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WO2018069232A1 - Procédés de prédiction du risque de présenter une hypertrophie cardiaque - Google Patents

Procédés de prédiction du risque de présenter une hypertrophie cardiaque Download PDF

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Publication number
WO2018069232A1
WO2018069232A1 PCT/EP2017/075648 EP2017075648W WO2018069232A1 WO 2018069232 A1 WO2018069232 A1 WO 2018069232A1 EP 2017075648 W EP2017075648 W EP 2017075648W WO 2018069232 A1 WO2018069232 A1 WO 2018069232A1
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Prior art keywords
cfgf23
concentration
risk
subject
patients
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Dominique PRIE
Marie COURBEBAISSE
Gérard FRIEDLANDER
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Centre National de la Recherche Scientifique CNRS
Assistance Publique Hopitaux de Paris APHP
Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris Descartes
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Centre National de la Recherche Scientifique CNRS
Assistance Publique Hopitaux de Paris APHP
Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris Descartes
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Publication of WO2018069232A1 publication Critical patent/WO2018069232A1/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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere

Definitions

  • This invention is in the field of haematology and cardiology. Particularly, this invention relates to use of cFGF23 as a biomarker to predict the risk of having hypertrophy cardiac in a subject suffering from SCD.
  • SCD Sickle cell disease
  • Sickle cell disease was recently declared as a public health priority issue worldwide. It is estimated that in Africa 6 million individuals are affected, this number approaches 100,000 in the US 2 and 0.1% of newborns in France, which has a screening program at birth in populations at risk 3 . Despite improvements in the last 50 years, the average age at death of people affected with SCD is 42 years in Western countries 4 . Sickle cell disease patients suffer from chronic organ damage like cardiomyopathy. Cardiac disorders are present in 13% to 31% of SCD patients 5"7 . The cardiac anomalies range from cardiomegaly to congestive heart failure 8"10 .
  • Cardiac disease is one of the causes of premature death of SCD patients 11 and diastolic dysfunction is an independent risk factor of death in these patients 7 .
  • Cardiac dysfunction in SCD is related to chronic anemia and low oxygen saturation 10 ' 12 and is independent of iron deposition 13 .
  • the mechanisms whereby anemia and low oxygen saturation can induce cardiac dysfunction are incompletely understood and additional factors are still to be identified.
  • Fibroblast growth factor 23 is a 32-kdalton peptide secreted by bone cells (osteocytes and osteoblasts). This peptide can be cleaved between amino-acids 176-179 in a N-terminal and a C-terminal fragments 14 . The enzyme responsible for this cleavage has not been clearly identified. Under physiological condition FGF23 circulates as an intact peptide. It is uncertain whether FGF23 fragments have any biological effects. The physiological function of intact FGF23 (iFGF23) is to control calcitriol and serum phosphate concentrations. iFGF23 lowers renal phosphate reabsorption, decreases calcitriol synthesis and stimulates calcitriol catabolism in the renal proximal tubule. In return plasma phosphate and calcitriol concentrations exert a feedback on iFGF23 production. iFGF23 concentration increases when strig
  • the invention relates to a method for predicting the risk of having cardiac hypertrophy in a subject suffering from sickle cell disease comprising the steps of: i) measuring the concentration of cFGF23 in a sample obtained from said subject, ii) comparing the concentration obtained at step (i) to a predetermined value, and iii) concluding that the subject has the risk of cardiac hypertrophy when the concentration of cFGF23 is higher than the predetermined value or concluding that the subject has not the risk of cardiac hypertrophy when the concentration of cFGF23 is lower than the predetermined value.
  • the present invention is defined by the claims.
  • cFGF23 plasma iFGF23 and C-terminal FGF23 (cFGF23) concentrations in 77 young adult SCD patients and in 172 healthy control subjects. Plasma cFGF23 but not iFGF23 concentration was higher in SCD patients than in control subjects (median cFGF23 419 vs 55 RU/ml p ⁇ 0.0001). In SCD subjects, cFGF23 concentration associated inversely with hemoglobin levels and correlated positively with left ventricular mass index (LVMI), left ventricle end diastolic and systolic diameters (LVEDD and LVESD). These associations with LVMI, LVEDD and LVESD persisted after correction for hemoglobin levels.
  • LVMI left ventricular mass index
  • LVEDD and LVESD left ventricle end diastolic diameters
  • Plasma cFGF23 concentration was higher and echocardiographic anomalies were more severe in homozygous SS-SCD patients than in compound heterozygous SCD subjects. They have analyzed the effects of cFGF23 on normal adult rat ventricular myocytes (ARVMs). Treatment of ARVMs in culture with cFGF23 induced within 24 hours a hypertrophy similar to that induced by FGF2 and beta-adrenergic agonists. Incubation of ARVMs with a FGF receptor inhibitor prevented cFGF23 hypertrophic effect. These results indicate that a cleaved form of FGF23 is released in the blood of SCD patients and demonstrate for the first time that cFGF23 can induce cardiac hypertrophy via activation of a FGF receptor. Method of predicting the risk of having cardiac hypertrophy
  • the invention relates to a method for predicting the risk of having cardiac hypertrophy in a subject suffering from sickle cell disease comprising the steps of: i) measuring the concentration of cFGF23 in a sample obtained from said subject, ii) comparing the concentration obtained at step (i) to a predetermined value, and iii) concluding that the subject has the risk of cardiac hypertrophy when the concentration of cFGF23 is higher than the predetermined value or concluding that the subject has not the risk of cardiac hypertrophy when the concentration of cFGF23 is lower than the predetermined value.
  • the term "subject” refers to any mammals, such as a rodent, a feline, a canine, and a primate. Particularly, in the present invention, the subject is a human. In a particular embodiment, the subject is a human afflicted or susceptible to be afflicted with SCD.
  • SCD sickle cell disease
  • SCA sickle-cell anemia
  • drepanocytosis refers to an autosomal recessive genetic blood disorder caused by a point mutation in the ⁇ -globin chain of hemoglobin.
  • SCD is characterized by red blood cells that adopt an abnormal, rigid, sickle shape, referred to as “sickling" under low-oxygen conditions. Repeated episodes of sickling can damage the blood cell's membrane and decrease its elasticity. Sickled cells can fail to return to normal shape when normal oxygen tension is restored. As a consequence, these rigid blood cells are unable to deform as they pass through narrow capillaries, leading to vessel occlusion and ischemia.
  • the actual anemia of the illness is caused by hemolysis, the destruction of the red cells, caused by their misshapes.
  • cardiac hypertrophy refers to an adaptive response of the heart to virtually all forms of cardiovascular disease, including those arising from hypertension, mechanical load, myocardial infarction, cardiac arrhythmias, endocrine disorders, and genetic mutations in cardiac contractile protein genes.
  • Adult cardiac myocytes respond to stress through hypertrophic growth. Such growth is characterized by cell size increases without cell division or proliferation, assembling of additional sarcomeres within the cell to maximize force generation, and an activation of a fetal cardiac gene program.
  • Cardiac hypertrophy is often associated with increased risk of morbidity and mortality, and thus studies aimed at understanding the molecular mechanisms of cardiac hypertrophy could have a significant impact on human health.
  • the term "predicting" means that the subject to be analyzed by the method of the invention is allocated either into the group of subjects who will develop cardiac dependency
  • cardiac hypertrophy referred to in accordance with the invention means that the subject will have higher risk to develop cardiac hypertrophy.
  • said risk is elevated as compared to the average risk in a cohort of subjects suffering from SCD.
  • the risk of having the cardiac hypertrophy in a subject suffering from SCD shall be predicted.
  • the term "predicting the risk”, as used herein, refers to assessing the probability according to which the patient as referred to herein will develop cardiac hypertrophy. As will be understood by those skilled in the art, such an assessment is usually not intended to be correct for 100% of the subjects to be investigated.
  • the probability envisaged by the invention allows that the prediction of an increased risk will be correct for at least 60%>, at least 70%>, at least 80%>), or at least 90%> of the subjects of a given cohort or population.
  • the term preferably, relates to predicting whether or not there is an increased risk of developing cardiac hypertrophy compared to the average risk of cardiac hypertrophy in a population of subjects rather than giving a precise probability for the said risk.
  • Fibroblast growth factor 23 refers to C-terminal Fibroblast growth factor 23.
  • FGF23 fibroblast growth factor 23
  • Fibroblast growth factor 23 is a 32-kdalton peptide secreted by bone cells (osteocytes and osteoblasts). This peptide can be cleaved between amino-acids 176-179 in a N-terminal and a C-terminal fragments (Zisman AL et al 2010). The enzyme responsible for this cleavage has not been clearly identified. Under physiological condition FGF23 circulates as an intact peptide.
  • the "predetermined value" according to the invention can be a single value such as a reference value derived from the concentration of cFGF23 in samples obtained from subjects who are suffering from SCD, or a control value derived from the concentration of cFGF23 in samples from healthy subjects.
  • a predetermined reference value can be relative to a number or value derived from population studies, including without limitation, such subjects having similar body mass index, total cholesterol levels, LDL/HDL levels, systolic or diastolic blood pressure, subjects of the same or similar age range, subjects in the same or similar ethnic group, and subjects having the same severity of heart failure.
  • Such predetermined reference values can be derived from statistical analyses and/or risk prediction data of populations obtained from mathematical algorithms and computed indices of metabolic syndrome.
  • the predetermined reference values are derived from the level of cFGF23 in a control sample derived from one or more subjects who were not subjected to cardiac hypetrophy. Furthermore, retrospective measurement of the level of cFGF23 in properly banked historical subject samples may be used in establishing these predetermined reference values.
  • the predetermined reference value has to be determined in order to obtain the optimal sensitivity and specificity according to the function of the test and the benefit/risk balance (clinical consequences of false positive and false negative).
  • the optimal sensitivity and specificity can be determined using a Receiver Operating Characteristic (ROC) curve based on experimental data.
  • ROC Receiver Operating Characteristic
  • ROC curve is receiver operator characteristic curve, which is also known as receiver operation characteristic curve. It is mainly used for clinical biochemical diagnostic tests. ROC curve is a comprehensive indicator that reflects the continuous variables of true positive rate (sensitivity) and false positive rate (1 -specificity). It reveals the relationship between sensitivity and specificity with the image composition method. A series of different cut-off values (thresholds or critical values, boundary values between normal and abnormal results of diagnostic test) are set as continuous variables to calculate a series of sensitivity and specificity values.
  • sensitivity is used as the vertical coordinate and specificity is used as the horizontal coordinate to draw a curve.
  • AUC area under the curve
  • the point closest to the far upper left of the coordinate diagram is a critical point having both high sensitivity and high specificity values.
  • the AUC value of the ROC curve is between 1.0 and 0.5. When AUO0.5, the diagnostic result gets better and better as AUC approaches 1. When AUC is between 0.5 and 0.7, the accuracy is low. When AUC is between 0.7 and 0.9, the accuracy is moderate. When AUC is higher than 0.9, the accuracy is quite high.
  • This algorithmic method is preferably done with a computer.
  • Existing software or systems in the art may be used for the drawing of the ROC curve, such as: MedCalc 9.2.0.1 medical statistical software, SPSS 9.0, r
  • a concentration of cFGF23 higher than the predetermined value is indicative of an increased risk of having cardiac hypertrophy.
  • sample is a biological sample and refers to a sample obtained or isolated from a subject, for example blood, semen, blood plasma, synovial fluid, serum or a tissue.
  • sample is a blood sample obtained from a subject suffering from SCD.
  • the concentration of cFGF23 may be measured by any known method in the art.
  • the measurement of the concentration of cFGF23 in the sample is typically carried out using standard protocols known in the art.
  • the method may comprise contacting the blood sample with a binding partner capable of selectively interacting with cFGF23 in the sample.
  • the binding partners are antibodies, such as, for example, monoclonal antibodies or even aptamers.
  • the binding may be detected through use of a competitive immunoassay, a noncompetitive assay system using techniques such as western blots, a radioimmunoassay, an ELISA (enzyme linked immunosorbent assay), a "sandwich” immunoassay, an immunoprecipitation assay, a precipitin reaction, a gel diffusion precipitin reaction, an immunodiffusion assay, an agglutination assay, a complement fixation assay, an immunoradiometric assay, a fluorescent immunoassay, a protein A immunoassay, an immunoprecipitation assay, an immunohistochemical assay, a competition or sandwich ELISA, a radioimmunoassay, a Western blot assay, an immunohistological assay, an immunocytochemical assay, a dot blot assay, a fluorescence polarization assay, a scintillation proximity assay, a homogeneous time resolved fluorescence as
  • the aforementioned assays generally involve the binding of the partner (ie. antibody or aptamer) to a solid support.
  • Solid supports which can be used in the practice of the invention include substrates such as nitrocellulose (e.g., in membrane or microtiter well form); polyvinylchloride (e.g., sheets or microtiter wells); polystyrene latex (e.g., beads or microtiter plates); polyvinylidine fluoride; diazotized paper; nylon membranes; activated beads, magnetically responsive beads, and the like.
  • An exemplary biochemical test for identifying specific proteins employs a standardized test format, such as ELISA test, although the information provided herein may apply to the development of other biochemical or diagnostic tests and is not limited to the development of an ELISA test (see, e.g., Molecular Immunology: A Textbook, edited by Atassi et al. Marcel Dekker Inc., New York and Basel 1984, for a description of ELISA tests). Therefore ELISA method can be used, wherein the wells of a microtiter plate are coated with a set of antibodies which recognize cFGF23. A sample containing or suspected of containing cFGF23 is then added to the coated wells.
  • the plate(s) can be washed to remove unbound moieties and a detectably labelled secondary binding molecule added.
  • the secondary binding molecule is allowed to react with any captured sample marker protein, the plate washed and the presence of the secondary binding molecule detected using methods well known in the art.
  • Measuring the level of cFGF23 may also include separation of the compounds: centrifugation based on the compound's molecular weight; electrophoresis based on mass and charge; HPLC based on hydrophobicity; size exclusion chromatography based on size; and solid-phase affinity based on the compound's affinity for the particular solid-phase that is used.
  • said one or two biomarkers proteins may be identified based on the known "separation profile" e.g., retention time, for that compound and measured using standard techniques.
  • the separated compounds may be detected and measured by, for example, a mass spectrometer.
  • levels of immunoreactive cFGF23 in a sample may be measured by an immunometric assay on the basis of a double-antibody "sandwich” technique, with a monoclonal antibody specific for cFGF23 (Cayman Chemical Company, Ann Arbor, Michigan).
  • said means for measuring cFGF23 level are for example i) a cFGF23 buffer, ii) a monoclonal antibody that interacts specifically with cFGF23, iii) an enzyme-conjugated antibody specific for cFGF23 and a predetermined reference value of cFGF23.
  • the invention in a second aspect, relates to a method of preventing the risk of having cardiac hypertrophy in a subject suffering from SCD comprising a step of administrating to said subject a therapeutically amount of cFGF23 antagonist.
  • the invention relates to a method , wherein the method of preventing the risk of having cardiac hypertrophy comprising i) a first step consisting in determining whether the subject is at risk of having cardiac hypertrophy by the method as described above and ii) administering to said subject a therapeutically amount of cFGF23 antagonist.
  • the term "preventing the risk” or prophylactic treatment” as used herein refers to treatment as well as curative or disease modifying treatment, including treatment of subject at risk of contracting the disease or suspected to have contracted the disease as well as subject who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
  • the treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.
  • therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • the phrase “induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
  • the general goal of an induction regimen is to provide a high level of drug to a subject during the initial period of a treatment regimen.
  • An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
  • maintenance regimen refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a subject during treatment of an illness, e.g., to keep the subject in remission for long periods of time (months or years).
  • a maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.]).
  • cFGF23 antagonist refers to any cFGF23 antagonist that is currently known in the art or that will be identified in the future. It includes any chemical entity that, upon administration to a subject, results in inhibition of a biological activity of cFGF23 associated with activation of the FGFR or in inhibition of FGFR (and more precisely FGFR type 1, 2, 3 or 4) in the subject, including any of the downstream biological effects otherwise resulting from the binding to FGFR.
  • Such an antagonist can act by binding directly to the intracellular domain of the receptor and inhibiting its kinase activity.
  • such an antagonist can act by occupying the ligand binding site or a portion thereof of the FGFR, thereby making the receptor inaccessible to its natural ligand so that its normal biological activity is prevented or reduced.
  • such an antagonist can also act by binding directly to the cFGF23, thereby preventing the binding of cFGF23 to FGFR (i.e. FGFR-1, FGFR-2, FGFR- 3 or FGFR-4).
  • FGFR-1, FGFR-2, FGFR- 3 or FGFR-4 FGFR-1, FGFR-2, FGFR- 3 or FGFR-4.
  • the cFGF23 antagonist is an inhibitor of the interaction between cFGF23 and FGFR.
  • blocking the interaction is used herein to mean preventing or reducing the direct or indirect association of one or more molecules, peptides, proteins, enzymes or receptors; or preventing or reducing the normal activity of one or more molecules, peptides, proteins, enzymes, or receptors.
  • inhibitor of the interaction between cFGF23 and FGFR refers to a molecule which can prevent the interaction between cFGF23 and FGFR by competition or by fixing to one of the molecules.
  • the cFGF23 antagonist may be a molecule which binds to cFGF23 or FGFR selected from the group consisting of antibodies, aptamers, polypeptides and small organic molecules.
  • the cFGF23 antagonist is an antibody that can block the interaction of FGFR with cFGF23.
  • the cFGF23 antagonist is an antibody directed against the cFGF23 or FGFR, in such a way that said antibody impairs the binding of a cFGF23 to FGFR ("neutralizing antibody").
  • the antibody is a monoclonal antibody or a fragment thereof (e.g. scFv) or a single chain antibody such as a VHH.
  • the antibody is a chimeric antibody, a humanized antibody or a human antibody.
  • the cFGF23 antagonist is an anti-cFGF23 monoclonal antibody produced by hybridoma CIO (Accession No. FERM BP- 10772) as described in the patent application US2009148461, which is hereby incorporated by reference in its entirety.
  • the cFGF23 antagonist is anti-cFGF23 antibodies such as described in the patent US7981419 which is hereby incorporated by reference in its entirety.
  • the anti-cFGF23 antibody is KRN23 (Kyowa Hakko Kirin Pharma, Inc.) which is a recombinant fully human monoclonal antibody.
  • the cFGF23 antagonist is an antibody directed against FGFR.
  • the antibody directed against FGFR could be mmonoclonal antibodies which are capable of blocking the function of FGFRs.
  • the antibody is directed against FGFR 2.
  • the antibody is BAY 1179470 (Schatz et al 2014), which is developed by Bayer. Others antibodies directed against FGFR2 are described in Zhao et al 2010.
  • the antibody is directed against FGFR 3.
  • the antibody is RG7444/MFGR1877S, which blocks FGFR3 activity.
  • the antibody is directed against FGFR4. Examples of such antibodies are described in U.S. Pub. No.: 20100169992.
  • the cFGF23 antagonist is an aptamer directed against cFGF23.
  • Aptamers are a class of molecule that represents an alternative to antibodies in term of molecular recognition. Aptamers are oligonucleotide or oligopeptide sequences with the capacity to recognize virtually any class of target molecules with high affinity and specificity.
  • the cFGF23 antagonist is an aptamer directed against FGFR. Such aptamers against FGFR are described in US8916696.
  • the cFGF23 antagonist is a polypeptide.
  • polypeptide refers to a polypeptide that specifically bind to cFGF23, can be used as a cFGF23 antagonist that bind to and sequester the cFGF23 protein, thereby preventing it from signaling.
  • the cFGF23 antagonist is a polypeptide which binds specifically to FGFRs.
  • the cFGF23 antagonist is a small molecule.
  • small organic molecule refers to a molecule of a size comparable to those organic molecules generally used in pharmaceuticals. The term excludes biological macro molecules (e. g. proteins, nucleic acids, etc.). Typically, small organic molecules range in size up to about 5000 Da, more preferably up to 2000 Da, and most preferably up to about 1000 Da.
  • the cFGF23 antagonist is a small molecule which inhibits FGFRs activity.
  • the cFGF23 antagonist useful in invention is a tyrosine kinase inhibitor (TKI) that inhibits FGFR activity.
  • TKI tyrosine kinase inhibitor
  • A'TKI that inhibits FGFR activity means an inhibitor of receptor tyrosine kinase activity that selectively or non- selectively reduces the tyrosine kinase activity of a FGFR receptor. Such an inhibitor generally reduces FGFR tyrosine kinase activity without significantly effecting the expression of FGFR and without effecting other FGFR activities such as ligand-binding capacity.
  • TKI that inhibits FGFR activity is PD 173074 and other pyrido[2,3-d] pyrimidine compounds described in the patent US5733913.
  • Other small molecule inhibitors of FGFR which may be used include SU6668 and SU5402.
  • the inhibitor of FGFR is PD 166866 such as described in Panek et al 1998 and Risuleo et al 2009.
  • the cFGF23 antagonist is an inhibitor of cFGF23 gene expression.
  • the term "inhibitor of cFGF23 gene expression" refers to a natural or synthetic compound that has a biological effect to inhibit or significantly reduce the expression of the gene encoding for cFGF23.
  • the inhibitor of cFGF23 expression has a biological effect on one or more of the following events: (1) production of an RNA template from a ⁇ ⁇
  • the inhibitor of cFGF23 expression is an antisense oligonucleotide.
  • Anti-sense oligonucleotides including anti-sense RNA molecules and anti-sense DNA molecules, would act to directly block the translation of cFGF23 mRNA by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level of cFGF23 proteins, and thus activity, in a cell.
  • antisense oligonucleotides of at least about 15 bases and complementary to unique regions of the mRNA transcript sequence encoding cFGF23 can be synthesized, e.g., by conventional phosphodiester techniques and administered by e.g., intravenous injection or infusion.
  • Methods for using antisense techniques for specifically alleviating gene expression of genes whose sequence is known are well known in the art (e.g. see U.S. Pat. Nos. 6,566,135; 6,566,131; 6,365,354; 6,410,323; 6,107,091; 6,046,321; and 5,981,732).
  • the inhibitor of cFGF23 expression is a small inhibitory RNAs
  • cFGF23 expression can be reduced by contacting the subject or cell with a small double stranded RNA (dsRNA), or a vector or construct causing the production of a small double stranded RNA, such that cFGF23 expression is specifically inhibited (i.e. RNA interference or RNAi).
  • dsRNA small double stranded RNA
  • RNAi RNA interference or RNAi
  • inhibitor of cFGF23 expression is ribozyme.
  • Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cleavage of RNA. The mechanism of ribozyme action involves sequence specific hybridization of the ribozyme molecule to complementary target RNA, followed by endonucleolytic cleavage. Engineered hairpin or hammerhead motif ribozyme molecules that specifically and efficiently catalyze endonucleolytic cleavage of cFGF23 mRNA sequences are thereby useful within the scope of the present invention.
  • ribozyme cleavage sites within any potential RNA target are initially identified by scanning the target molecule for ribozyme cleavage sites, which typically include the following sequences, GUA, GUU, and GUC. Once identified, short RNA sequences of between about 15 and 20 ribonucleotides corresponding to the region of the target gene containing the cleavage site can be evaluated for predicted structural features, ⁇ fret
  • oligonucleotide sequence unsuitable.
  • the suitability of candidate targets can also be evaluated by testing their accessibility to hybridization with complementary oligonucleotides, using, e.g., ribonuclease protection assays.
  • the inhibitor of cFGF23 expression is an endonuclease.
  • the mechanism behind endonuclease-based genome inactivating generally requires a first step of DNA single or double strand break, which can then trigger two distinct cellular mechanisms for DNA repair, which can be exploited for DNA inactivating: the errorprone nonhomologous end-joining (NHEJ) and the high-fidelity homology-directed repair (HDR).
  • Endonucleases for gene inactivation have come in various forms, which includes CRISPR)/CRISPR associated (Cas) systems, mega nucleases (MN), zinc finger nucleases (ZFN), and transcription activator-like effector nucleases (TALEN).
  • CRISPR-cas CRISPR-cas.
  • CRISPR-cas has its general meaning in the art and refers to clustered regularly interspaced short palindromic repeats associated which are the segments of prokaryotic DNA containing short repetitions of base sequences.
  • the endonuclease is CRISPR-cas9 which is from Streptococcus pyogenes.
  • the CRISPR/Cas9 system has been described in US 8697359 Bl and US 2014/0068797. Originally an adaptive immune system in prokaryotes (Barrangou and Marraffmi, 2014), CRISPR has been recently engineered into a new powerful tool for genome editing. It has already been successfully used to target important genes in many cell lines and organisms, including human (Mali et al, 2013, Science, Vol. 339 : 823-826), bacteria (Fabre et al, 2014, PLoS Negl. Trap. Dis., Vol.
  • the endonuclease is CRISPR-Cpfl which is the more recently characterized CRISPR from Provotella and Francisella 1 (Cpfl) in Zetsche et al. ("Cpfl is a Single RNA-guided Endonuclease of a Class 2 CRISPR-Cas System (2015); Cell; 163, 1-13).
  • Antisense oligonucleotides, siRNAs and ribozymes as described above may be delivered in vivo alone or in association with a vector.
  • a "vector" is any vehicle capable of facilitating the transfer of the antisense oligonucleotide, siRNA or ribozyme nucleic acid to the cells and preferably cells expressing cFGF23.
  • the vector transports the nucleic acid to cells with reduced degradation relative to the extent of degradation that would result in the absence of the vector.
  • the vectors useful in the invention include, but are not limited to, plasmids, phagemids, viruses, other vehicles derived from viral or bacterial sources that have been manipulated by the insertion or incorporation of the antisense oligonucleotide, siRNA or ribozyme nucleic acid sequences.
  • Viral vectors are a preferred type of vector and include, but are not limited to nucleic acid sequences from the following viruses: retrovirus, such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rouse sarcoma virus; adenovirus, adeno-associated virus; SV40-type viruses; polyoma viruses; Epstein-Barr viruses; papilloma viruses; herpes virus; vaccinia virus; polio virus; and RNA virus such as a retrovirus.
  • retrovirus such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rouse sarcoma virus
  • retrovirus such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rouse sarcoma virus
  • adenovirus adeno
  • Non-cytopathic viruses include retroviruses (e.g., lentivirus), the life cycle of which involves reverse transcription of genomic viral RNA into DNA with subsequent proviral integration into host cellular DNA. Retroviruses have been approved for human gene therapy trials. Most useful are those retroviruses that are replication-deficient (i.e., capable of directing synthesis of the desired proteins, but incapable of manufacturing an infectious particle).
  • retroviruses e.g., lentivirus
  • Viruses for certain applications are the adeno-viruses and adeno-associated viruses, which are double-stranded DNA viruses that have already been approved for human use in ⁇ ndu.
  • the adeno-associated virus can be engineered to be replication deficient and is capable of infecting a wide range of cell types and species. It further has advantages such as, heat and lipid solvent stability; high transduction frequencies in cells of diverse lineages, including hemopoietic cells; and lack of superinfection inhibition thus allowing multiple series of transductions.
  • the adeno-associated virus can integrate into human cellular DNA in a site-specific manner, thereby minimizing the possibility of insertional mutagenesis and variability of inserted gene expression characteristic of retroviral infection.
  • wild-type adeno-associated virus infections have been followed in tissue culture for greater than 100 passages in the absence of selective pressure, implying that the adeno- associated virus genomic integration is a relatively stable event.
  • Plasmid vectors have been extensively described in the art and are well known to those of skill in the art. See e.g., SANBROOK et al., "Molecular Cloning: A Laboratory Manual," Second Edition, Cold Spring Harbor Laboratory Press, 1989. Some commonly used plasmids include pBR322, pUC18, pUC19, pRC/CMV, SV40, and pBlueScript. Other plasmids are well known to those of ordinary skill in the art. Additionally, plasmids may be custom designed using restriction enzymes and ligation reactions to remove and add specific fragments of DNA. Plasmids may be delivered by a variety of parenteral, mucosal and topical routes.
  • the DNA plasmid can be injected by intramuscular, intradermal, subcutaneous, or other routes. It may also be administered by intranasal sprays or drops, rectal suppository and orally. It may also be administered into the epidermis or a mucosal surface using a gene-gun.
  • the plasmids may be given in an aqueous solution, dried onto gold particles or in association with another DNA delivery system including but not limited to liposomes, dendrimers, cochleate and microencapsulation.
  • the cFGF23 antagonist is an inhibitor of FGFR gene expression.
  • the cFGF23 antagonist is a small inhibitory RNAs (siRNAs), a ribozyme, or an endonuclease as described above.
  • a “therapeutically effective amount” is meant a sufficient amount of the FGF23 antagonist improve survival time of a patient suffering from SCD and having a risk of mortality at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, 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 patient 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 patient; 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 coincidential with the specific polypeptide employed; and like factors well known in the medical arts.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day.
  • the 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 patient to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably 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.
  • cFGF23 antagonists as described above may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form pharmaceutical compositions.
  • pharmaceutically acceptable excipients such as a carboxylate, a carboxylate, a carboxylate, a carboxylate, a carboxylate, a carboxylate, a carboxylate, a carboxylate, a carboxylate, a pharmaceutically acceptable.
  • 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.
  • compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings.
  • 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 contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
  • 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 1 r
  • compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • Solutions comprising compounds of the invention as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the polypeptide (or nucleic acid encoding thereof) can be formulated into a composition in a neutral or salt form.
  • Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
  • inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like.
  • Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine,
  • the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active polypeptides in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • sterile powders for the preparation of sterile injectable solutions
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
  • the formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed.
  • parenteral administration in an aqueous solution for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure.
  • one dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
  • the invention will be further illustrated by the following figures and examples.
  • FIGURES are a diagrammatic representation of FIGURES.
  • FIG. 1 FGF23 concentration in patients with sickle cell disease (SCD) and controls.
  • C-terminal FGF23 (cFGF23) plasma concentration is higher in SCD patients with SS (circle) or non- SS (diamond) genotype than in control subjects (square).
  • FIG. 2 Effects of C-terminal FGF23 (cFGF23) on adult rat ventricular cardiomyocyte size (ARVMs).
  • Plasma concentration of FGF23 was measured the day of glomerular filtration rate (GFR) measurement. Echocardiography was performed within the year preceding or following the measurement of GFR. The data analyzed in the present study were obtained between January 2007 and December 2013 from 77 SCD patients. As a control we measured plasma FGF23 concentration in healthy subjects of similar ethnic origin as SCD patients. We checked by hemoglobin electrophoresis that the control subjects had no SCD, sickle cell trait, thalassemia major or intermedia.
  • the control subjects were recruited in a French health center (Health Center of the Health Insurance Fund of Seine- Saint-Denis, CPAM, Bobigny, France) and lived in the same area as the SCD patients. One hundred and seventy-two subjects were enrolled as controls.
  • the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki, and has been approved by a local ethic committee (number: 2011531-RCEB).
  • Glomerular filtration rate was measured using the plasma clearance of iohexol. After the injection of 5 ml of iohexol 300 mg of Iodine/ml, a blood sample was drawn every hour for 5 hours. Clearance of iohexol was calculated by the following formula: Clearance Dose/AUC, where AUC is the area under the plasma concentration curve. During the three months preceding the investigation, the patient had no acute illness, no vaso-occlusive crisis, no acute chest syndrome, no infection, and no red blood cells transfusion. Pregnant and breast feeding women and patients allergic to iodine were not eligible for this exploration. Estimated GFR was calculated using CKD-EPI formula without correction for ethnicity 22 .
  • Biochemical measurements We measured hemoglobin levels, reticulocyte counts, mean corpuscular volume (MCV), serum ferritin, iron, creatinine, calcium, phosphate, 25(OH)-vitamin D and l,25(OH)2-vitamin D concentrations and plasma cFGF23 in SCD patients and in controls.
  • MCV mean corpuscular volume
  • serum ferritin serum ferritin
  • iron creatinine
  • calcium phosphate
  • phosphate 25(OH)-vitamin D
  • l 25(OH)2-vitamin D concentrations
  • plasma cFGF23 plasma cFGF23
  • FGF23 plasma concentration was measured using Immutopics C-terminal Elisa kits (Human FGF23 cterminal Elisa kit, Immutopics International, San Clemente California USA) and Kainos intact FGF23 Elisa kit (Kainos Laboratories Japan).
  • Immutopics C-terminal Elisa kits Human FGF23 cterminal Elisa kit, Immutopics International, San Clemente California USA
  • Kainos intact FGF23 Elisa kit Kernos Laboratories Japan
  • Systolic pulmonary artery pressure was calculated by adding an assumed right atrial pressure of 10 mm Hg to the regurgitation jet gradient across the tricuspid valve. Pulmonary artery systolic hypertension was defined as PASP > 30 mm Hg. Mitral flow velocity measurements. The transmural pulsed wave Doppler flow signals were recorded in the apical four-chamber view. Peak mitral flow velocities in early diastole (E) and during atrial contraction (A) were measured. The E/A ratio was calculated. Measurements of myocardial tissue Doppler imaging (TDI) velocities. TDI myocardial velocities were measured in the longitudinal axis from the apical four-chamber view.
  • TDI myocardial tissue Doppler imaging
  • Myocardial velocities were sampled at the level of the mitral annulus on the lateral aspects.
  • the peak velocity during early diastole ( ⁇ ') was measured.
  • the early mitral inflow/annular movement ratio ( ⁇ / ⁇ ') was also calculated.
  • Diastolic dysfunction assessment Diastolic dysfunction was assessed using the American Society of Echocardiography guidelines. Diastolic function was determined to be normal by tissue Doppler imaging when both peak septal E' (mitral annulus) velocity was>8 _
  • Diastolic dysfunction was evaluated using tissue Doppler imaging and pulsed Doppler peak E and A velocities, E/A ratio. Diastolic dysfunction was defined as an E/A ratio of >2, and an E/E ratio of >12.
  • ARVMs Adult rat ventricular myocytes
  • MEM Minimum Essential Medium
  • FBS fetal bovine serum
  • penicillin-streptomycin 1% penicillin-streptomycin
  • HEPES pH 7.6
  • laminin-coated culture dishes (10 ⁇ g/ml laminin) at a density of 3.105 cells per dish.
  • ARVMs were left to adhere for 2 h in a 95% 02, 5%) C02 atmosphere at 37°C, before the medium was replaced with FBS-free MEM.
  • the cDNA sequence encoding cFGF23 corresponding to amino acid 178 to 251 of the intact peptide was generated from RC210127 plasmid (Origene) by PCR overlap extension. Both C-terminal sequence and RC210127 plasmid were digested with AsiSI and Kfll enzymes. The empty vector obtained from RC210127 digestion was purified and then cFGF23 cDNA fragment was introduced by ligation. The identity of cDNA was confirmed by DNA sequence analysis. Production of cFGF23 protein. Chinese hamster ovary cells were seeded on a 100mm culture dish in F12-K medium containing 10% fetal bovine serum.
  • cFGF23 protein tagged with c-Myc was purified using a column purification procedure using anti-c-Myc agarose according toêt ⁇
  • cFGF23 peptide was determined using Immutopics C-terminal Elisa kits (Human FGF23 c-terminal Elisa kit, Immutopics International, San Clemente California USA).
  • PMHC beta-myosin heavy chain
  • HbSS hemoglobin SS genotype
  • HbSC hemoglobin SC
  • HbS ⁇ sickle cell hemoglobin S- ⁇ thalassemia
  • HbSD hemoglobin SD
  • cFGF23 plasma concentration was significantly higher in SCD patients than in controls and above normal values of 150 RU/ml in 58 (75.3%) SCD patients and in 18 _
  • the LVMI was above normal value (male >115g/m2, female > 95 g/m 2 ) in 68.8% of SCD patients, 18 males (62%) and 35 females (73%) and was significantly higher in SS than in non-SS patients.
  • Left ventricle end diastolic diameter (LVEDD) was increased in 27 SCD patients (35.1%), 14 males (48.3%) and 13 females (27.1%) and LVEDD was significantly higher in SS than in non-SS patients.
  • left ventricle end systolic diameter (LVESD) was significantly higher in SS than in non-SS patients.
  • the LVEF was equal or below 55% in 7 patients among whom 6 had SS genotype.
  • LVEF was also significantly lower in SS than in non-SS patients.
  • the fraction of shortening (FS) was above 27% in all patients however SS patients had significantly lower FS than non-SS patients.
  • ARVMs were cultivated in the presence of increasing concentration of purified cFGF23. Exposure to cFGF23 for 24hrs significantly increased in a concentration dependent manner the cell surface area of ARVMs (Figure 2A). This effect was similar to that observed with FGF2 a fibroblast growth factor known to induce cardiac hypertrophy via a FGFR ( Figure 2B). RT-PCR did not show aKlotho mRNA expression in ARVMs, however various types of FGFR were detected by western blot (data not shown).
  • cFGF23 could prevent cardiac hypertrophy without altering intact FGF23 effect.
  • Measurements of cFGF23 and not iFGF23 could be used as a prognostic marker of heart hypertrophy and to manage therapy.
  • Hassell KL Population estimates of sickle cell disease in the u.S. American journal of preventive medicine. 2010;38:S512-521

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Abstract

Les inventeurs ont mesuré les concentrations d'iFGF23 plasmatique et de FGF23 C-terminal (cFGF23) chez 77 patients SCD jeunes adultes et chez 172 sujets témoins sains. La concentration plasmatique de cFGF23, mais non celle de l'iFGF23, était plus élevée chez les patients SCD que chez les sujets témoins (médiane 419 vs 55 UR/ml de cFGF23 p < 0,0001). En conséquence, la présente invention concerne un procédé de prédiction du risque de présenter une hypertrophie cardiaque chez un sujet souffrant d'une drépanocytose comprenant les étapes consistant : i) à mesurer la concentration de cFGF23 dans un échantillon prélevé chez ledit sujet, ii) à comparer la concentration obtenue à l'étape (i) à une valeur prédéterminée, et iii) à conclure que le sujet présente un risque d'hypertrophie cardiaque lorsque la concentration de cFGF23 est supérieure à la valeur prédéterminée ou à conclure que le sujet n'a pas de risque d'hypertrophie cardiaque lorsque la concentration de cFGF23 est inférieure à la valeur prédéterminée.
PCT/EP2017/075648 2016-10-10 2017-10-09 Procédés de prédiction du risque de présenter une hypertrophie cardiaque Ceased WO2018069232A1 (fr)

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