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WO2008141177A1 - Procédés et compositions pour le traitement du sarcome - Google Patents

Procédés et compositions pour le traitement du sarcome Download PDF

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Publication number
WO2008141177A1
WO2008141177A1 PCT/US2008/063241 US2008063241W WO2008141177A1 WO 2008141177 A1 WO2008141177 A1 WO 2008141177A1 US 2008063241 W US2008063241 W US 2008063241W WO 2008141177 A1 WO2008141177 A1 WO 2008141177A1
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Prior art keywords
cells
rnai
composition
gene
bcl
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PCT/US2008/063241
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English (en)
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Francis Y. Lee
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Columbia University in the City of New York
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Columbia University in the City of New York
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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
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0038—Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy
    • 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
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
    • 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
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1135—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against oncogenes or tumor suppressor genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1138—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against receptors or cell surface proteins
    • 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]
    • 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
    • C12N2320/00—Applications; Uses
    • C12N2320/30—Special therapeutic applications
    • C12N2320/31—Combination therapy
    • 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
    • C12N2830/00—Vector systems having a special element relevant for transcription
    • C12N2830/008—Vector systems having a special element relevant for transcription cell type or tissue specific enhancer/promoter combination

Definitions

  • XIAP (alternate names: MIHA/ hlLP/BIRC4) is a member of the inhibitors of apoptosis protein (IAP) family, which has been identified as the key post-mitochondrial caspase inhibitor (see Devi (2004) Drug News Perspect. 17, 127-134; Holcik et al. (2001 ) Apoptosis 6, 253-26). Unlike the Bcl-2 family proteins, XIAP inhibits both the mitochondria-dependent and -independent apoptotic pathways (see Ghobrial et al. (2005) CA Cancer J Clin 55, 178-194; Devi (2004) Drug News Perspect. 17, 127-134).
  • the present teachings also include a method of treating a sarcoma resistant to chemotherapy or radiotherapy with an RNA interference molecule specific for an anti-apoptotic gene and/or a multi-drug resistance gene to sarcoma cells.
  • the stem cell is a mesenchymal stem cell.
  • the transformed stem cell also includes a nucleic acid encoding a connexin protein, wherein the transformed stem cell expresses the connexin protein and the connexin protein facilitates transfer of RNAi molecules from the transformed stem cell to a sarcoma cell.
  • the nucleic acid has a promoter that is upregulated by expression of the connexin protein.
  • the connexin protein is a connexin32 protein, connexin37 protein, connexin40 protein, connexin43 protein, or connexin45 protein.
  • Figure 10 depicts a fluorescent micrograph of transfected cells and a series of immunoblots.
  • Figure 10A shows fluorescent (light-grey) cytoplasm in chondrosarcoma cells 24 hours after transfection with fluorescence- tagged siRNA.
  • Figure 1 OB shows target protein expression of each siRNA is significantly decreased in comparison to control groups.
  • Figure 13 depicts a schematic representation of targeted siRNA delivery via hMSC.
  • Silencing of multi-drug resistance genes can have a therapeutic role as a molecular adjuvant treatment of sarcomas, such as chondrosarcoma, when combined with other modalities of treatment, such as radiation treatment, chemotherapy treatment, and/or surgical resection. Furthermore, silencing of multiple multi-drug resistance genes can further enhance the efficacy of other treatment modalities. For example, double gene silencing can further enhance chemo-sensitivity (see Example 4). Preferably, there is a synergistic effect of multiple multi-drug resistance gene silencing on apoptosis of tumor cells in conjunction with other treatment modalities.
  • Such methods generally include contacting a composition containing RNAi molecules specific for one or more multi-drug resistance genes with chondrosarcoma cells, for example via RNAi loaded progenitor cells, preferably via RNAi loaded stem cells, and more preferably RNAi loaded stem cells expressing or overexpressing a connexin protein.
  • tissue progenitor cell can be, for example, a mesenchymal stem cell (MSC), MSC-dehved cell, osteoblast, chondrocyte, myocyte, adipocyte, neuronal cell, neuronal supporting cells such as Schwann cells, neural glial cells, fibroblastic cells including interstitial fibroblasts, tendon fibroblasts or tenocytes, ligament fibroblasts, periodontal fibroblasts, craniofacial fibroblasts, gingival fibroblasts, periodontal fibroblasts, cardiomyocytes, epithelial cells, dermal fibroblasts, liver cells, uretheral cells, kidney cells, periosteal cells, bladder cells, or beta-pancreatic islet cell.
  • MSC mesenchymal stem cell
  • osteoblast osteoblast
  • chondrocyte myocyte
  • adipocyte neuronal cell
  • neuronal supporting cells such as Schwann cells, neural glial cells
  • fibroblastic cells including inter
  • Tissue progenitor cells preferably stem cells and more preferably mesenchymal stem cells
  • stem cells and/or mesenchymal stem cells can be isolated by a variety of means known to the art.
  • stem cells and/or mesenchymal stem cells Such further discussion is understood to also apply, or be adaptable, to tissue progenitor cells generally.
  • RNAi molecules specific for one or more anti-apoptotic genes and/or multi-drug resistance genes can be transfected into stem cells (e.g., mesenchymal stem cells), so as to be stably expressed, by a variety of ways known to the art.
  • stem cells e.g., mesenchymal stem cells
  • Molecular transfection processes are well known (see e.g. Sambrook and Russel (2006), Condensed Protocols from Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, ISBN 0879697717; Sambrook and Russel (2001 ) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, ISBN 0879695773; Ausubel et al. (2002) Short Protocols in Molecular Biology, Current Protocols, ISBN 0471250929; Spector et al.
  • connexin43 can facilitate transfer of RNAi molecules specific for one or more anti-apoptotic genes from the mesenchymal stem cell into a target chondrosarcoma cell and/or upregulate expression of RNAi molecules linked to promoters such as the OC promoter or the BSP promoter.
  • RNAi-loaded stem cells can be administered to a given subject by taking into account factors such as the size and weight of the subject; the extent of the sarcoma penetration; the age, health and sex of the subject; the route of administration; and whether the administration is regional or systemic.
  • An effective amount of cells can be, for example, about 1 x10 8 to about 100 cells.
  • about 1 x10 6 to about 1 x10 5 cells are introduced. It is contemplated that greater or lesser amounts of RNAi loaded stem cells can be administered.
  • a determination of the need for treatment will typically be assessed by a history and physical exam consistent with the sarcoma (e.g., chondrosarcoma) at issue.
  • the diagnosis of chondrosarcoma can serve to identify a subject with a need for a therapy described herein.
  • the subject is preferably an animal, including, but not limited to, mammals, reptiles, and avians, more preferably horses, cows, dogs, cats, sheep, pigs, and chickens, and most preferably human. Diagnosis of sarcoma, including chondrosarcoma, is within the skill of the art (see generally, Longe, ed.
  • compositions containing RNAi loaded stem cells are directly introduced directly into tissues containing chondrosarcoma cells, in vivo.
  • a composition comprising transformed stem cells that express RNAi molecules specific for one or more anti-apoptotic genes and/or multi-drug resistance genes, along with pharmaceutically acceptable additives, can be applied topically. Topical application can occur in conjunction with a surgical procedure, so as to apply the composition directly to the chondrosarcoma site.
  • a composition comprising transformed stem cells that express RNAi molecules specific for one or more anti-apoptotic genes and/or multi-drug resistance genes, along with pharmaceutically acceptable additives can be injected directly into a chondrosarcoma.
  • lmmunoblotting assays were conducted in order to determine the expression of P-glycoprotein and anti-apoptotic proteins by chondrosarcoma cells and the effect of gene silencing.
  • the cells were lysed using buffer IP (10 mM Ths-HCI, pH 7.4, 150 mM NaCI, 1 % Triton X-100, 0.25% Nonidet P-40, and 2 mM EDTA) supplemented with protease inhibitor cocktail (Roche, Branchburg, NJ).
  • Equivalent protein extracts (10 ⁇ g) from each sample were electrophoresed in 4-20% Ths-Glycine gels (Invitrogen, Carlsbad, CA). The total amount of protein was quantified using the BCA assay.
  • Tumor recurrence is one of the prognostic factors which negatively affects the clinical outcome following radiation or chemotherapy.
  • Clonogenic cell survival assays were conducted and showed that chondrosarcoma cells retain their ability to proliferate and form multiple colonies after doxorubicin treatment (see e.g. Figure 12).
  • the number of colonies decreased significantly (p ⁇ 0.05).
  • the silencing of those genes resulted in a decreased colony formation by up to three fold (p ⁇ 0.05) at 0.1 ⁇ M in comparison to control group.
  • P-glycoprotein gene silencing also showed the significant decrease in colony formation at 0.1 ⁇ M (p ⁇ 0.05).
  • At the highest dose of doxorubicin (1 ⁇ M) there was no significant colony formation at all in any of the siRNA treated groups.
  • hMSCs can be used in vivo for targeted delivery of siRNA to osteosarcoma cells, and as valuable cellular vehicles for the delivery of biologic agents for targeting anti-apoptotic genes (see e.g. Fig. 16).
  • This therapeutic approach can avoid the toxicity of systemically distributed anti-cancer agents and contribute to targeted delivery of chemotherapeutic agents to microscopic metastatic centers and increase the survival of osteosarcoma patients.

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  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

L'invention concerne des compositions et des procédés utilisés dans le traitement de sarcomes, par exemple les chondriosomes, qui sont généralement résistants aux modalités de traitement traditionnelles, comme la radiothérapie ou la chimiothérapie. Selon divers aspects, l'invention consiste à augmenter la sensibilité d'un sarcome à la chimiothérapie et/ou la radiothérapie en l'exposant à une cellule souche transformée, telle qu'une cellule souche mésenchymateuse, qui exprime des molécules d'ARNi spécifiques d'un ou plusieurs gènes anti-apoptotiques et/ou gènes de résistance multi-drogues, et qui exprime facultativement une protéine connexine facilitant le transfert des molécules d'ARNi dans les cellules du sarcome.
PCT/US2008/063241 2007-05-11 2008-05-09 Procédés et compositions pour le traitement du sarcome Ceased WO2008141177A1 (fr)

Applications Claiming Priority (2)

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US91750607P 2007-05-11 2007-05-11
US60/917,506 2007-05-11

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017165641A1 (fr) * 2016-03-23 2017-09-28 The Trustees Of Columbia University In The City Of New York Traitement du cancer basé sur l'administration d'oligonucléotides par l'intermédiaire de jonctions lacunaires provenant de cellules souches mésenchymateuses humaines (hmsc)
WO2019102268A1 (fr) * 2017-11-22 2019-05-31 Mesoblast International Sarl Compositions cellulaires et méthodes de traitement
US12410405B2 (en) 2010-10-08 2025-09-09 Mesoblast International Sàrl Enhanced MSC preparations

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070093437A1 (en) * 2001-05-18 2007-04-26 Sirna Therapeutics, Inc. Rna interference mediated inhibition of xiap gene expression using short interfering nucleic acid (sina)

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070093437A1 (en) * 2001-05-18 2007-04-26 Sirna Therapeutics, Inc. Rna interference mediated inhibition of xiap gene expression using short interfering nucleic acid (sina)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12410405B2 (en) 2010-10-08 2025-09-09 Mesoblast International Sàrl Enhanced MSC preparations
WO2017165641A1 (fr) * 2016-03-23 2017-09-28 The Trustees Of Columbia University In The City Of New York Traitement du cancer basé sur l'administration d'oligonucléotides par l'intermédiaire de jonctions lacunaires provenant de cellules souches mésenchymateuses humaines (hmsc)
CN108882705A (zh) * 2016-03-23 2018-11-23 纽约市哥伦比亚大学理事会 基于经由来自人间充质干细胞(hMSC)的间隙连接递送寡核苷酸的癌症治疗
JP2019509297A (ja) * 2016-03-23 2019-04-04 ザ・トラスティーズ・オブ・コロンビア・ユニバーシティ・イン・ザ・シティ・オブ・ニューヨーク ヒト間葉系幹細胞（ｈＭＳＣ）からギャップジャンクションを介するオリゴ送達に基づく癌治療
EP3432714A4 (fr) * 2016-03-23 2019-11-13 The Trustees of Columbia University in the City of New York Traitement du cancer basé sur l'administration d'oligonucléotides par l'intermédiaire de jonctions lacunaires provenant de cellules souches mésenchymateuses humaines (hmsc)
AU2017238505B2 (en) * 2016-03-23 2021-09-23 The Research Foundation For The State University Of New York Cancer treatment based on delivery of oligoes via gap junctions from human mesenchymal stem cells (hMSC)
WO2019102268A1 (fr) * 2017-11-22 2019-05-31 Mesoblast International Sarl Compositions cellulaires et méthodes de traitement
CN112004923A (zh) * 2017-11-22 2020-11-27 迈索布拉斯特国际有限公司 细胞组合物及治疗方法
JP2021507683A (ja) * 2017-11-22 2021-02-25 メゾブラスト・インターナショナル・エスアーエールエル 細胞組成物及び処置の方法
JP7463275B2 (ja) 2017-11-22 2024-04-08 メゾブラスト・インターナショナル・エスアーエールエル 細胞組成物及び処置の方法
US12473547B2 (en) 2017-11-22 2025-11-18 Mesoblast International Sàrl Use of mesenchymal lineage precursor cells or stem cells (MLPSCs) for delivery of oligonucleotides in the treatment of cancer

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