are shown, as are a selection of targets for each miRNA.
  • Figure 1C Transcription-independent functions of p53 relying on its participation in protein-protein interactions. Examples of miRNAs upregulated post-transcriptionally by p53 and a selection of their target genes are shown. Examples of apoptotic regulators bound by p53 are shown.
  • Figure 2 shows the regulation of p53. Left: miRNAs directly repressing p53 through binding to sites in the p53 3'UTR. Right: Examples of miRNAs positively regulating p53 through repression of a selection of other targets that antagonize p53 function. Block arrows indicate repression. Feedback loops where p53 is also capable of increasing the miRNA levels are indicated with arced arrows.
  • Figures 3A-C show the processing of the umbilical cord to isolate Wharton' s Jelly cells.
  • Figure 3A shows an umbilical cord.
  • Figure 3B shows a partially processed umbilical cord.
  • Figure 3C shows that veins and arteries are removed prior to further processing.
  • Figures 4A-C show the isolation of MSCs from WJCs.
  • Figure 4A shows the enzymatic digestion of WJCs.
  • Figures 4B-C show isolated MSCs.
  • Figures 5A-B show the formation of microparticles (MPs) from the MSCs.
  • Figure 5A show the formation of MPs on the MSCs.
  • Figure 5B shows the release of a MP from the MSC.
  • Figures 6A-B are magnified views of isolated MPs.
  • Figure 6A shows 16,000X magnification and
  • Figure 6B shows 30,000x magnification.
  • the arrows point to MPs of various sizes.
  • Figures 7A-C show the selective targeting of MPs to cancer cells and the transfer of genetic material to the cancer cell.
  • Figure 7A shows the MP uptake at the cancer cell.
  • Figure 7B shows MPs on the surface of the cancer cell.
  • Figure 7C shows miRNA uptake from the MP to the cancer cell.
  • Figures 8A-B show the biodistribution and homing kinetics of MPs in an orthotopic cancer model.
  • Figure 8A shows flow cytometric analysis of the distribution of DiD labelled MPs in mice.
  • Figure 8B shows clusters of WJC derived MPs.
  • Figures 9A-C show the reduction of tumor burden following administration of MPs.
  • Figure 9A shows day 0 following administration.
  • Figure 9B shows day 10 following administration.
  • Figure 9C shows day 15 following administration.
  • the present invention is based on methods for treating cancer by administering a microparticle containing microRNA to a patient.
  • the present invention also provides methods for downregulating a cancer associated protein by contacting a tumor cell with a microparticle containing microRNA.
  • the present invention also provides kits comprising microparticles for use in the methods of the invention.
  • Cancer is a malignant and invasive growth or tumor, especially one originating in epithelium, tending to recur after excision and to metastasize to other sites or any disease characterized by such growths.
  • Exemplary cancers described by the national cancer institute include: Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS-Related Lymphoma; AIDS-Related Malignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood; Bone Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor, Cerebral Astrocytoma/Malignant Glioma, Childhood; Brain Tumor, Ependy
  • cancer associated protein refers to any protein associated with the development or furtherance of cancer or any protein that is upregulated or downregulated in cancer.
  • cancer related proteins include, but are not limited to, E2F 1, HBP l, CDKNIA, NCOA3, ERa, PTEN, MECP2, HOXA5, VPS4B, MYCN, RAB 14, DPYSL2, TGFBR2, TSG101, ARHGAP12, BACE1, PDCD4, PTEN, RECK, PPARa, TIMP3, FasL, TGFBR2, SERINB5, CDK2AP1, TPM1, CDKN1B, KIT, PPP2R2A, p27kip l, CDKN1 C, ERa, KIT, DDIT4, BNIP3L, ZEB2, TBK1, CREBZF, MYBL1 , DKK2, NIRF, NF2, CASP3, TRIM71, BACE1, DMTF 1, C22orf
  • treatment refers to any method of preventing, treating, or ameliorating the damage caused by cancer.
  • Typical treatment for cancer includes the administration of ch em other apeutic agents, radiation and surgery.
  • Exemplary ch em other apeutic agents described by the national cancer institute include: Abiraterone Acetate, Abitrexate (Methotrexate), Abraxane (Paclitaxel Albumin), ABVD, ABVE, ABVE-PC, AC, AC-T, Adcetris (Brentuximab Vedotin), ADE, Ado-Trastuzumab Emtansine, Adriamycin (Doxorubicin Hydrochloride), Afatinib Dimaleate, Afinitor (Everolimus), Akynzeo (Netupitant and Palonosetron Hydrochloride), Aldara (Imiquimod), Aldesleukin, Alecensa (Alectinib), Alectinib, Alemtuzumab, Alkeran for Injection (Melphalan Hydrochloride), Alkeran Tablets(Melphalan), Alimta (Pemetrexed Disodium), Aloxi
  • the term “Pharmaceutically acceptable carrier” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subj ect, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • Non-coding RNA is an RNA molecule that is not translated into a protein. Less-frequently used synonyms are non-protein-coding RNA (npcRNA), non- messenger RNA (nmRNA), functional RNA (fRNA) or simply RNA. The DNA sequence from which a functional non-coding RNA is transcribed is often called an RNA gene.
  • Non-coding RNA genes include highly abundant and functionally important RNAs such as transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), as well as RNAs such as snoRNAs, microRNAs, siRNAs, snRNAs, exRNAs, piRNAs and scaRNAs and the long ncRNAs that include examples such as Xist and HOTAIR.
  • tRNAs transfer RNAs
  • rRNAs ribosomal RNAs
  • RNAs such as snoRNAs, microRNAs, siRNAs, snRNAs, exRNAs, piRNAs and scaRNAs and the long ncRNAs that include examples such as Xist and HOTAIR.
  • the number of ncRNAs encoded within the human genome is unknown; however, recent transcriptomic and bioinformatic studies suggest the existence of thousands of ncRNAs. Since many of the newly identified ncRNAs have not been validated for their function, it is possible
  • Non-coding RNA have roles in several biological functions RNA splicing, DNA replication, gene regulation, genome defense, chromosome structure and also have a role in several diseases and disorders such as cancer, Autism, Alzheimer's disease and hearing loss.
  • Many ncRNAs show abnormal expression patterns in cancerous tissues. These include miRNAs, long mRNA-like ncRNAs, GAS 5, SNORD50, telomerase RNA and Y RNAs.
  • the miRNAs are involved in the large scale regulation of many protein coding genes, the Y RNAs are important for the initiation of DNA replication, telomerase RNA that serves as a primer for telomerase, an RNP that extends telomeric regions at chromosome ends .
  • the direct function of the long mRNA-like ncRNAs is less clear.
  • MicroRNAs are a class of non-coding RNA gene whose products are ⁇ 22 nt sequences that play important roles in the regulation of translation and degradation of mRNAs through base pairing to partially complementary sites in the untranslated regions (UTRs) of the message. Since the discovery of the founding members of the class, let-7 and lin-4 miRNAs in Caenorhabditis elegans, more than 300 miRNAs have been found in animals and plants. In animals, the expression of miRNAs has been shown to involve at least two processing steps. miRNAs are transcribed as long primary transcipts (pri -miRNAs), which may contain more than one miRNA.
  • pri -miRNAs long primary transcipts
  • the primary transcript is processed in the nucleus to give one or more hairpin precursor sequences (pre-miRNAs).
  • This processing step defines one end of the mature miRNA sequence, which is contained in one arm of the hairpin precursor.
  • the hairpin precursor is exported to the cytoplasm where the mature miRNA is excised by the RNase Ill-like enzyme Dicer, suggesting a relationship with RNA interference (RNAi).
  • RNAi RNA interference
  • miRNA expression seems to be altered in many human diseases, including cancer (Table 1). Tissue-specific/tissue-enriched miRNAs are often downregulated and play a role in cancer. For example, brain-specific neuromiR-124 is downregulated in glioblastomas and myomiR-1/206 are downregulated in RMS.
  • Lung-specific pneumomiR-29 suppresses tumorigenicity in non-small cell lung cancer cells.
  • Let-7 which is normally expressed at higher levels in normal lung, is downregulated in lung cancer and associated with poor survival.
  • miR-143 and miR-145 have been shown to be downregulated in breast, cervical, and colorectal.
  • Inhibiting miRNA biogenesis tends to enhance tumorigenesis. Downregulation may be achieved through mutation or by epigenetic silencing of the miRNA, resulting in loss of tissue-specific miRNA synthesis and overexpression of pro- proliferation genes (i.e., oncogenes); these miRNAs normally function as tumor suppressors. Of course, miRNAs can also act as oncogenes. It was demonstrated that expression of specific miRNAs regulating skeletal muscle development, miR-l/miR-206 (also known as myomiRs), is reduced in rhabdomyosarcoma (RMS).
  • miR-l/miR-206 also known as myomiRs
  • RMS tumors the most common soft tissue sarcomas in pediatric patients and young adults, are thought to arise from the skeletal muscle lineage, coexpressing markers of proliferation and myogenic differentiation. Reexpression of these myomiRs to physiological levels suppressed many aspects of the transformed phenotype and induced myogenic differentiation, raising the possibility that miRNA reexpression may represent effective differentiation therapy for RMS and perhaps other cancer types.
  • oncogenes and tumor suppressors targets of drugs currently used in the clinic.
  • miRNAs are overexpressed in cancer and seem to function as oncogenes themselves, a greater number of miRNAs have been shown to be downregulated in cancer and have the potential to act as tumor suppressors (i.e., Let-7, miR-15/miR-16, miR-l/miR-206, miR-29, miR-124, miR-143/miR-145; see Table 1).
  • miRNA reexpression and downregulation have both been shown to have antitumor effects.
  • Silencing an oncogenic miRNA could allow reexpression of tumor suppressor genes, while reexpressing a tumor suppressor miRNA could downregulate multiple oncogenes. Reexpression, to physiological levels, of tissue-specific miRNAs that are lost in cancer can induce the dedifferentiation of cancer cells.
  • miRNAs are easy to synthesize and can potentially target any gene, including otherwise non-druggable targets.
  • miRNA therapy has many advantages over the originally envisioned RNA interference-based therapeutics (siRNA therapy).
  • the major advantage of miRNA therapy is that miRNA reexpression can influence the expression of hundreds of genes involved in many cellular pathways. While siRNA therapy is more gene-specific, miRNA therapy can target an array of different gene products, more closely resembling the action of the so-called "dirty drugs" used in the clinic today; in fact, both the sense and antisense strands of miRNAs might target different mRNAs.
  • miRNAs are evolutionarily conserved, and targeting the upregulation or downregulation of a tissue-specific tumor suppressor miRNA or oncogenic miRNA, respectively, to its "physiological level" may incite fewer of the nonspecific, off-target effects often associated with artificial siRNAs or currently available dirty drugs.
  • miRNA therapy shares many of the disadvantages of siRNA- therapy, including delivery limitations, instability, and off target effects.
  • a major obstacle to effective miRNA-based therapy is the requirement for successful delivery. Unlike many other drugs, miRNAs do not freely diffuse into cells; therefore, miRNAs may require special delivery approaches to achieve the desired effect.
  • RNAs tend to be unstable and might be degraded upon entering a cell; new methods may be required to stabilize these small sequences.
  • Another factor is that double- stranded RNA and unmethylated CpG sequences are potentially immunogenic; their presence might increase IFN production and induce an immune response in patients.
  • miRNA reexpression therapy of cancer preventing miRNA expression from exceeding physiological levels also represents a therapeutic challenge.
  • microparticles can be used for in vivo delivery of miRNAs and tumor targeting.
  • Microparticles were first described as 'platelet dust' if was discovered that of eukaryotic cells have the ability to shed components off their plasma membrane into the extracellular space.
  • MPs usually refer to intact vesicles formed from the plasma membrane, have heterogeneous density and size (0.1-1.0 ⁇ ) and can be easily separated from apoptotic bodies, exosomes and matrix vesicles by differential centrifugation.
  • MPs originate from many cell types, including endothelial cells, platelets, monocytes, erythrocytes, smooth muscle cells and mesenchymal stem cells.
  • MPs in the blood with circulating MPs in plasma predominantly derived from platelets.
  • modifications of the plasma membrane such as phosphatidylserine externalization, and an increase in bleb formation take place.
  • MPs and more specifically platelet MPs are present in circulating blood contributing to vascular repair, remodeling, and atherosclerotic lesion formation.
  • the intercellular transport of proteins by extracellular secretory membrane bodies has important implications: First, if surface proteins can be transferred, marker positivity could, at least in part, reflect the exposure to tissue- specific set of MPs rather than cellular progeny. Second, the release of vesicles by injured tissue may be a means of disposal of membrane microdomains that endow mononuclear cells with properties required for tissue repair. Because the formation of MPs is accompanied by selective enrichment of specific subsets of the proteome, the characterization of their protein content is pivotal to the understanding of their function. Besides proteins, MPs also contain non-coding regulatory RNA, known as microRNA (miRNA), which act as translational repressors. It has been estimated that the human genome encodes up to 1000 miRNAs, predicted to regulate a third of all genes.
  • miRNA non-coding regulatory RNA
  • microparticles derived from mesenchymal cells of umbilical cord origin (Wharton's Jelly) is described below in the Examples.
  • the membranes consist mainly of lipids such as phosphatidylserine and several proteins.
  • Specific MPs have been designed to retain their chemokine profile allowing them to home into tumor cells in vitro and in vivo and have also been designed to contain specific upregulated microRNA sequences with therapeutic potential directed against human and animal ailments.
  • MSCs Mesenchymal stem cells
  • the rationale for using MSCs for delivering therapeutic agents to tumors is based on the concept that MSCs have the ability to home from the bone marrow to sites of injured tissues. As the microenvironment of solid tumors is relative similar to that of injured sites, exogenous given MSCs may migrate and engraft with ease to tumor sites.
  • MSCs are non-hematopoietic stem cells that have an inherent ability both to self renew and to differentiate into multiple lineages including osteoclasts, chondrocytes and adipocytes.
  • the cells are readily isolated from the stromal compartment of bone marrow, along with a number of other sources including adipose tissue, skeletal muscle, fetal blood, umbilical cord blood and even liposuction material.
  • fetal MSCs appear to have greater expansion capacity in vitro and faster doubling time than adult MSCs, which may be due to their longer telomeres.
  • fetal MSCs have been isolated from umbilical cord blood, umbilical vein subendothelium and the Wharton's j elly.
  • WJCs Wharton's j elly cells
  • WJCs can be isolated from close to 100% of the samples, even from umbilical cords that are delayed in their processing up to 48 hours. Furthermore, this source of stem cells allows the rapid initial isolation of large numbers of cells, avoiding the necessity of extensive multiplication and potential epigenetic damage and maybe better tolerated following transplantation with less incidence of graft versus host disease.
  • WJCs are CD45, CD34,CD14, CD33, CD56, CD3 1 and HLA class II negative; CD73, CD90, CD 105 and HLA class I positive, plastic adherent and multipotent. Additionally, WJCs express GD2 synthase, a marker that has been proposed to uniquely identify MSCs in a bone marrow aspirate. Most importantly, WJCs are karyotypically stable over many passages and so not lose anchorage dependence, contact inhibition or serum dependence as cancer cells. Moreover, when large numbers of WJCs were transplanted into SCID mice there was no evidence of tumor formation..
  • WJCs enriched in specific miRNAs could be activated in order to release miRNA-rich MPs.
  • these WJC-derived MPs could target and fuse with tumor cells, in order to deliver miRNAs and down regulate specific targeted genes.
  • Preliminary data has suggested that when PMPs are in close proximity with other cell types e.g. monocytes could transfer or induce miRNA changes in the receptor cell.
  • MPs can be done through serum deprivation, apoptosis or activation of WJCs. The expression levels of specific miRNAs are then identified in the WJC-derived MPs. If low levels of the miRNA of interest are present then a transfection step of overexpression of miRNAs in WJCs is performed. Also described below in the Examples are in vitro experiments demonstrating the ability of WJC-derived MPs to fuse and transfer the miRNAs to cancer cells/tumors. Further, the Examples provide evidence of the downregulation of specific targets. The Examples additionally demonstrate the in vivo delivery of the WJCs-derived MPs.
  • the present invention provides a method of treating cancer comprising administering a Wharton' s Jelly cell derived microparticle to a patient in need thereof, thereby treating the cancer.
  • the microparticle targets cancer cells.
  • the microparticle comprises exogenous microRNA.
  • the microRNA is miR-34, miR-192, miR-145, miR-143, miR-16-1 , miR125b, miR-30, miR-128, miR-504, miR380, miR-33, miR-25, miR-449, miR-215, miR605, miR-29, miR-17-92, miR-21, let-7, miR-15/16, miR-200 or miR-34.
  • the administration of the microparticle downregulates a cancer associated protein.
  • the cancer associated protein is E2F 1, HBP 1, CDKN1A, NCOA3, ERa, PTEN, MECP2, HOXA5, VPS4B, MYCN, RAB 14, DPYSL2, TGFBR2, TSG101, ARHGAP12, BACE1, PDCD4, PTEN, RECK, PPARa, TIMP3, FasL, TGFBR2, SERINB5, CDK2AP1 , TPM1, CDKN1B, KIT, PPP2R2A, p27kipl, CDKN1C, ERa, KIT, DDIT4, BNIP3L, ZEB2, TBKl, CREBZF, MYBLl, DKK2, NIRF, NF2, CASP3, TRIM71 , BACE1, DMTF 1 , C22orf5, BCL2, ARL2, CCNT2, TPPP3, VEGFA, RARS,
  • the cancer is breast cancer, lung cancer, colorectal cancer, pancreatic cancer, head and neck cancer, brain cancer, melanoma, skin cancer, prostate cancer, thyroid cancer, kidney cancer or bladder cancer.
  • the method further comprises administering a chemotherapeutic agent or radiation.
  • the present invention provides for a method of downregulating a cancer associated protein comprising identifying the cancer associated protein in a tumor sample; generating a Wharton' s Jelly cell derived microparticle comprising microRNA; and contacting the tumor with the microparticle, thereby downregulating the cancer associated protein.
  • the cancer associated protein is E2F 1, HBP 1, CDKN1A, NCOA3, ERa, PTEN, MECP2, HOXA5, VPS4B, MYCN, RAB 14, DPYSL2, TGFBR2, TSGlOl , ARHGAP12, BACEl , PDCD4, PTEN, RECK, PPARa, TIMP3, FasL, TGFBR2, SERINB5, CDK2AP1, TPM1 , CDKN1B, KIT, PPP2R2A, p27kip l, CDKN1C, ERa, KIT, DDIT4, BNIP3L, ZEB2, TBK1, CREBZF, MYBL1, DKK2, NIRF, NF2, CASP3, TRIM71, BACEl, DMTF 1, C22orf5, BCL2, ARL2, CCNT2, TPPP3, VEGFA, RARS, FGF2, ZNF622, DNAJB4, PURA, SHOC2, LU
  • the microparticle is transfected with exogenous microRNA.
  • the microRNA is miR-34, miR-192, miR-145, miR-143, miR-16-l cramp miR125b, miR-30, miR-128, miR-504, miR380, miR-33, miR-25, miR-449, miR-215, miR605, miR-29, miR-17-92, miR-21 , let-7, miR-15/16, miR-200 or miR-34.
  • the cancer is breast cancer, lung cancer, colorectal cancer, pancreatic cancer, head and neck cancer, brain cancer, melanoma, skin cancer, prostate cancer, thyroid cancer, kidney cancer or bladder cancer.
  • the present invention provides a composition comprising a Wharton' s Jelly cell derived microparticle and exogenous microRNA.
  • the exogenous microRNA downregulates a cancer associated protein.
  • the microRNA is miR-34, miR-192, miR-145, miR-143, miR- 16-1,, miR125b, miR-30, miR-128, miR-504, miR380, miR-33, miR-25, miR-449, miR- 215, miR605, miR-29, miR-17-92, miR-21 , let-7, miR-15/16, miR-200 or miR-34.
  • the present invention provides a kit for the downregulation of a cancer associated protein comprising a Wharton's Jelly cell derived microparticle and instructions for use.
  • the microparticle is transfected with exogenous microRNA.
  • the cancer associated protein is E2F 1, HBP1, CDKN1A, NCOA3, ERa, PTEN, MECP2, HOXA5, VPS4B, MYCN, RAB 14, DPYSL2, TGFBR2, TSG101, ARHGAP 12, BACEl, PDCD4, PTEN, RECK, PPARa, TIMP3, FasL, TGFBR2, SERINB5, CDK2AP1, TPM1, CDKN1B, KIT, PPP2R2A, p27kip l, CDKN1C, ERa, KIT, DDIT4, BNIP3L, ZEB2, TBK1 , CREBZF, MYBL1 , DKK2, NIRF, NF2, CASP3, TRIM71 , BACEl, DMTF l, C22orf5, BCL2, ARL2, CCNT2, TPPP3, VEGFA, RARS, FGF2, ZNF622, DNAJB4, PURA, SHOC2, LU
  • MSCs were isolated from the Wharton' s j elly of human umbilical cords.
  • the MSC cultures were subj ected to serum deprivation, leading to the formation of MPs (secreted membrane vehicles ⁇ 1 ⁇ ) which were harvested and characterized ( Figures 3A-C).
  • MPs secreted membrane vehicles ⁇ 1 ⁇
  • the veins and arteries are removed from the umbilical cord before enzymatic digestion and MSC isolation.
  • WJCs were subjected to a mixed enzymatic digestion using Collagenase, Hyaluronidase and Trypsin) ( Figures 4A-C).
  • the MSC cultures were subj ected to serum deprivation for 2 days leading to the generation of MPs which were secreted as intact membrane vesicles ( ⁇ 1 ⁇ ) ( Figures 5A-B).
  • the MSC derived MPs were harvested and characterized by SEM, PCR, FACS, Fluorescence Microscopy & miRNA profiling.
  • the generated MPs are of various sizes from approximately 0.1-1 ⁇ in diameter ( Figure 6).
  • MPs incorporate into cancer cells, transfer proteomic and genetic material into the cancer cells and reduced tumor cell proliferation.
  • Different cell lines (breast, colon & ovarian adenocarcinoma) were exposed to MPs and the response to treatment was evaluated by cell morphology, proliferation, migration, gene expression and apoptosis assays. It was shown that MP preferentially migrate to the tumor cells. Further, MPs facilitate incorporation of miRNAs into the targeted tumor cells by fusing directly with the cell membrane ( Figures 7A-C). MPs can carry multiple, pre-selected therapeutic miRNAs against cell targets for most cell types.
  • MSC-derived MPs can be internalized by cancer cells and induce a biological effect as evidenced by damage/shrinkage of the recipient cell, induction of apoptosis, inhibition of cell proliferation and tumor growth attenuation in a dose-dependent manner.
  • In vivo studies monitored and quantified fluorescently labelled MPs in circulation and detected the biodistribution and incorporation in cells and organs in healthy and tumor-bearing mice.
  • MSC-MPs containing miRNAs possess tumor inhibitory properties, transfer miRNAs and affect the action of cancer genes.

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Abstract

Les micro-ARN (miARN) ont été décrits comme impliqués dans le développement de certains types de cancers, sinon de tous, et ont été identifiés comme des cibles thérapeutiques intéressantes. Cependant, l'administration systémique de miARN fait face à son propre lot de limites du fait de leur dégradation par les RNases et de la filtration et excrétion par le rein. L'invention concerne une nouvelle classe d'agents thérapeutiques, basés sur des microparticules (MP) dérivées de cellules souches mésenchymateuses (CSM) qui peuvent cibler des tumeurs de manière sélective in vivo, contenant et administrant des miARN qui affectent l'action de gènes associés à la croissance cancéreuse, à la néovascularisation et à la métastase, et applicables à une administration aussi bien systémique que locale.
PCT/IB2016/000563 2015-04-15 2016-04-15 Administration de micro-arn à l'aide de microparticules de cellules souches mésenchymateuses Ceased WO2016166600A1 (fr)

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US11535670B2 (en) 2016-05-11 2022-12-27 Huyabio International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
US10385130B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US10385131B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
US12122833B2 (en) 2016-05-11 2024-10-22 Huyabio International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US10287353B2 (en) 2016-05-11 2019-05-14 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
JP7545970B2 (ja) 2018-08-08 2024-09-05 テラミール エルティーディー Ｌｃｐ－１陽性がんを標的としたマイクロｒｎａベースの治療
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JP2024095750A (ja) * 2018-08-08 2024-07-10 テラミール エルティーディー Ｌｃｐ－１陽性がんを標的としたマイクロｒｎａベースの治療
CN112567034A (zh) * 2018-08-08 2021-03-26 微核糖核苷酸治疗有限公司 针对lcp-1阳性癌症的基于微小rna的治疗
WO2020030750A1 (fr) * 2018-08-08 2020-02-13 Theramir Ltd Thérapie à base de microarn ciblant des cancers positifs à lcp-1
US12133860B2 (en) * 2018-08-08 2024-11-05 Theramir Limited MicroRNA-based therapy targeted against LCP-1 positive cancers
EP4424380A3 (fr) * 2018-08-08 2024-11-20 Theramir Ltd Thérapie à base de microarn ciblée contre les cancers positifs au lcp-1
CN113215105B (zh) * 2021-05-28 2022-11-29 中山大学附属第八医院（深圳福田） Elmo2过表达间充质干细胞的构建及其在骨折治疗中的应用
CN113215105A (zh) * 2021-05-28 2021-08-06 中山大学附属第八医院（深圳福田） Elmo2过表达间充质干细胞的构建及其在骨折治疗中的应用
WO2023076670A1 (fr) * 2021-11-01 2023-05-04 MAM Holdings of West Florida, L.L.C. Cellules souches mésenchymateuses destinées à la prévention et au traitement ciblé du cancer et d'autres troubles

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