EP1365754A2 - Inhibition de proteasomes pour la prevention de la restenose - Google Patents

Inhibition de proteasomes pour la prevention de la restenose

Info

Publication number
EP1365754A2
EP1365754A2 EP02713482A EP02713482A EP1365754A2 EP 1365754 A2 EP1365754 A2 EP 1365754A2 EP 02713482 A EP02713482 A EP 02713482A EP 02713482 A EP02713482 A EP 02713482A EP 1365754 A2 EP1365754 A2 EP 1365754A2
Authority
EP
European Patent Office
Prior art keywords
stent
ubiquitin
inhibiting
compound
restenosis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02713482A
Other languages
German (de)
English (en)
Inventor
Stephen E. Epstein
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
MedStar Health
Original Assignee
MedStar Health
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by MedStar Health filed Critical MedStar Health
Publication of EP1365754A2 publication Critical patent/EP1365754A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/432—Inhibitors, antagonists
    • A61L2300/434—Inhibitors, antagonists of enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings

Definitions

  • This invention relates to methods of preventing restenosis after angioplasty and more particularly to methods of preventing restenosis by applying a stent coated with a material capable of inhibiting the action of cellular proteasomes .
  • Surgical intervention by means of balloon angioplasty or bypass grafting has become a common strategy for alleviating stenosis of cardiac arteries that have become narrowed or obstructed by accumulation of atheromatous plaque.
  • SMCs within the vessel wall are normally in a quiescent state.
  • early response genes are expressed and the cells enter the cell cycle, wherein their replication is tightly regulated by an array of cell cycle regulatory proteins acting conjointly and in sequence at various points of the cycle.
  • These regulatory proteins include cyclin- dependent kinases (cdc2 and cdk2), which phosphorylate critical regulatory proteins, and the interaction of such kinases with cyclin-dependent kinase inhibitors, such as pl6, p21, and p27kipl. Changes in the levels of these inhibitors exert marked effects on cell-cycle progression, through inhibition of critical phosphorylation reactions.
  • pRb tumor suppressor protein retinoblastoma protein
  • E2F DNA binding and gene activating proteins
  • the microtubular system has been shown to modulate the response of cells to various mitogens and cytokines through activation of transmembrane signalling cascades. Targets of these pathways include activation of kinases, including mitogen-activated protein kinase activity, changes associated with microtubular depolymerization.
  • the microtubules have also shown to play a part in the changes in SMCs that lead to their contributing to the restenosis lesion.
  • paclitaxel Taxol
  • rapamycin paclitaxel
  • the success of these drugs is based on the cellular and molecular effects on the two processes described above: microtubular modulation of the response of cells to mitogens and cytokines, and proteins controlling progress of cells through the cell-cycle.
  • Paclitaxel favors stabilization of microtubule assembly, forming numerous disorganized microtubules within the cytoplasm, and thereby inhibiting many of the microtubular mediated cell signaling cascades cited above, including inhibition of cell division, predominantly in the G 0 /G ⁇ and G 2 /M phases of the cell cycle. Importantly, paclitaxel in biologically relevant concentrations does not appear to induce apoptosis. Taxol inhibited, in vitro, both platelet-derived growth factor-stimulated SMC migration and SMC proliferation, and in vivo, inhibited neointimal accumulation in the rat carotid artery injury model.
  • Rapamycin a macrolide antibiotic
  • Rapamycin is a potent inhibitor of cell proliferation. It has recently been shown in a pig coronary artery injury model to significantly reduce the neointimal response to injury. The mechanism of action of rapacmycin almost certainly largely derives from its ability to interfere with cell cycling. Thus, downregulation of p27kip by mitogens is blocked by rapamycin; consistent with this activity, in the porcine injury model cited above, rapamycin administration was associated with increased p27 levels and inhibition of pRb phosphorylation within the vessel wall.
  • the active ingredient In order to assure a satisfactory therapeutic response, the active ingredient must be provided to the cells to be affected in a sufficiently high concentration.
  • a number of strategies for drug delivery have been tried, for example, catheter delivery and coated stents.
  • Catheter delivery systems Therapeutic strategies began to focus on local delivery, as it became apparent that high concentrations of active agent were needed at the target site. It would be very unlikely that such high concentrations could be achieved by any other approach than local delivery. Unfortunately, despite years of development and testing, the consensus is that catheter delivery systems are too inefficient to be successful- -only one percent or less of the delivered product appears to persist for any period of time in the vessel wall .
  • Coated stents to deliver proteins or small molecules The concept that drugs could be incorporated into the coating of stents has become popularized, with mixed results. Most studies have shown no effect, but preliminary encouraging results of stents in which their coating is impregnated with either paclitaxel or rapamycin, or their derivatives, have been reported at several international meetings.
  • inhibition of cell proliferation is achieved by inhibiting the ubiquitin-proteasome protein degradation pathway, thereby interfering with proliferation of cells that could contribute to restenosis.
  • a further object is to provide a method for inhibiting the ubiquitin-proteasome protein degradation pathway in cells capable of proliferating to cause restenosis.
  • a further object is to provide a method for local delivery of an effective concentration of a drug capable of inhibiting the ubiquitin-proteasome protein degradation pathway in cells capable of proliferating to cause restenosis.
  • a further object is to provide an intravascular stent coated with a compound capable of inhibiting the ubiquitin- proteasome protein degradation pathway in cells capable of proliferating to cause restenosis.
  • ubiquitin-proteasome pathway is responsible for the degradation of multiple proteins. Specific proteins targeted for degradation by this pathway are identified as targets by undergoing ubiquitinization. Proteasomes, which are large complexes of proteolytic enzymes, recognize these ubiquitin molecular tags and initiate the process of intracellular degradation. By degrading signaling proteins, the proteasome is involved in altering many cellular signals, including those involved in growth and differentiation.
  • p53 is a suppressor gene with multiple critical cellular functions, including the activation of a p53- modulated apoptosis pathway, and p53-mediated inhibition of cell cycle progression.
  • MDM2 a protein, called MDM2 , binds to the p53 protein, and in so doing, enhances the transfer of ubiquitin to p53. This maintains p53 at low levels by increasing proteasome-mediated p53 degradation. Inhibition of this pathway would result in elevated levels of p53, which would thereby predispose to apoptosis and inhibit cell cycle progression.
  • IFN ⁇ inhibits proliferation of certain cell types.
  • IFN ⁇ -induced inhibition of ubiquitin-proteasome-mediated degradation of p21 a potent inhibitor of cell cycle progression.
  • LDP-341 has been found to induce apoptosis through the stabilization of proteins critical for cell cycle progression and control of apoptosis.
  • the drug was found to be effective in reducing the volume of various tumors. Although the drug was described as an anti-cancer agent, its activities suggest that LDP-341 will also exhibit potent anti-restenosis efficacy.
  • LDP-341 appears very active in tumor treatment when given in combination with standard chemotherapeutic agents or radiation. Because restenosis is treated by chemotherapeutic agents and by radiation, it is believed that LDP-341 will have additive, or even synergistic, effects in preventing restenosis when given in conjunction with these agents.
  • this drug when administered via a stent-based platform, by achieving high local concentrations at the vessel wall and low systemic concentrations, will be effective with minimal systemic side effects.
  • a protein or small molecule with ubiquitin-proteasome-inhibiting activity, or plasmid DNA or a viral vector encoding such a protein or small molecule is incorporated into a stent coating.
  • the stent coating comprises a substance that adheres to the stent, and which will incorporate the molecule or DNA or viral vector without damaging it. Accordingly, when the stent is implanted after an angioplastic procedure, the protein or small molecule is delivered directly to the cells within the injured vessel wall (or to the cells that are migrating from the media and/or adventitia to form the neointima) .
  • a coated stent according to the invention can be performed in any artery or interposed vein (such as, but not limited to, a saphenous vein graft to a coronary artery) that is obstructed and thereby impairs blood flow to the target tissue (whether it be heart or leg) .
  • the stent platform will facilitate transduction of cells within the vessel wall (or transduction of cells that are migrating from the media and/or adventitia to form the neointima) with the gene encoding the inhibitory molecule.
  • the invention will employ any coating that can be attached to a stent and that has the above characteristics, and any molecule with ubiquitin-proteasome- inhibiting activity, or gene that encodes such a molecule.
  • the therapuetic concept on which the invention is based is as follows.
  • the intimate and prolonged contact between the ubiquitin-proteasome- inhibiting activity of the protein or small molecule (or the gene encoding such a protein) that is contained within the stent coating, and vessel wall cells, will lead to high levels of ubiquitin-proteasome-inhibiting activity.
  • This will exert the desired therapeutic effects on these cells, such as (but not limited to) inhibition of smooth muscle cell (SMC) proliferation or migration, and induction of SMC apoptosis.
  • SMC smooth muscle cell
  • the invention includes 1) the delivery system consisting of a stent coating that can be impregnated with the ubiquitin-proteasome-inhibiting protein, small molecule, or gene encoding such a product, and 2) the ubiquitin-proteasome- inhibiting protein, small molecule, or gene encoding such a product.
  • the invention will have the benefits of substantially reducing the incidence of restenosis with minimal incidence of untoward complications, a result that has been achieved to only a limited extent (or, as with radiation therapy, carrying unknown future risk) with other anti- restenosis strategies.
  • the method of the invention can also provide synergistic effects when applied with interventions targeting different molecular mechanisms involved in restenosis.
  • the therapeutic agents used in this invention can be any ubiquitin-proteasome- inhibiting protein, small molecule, or gene, e.g., plasmid DNA or viral vector.
  • An example of a suitable therapeutic agent is LDP-341 of Millenium Pharmaceuticals, Inc.
  • any compound, protein or small molecule, that inhibits the ubiquitin-proteasome protein degradation pathway, or any gene that codes for such a compound is suitable use in the method of the invention.
  • the coated stent used to administer the ubiquitin- proteasome inhibitor to the wall of the blood vessel after angioplasty may be any conventional stent suitable for supporting the vessel wall and maintaining the lumen thereof as is conventional in angioplastic procedures.
  • the ubiquitin- proteasome inhibitor is coated onto the surface of the stent by incorporation into a coating that is adherent to the stent surface. Any stent coating that has the proper release kinetics for the ubiquitin-proteasome-inhibiting protein, small molecule, or gene encoding such a product, and that allows for viable incorporation of such a molecule, and that allows for such product to reside in the coating for days or weeks, will be appropriate.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biomedical Technology (AREA)
  • Vascular Medicine (AREA)
  • Surgery (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Le procédé décrit permet de prévenir la resténose des vaisseaux sanguins après une angioplastie. Ce procédé consiste à empêcher la prolifération cellulaire, en particulière celle des cellules des muscles lisses, dans les parois du vaisseau sanguin, en inhibant la voie de dégradation ubiquitine-protéasome des protéines. On obtient cette inhibition en administrant aux cellules des parois des vaisseaux sanguins un composé, p. ex. une protéine ou une petite molécule, capable d'inhiber la voie de dégradation ubiquitine-protéasome des protéines. On administre de préférence ce composé inhibiteur en l'appliquant sur une endoprothèse puis en implantant cette endoprothèse dans le vaisseau sanguin après l'angioplastie.
EP02713482A 2001-01-30 2002-01-29 Inhibition de proteasomes pour la prevention de la restenose Withdrawn EP1365754A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US26473501P 2001-01-30 2001-01-30
US264735P 2001-01-30
PCT/US2002/002367 WO2002060341A2 (fr) 2001-01-30 2002-01-29 Inhibition de proteasomes pour la prevention de la restenose

Publications (1)

Publication Number Publication Date
EP1365754A2 true EP1365754A2 (fr) 2003-12-03

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP02713482A Withdrawn EP1365754A2 (fr) 2001-01-30 2002-01-29 Inhibition de proteasomes pour la prevention de la restenose

Country Status (3)

Country Link
EP (1) EP1365754A2 (fr)
AU (1) AU2002245330A1 (fr)
WO (1) WO2002060341A2 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RS61840B1 (sr) 2004-07-02 2021-06-30 Geron Corp Sinteza zaštićenih 3'-amino 5'-fosforamidit nukleozidnih monomera

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO02060341A3 *

Also Published As

Publication number Publication date
WO2002060341A2 (fr) 2002-08-08
WO2002060341A3 (fr) 2002-10-17
AU2002245330A1 (en) 2002-08-12

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