WO2000038518A9 - Transfert efficace et stable in vivo de genes dans des cardiomyocytes a l'aide de vecteurs viraux adeno-associes de recombinaison - Google Patents

Transfert efficace et stable in vivo de genes dans des cardiomyocytes a l'aide de vecteurs viraux adeno-associes de recombinaison

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Publication number
WO2000038518A9
WO2000038518A9 PCT/US1999/031093 US9931093W WO0038518A9 WO 2000038518 A9 WO2000038518 A9 WO 2000038518A9 US 9931093 W US9931093 W US 9931093W WO 0038518 A9 WO0038518 A9 WO 0038518A9
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WO
WIPO (PCT)
Prior art keywords
aav
body weight
infused
per gram
cardiomyocytes
Prior art date
Application number
PCT/US1999/031093
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English (en)
Other versions
WO2000038518A1 (fr
Inventor
Jeffrey M Leiden
Eric Svensson
Original Assignee
Arch Dev Corp
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.)
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Application filed by Arch Dev Corp filed Critical Arch Dev Corp
Priority to JP2000590483A priority Critical patent/JP2002533359A/ja
Priority to EP99967703A priority patent/EP1139751A4/fr
Priority to CA002356551A priority patent/CA2356551A1/fr
Priority to AU23942/00A priority patent/AU763049B2/en
Publication of WO2000038518A1 publication Critical patent/WO2000038518A1/fr
Publication of WO2000038518A9 publication Critical patent/WO2000038518A9/fr

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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
    • C12N15/86—Viral vectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • 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
    • C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
    • C12N2750/00011—Details
    • C12N2750/14011—Parvoviridae
    • C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
    • C12N2750/14141—Use of virus, viral particle or viral elements as a vector
    • C12N2750/14143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

  • this invention relates to the use of recombinant adeno-associated virus (rAAV) vectors to transduce cardiomyocytes in vivo by infusing the rAAV into a coronary artery or coronary sinus.
  • rAAV adeno-associated virus
  • coronary artery perfusion of mouse hearts with a rAAV encoding the LacZ gene produced efficient transduction of cardiomyocytes which was stable for at least 8 weeks.
  • rAAV infection is not associated with detectable myocardial inflammation or myocyte necrosis.
  • rAAV is a useful vector for the stable expression of therapeutic genes in the myocardium and can be used to deliver genes for inducing angiogenesis, inhibiting angiogenesis, stimulating cell proliferation, inhibiting cell proliferation and/or treating or ameliorating other cardiovascular conditions.
  • Myocardial gene therapy can be used for the treatment of a number of cardiovascular diseases, including ischemic cardiomyopathies, congestive heart failure, and malignant arrhythmias (Nabel (1995) Circulation 91 :541-548).
  • a useful vector for myocardial gene delivery will allow efficient and stable transduction of cardiomyocytes with a variety of transgenes after either direct intramyocardial injection or infusion into the coronary arteries or sinuses.
  • plasmid DNA vectors injected directly into the left ventricular myocardium have been expressed for >6 months by cardiomyocytes adjacent to the area of injection (Lin et al.
  • rAAV vectors have been shown to program efficient and stable recom- binant gene expression in skeletal muscle and liver in both rodents and primates (Fisher et al.(1997) N ⁇ t. Med. 3:306-312; Kessler et al. (1996) Proc. Natl. Acad. Sci. USA 93: 14082-14087; and Snyder et al. (1997) Nat. Genet. 16: 270-276) and in cardiac muscle directly injected with rAAV (U.S. Patent No. 5,858,351 to Podsakoff et al.).
  • rAAV vectors used in gene therapy applications unlike RDAd, do not encode viral proteins, the rAAV vectors have not been associated with immune responses to foreign transgene proteins.
  • this invention establishes that by infusing rAAV in much higher amounts proportional to body weight of the animal and for particular time periods, then rAAV provides unexpected efficient and stable gene transfer into the heart, opening up use of rAAV vectors to deliver therapeutically-effective molecules to cardiomyocytes in amounts useful for treating or ameliorating cardiac diseases or conditions.
  • the present invention is directed to a method of treating a cardiovascular condition by infusing an rAAV vector into a coronary artery or a coronary sinus for a time and in an amount sufficient to stably and efficiently transduce the cardiomyocytes perfused by the artery or sinus.
  • the rAAV vector encodes at least one nucleic acid which is operably linked to a control region and which encodes a therapeutically-effective molecule. After infusion and transduction of the cardiomyocytes, the therapeutically- effective molecule is expressed in an amount effective to treat or ameliorate the cardiovascular condition.
  • this method provides a means of delivering AAV vectors in a stable and efficient manner.
  • the vector can be infused by any convenient means and in conjunction with surgery or other cardiac procedure, if desired.
  • Figure 1 Schematic of AAV CMV . LacZ . ITR indicates inverted terminal repeats; BGH pA, bovine growth hormone polyadenylation signal; CMV Pr, CMV immediate- early promoter; LacZ, bacterial LacZ gene.
  • Figure 2 Gene transfer into cardiomyocytes in vivo with AAV CMV .
  • This invention relates to treating cardiovascular conditions using rAAV vectors.
  • an rAAV vector encoding a therapeutically effective molecule is infused into a coronary artery or a coronary sinus to deliver the vector to the heart in a manner which stably and efficiently transduces cardiomyocytes. It has unexpectedly been found that the ability to obtain stable and efficient transduction of cardiomyocytes by rAAV depends upon the duration of the infusion period and the amount of virus infused relative to body weight.
  • rAAV displays significant advantages for myocardial gene transfer compared with plasmid DNA or adenovirus vectors.
  • rAAV when delivered as described herein, allows efficient transduction of cardiomyocytes.
  • rAAV vectors program stable expression of foreign transgenes in immunocompetent hosts. The stability of transgene expression observed with rAAV even after expression of a foreign transgene protein likely reflects the fact that rAAV vectors, unlike their adenovirus counterparts, do not express any viral gene products and are therefore significantly less immunogenic. This lack of immunogenicity represents a major advantage of rAAV for myocardial gene transfer.
  • the invention is directed to a method of treating a cardiovascular condition which comprises infusing an rAAV vector into a coronary artery or sinus of an animal for a time and in an amount sufficient to stably and efficiently transduce cardiomyocytes perfused by the artery or sinus, wherein that vector encodes at least one nucleic acid, i.e., the transgene, encoding a therapeutically-effective molecule; and expressing the therapeutically-effective molecule in an amount effective to treat or ameliorate the cardiovascular condition.
  • the nucleic acid is operably linked to a control region, e.g., promoters, enhancers, termination signals and the like, to permit expression of the molecule.
  • rAAV vectors useful in the present invention can be any rAAV vector with one or more transgenes (or nucleic acids of interest) inserted therein in a manner allowing expression of the transgene under control of appropriate regulatory elements such as promoters, enhancers, transcription terminators and the like.
  • rAAV vectors are well known in the art and can be prepared by standard methodology know to those of ordinary skill in the art. For example, U.S. Patent No.
  • a “transgene” or “nucleic acid of interest” or the “nucleic acid encoded in the rAAV vector” as used herein refers to any nucleotide sequence which encodes a therapeutically-effective molecule that can be used to treat a cardiovascular condition.
  • transgenes may normally be foreign to the animal being treated or may be a gene normally found in that animal for which altered expression (e.g., temporal, spatial or amount of expression) is desired to achieve a particular therapeutic effect.
  • the therapeutically-effective molecule encoded by the transgene is protein or an anti-sense RNA that imparts a benefit to the animal or subject undergoing treatment or amelioration of a cardiac condition or disease in accordance with this invention.
  • Proteins that can be administered to treat or ameliorate cardiovascular conditions are numerous and include, but are not limited to, molecules competent to induce angiogenesis, e.g., angiogenesis factors; anti-angiogenesis factors; proteins capable of inhibiting vascular smooth muscle cell proliferation; proteins useful for treating atherosclerosis; proteins useful for treating restenosis, proteins useful for stimulating cardiomyocyte activity; proteins capable of secretion from cardiomyocytes that exert their effect in the heart or capable of transport to other locales for treatment of a cardiovascular condition or disease; hormones, cytokines or growth factors useful for treating cardiac conditions or diseases; and proteins capable of stimulating vascular smooth muscle cell proliferation.
  • Other genes encoding proteins useful in this invention include ion channel genes, contractile protein genes, phospholamban encoding genes and genes encoding ⁇ adrenergic receptors or ⁇ adrenergic kinases.
  • Angiogenic factors include, but are not limited to FGF-1, FGF-2, FGF-5, VEGF, HIF-1 and the like.
  • Proteins useful for treating restenosis include thymidine kinase, cytosine deaminase, p21, p27, p53, Rb, and NF- ⁇ B.
  • this invention can be used to deliver any protein via an rAAV vector that has a therapeutic benefit for treating or ameliorating a cardiovascular condition or disease.
  • a protein competent to induce angiogenesis or an "angiogenesis factor” as used herein is a protein or substance that causes proliferation of new blood vessels and includes fibroblast growth factors, endothelial cell growth factors or other proteins with such biological activity. Particular proteins known to induce angiogenesis are FGF-1, FGF-2, FGF-5, VEGF and active fragment thereof, and HIF-1. Proteins competent to inhibit angiogenesis or "anti-angiogenesis factors” are proteins or substances that inhibit the formation of new blood vessels.
  • Anti -sense RNA that can be administered to treat or ameliorate cardiovascular conditions have one of the same activities as proteins useful in the invention. Such RNA include, but are not limited to, c-myb, c-myc and others.
  • Anti-sense RNA molecules including how to design and use such molecules in expression vectors are well know in the art and can be contructed by routine methodology.
  • a strand of RNA whose sequence of bases is complementary to the sense, or translated, RNA strand can form a duplex to block translation or degradation of a particular mRNA or otherwise control or alter expression of the desired mRNA.
  • control region or “regulatory element” refers to polyadenylation signals, upstream regulatory domains, promoters, enhancers, transcription termination sequences and the like which regulate the transcription and translation of a nucleic acid sequence.
  • operably linked refers to an arrangement of elements wherein the components are arranged so as to perform their usual function.
  • control regions or regulatory elements operably linked to a coding sequence are capable of effecting the expression of the coding sequence.
  • the control elements need not be contiguous with the coding sequence, so long as they function to direct the expression thereof.
  • intervening untranslated yet transcribed sequences can be present between a promoter sequence and the coding sequence and the promoter sequence can still be considered “operably linked" to the coding sequence.
  • the regulatory elements of the invention can be derived from any source, e.g., viruses, mammals, insects or even synthetic, provided that they function in cardiomyocytes.
  • any promoter can used to control expression of the transgene.
  • Such promoters can be promiscous, i.e., active in many cell types, such as the SV40 early promoter, the mouse mammary tumor virus LTR promoter, the adenovirus major late promoter (Ad MLP), a herpes simplex promoter, a CMV promoter such as the CMV immediate early promoter, a rous sarcoma virus (RSV) promoter.
  • the promoter can be tissue-specific for expression in cardiomyocytes.
  • the rAAV is delivered to cardiac myocytes by infusion into a coronary artery or coronary sinus.
  • This mode of delivery has also been referred to as intraluminal delivery through a coronary artery, intracoronary delivery or intraarterial delivery.
  • infusion into a coronary artery includes intracoronary perfusion.
  • the rAAV vector can be infused when the heart is in situ, i.e., in the body cavity or when the heart or heart tissue (cardiac tissue) has been removed from the body as might occur when the heart is being donated for transplant into a recipient.
  • the vector can be infused through any artery or vein attached thereto, by contacting with or soaking the heart in an appropriately concentrated solution of the vector, or by a combination of both.
  • infusion includes delivering rAAV to a heart or heart tissue ex vivo by the means disclosed herein. If necessary, the infusion can be repeated at intervals such as 3 months, 6 months, one year, or as appropriately determined.
  • treating cardiac conditions include treating cardiac or cardiovascular diseases.
  • cardiac conditions subject to treatment or amelioration according to the method of the present invention include, but are not limited to, myocardial ischemia, myocardial infarction, congestive heart failure, dilated and hypertrophic cardiomyopathy, cardiac arryfhmia, cardiac hypertrophy, cardiac transplantation and rejection.
  • the cardiac condition such as ischemia
  • the rAAV vector used in accordance with the method of this invention would encode an angiogenesis factor.
  • the rAAV vector is infused into a coronary artery for a time and in an amount sufficient to stably and efficiently transduce cardiac tissue perfused by the artery, wherein the AAV vector encodes a therapeutically-effective molecule which is expressed in the cardiac tissue in an amount effective to treat or ameliorate a cardiovascular condition including, but not limited to, inducing angiogenesis, inhibiting angiogenesis, stimulating or inhibiting cell proliferation, treating restenosis, treating atherosclerosis, treating congestive heart failure, treating ischemic cardiomyopathies or treating malignant arrhythmias, myocardial infarction, congestive heart failure, or dilated and hypertrophic cardiomyopathy.
  • a cardiovascular condition including, but not limited to, inducing angiogenesis, inhibiting angiogenesis, stimulating or inhibiting cell proliferation, treating restenosis, treating atherosclerosis, treating congestive heart failure, treating ischemic cardiomyopathies or treating malignant arrhythmias, myocardial infarction, congestive heart failure, or
  • the method of the present invention can be used with any animal, including but not limited to, mammals such as rodents, dogs, cats, cattle, primates and humans.
  • the method is used for gene therapy to treat human acquired or inherited cardiac conditions or diseases.
  • the present invention thus provides a method of treating and/or ameliorating a cardiovascular condition by infusing an rAAV vector for a time and in and amount sufficient to stable and efficiently transduce cardiomyocytes which was heretofore unachievable by methods known in the art.
  • stable and efficient transduction means that significant number of cardiomyocytes are transduced and are capable of expressing the protein for a prolonged period of time.
  • Stable and efficient transduction occurs over a period of time and can actually be observed over time as an increase in the percentage of transduced cardiomyocytes, as continued expression of the transgene, or as continued observation of the therapeutic effect at a molecular, microscopic or macroscopic level.
  • efficient transduction occurs when at least about 10%, and preferably more, of the cardiomyocytes have been transduced, i.e., infected by, the rAAV.
  • efficient transduction occurs when at least about 10%, and preferably more, of the cardiomyocytes have been transduced, i.e., infected by, the rAAV.
  • about 25%, about 40% or even about 50% of the cardiomyocytes will be transduced. While about 10% of the cardiomyocytes can be transduced using only rAAV, this percentage can be increased by co-infusing adenovirus as a helper virus without adverse effects.
  • the time of infusion contributes to acheiving stable and efficient transduction of the cardiomyocytes as well.
  • the infusion time ranges from about 2 minutes to about 30 minutes, more preferably from about 5 minutes to about 20 minutes and most perferably is about fifteen minutes.
  • the amount of rAAV infused into the animal is proportional to the body weight of the animal.
  • stable and efficient transduction occurs when the amount of rAAV infused ranges from about 1 x 10 5 IU (infectious units) of AAV per gram body weight to about 1 x 10 9 IU AAV per gram body weight, and preferably from about 1 x 10 6 IU AAV per gram body weight to about 1 x 10 8 IU AAV per gram body weight, and most preferably is about 5-6 x 10 7 IU AAV per gram body weight.
  • Ad CMV.LacZ and the E3-deleted adenovirus, Ad dl309 were propagated and purified as described (Barr 1994).
  • Propagation and Purification of rAAV rAAV was prepared as described (Rolling et al. (1995) Mol. Biotechnol. 3:9-15) and purified by cesium chloride gradient centrifugation.
  • Viral titer was assessed by a dot blot hybridization assay to determine the number of viral genomes per milliliter and by infecting HeLa cells with the virus and staining with X-gal 24 hours after infection. All viral preparations had titers of 1 to 2X10" genomes/mL, and 2 to 3X10 9 infectious units (IU)/mL.
  • Freshly isolated hearts were fixed in PBS plus 1.25% glutaraldehyde for 10 minutes at room temperature, stained overnight with X-gal (Lin 1990a), and counterstained with eosin.
  • rAAV delivered by coronary artery perfusion can be used to stably transduce cardiomyocytes throughout the myocardium.

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Abstract

L'invention concerne l'utilisation de vecteurs viraux adéno-associés de recombinaison (rAAV) pour la transduction de cardiomyocytes in vivo par injection de vecteurs rAAV dans une artère ou un sinus coronaire. L'infection au virus rAAV n'est pas associée à une inflammation du myocarde ou à la nécrose des myocytes détectable. Ainsi, le vecteur rAAV est un vecteur utile pour l'expression stable de gènes thérapeutiques dans le myocarde, et il peut être utilisé pour un apport de gènes destiné à induire l'angiogenèse, à inhiber l'angiogenèse, à stimuler la prolifération cellulaire, à inhiber la prolifération cellulaire et/ou à traiter ou à soulager d'autres troubles cardiovasculaires.
PCT/US1999/031093 1998-12-28 1999-12-28 Transfert efficace et stable in vivo de genes dans des cardiomyocytes a l'aide de vecteurs viraux adeno-associes de recombinaison WO2000038518A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2000590483A JP2002533359A (ja) 1998-12-28 1999-12-28 組換えアデノ随伴ウイルスベクターを用いる、心筋細胞への効率的かつ安定なインビボでの遺伝子移入
EP99967703A EP1139751A4 (fr) 1998-12-28 1999-12-28 TRANSFERT EFFICACE ET STABLE $i(IN VIVO) DE GENES DANS DES CARDIOMYOCYTES A L'AIDE DE VECTEURS VIRAUX ADENO-ASSOCIES DE RECOMBINAISON
CA002356551A CA2356551A1 (fr) 1998-12-28 1999-12-28 Transfert efficace et stable in vivo de genes dans des cardiomyocytes a l'aide de vecteurs viraux adeno-associes de recombinaison
AU23942/00A AU763049B2 (en) 1998-12-28 1999-12-28 Efficient and stable (in vivo) gene transfer to cardiomyocytes using recombinantadeno-associated virus vectors

Applications Claiming Priority (2)

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US11392398P 1998-12-28 1998-12-28
US60/113,923 1998-12-28

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WO2000038518A1 WO2000038518A1 (fr) 2000-07-06
WO2000038518A9 true WO2000038518A9 (fr) 2002-04-11

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EP (1) EP1139751A4 (fr)
JP (1) JP2002533359A (fr)
AU (1) AU763049B2 (fr)
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WO (1) WO2000038518A1 (fr)

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US7745416B2 (en) * 1995-04-11 2010-06-29 The Regents Of The University Of California Method for in vivo regulation of cardiac muscle contractility
KR20020049031A (ko) * 1999-11-05 2002-06-24 더 리젠츠 오브 더 유니버시티 오브 캘리포니아 생체내 유전자 송달에 의하여 심혈관 질환을 치료하기위한 기술 및 조성물
EP1870473A1 (fr) * 2000-08-17 2007-12-26 Keiya Ozawa Libération de facteurs angiogéniques à médiation virale et adéno associée
ATE366319T1 (de) * 2000-08-17 2007-07-15 Keiya Ozawa Adeno-assoziierte virus-vermittelte übertragung von angiogenesefaktoren
WO2002019966A2 (fr) * 2000-09-06 2002-03-14 Johns Hopkins University Procedes de traitement de l'arrhythmie cardiaque
US20030022870A1 (en) * 2001-06-01 2003-01-30 Victor Dzau Methods of treating cardiac disorders
AU2003299204A1 (en) 2002-10-02 2004-04-23 The Johns Hopkins University Focal calcium channel modulation
US20070134204A1 (en) * 2005-12-09 2007-06-14 Henrich Cheng Method for treating nerve injury and vector construct for the same
JP5623740B2 (ja) * 2006-07-25 2014-11-12 セラドン・コーポレーション 遺伝子治療用アデノ随伴ウイルスベクターの長期順行性の心外膜冠動脈注入
US8221738B2 (en) 2008-02-19 2012-07-17 Celladon Corporation Method for enhanced uptake of viral vectors in the myocardium
EP2714709B1 (fr) * 2011-05-26 2018-04-18 University of Washington Compositions pour utilisations dans des procédés basés sur des cellules et des gènes permettant d'améliorer la fonction cardiaque
EP3710043B1 (fr) * 2017-11-16 2024-04-17 Universite d'Aix-Marseille Fgf10 pour le traitement de maladies cardiaques

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US5792483A (en) * 1993-04-05 1998-08-11 Vickers, Inc. Injection molding machine with an electric drive
US6162796A (en) * 1995-09-27 2000-12-19 The Rockefeller University Method for transferring genes to the heart using AAV vectors

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CA2356551A1 (fr) 2000-07-06
WO2000038518A1 (fr) 2000-07-06
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AU2394200A (en) 2000-07-31
EP1139751A4 (fr) 2003-03-19
EP1139751A1 (fr) 2001-10-10

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