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WO2018178051A1 - Polymorphisme scgb1a1 pour la prédiction et la thérapie ou la prévention d'une dysfonction primaire du greffon - Google Patents

Polymorphisme scgb1a1 pour la prédiction et la thérapie ou la prévention d'une dysfonction primaire du greffon Download PDF

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WO2018178051A1
WO2018178051A1 PCT/EP2018/057728 EP2018057728W WO2018178051A1 WO 2018178051 A1 WO2018178051 A1 WO 2018178051A1 EP 2018057728 W EP2018057728 W EP 2018057728W WO 2018178051 A1 WO2018178051 A1 WO 2018178051A1
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ccsp
functional equivalent
lungs
protein
nucleic acid
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PCT/EP2018/057728
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English (en)
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Pierre MORDANT
Angela HIN
Caroline KANNENGIESSER
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INSERM (Institut National de la Santé et de la Recherche Médicale)
Université Paris Diderot - Paris 7
Assistance Publique-Hôpitaux De Paris (Aphp)
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Publication of WO2018178051A1 publication Critical patent/WO2018178051A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/42—Respiratory system, e.g. lungs, bronchi or lung cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the invention is in the field of primary graft dysfunction prediction and therapy or prevention.
  • the invention relates to a specific mutation (or Single Nucleotide Polymorphism, SNP) in human gene SCGBIAI that is associated with a decreased risk of primary graft dysfunction.
  • PGD primary graft dysfunction
  • ischemia is defined by an oxygen deficiency in the lung caused by an obstruction of the blood flow to the lung, in this case when the donor lung is collected, and reperfusion occurs when the blood flow to the organ is restored, in this case when connected to the recipient's circulation.
  • Ischemia-reperfusion can lead to lesions of the respiratory epithelium, as the injured lung capillary endothelium leads to protein leakage from the vascular bed into the alveolar space.
  • PGD represents a multifactorial injury to the transplanted lung that develops in the first 72 hours after transplantation. The natural history of PGD remains poorly delineated, but its lethal potential is well recognized.
  • PGD is the leading cause of early morbidity and mortality after lung transplantation. Unfortunately, predicting which lung transplant recipients go on to develop PGD remains partially unknown. Recognized risk factors of PGD include donor factors (tobacco use, poor graft oxygenation before harvest), recipient factors (primary and secondary pulmonary hypertension) and factors associated with the procedure itself (high emergency procedure, longer ischemic time). However, not all risk factors of PGD have been identified to date. In this setting, the identification of additional risk factors of PGD is of tremendous importance to better select lung grafts and to identify new therapeutic target that might improve the postoperative outcome following lung transplantation. Club Cell Secretory Protein (CCSP), produced by the non-ciliated lung epithelium, is abundant in the airways. CCSP has anti-inflammatory and immunomodulatory properties besides playing a role in host defence and control of oxidative stress (6). The gene encoding CCSP is SCGBIAI.
  • A 0.3451 / 40794 from ExAC
  • the present invention relates to SCGBIAI gene polymorphism for the prediction and therapy or prevention of primary graft dysfunction.
  • the present invention is defined by the claims.
  • a subject denotes a mammal, such as a rodent, a feline, a canine, and a primate.
  • a subject according to the invention is a human.
  • PGD primary graft dysfunction
  • PGD has its general meaning in the art and refers to a syndrome encompassing a spectrum of mild to severe lung injury that occurs within the first 72 hours after lung transplantation (1, 2).
  • PGD is a serious immediate postoperative complication that is a direct consequence of ischemia-reperfusion injury.
  • PGD is a complex inflammatory state associating hypoxemia, pulmonary oedema, systemic inflammatory response syndrome and radiographic appearance of diffuse pulmonary opacities without other identifiable cause.
  • the natural history of PGD remains poorly delineated, but its lethal potential is well recognized.
  • PGD has a significant impact on early morbidity and mortality after lung transplantation, resulting in prolonged length of mechanical ventilation, more frequent use of postoperative Extracorporeal Membrane Oxygenation (ECMO) support, prolonged intensive care unit (ICU) and hospital stay and increased cost. In addition, all grades of PGD are associated with an increased risk of chronic rejection.
  • ECMO Extracorporeal Membrane Oxygenation
  • SCGB1A1 gene has its general meaning in the art and refers to the secretoglobin family 1A member 1 gene (NCBI Reference Sequence: NG_021331.1) that encodes CCSP protein. SCGB1A1 gene has 3 short exons and 2 introns (4.1 kb in length), located on chromosome l lql2.3-13.1 in the vicinity of other genes associated with inflammatory and immune processes (16, 20).
  • CCSP Club Cell Secretory Protein secreted by Club cells (previously named Clara cells) in lung.
  • This protein is known by many names including: secretoglobin family 1A member 1 (SCGBIAI, current gene symbol), club cell protein (CC16 or CC10), human protein 1 (PI), urine protein 1, uteroglobin, and blastokinin.
  • the Human protein CCSP (mass: 15.8 kDa) secreted by Club cells is a homodimer without sugar residues; each unit is composed of 70 amino acid residues bound with covalent bonds. Its structure includes a hydrophobic pocket for binding lipophobic ligands. It is resistant to the action of proteases, low temperature, and pH changes.
  • CCSP abundant in the airways has anti- inflammatory and immunomodulatory properties besides playing a role in host defense and control of oxidative stress. Uniprot reference is PI 1684.
  • treatment is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread of the disease, preventing or delaying the recurrence of the disease, delaying or slowing the progression of the disease, ameliorating the disease state, providing a remission (partial or total) of the disease, decreasing the dose of one or more other medications required to treat the disease, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
  • treatment encompasses the prophylactic treatment.
  • the term “prevent” refers to the reduction in the risk of acquiring or developing a given condition.
  • preventing refers to minimizing, reducing or suppressing the risk of developing a disease state or parameters relating to the disease state or progression or other abnormal or deleterious conditions.
  • sample in the context of the present invention is a biological sample isolated from a subject or an organ ex vivo and can include, by way of example and not limitation, bodily fluids and/or tissue extracts such as homogenates or solubilized tissue.
  • the sample to be tested is blood or lung biopsy.
  • blood includes whole blood, plasma, serum, circulating epithelial cells, constituents, or any derivative of blood.
  • organ refers a group of several tissue types that perform a given function.
  • exemplary organs include, but are not limited to heart, kidney, liver, pancreas, and lung.
  • lungs has its general meaning in the art and refers to saccular thoracic organs that constitute the basic respiratory organ of air-breathing vertebrates.
  • Risk in the context of the present invention, relates to the probability that an event (i.e PGD) will occur over a specific time period.
  • risk of having or developing a primary graft dysfunction refers to the predisposition of lungs to suffer or develop a primary graft dysfunction.
  • allele(s) means any of one or more alternative forms of a gene at a particular locus.
  • alleles of a given gene are located at a specific location or locus (loci plural) on a chromosome.
  • loci plural locus
  • One allele is present on each chromosome of the pair of homologous chromosomes.
  • allelic variant means a sequence variation of a gene. Allelic variants can be found in the exons, introns, untranslated regions of the gene, or in the sequences that control expression of the gene. Complete gene sequencing often identifies numerous allelic variants (sometimes hundreds) for a given gene. The significance of allelic variants is often unclear until further study of the genotype and corresponding phenotype occurs in a sufficiently large population.
  • single nucleotide polymorphism refers to single nucleotide position in a genomic sequence for which two or more alternative alleles are present at appreciable frequency (e.g., at least 1%) in a population.
  • graft refers to the tissue and/or organ derived from a donor for transplantation into a recipient.
  • donor refers to the subject that provides the organ and/or tissue transplant or graft to be transplanted into the recipient and/or host.
  • potential donor refers to a subject which is likely to provide the organ and/or the tissue transplant or graft to be grafted. In others words, a potential donor may provide or not the organ and/or the tissue transplant or graft to be grafted.
  • recipient or "host” as used herein refers to any subject that receives an organ and/or tissue transplant or graft.
  • ex vivo means that which takes place outside an organism.
  • An "ex vivo organ” refers to an organ which has been removed from an organism.
  • Ex vivo lungs refers to lungs which have been removed from an organism.
  • Ex vivo" lungs can be stored on ice (topical cooling), perfused through the pulmonary artery and/or the left atrium using cellular or acellular solution, and/or ventilated through the trachea, in hypothermia or in normothermia.
  • the inventors studied the link between the presence of a SCGB1A1 polymorphism (such as G38A) in the donor or the recipient, and ultimately the occurrence of PGD. Indeed, the inventors put forth the hypothesis that the concentration of CCSP in the lung or the blood of the donor or the recipient might play a role in the answer to the epithelial aggression related to the phenomena of ischemia-reperfusion injury in pulmonary transplantation, in other words as mediators or indicators on the potential occurrence of severe PGD. For the first time, they showed that the presence of a AG genotype in SCGB1A1 gene (G38A polymorphism) in the donor was associated with a decreased frequency of PGD in the recipient after lung transplantation.
  • a SCGB1A1 polymorphism such as G38A
  • a first aspect of the present invention relates to a method of identifying lungs harvested from a donor and to be grafted to a recipient, having or at risk of having or developing a primary graft dysfunction (PGD), comprising determining, in a sample obtained from said donor or from said lungs, the presence or absence of a single nucleotide polymorphism (SNP) located in SCGB1A1 gene.
  • PGD primary graft dysfunction
  • the SNP is selected from the group consisting of SCGB1A1 dbSNP rs3741240 G>A and: - the presence of the allele (A) of SCGB1A 1 dbSNP rs3741240 G>A indicates a decreased risk of having or developing primary graft dysfunction.
  • the sample is a blood sample or a lung biopsy.
  • the determination of the presence or absence of said SNP may be determined by nucleic acid sequencing, PCR analysis or any genotyping method known in the art.
  • methods include, but are not limited to, chemical assays such as allele specific hybridation, primer extension, allele specific oligonucleotide ligation, sequencing, enzymatic cleavage, flap endonuclease discrimination; and detection methods such as fluorescence, chemiluminescence, and mass spectrometry.
  • the presence or absence of said variant may be detected in a DNA sample, preferably after amplification.
  • the isolated DNA may be subjected to amplification by polymerase chain reaction (PCR), using specific oligonucleotide primers that are specific for the SNP or that enable amplification of a region flanking the SNP.
  • PCR polymerase chain reaction
  • conditions for primer annealing may be chosen to ensure specific amplification; so that the appearance of an amplification product be a diagnostic of the presence of the SNP according to the invention.
  • DNA may be amplified, after which a mutated site may be detected in the amplified sequence by hybridization with a suitable probe or by direct sequencing, or any other appropriate method known in the art.
  • nucleic acid molecule may be tested for the presence or absence of a restriction site.
  • a base polymorphism creates or abolishes the recognition site of a restriction enzyme, this allows a simple direct PCR genotype of the polymorphism.
  • RNA sequencing includes, but are not limited to, direct sequencing, restriction fragment length polymorphism (RFLP) analysis; hybridization with allele-specific oligonucleotides (ASO) that are short synthetic probes which hybridize only to a perfectly matched sequence under suitably stringent hybridization conditions; allele-specific PCR; PCR using mutagenic primers; ligase- PCR, HOT cleavage; denaturing gradient gel electrophoresis (DGGE), temperature denaturing gradient gel electrophoresis (TGGE), single-stranded conformational polymorphism (SSCP) and denaturing high performance liquid chromatography (Kuklin et al., 1997).
  • DGGE denaturing gradient gel electrophoresis
  • TGGE temperature denaturing gradient gel electrophoresis
  • SSCP single-stranded conformational polymorphism
  • Direct sequencing may be accomplished by any method, including without limitation chemical sequencing, using the Maxam-Gilbert method ; by enzymatic sequencing, using the Sanger method ; mass spectrometry sequencing ; sequencing using a chip-based technology; and real- time quantitative PCR.
  • DNA from a subject is first subjected to amplification by polymerase chain reaction (PCR) using specific amplification primers.
  • PCR polymerase chain reaction
  • RCA rolling circle amplification
  • InvaderTMassay or oligonucleotide ligation assay (OLA).
  • OLA may be used for revealing base polymorphisms.
  • two oligonucleotides are constructed that hybridize to adjacent sequences in the target nucleic acid, with the join sited at the position of the polymorphism.
  • DNA ligase will covalentlyjoin the two oligonucleotides only if they are perfectly hybridized to one of the allele.
  • short DNA sequences in particular oligonucleotide probes or primers, according to the present invention include those which specifically hybridize the one of the allele of the polymorphism.
  • Oligonucleotide probes or primers may contain at least 10, 15, 20 or 30 nucleotides.
  • a second object of the invention is a kit suitable for identifying whether lungs have or are at risk of having or developing primary graft dysfunction, comprising:
  • the kit according to the invention comprises: - at least one primer and/or at least one probe for amplification of a sequence comprising a SNP consisting of SCGBIAI dbSNP rs3741240 G>A,
  • the primer or probe may be labelled with a suitable marker. In another embodiment of the invention, the primer or probe may be coated on an array.
  • primer sequences for PCR amplification of the SCGBIAI gene are: SEQ ID N°3: 5' - TCCCTTCACTGCCTCCAG - 3' (forward : 18nt)
  • SCGBIAI gene (G38A polymorphism) was associated with a decreased frequency of PGD.
  • GG genotype identification associated with high risk of PGD, it would be decided to administer the donor or the recipient or to deliver to the ex vivo lungs an appropriate treatment(s) for the prevention or treatment of PGD.
  • the present invention relates to a method of grafting lungs comprising the following steps:
  • the present invention relates to a method for treating or preventing primary graft dysfunction comprising administering to a subject in need thereof a therapeutically effective amount of CSSP protein or functional equivalent thereof.
  • the present invention relates to a method for treating or preventing primary graft dysfunction comprising delivering to ex vivo lungs a therapeutically effective amount of CSSP protein or functional equivalent thereof.
  • the present invention relates to a method for preparing ex vivo lungs comprising delivering to said ex vivo lungs a therapeutically effective amount of CSSP protein or functional equivalent thereof.
  • said ex vivo lungs are maintained into a device comprising an organ container filled with a preservation solution.
  • the present invention relates to a method of grafting lungs comprising the following steps:
  • the present invention relates to a method of grafting lungs comprising the following steps:
  • the present invention relates to a method of grafting lungs comprising the following steps:
  • a “functional equivalent of CCSP” is a polypeptide in which a given amino acid residue has been changed without altering the overall conformation and function of the CCSP protein.
  • the term “functionally equivalent” thus includes any equivalent of CCSP obtained by altering the amino acid sequence, for example by one or more amino acid deletions, substitutions (replacement of an amino acid with one having similar properties such as, for example, polarity, hydrogen bonding potential, acidic, basic, hydrophobic, aromatic, and the like) or additions such that the protein analogue retains the function of CCSP. Amino acid substitutions may be made, for example, by point mutation of the DNA encoding the amino acid sequence.
  • the term “functional equivalent” includes fragments, mutants, and muteins of CCSP.
  • the functional equivalent of CCSP is at least 70% homologous to the amino acids sequence SEQ ID NO:2.
  • the functional equivalent of CCSP is at least 80% homologous to the amino acids sequence SEQ ID NO:2. In some embodiments, the functional equivalent of CCSP is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% homologous to the amino acids sequence SEQ ID NO:2.
  • the functional equivalent of CCSP is at least 90% homologous to the amino acids sequence SEQ ID NO:2 as assessed by any conventional analysis algorithm such as for example, the Pileup sequence analysis software (Program Manual for the Wisconsin Package, 1996).
  • homologous refers to amino acid sequence similarity between two polypeptides. When an amino acid position in both of the polypeptides is occupied by identical amino acids, they are homologous at that position.
  • amino acid changes may be achieved by changing codons in the DNA sequence, according to Table 1.
  • Isoleucine lie I AUA, AUC, AUU
  • amino acids may be substituted for other amino acids in a protein structure without appreciable loss of protein function. Since it is the interactive capacity and nature of a protein that defines that protein's biological functional activity, certain amino acid substitutions can be made in a protein sequence, and, of course, in its DNA encoding sequence, and nevertheless obtain a protein with like properties. It is thus contemplated that various changes may be made in the polypeptide sequences of the invention, or corresponding DNA sequences which encode said polypeptides, without appreciable loss of their biological activity.
  • the hydropathic index of amino acids may be considered.
  • the importance of the hydropathic amino acid index in conferring interactive biologic function on a protein is generally understood in the art. It is accepted that the relative hydropathic character of the amino acid contributes to the secondary structure of the resultant protein, which in turn defines the interaction of the protein with other molecules, for example, enzymes, substrates, receptors, DNA, antibodies, antigens, and the like.
  • Each amino acid has been assigned a hydropathic index on the basis of their hydrophobicity and charge characteristics these are: iso leucine (+4.5); valine (+4.2); leucine (+3.8) ; phenylalanine (+2.8); cysteine/cystine (+2.5); methionine (+1.9); alanine (+1.8); glycine (-0.4); threonine (-0.7); serine (-0.8); tryptophane (-0.9); tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamate (-3.5); glutamine (-3.5); aspartate (-3.5); asparagine (-3.5); lysine (- 3.9); and arginine (-4.5).
  • Amino acid substitutions are generally therefore based on the relative similarity of the amino acid side-chain substituents, for example, their hydrophobicity, hydrophilicity, charge, size, and the like.
  • Exemplary substitutions which take various of the foregoing characteristics into consideration are well known to those of skill in the art and include: arginine and lysine; glutamate and aspartate; serine and threonine; glutamine and asparagine; and valine, leucine and isoleucine.
  • polypeptides of the invention may be produced by any suitable means, as will be apparent to those of skill in the art such as, without limitation, any chemical, biological, genetic or enzymatic technique, either alone or in combination.
  • expression may conveniently be achieved by culturing under appropriate conditions recombinant host cells containing the polypeptide of the invention.
  • the polypeptide is produced by recombinant means, by expression from an encoding nucleic acid molecule.
  • the polypeptide When expressed in recombinant form, the polypeptide is in particular generated by expression from an encoding nucleic acid in a host cell.
  • a host cell Any host cell may be used, depending upon the individual requirements of a particular system. Suitable host cells include bacteria mammalian cells, plant cells, yeast and baculovirus systems. Mammalian cell lines available in the art for expression of a heterologous polypeptide include Chinese hamster ovary cells. HeLa cells, baby hamster kidney cells and many others. Bacteria are also preferred hosts for the production of recombinant protein, due to the ease with which bacteria may be manipulated and grown. A common, preferred bacterial host is E coli.
  • polypeptides of the invention and fragments thereof can exhibit post-translational modifications, including, but not limited to glycosylations, (e.g., N-linked or O-linked glycosylations), myristylations, palmitylations, acetylations and phosphorylations (e.g., serine/threonine or tyrosine).
  • glycosylations e.g., N-linked or O-linked glycosylations
  • myristylations e.g., palmitylations
  • acetylations e.g., serine/threonine or tyrosine
  • polypeptides used in the therapeutic methods of the present invention may be modified in order to improve their therapeutic efficacy.
  • modification of therapeutic compounds may be used to decrease toxicity, increase circulatory time, or modify biodistribution.
  • the toxicity of potentially important therapeutic compounds can be decreased significantly by combination with a variety of drug carrier vehicles that modify biodistribution.
  • adding dipeptides can improve the penetration of a circulating agent in the eye through the blood retinal barrier by using endogenous transporters.
  • the present invention relates to a method for treating or preventing primary graft dysfunction comprising administering to a subject in need thereof a therapeutically effective amount of a vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof.
  • the present invention relates to a method for treating or preventing primary graft dysfunction comprising delivering to ex vivo lungs a therapeutically effective amount of a vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof.
  • the present invention relates to a method for preparing ex vivo lungs comprising delivering to said ex vivo lungs a therapeutically effective amount of a vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof.
  • said ex vivo lungs are maintained into a device comprising an organ container filled with a preservation solution.
  • the present invention relates to a method of grafting lungs comprising the following steps:
  • the present invention relates to a method of grafting lungs comprising the following steps:
  • the present invention relates to a method of grafting lungs comprising the following steps:
  • a therapeutically effective amount of a vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof when the absence of SCGB1A1 dbSNP rs3741240 G>A polymorphism in said sample is detected;
  • the vector used according to the present invention comprises a nucleic acid sequence encoding for CCSP protein (SEQ ID NOT) or a nucleic acid sequence encoding for a functional equivalent of CCSP protein.
  • vector means the vehicle by which a DNA or RNA sequence (e.g. a foreign gene) can be introduced into a host cell, so as to transform the host and promote expression (e.g. transcription and translation) of the introduced sequence.
  • a DNA or RNA sequence e.g. a foreign gene
  • Such vectors may comprise regulatory elements, such as a promoter, enhancer, terminator and the like, to cause or direct expression of said polypeptide upon administration to a subject.
  • the vectors may further comprise one or several origins of replication and/or selectable markers.
  • the promoter region may be homologous or heterologous with respect to the coding sequence, and provide for ubiquitous, constitutive, regulated and/or tissue specific expression, in any appropriate host cell, including for in vivo use. Examples of promoters include bacterial promoters (T7, pTAC, Trp promoter, etc.), viral promoters (LTR, TK, CMV- IE, etc.), mammalian gene promoters (albumin, PGK, etc), and the like.
  • plasmids include replicating plasmids comprising an origin of replication, or integrative plasmids, such as for instance pUC, pcDNA, pBR, and the like.
  • viral vector include adenoviral, retroviral, herpes virus and AAV vectors.
  • recombinant viruses may be produced by techniques known in the art, such as by transfecting packaging cells or by transient transfection with helper plasmids or viruses.
  • virus packaging cells include PA317 cells, PsiCRIP cells, GPenv+ cells, 293 cells, etc.
  • the present invention relates to a method for treating or preventing primary graft dysfunction comprising administering to a subject in need thereof a therapeutically effective amount of cells which have been transduced or transfected with an amino acid sequence encoding for CCSP protein or functional equivalent thereof or a vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof.
  • the present invention relates to a method for treating or preventing primary graft dysfunction comprising delivering to ex vivo lungs a therapeutically effective amount of cells which have been transduced or transfected with an amino acid sequence encoding for CCSP protein or functional equivalent thereof or a vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof.
  • the present invention relates to a method for preparing ex vivo lungs comprising delivering to said ex vivo lungs a therapeutically effective amount of cells which have been transduced or transfected with an amino acid sequence encoding for CCSP protein or functional equivalent thereof or a vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof.
  • said ex vivo lungs are maintained into a device comprising an organ container filled with a preservation solution.
  • the present invention relates to a method of grafting lungs comprising the following steps:
  • the present invention relates to a method of grafting lungs comprising the following steps:
  • the present invention relates to a method of grafting lungs comprising the following steps:
  • the cells used according to the invention are transduced or transfected cells with CCSP amino acid sequence or CCSP functional equivalent amino acid sequence or a vector comprising a nucleic acid encoding for CCSP or a CCSP functional equivalent.
  • transduction refers to the delivery of a gene using a retroviral vector particle by means of infection, in particular, introduction of a gene carried by the retroviral vector into a cell via lentivirus or vector infection and provirus integration.
  • transfection refers to the use of methods, such as chemical methods, to introduce exogenous nucleic acids, such as the synthetic, modified RNAs described herein, into a cell, preferably a eukaryotic cell.
  • methods of transfection include physical treatments (electroporation, nanoparticles, magnetofection), and chemical-based transfection methods.
  • Chemical-based transfection methods include, but are not limited to, cyclodextrin, polymers, liposomes, and nanoparticles.
  • the transduced or transfected cells used according to the invention are mesenchymal cells.
  • mesenchymal cells has its general meaning in the art and refers to cells from mesenchyme tissue.
  • the transduced or transfected cells used according to the invention are mesenchymal stem cells.
  • meenchymal stem cells As used herein, the terms “mesenchymal stem cells” or “MSCs” has its general meaning in the art and refers to multipotent stem cells that can differentiate into a variety of cell types such as cartilage chondrocytes, osteoblasts and fat cells.
  • transduced or transfected cells used according to the invention are obtained for instance from bone marrow, umbilical cord, peripheral blood, fallopian tube or cells banks.
  • the transduced or transfected cells used according to the invention derive from the donor. In one embodiment, the transduced or transfected cells used according to the invention derive from the recipient. In one embodiment, the transduced or transfected cells used according to the invention derive from a person other than the subject who received the cell therapy.
  • the CCSP protein or functional variant thereof, the vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof, or the transduced or transfected cells with an amino acid sequence encoding CCSP protein or functional equivalent thereof or a vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof are administered to the donor, before the lungs transplantation.
  • the CCSP protein or functional variant thereof, the vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof, or the transduced or transfected cells with an amino acid sequence encoding CCSP protein or functional equivalent thereof or a vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof are administered to the recipient, after the lungs transplantation.
  • the CCSP protein or functional variant thereof, the vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof, or the transduced or transfected cells with an amino acid sequence encoding CCSP protein or functional equivalent thereof or a vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof are delivered to the ex vivo lungs, before the lungs transplantation.
  • the CCSP protein or functional variant thereof, the vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof, or the transduced or transfected cells with an amino acid sequence encoding CCSP protein or functional equivalent thereof or a vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof are administered to the donor or delivered to the ex vivo lungs, before the lungs transplantation.
  • the ex vivo lungs are perfused with a preservation solution comprising the CCSP protein or functional variant thereof, the vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof, or the transduced or transfected cells with an amino acid sequence encoding CCSP protein or functional equivalent thereof or a vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof.
  • the ex vivo lungs are preserved into a device comprising an organ container filled with a preservation solution comprising CCSP protein or functional variant thereof, the vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof, or the transduced or transfected cells with an amino acid sequence encoding CCSP protein or functional equivalent thereof or a vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof.
  • preservation solution refers to an aqueous solution having a pH between 6.5 and 7.5, including salts, preferably chloride, sulfate, sodium, calcium, magnesium and potassium; sugars, preferably mannitol, raffinose, sucrose, glucose, fructose, lactobionate (which is a water resistant), or gluconate; antioxidants, for instance glutathione; active agents, for instance xanthine oxidase inhibitors such as allopurinol, lactates, amino acids such as histidine, glutamic acid (or glutamate), tryptophan; and optionally colloids such as hydroxyethyl starch, polyethylene glycol or dextran.
  • salts preferably chloride, sulfate, sodium, calcium, magnesium and potassium
  • sugars preferably mannitol, raffinose, sucrose, glucose, fructose, lactobionate (which is a water resistant), or gluconate
  • antioxidants for
  • the organ preservation solution is selected from:
  • - IGL-1® having an osmolality of 320 mOsm / kg and a pH of 7.4, of the following formulation, per liter in water: NaCL:125 mM, KH2P04: 25 mM, MgS04: 5 mM, Raffinose: 30 mM, potassium lactobionate: 100 mM, Glutathione: 3 mM, Allopurinol: 1 mM, Adenosine: 5 mM, Polyethylene glycol (molecular weight: 35 kDa): 1 g / L, - Celsior®, having an osmolality of 320 mOsm / kg and a pH of 7.3, of the following formulation per liter in water: Glutathione: 3 mM, Mannitol: 60 mM, lactobionic acid: 80 mM, Glutamic acid: 20 mM, NaOH: 100 mM, calcium chloride dehydrate: 0.25 m
  • - Perfadex® having an osmolarity of 295 mOsmol / L and the following formulation in water: 50 g / L of Dextran 40 (molecular weight: 40,000), Na + 138 mM, K + 6 mM, Mg2 +: 0.8 mM, CI - 142 mM, S042 0.8 mM, (+ H2P04- HP042-): 0.8 mM, glucose 5 mM,
  • the preservation solution according to the invention is the solution from the University of Wisconsin (UW or Viaspan®).
  • the CCSP protein or functional variant thereof, the vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof, or the transduced or transfected cells with an amino acid sequence encoding CCSP protein or functional equivalent thereof or a vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof are administered to the subject or delivered to the ex vivo lungs with a therapeutically effective amount.
  • a “therapeutically effective amount” is meant a sufficient amount of CCSP protein or functional variant thereof, vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof, or transduced or transfected cells with an amino acid sequence encoding CCSP protein or functional equivalent thereof or a vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof to treat or prevent primary graft dysfuntion at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific polypeptide employed; and like factors well known in the medical arts.
  • the daily dosage may be varied over a wide range from 0.01 to 1,000 mg per adult per day.
  • compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, in particular from 1 mg to about 100 mg of the active ingredient.
  • An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg kg to 7 mg/kg of body weight per day.
  • compositions according to the invention are formulated for parenteral, transdermal, oral, rectal, subcutaneous, sublingual, topical, intrapulmonary or intranasal administration.
  • Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms.
  • the pharmaceutical compositions are formulated for parenteral administration.
  • the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected. These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.
  • the CCSP protein or functional variant thereof, the vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof, or the transduced or transfected cells with an amino acid sequence encoding CCSP protein or functional equivalent thereof or a vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof are administrated by intratracheal or intrabronchial route.
  • the pharmaceutical compositions are formulated for ex vivo lungs delivering. More particularly, the pharmaceutical compositions are formulated for intravascular route, through the perfusate (for instance the perfusate is the preservation solution) or for intratracheal or intrabronchial route.
  • the CCSP protein or functional variant thereof, the vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof, or the transduced or transfected cells with an amino acid sequence encoding CCSP protein or functional equivalent thereof or a vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof may be combined with pharmaceutically acceptable excipients, and optionally sustained- release matrices, such as biodegradable polymers, to form therapeutic compositions.
  • “Pharmaceutically” or “pharmaceutically acceptable” refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to a mammal, especially a human, as appropriate.
  • a pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • the CCSP protein or functional variant thereof, the vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof, or the transduced or transfected cells with an amino acid sequence encoding CCSP protein or functional equivalent thereof or a vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof may be administered in combination with conventional treatment usually used for treating or preventing primary graft dysfunction, such as the parenteral corticosteroids administered to the donor before aortic cross clamp and pneumoplegia.
  • the CCSP protein or functional variant thereof, the vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof, or the transduced or transfected cells with an amino acid sequence encoding CCSP protein or functional equivalent thereof or a vector comprising a nucleic acid encoding for CCSP protein or functional equivalent thereof may be administered in combination with conventional treatment usually used before, during or after the organ transplantation, such as the immune suppression administered to the recipient during and after transplantation
  • FIGURES are a diagrammatic representation of FIGURES.
  • FIG. 1 Serum CCSP concentrations in donors and recipients (two-tailed Wilcoxon matched-pairs signed rank test, p ⁇ 0.001).
  • B Serum CCSP concentrations in recipients according to underlying diagnosis (two-tailed Mann Whitney test, p ⁇ 0.001).
  • Figure 3. (A).
  • COLT is a French national, multicentric, prospective study initiated in 2009 with the goal to follow a cohort of LT candidates and recipients, and to identify biological risk factors of CLAD (http://clinicaltrials.gov/ identification : NCT00980967).
  • This cohort is associated with a collection of whole blood, serum, and DNA harvested from the donor and the recipient at various time points pre- and post-transplantation.
  • CCSP G38A (rs3741240) polymorphism assessment.
  • Genomic DNA was isolated from peripheral blood samples using a DNA extraction kit (Qiagen ® ). Genomic DNA was normalized to a concentration of 20 ng ⁇ L for a 500 volume and stored in 96-well plates.
  • Specific PCPv amplification of the CCSP coding gene SCGB1A1 (5'UTR of exon 1) was achieved as follows: 40 ng of genomic DNA was added to a PCR master mix containing H 2 0, MgCi2 25mM, dNTP mix 5mM, lOpmol of forward and revers primers, Buffer Gold 10X and Taq Gold (5 ⁇ / ⁇ 1).
  • Primers were designed with Primer3, further verified using BLAST and SNPCheck version:3.2.1 , Reference Genome Build version:37.1 and dbSNP Build version: 141 for alternative unwanted amplifications and primer slipping. Primers used were: 5' - TCCCTTCACTGCCTCCAG - 3' (forward: 18nt) (SEQ IDN°3) and 5 ' - CTCCTCCCTCCAGGCTATTC - 3' (reverse: 20nt) (SEQ ID N°4).
  • PCR thermocycler run following an initial denaturation at 95 °C for seven minutes the reactions were cycled 38 times through a temperature profile of 96°C for 30 seconds, 60°C for one minute, and 72°C for one minute.
  • CCSP serum measurements Serum was isolated from peripheral blood samples and stored at -80°C. CCSP serum measurements were performed using the Human Uteroglobin (CCSP) DuoSet ELISA (R&D Systems). Preparation of 96-well plate coated with 2 ⁇ in PBS of capture rat anti-human uteroglobin (CCSP) antibody (843195) and then blocked with reagent diluent 1% BSA in PBS, pH 7.2-7.4, 0.2 ⁇ filtered (R&D Systems Catalog # DY995) for lh at room temperature. Serum samples were diluted at 1/100, loaded in duplicates on the 96-well plate, and incubated for 2h at room temperature.
  • CCSP Human Uteroglobin
  • CCSP capture rat anti-human uteroglobin
  • Detection biotinylated rat anti-human uteroglobin (CCSP) antibody (843196) was added for an additional 2h at room temperature. Streptavidin-HRP (890803) was then incubated for 20 minutes at room temperature in the dark. The reaction was visualized by the addition of 100 chromogenic substrate (TMB) for 10 min. The reaction was stopped with 50 ⁇ , of stop solution 2 NH2SO4. Absorbance at 450 nm was measured with reductions using ELISA plate reader. As a reference for quantification, a standard curve was established by serial dilution of recombinant human uteroglobin (CCSP) to allow detection ranging from 31.20 to 2,000 pg/mL. Statistical analysis.
  • Continuous variables with normal distribution were reported as mean and standard deviation, and compared using Student t test.
  • Continuous variable with non-normal distribution were reported as mean, median and interquartile range (IQR) and compared using Mann Whitney test.
  • Categorical variables were reported as count and proportion, and compared using Fisher or Chi Square tests when appropriate.
  • IQR median and interquartile range
  • Categorical variables were reported as count and proportion, and compared using Fisher or Chi Square tests when appropriate.
  • matched analyses were performed when comparing variables between donors and recipients.
  • Continuous variables were compared using paired Student test or paired Mann Whitney test as appropriate and McNemar test was used for categorical variables.
  • Primary outcome was severe PGD, defined as the occurrence of a grade 3 PGD at anytime during the first 72 hours following lung transplantation. Multivariate analysis was performed using Generalized Linear Models.
  • Pretransplant CCSP serum concentration was significantly higher in donors (mean 33.32 ng/mL, median 22.54, IQR 9.6-43.9) than in recipients (mean 19.85 ng/mL, median 7.03, IQR 0.89-19.2, p ⁇ 0.001 , figure 2.A).
  • CCSP serum concentration was significantly higher in patients with interstitial lung disease (ILD, mean 45.21 ng/mL, median 43.02, IQR 28.51-57.53) than in patients with chronic obstructive pulmonary disease (COPD, mean 8.19 ng/mL, median 6.06, IQR 1.31- 37.14) and cystic fibrosis (CF, mean 18.47 ng/mL, median 4.15 ng/mL, IQR 0.11-8.70) when bronchial diseases were considered together (p ⁇ 0.001 , figure 2.B).
  • ILD interstitial lung disease
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary
  • donor CCSP G38A polymorphism to be associated (i) with a decreased concentration of CCSP in the peripheral blood prior to LT; and (ii) with a decreased risk of severe PGD following LT.
  • CCSP and lung transplantation The first clinical study exploring the role of CCSP after LT focused on Bronchiolitis Obliterans Syndrome (BOS), the most frequent pattern of chronic lung allograft dysfunction (CLAD) characterized by a fibrosing process of the small airways causing irreversible airway obstruction. Following 22 LT recipients over 2 years, Nord et al. found that levels of CCSP in serum and BAL were lowered in BOS patients, suggesting that recipient serum CCSP concentration could be an early marker for BOS (16). Ten years later, Diamond et al. focused on PGD on a prospective cohort of 104 LT recipients, and determined levels of plasma CCSP at three time points: pre-transplant, 6h post-transplant, and 24h post-transplant.
  • BOS Bronchiolitis Obliterans Syndrome
  • CLAD chronic lung allograft dysfunction
  • CCSP G38A polymorphism In humans, the gene encoding CCSP has 3 short exons and 2 introns for a total length of 4.1 kb. It is located on chromosome 1 l ql2.3-13.1 in the vicinity of other genes associated with inflammatory and immune processes (19, 20). Studies of the non-coding region of the exon 1 of CCSP gene have identified a number of binding sites for transcription factors (1 ). This region is also subject to a single nucleotide polymorphism (SNP) located 38 bp downstream of the transcription initiation site, defined as dbSNP rs3741240, and characterized by an adenine/guanine substitution (21 , 22).
  • SNP single nucleotide polymorphism
  • CCSP G38A polymorphism is found in 34% of the population and associated with 25% reduced transcription levels as compared with the G allele (11, 12).
  • CCSP polymorphism is associated with decreased serum CCSP levels, but that in patients with end-stage lung disease such as lung recipients, CCSP polymorphism is associated with sustained serum CCSP levels - i.e that CCSP G38A polymorphism could be associated with a resistance to cell signals associated with end-stage respiratory disease.
  • CCSP G38A polymorphism has been studied mostly in sarcoidosis and asthma. The association between the presence of an A allele and the development of asthma in the general population is still questioned (13, 23), while serum CCSP levels has been independently related to small airway hyperresponsiveness in asymptomatic individuals (24), COPD patients (7) and asthmatic patients (25). The fact that CCSP polymorphism has not been formally associated with the development of asthma, but serum CCSP levels has been associated with small airway hyperresponsiveness in various situations, could be explained by confounding factors. Individual exposure to cigarette smoke, air pollution, and professional toxics could indeed interact with individual genetic susceptibility to impact the serum concentration of CCSP and the development of symptoms (15).
  • this binding site is located at the position of the G38A polymorphism site, thus explaining the resistance of CCSP G38A to p53-mediated CCSP down regulation in vitro (15).
  • IR causes an increase in p5 associated with an increase in apoptosis and a decrease in the production of CCSP in lung epithelial cells, thus constituting a vicious circle that may lead to PGD.
  • IR-induced p53 increase has no effect on CCSP expression and CCSP levels (not shown). This p53 resistance of G38A binding site may therefore explain the decrease frequency of PGD in grafts harboring the CCSP G38A genotype.
  • donor CCSP A38G gene polymorphism is associated with a decreased concentration of CCSP in the peripheral blood prior to LT, and a decreased risk of severe PGD following LT.
  • PaO2/Fi02 (mmHg) 358 (183- 365 (176- 343 (273- 0.73
  • Serum club cell protein 16 is associated with asymptomatic airway responsiveness in adults: Findings from the French epidemiological study on the genetics and environment of asthma. Respirology. 2015;20: 1198-205.

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Abstract

La présente invention concerne le polymorphisme SCGB1A1 pour la prédiction et la thérapie ou la prévention d'une dysfonction primaire du greffon (DPG). Le résultat suivant une transplantation pulmonaire est actuellement limité par l'apparition d'une DPG, une complication post-opératoire immédiate grave qui est une conséquence directe d'une lésion d'ischémie-reperfusion. Les inventeurs ont montré que la présence d'un génotype AG dans le gène SCGB1A1 (polymorphisme G38A) chez le donneur est associée à une fréquence réduite de DPG chez le receveur après une transplantation pulmonaire. En particulier, la présente invention concerne un procédé d'identification de poumons collectés à partir d'un donneur et destinés à être greffés à un receveur, présentant ou risquant de présenter ou de développer une dysfonction primaire de greffon (DPG), comprenant la détermination, dans un échantillon obtenu à partir dudit donneur ou desdits poumons, de la présence ou de l'absence d'un polymorphisme mononucléotidique (SNP) situé dans le gène SCGB1A1.
PCT/EP2018/057728 2017-03-28 2018-03-27 Polymorphisme scgb1a1 pour la prédiction et la thérapie ou la prévention d'une dysfonction primaire du greffon WO2018178051A1 (fr)

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