WO2004022047A1 - Utilisation d'un agoniste du recepteur alpha active par proliferation du peroxysome (ppar$g(a)) dans le traitement de deficiences de la carnitine palmitoyl transferase-2 - Google Patents

Utilisation d'un agoniste du recepteur alpha active par proliferation du peroxysome (ppar$g(a)) dans le traitement de deficiences de la carnitine palmitoyl transferase-2 Download PDF

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WO2004022047A1
WO2004022047A1 PCT/IB2003/003527 IB0303527W WO2004022047A1 WO 2004022047 A1 WO2004022047 A1 WO 2004022047A1 IB 0303527 W IB0303527 W IB 0303527W WO 2004022047 A1 WO2004022047 A1 WO 2004022047A1
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cpt2
patient
deficiency
bezafibrate
pparα
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Jean Bastin
Fatima Djouadi
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Institut National De La Sante Et De La Recherche Medicale (Inserm)
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients

Definitions

  • PPAR ⁇ peroxisome proliferator-activated receptor alpha
  • the present invention relates to the use of a peroxisome proliferator- activated receptor alpha (PPAR ⁇ ) agonist for the treatment of a Carnitine palmitoyltransferase 2 (CPT2) deficiency.
  • PPAR ⁇ peroxisome proliferator- activated receptor alpha
  • the PPAR ⁇ agonist may be a fibrate, in particular bezafibrate.
  • CPT2 Carnitine palmitoyltransferase 2
  • FEO mitochondrial fatty acid ⁇ -oxidation
  • CPT2 EC 2.3.1.21
  • LCFA long-chain fatty acids
  • CPT1 and CPT2 catalyse the transesterification of long-chain acyl-CoA into long-chain acylcamitine in the cytosol, and the reverse reaction in the mitochondrial matrix, respectively.
  • This "acylcamitine shuttle" is completed by the action of the camitine/acylcarnitine translocase.
  • fatty acids are oxidized to acetyl-CoA through the four steps of intra- mitochondrial ⁇ -oxidation leading to ATP production.
  • CPT2 deficiency The clinical phenotypes of CPT2 deficiency can be divided into two major groups (Bonnefont, et a/., 1999; Brivet et al., 1999).
  • the adult form has its onset in teenagers and young adults, and most often expresses as recurrent attacks of rhabdomyolysis, usually triggered by prolonged exercise, fasting or infection.
  • Two kinds of life-threatening complications e.g. acute renal failure and respiratory insufficiency may occasionally occur during episodes of rhabdomyolysis.
  • the infantile form of CPT2 deficiency is a more severe condition characterized by acute liver failure with hypoketotic hypoglycemia and serious cardiac damages occurring in the neonatal period or infancy.
  • Severity of the clinical phenotype of some fatty acid oxidation disorders correlates to some extent with the severity of the metabolic block (Gregersen et al., 2001 ).
  • severe neonatal/infantile forms are generally associated with extremely low enzyme activity in the patient's fibroblasts, whereas an appreciable residual enzyme activity is often measured in the milder adult forms (Bonnefont, et al., 1999; Bonnefont et al., 1996).
  • PPAR ⁇ peroxisome proliferator-activated receptor ⁇
  • PPAR ⁇ is a ligand-activated transcription factor that control gene expression by binding to specific PPAR responsive elements (PPREs) within promoters.
  • PPRE PPAR responsive elements
  • PPRE have been identified on 5'-flanking region of human CPT1 muscular isoform (Brandt et al., 1998; Mascara et al., 1998), and of human medium-chain acyl-CoA dehydrogenase (Gulick et al. 1994), which are enzymes involved in fatty acid ⁇ -oxydation.
  • CPT2 the structure of regulatory regions of this gene is still unknown.
  • the inventors thus demonstrate for the first time that CPT2 gene regulation by PPAR ⁇ signaling pathway operates in human cells. They further establish that PPAR ⁇ activators can stimulate CPT2 residual activity to a level sufficient to allow normal FAO flux in deficient human fibroblasts. The results obtained thus bring evidence that pharmacological approaches based on stimulation of residual capacities can successfully restore mitochondrial FAO in fibroblasts of CPT2-deficient patients and are useful in other inborn errors of mitochondrial ⁇ -oxidation.
  • CPT2 Carnitine palmitoyltransferase 2
  • CPT2 the enzyme that localizes in the mitochondrial inner membrane and that works with carnitine palmitoyltransferase 1 (outer membrane) and carnitine-acylcarnitine translocase (inner membrane) to move acyl-CoA into the mitochondrion for further fatty acid beta-oxidation. More particularly, CPT2 catalyses the formation of acyl-CoA from acylcamitine and CoA.
  • the CPT2 cDNA and amino acid sequence are shown in SEQ ID N°7 and SEQ ID N°8, respectively.
  • CPT2 deficiency is recognized as an orphan disease caused by a genetic defect linked to mutation in the CPT2 gene.
  • CPT2 deficiencies include adult and/or infantile and/or neonatal form.
  • Adult form of the disease generally declares between 6 and 20 years, but onset may be over 50 years or as early as 4 years. The disease is associated with recurrent attack of myalgias and muscle stiffness or weakness.
  • the neonatal form is the most severe form of the disease.
  • the onset is either prenatal or occurs very soon after delivery (few hours to 4 days) and generally leads to patient's death.
  • the CPT2 deficiency to be treated is preferably a "mild form" of the disease generally associated with at least 10%, residual CPT2 enzyme activity as compared to control value, as can be measured in control cells with no CPT2 mutation.
  • CPT2 enzyme activity can be assayed by measuring palmitoyl-L-(methyl- 14 C) carnitine formed from L- (methyl- 14 C) carnitine and palmitoyl-CoA as described in Demaugre et al., 1991.
  • Mild form usually corresponds to adult onset of CPT2 deficiency. "Severe form” of the disease is generally associated with residual CPT2 activity below 10% of control value. Severe form usually corresponds to infantile onset of CPT2 deficiency.
  • peroxisome proliferator-activated receptor alpha or "PPAR ⁇ ” describes one of the three isoforms of the nuclear receptor group called peroxisome proliferator-activated receptors. Cloning of the receptor has been described in Sher et al., 1993.
  • PPAR ⁇ is a ligand-activated transcription factor that control gene expression by binding to specific PPAR responsive elements (PPREs) within promoters.
  • PPAR ⁇ agonist is meant for a compound or composition which, when combined with PPAR ⁇ , directly or indirectly (preferably binding directly to PPAR ⁇ ) stimulates or increases an in vivo or in vitro reaction typical for the receptor, e.g. transcriptional regulation activity, as measured by an assay known to one skilled in the art, including, but not limited to, the "co-transfection” or “cistrans” assays such as described in Lehmann, et al. (1995) which is incorporated by reference herein.
  • agonist can bind directly to PPAR ⁇ and achieve PPAR ⁇ activation, i.e. heterodimerization of PPAR ⁇ with retinoic X receptor (RXR) and subsequent binding to PPRE.
  • RXR retinoic X receptor
  • Examples of PPAR ⁇ agonists include fibrates.
  • a preferred PPAR ⁇ agonist is a fibrate compound.
  • the term "fibrate” is intended for fibric acid derivatives, esters and pharmaceutically acceptable salts thereof.
  • Fibrate compounds include, but are not limited to, bezafibrate, fenofibrate, gemfibrozil, ciprofibrate, binifibrate, clinofibrate, clofibrate, clofibric acid, clofibride, etofibrate, nicofibrate, pirifibrate, plafibride, ronifibrate, theofibrate, tocofibrate, and analogs, derivatives and pharmaceutically acceptable salts thereof.
  • PPAR ⁇ compounds disclosed in Lehmann et al, 1995; Amri et al., 1991a; Kliewer et al., 1997; Amri et al., 1991 b; and Grimaldi et al., 1992 are incorporated by reference herein.
  • Other PPAR ⁇ ligands may be useful, such as Wy 14,463 ([4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid), ETYA (5,8,11 ,14-Eicosatetraynoic acid), BRL49653 (rosiglitazone) or fatty acids including linoleic acid, linolenic acid, oleic acid.
  • treatment is meant the prophylactic or curative treatment of a disease. More particularly, CPT2 deficiency treatment includes prevention of onset in a patient susceptible to develop the disease, i.e. a patient who carries a mutation in the CPT2 gene, prevention and/or treatment -of chronic attack occurrence, in particular of life- threatening events.
  • the inventors propose that PPAR ⁇ agonist increases CPT2 transcription and leads to a subsequent rise in CPT2 enzyme activity to a level sufficient to restore normal fatty acid oxidation flux.
  • the threshold as to sufficient CPT2 activity is regarded as being around 40% of control value.
  • the invention should not be limited to the proposed mechanism.
  • the term "patient” is intended for a mammal, in particular a human.
  • the present invention provides a method of treatment of a Carnitine Palmitoyl Transferase-2. (CPT2) deficiency comprising administration of a peroxisome proliferator-activated receptor alpha (PPAR ⁇ ) agonist to a patient in need thereof.
  • CPT2 Carnitine Palmitoyl Transferase-2.
  • PPAR ⁇ peroxisome proliferator-activated receptor alpha
  • the invention relates to the use of a
  • PPAR ⁇ agonist for the manufacture of a medicament intended for the treatment of a CPT2 deficiency.
  • the invention concerns the use of a PPAR ⁇ agonist for the manufacture of a medicament for increasing the CPT2 enzyme activity in a patient with CPT2 deficiency.
  • said CPT2 deficiency is a mild CPT2 deficiency.
  • Mild CPT2 deficiency can be associated with a 338C>T [S113L] mutation of CPT2 gene.
  • patient may be heterozygote or homozygote for said 338C>T [S113L] mutation of CPT2 gene.
  • said patient may comprise an additional mutation or polymorphism in the CPT2 gene.
  • patients susceptible to the method or use of the invention show at least 10% residual CPT2 enzyme activity as compared to CPT2 activity control value.
  • said PPAR ⁇ agonist is a fibrate, for instance a fibrate selected from the group consisting of bezafibrate, binifibrate, clinofibrate, clofibrate, clofibric acid, clofibride, etofibrate, nicofibrate, pirifibrate, plafibride, ronifibrate, theofibrate, and tocofibrate.
  • said fibrate is bezafibrate.
  • the method and medicament of this invention can be used to increase the level of CPT2 activity in patient cells, preferably by at least 25%, more preferably by at least 50%, still preferably by two fold, by administering to a patient an amount of a PPAR ⁇ agonist to achieve the desired effect.
  • the desired effect is observed when CPT2 activity is around 40% of control value.
  • the PPAR ⁇ agonist may be formulated for the purpose of oral, topical, parenteral, intranasal, intravenous, intramuscular, subcutaneous, intraocular, and the like, administration.
  • the preferred route is the oral route.
  • the quantity of PPAR ⁇ agonist to be administered depends on the subject to be treated, the capacity of the subject's system to utilize the active ingredient, and degree of therapeutic effect desired. Precise amounts of active ingredient required to be administered depend on the judgement of the practitioner and are peculiar to each individual. However, suitable dosage ranges depend on the route of administration. Suitable regimens for administration are also variable, but are typified by an initial administration followed by repeated doses at one or more hour intervals by a subsequent injection or other administration. Alternatively, continuous intravenous infusion sufficient to maintain concentrations in the blood in the ranges specified for in vivo therapies are contemplated.
  • the PPAR ⁇ agonist is administered in dosages substantially the same as the dosages in which they are administered in typical hyperlipidaemia therapy known to persons of ordinary skill in the art.
  • usual daily regimen comprises 10-1000 mg of bezafibrate, more usually about 200-500 mg, even more usually about 400 mg.
  • the PPAR ⁇ agonist can be mixed with "a pharmaceutically acceptable carrier" compatible with the PPAR ⁇ agonist and in amounts suitable for use in the therapeutic methods described herein.
  • Suitable carriers are, for example, water, saline, dextrose, glycerol, ethanol or the like and combinations thereof.
  • the composition can contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and the like, which enhance the effectiveness of the active ingredient.
  • “Pharmaceutically acceptable” as it refers to compositions, carriers, diluents and reagents, represents that the materials are capable of administration to or upon a mammal without the production of undesirable physiological effects such as nausea, dizziness, gastric upset and the like.
  • the preparation of a pharmacological composition that contains active ingredients dissolved or dispersed therein is well understood in the art and need not be limited based on formulation.
  • FIGURE The figure shows the genomic organization of the human CPT2 gene.
  • the exons are numbered from 1 to 5 and the position of the various mutations is indicated.
  • Patients 1-4 had a typical form of "adult-onset” CPT2 deficiency, with recurrent attacks of rhabdomyolysis, triggered by prolonged exercise and/or fasting and/or viral episodes.
  • Patients 5 and 6 suffered from "infantile-onset” form of CPT2 deficiency associating hypoketotic hypoglycaemia, hepatomegaly and hypertrophic cardiomyopathy with heart beat disorders (Bonnefont, et al., 1999).
  • CPT2 deficiency was ascertained by enzymatic assay in fibroblasts (Demaugre et al., 1991 ) and CPT2 mutations were identified in all six patients (see figure).
  • Fenofibrate, bezafibrate, ciprofibrate and gemfibrozil were from Sigma (St Louis, MO).
  • L-Aminocamitine was kindly provided by D. Muscat (Sigma- Tau, France).
  • (9,10- 3 H) Palmitic acid and (9,10- 3 H) Myristic acid were from NEN (Boston, MA).
  • Fibroblast culture Human skin fibroblasts from controls and CPT2-deficient patients were cultured as described by Manning et al. (1990). Briefly, fibroblasts were routinely cultured in Ham's F10 media with glutamine, 12% fetal bovine serum, 100 Units/ml penicillin, 0.1 mg/ml streptomycin. The cultures were incubated in humidified C0 2 incubator (5%C0 2 , 95% air) at 37°C. All fibrates were dissolved in DMSO. When ready for treatment, the media were removed and the cells were subsequently incubated with fresh media containing the indicated compound for the indicated period of time. Control cells were treated with vehicle (DMSO).
  • DMSO vehicle
  • Fatty acid oxidation was measured as production of 3 H 2 0 from (9,10- 3 H) Palmitate or (9,10- 3 H) Myristate as described elsewhere (9). Briefly, the fibroblasts were trypsinized, counted and plated as 6.10 4 cells per well in 24- well microplates and allowed to grow for 4 days. Tritiated water release experiments were performed in triplicates. Cultured fibroblast layers were washed 3 times with Dulbecco's phosphate buffered saline (PBS).
  • PBS Dulbecco's phosphate buffered saline
  • Fibroblast protein was determined by the Lowry method (Lowry et al., 1951 ). Palmitate or myristate oxidation rates in fibroblasts were expressed as nanomol of 3 H fatty acid ( 3 H FA) oxidized per hour per milligram of cell protein (nmol 3 H FA h "1 . mg "1 protein).
  • CPT2 enzyme activity was assayed as palmitoyl-L-(methyl- 14 C) carnitine formed from L-(methyl- 14 C) carnitine and palmitoyl-CoA as described in reference 8 with slight modifications.
  • CPT2 activity was measured after solubilization of mitochondrial membranes by incubating fibroblasts at 4°C for 1 hour in 0.5 M KCI 1 % Tween 20, pH 7.2.
  • the assay was performed at 30°C for 8 min with 200 ⁇ l of fibroblast extract in 500 ⁇ l of medium containing: 100 mM Tris pH 7.2, 2.5 mM reduced glutathione, 0.4% Tween 20, 0.23 M KCI, 1 mM palmitoyl-CoA and 2.5 mM L-(methyl- 14 C) carnitine (56 mCi/mmol, Amersham).
  • CPT2 enzyme activity was expressed as nanomol palmitoyl-L-(methyl- 14 C) carnitine formed per min per milligram of cell protein (nmol 14 C-PalCar. min "1 . mg "1 protein).
  • the real-time quantitative PCR (RTQ-PCR) was performed using a LightCycler instrument (Roche Diagnostics, Mannheim, Germany) according to the manufacturer's instructions.
  • RTQ-PCR primers shown in Table 2 were designed using the sequences available in GenBank. Table 2
  • EXAMPLE 2 Effects of hypolipidemic drugs on fatty acid oxidation in CPT2-deficient fibroblasts.
  • the effects of three different fibrates and of gemfibrozil on fatty acid oxidation flux were tested in fibroblasts of patient 3, which exhibited a significantly lower FAO rate compared to control fibroblasts (1.8 ⁇ 0.2 versus 3.3 ⁇ 0,3 nanomol 3 H 2 0/h/mg prot, p ⁇ 0.01 , respectively).
  • Patient 3' fibroblasts were cultured for three days in the presence of each tested compound, at concentrations varying from 50 to 800 ⁇ M. Treatment by bezafibrate resulted in a dose-dependant increase in 3 H-Palmitate oxidation rate.
  • EXAMPLE 3 Compared effects of bezafibrate on fatty acid oxidation in "mild” and “severe” CPT2-deficient patients.
  • EXAMPLE 4 Effects of bezafibrate on CPT2 or PPAR ⁇ transcription and CPT2 activity
  • Table 3 relative gene expression in cells treated with 800 ⁇ M bezafibrate for 24 h as compared to vehicle-treated cells (DMSO)
  • Bezafibrate generally induced comparable increases in CPT2 transcripts in patient and control cells, ranging from 1.32 to 1.45-fold, and all differences between bezafibrate-treated and vehicle-treated cells were found highly significant (p ⁇ 0.001 ). Furthermore, bezafibrate stimulated PPAR ⁇ gene expression from 1.39 to 1.98-fold (p ⁇ 0.01 ) in control and patients fibroblasts, as well.
  • EXAMPLE 5 Palmitate oxidation is increased by bezafibrate in control and CPT2-deficient myoblasts Since skeletal muscle is a main target of CPT2 deficiency, the inventors further tested the effects of bezafibrate in muscle cells (myoblasts) from CPT2-deficient patient.
  • Myoblasts were isolated from muscle biopsies performed in CPT2- deficient patient or in control individuals. These cells were grown in primary culture and were treated for 3 days with either vehicle (DMSO) or bezafibrate (100 ⁇ M) before measurement of FAO.
  • DMSO vehicle
  • bezafibrate 100 ⁇ M
  • results shown herein establish for the first time that fibroblast fatty acid oxidation capacities from CPT2-deficent patients are markedly improved after exposure to a drug of the fibrate class.
  • the stimulatory effects of bezafibrate are time- and dose-dependant, and lead to restore normal long- chain fatty acid oxidation rates in mild-type CPT2-deficient cells, under assay conditions which ensure exclusive measurement of the mitochondrial ⁇ - oxidation pathway.
  • bezafibrate beneficial effects of bezafibrate are obviously related to an increase in residual CPT2 activity. They were indeed observed only in "mild- type” CPT2 deficient cells with significant residual enzyme levels. In contrast, bezafibrate failed to stimulate FAO in "severe-type” CPT2 deficient cells harboring homozygous gene mutations close to the putative CPT2 catalytic site, responsible for an extremely low residual enzyme activity. This strongly suggests that correction of fatty acid oxidation flux primarily involves a direct stimulation of mutated CPT2 enzyme expression by bezafibrate, rather than possible indirect compensatory mechanisms.
  • Bezafibrate stimulates FAO through an overexpression of the S113L mutant gene, that results in an increase of enzyme activity, despite the proven instability of the S113L mutant protein (Taroni et al., 1993).
  • Bezafibrate is a known ligand of PPAR ⁇ (Vamecq and Latruffe, 1999), and was shown to potentially stimulate gene expression of mitochondrial ⁇ - oxidation enzymes, after specific binding to this nuclear receptor.
  • the molecular mechanisms underlying these effects involve binding of activated PPAR-RXR heterodimers on specific sequences of gene regulatory regions, called PPAR responsive elements (PPRE), leading to stimulation of gene transcription (Berger and Moller, 2002).
  • PPRE PPAR responsive elements
  • the peroxisome proliferator-activated receptor regulates mitochondrial fatty acid oxidation enzyme gene expression. Proc. Natl. Acad. Sci. 91 :11012-1 1016.

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Abstract

La présente invention concerne l'utilisation d'un agoniste du PPARα, notamment, un fibrate, plus spécifiquement, un bézafibrate, dans le traitement d'une déficience de la Carnitine palmitoyl transférase 2 (CPT2).
PCT/IB2003/003527 2002-09-03 2003-08-26 Utilisation d'un agoniste du recepteur alpha active par proliferation du peroxysome (ppar$g(a)) dans le traitement de deficiences de la carnitine palmitoyl transferase-2 WO2004022047A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015092043A1 (fr) * 2013-12-19 2015-06-25 Institut National De La Sante Et De La Recherche Medicale (Inserm) Combinaison de bézafibrate et de resvératrol ou de dérivés de resvératrol pour le traitement et la prévention des maladies impliquant un dysfonctionnement énergétique des mitochondries

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015092043A1 (fr) * 2013-12-19 2015-06-25 Institut National De La Sante Et De La Recherche Medicale (Inserm) Combinaison de bézafibrate et de resvératrol ou de dérivés de resvératrol pour le traitement et la prévention des maladies impliquant un dysfonctionnement énergétique des mitochondries
FR3015287A1 (fr) * 2013-12-19 2015-06-26 Inst Nat Sante Rech Med Combinaison de bezafibrate et de resveratrol pour le traitement et la prevention des maladies impliquant un dysfonctionnement energetique des mitochondries.
US10376484B2 (en) 2013-12-19 2019-08-13 Institut National De La Santé Et De La Recherche Médicale (Inserm) Combination of bezafibrate and of resveratrol or resveratrol derivatives for the treatment and prevention of diseases involving a mitochondrial energy dysfunction

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