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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
• • 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
  • A61K31/16—Amides, e.g. hydroxamic acids
• • 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
  • 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
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic 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
  • 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
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
  • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
• • 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
  • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
  • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
• • 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
  • A61K31/325—Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system

Definitions

• the present invention relates to the treatment of disease resulting from the deficiency of an adult gene in an individual through the re-expression of the homologous fetal gene.
• the invention is particularly interested in the long-term treatment of dystrophies and similar diseases comprising the administration, to a subject having a defective gene, of an adequate amount of a histone deacetylase inhibitor.
• Fetal metabolism is glycolitic and ammonotelic while adult metabolism is oxidative and ureotelic.
• One of the main compounds involved in fetal metabolism is butyrate which, combined with other products of glycolytic metabolism, inhibits in the nucleus, an essential enzyme: histone deacetylase.
• histone deacetylase an essential enzyme that inhibits in the nucleus.
• the relaxation of the DNA strand that follows allows transcription factors to reach the promoter and induce gene expression.
• the stimulation of the oxidative metabolism associated with the stimulation of methylases induces the synthesis of new products which replace those which were expressed during fetal life.
• fetal gene The transition between the expression of a fetal gene and that of the adult gene occurs because the metabolism becomes oxidative to adapt to air and gravity. This type of metabolism generates transmitters methylated and creatine phosphate which allow the muscles for example to adapt to life on earth (as opposed to fetal life which takes place in an aquatic environment).
• the need to switch from fetal genes to adult genes probably corresponds to an adaptation of the body to new sources of protein.
• fetal genes are extinguished in favor of their adult counterparts, or more generally that genes less adapted to the environment of the organism are extinguished in favor of homologs better adapted to this environment.
• the latter then express regulated proteins which respond more adequately to this environment.
• a new method of treating diseases in which the defective adult gene has a fetal counterpart has thus been described in the prior art.
• This method is based on the reactivation of this fetal gene.
• These include, for example, Duchenne and Becker's myopathies or thalassemia and sickle cell anemia.
• French patent application published under No. 2,794,647 shows that the use of L-arginine and NO donors makes it possible to reactivate the expression of fetal genes in adult tissues so as to restore the presence and localization of proteins. fetal.
• Spectacular effects have been obtained in the case of muscular dystrophy in mice, where re-expression of utrophin considerably improves the condition of the deficient muscles of the mdx mouse which is a mouse model of human disease.
• the human fetus has a fetal hemoglobin of high affinity for oxygen, which will be replaced, in the newborn, by a hemoglobin of low affinity, which will, moreover, negatively regulated by 2-3diphosphoglycerate (DPD).
• DPD 2-3diphosphoglycerate
• the adult hemoglobin is defective due to a mutation (anemia sickle cell), its regulatory ligand increases (Abekile, 1998).
• this ligand can then serve as an inducing signal for expressing fetal hemoglobin.
• This extinction-substitution mechanism depends on a "double switch".
• the first is general, non-specific and well known, it is linked to the state of histones, we know that their deacetylation for example decreases the expression of genes by "tightening the winding of the DNA strand”.
• the second is specific and would result from the decrease of an inducer which is no longer available when the adult or best suited gene is expressed because this inducer is then linked to the product of the specific gene.
• This specific switch is now highlighted by experiments showing that the same "general switch", histone deacetylase inhibitor, will "turn on” fetal hemoglobin in sickle cell anemia, and utrophin in dystrophy Duchenne or SMN2 in spinal muscular atrophy, etc.
• products active on a general expression mechanism are made permissive for the expression of the silent gene in each case, by the availability of the selective inducer, NO or cGMP for utrophin, 2-3DPG or derivative for l hemoglobin, Ch3SM, Ch3SmRNP or derivative for SMN2.
• This ligand no longer finding its specific target due to the mutation then authorizes the action of the general switch which preferentially turns on the silent gene corresponding to the mutation.
• Histone deacetylase inhibitors that promote the expression of fetal genes are not specific. Under these conditions, the fetal gene corresponding to the mutated adult gene is specifically activated (fetal hemoglobin in the case of sickle cell anemia, or utrophin in the case of Duchenne dystrophy) thanks to the existence of a another specific switch for each couple of fetal-adult genes.
• the mutation of the adult protein is reported and triggers the activation of the fetal protein.
• the adult proteins adapted to the partial pressure of oxygen in the air and the gravity for muscle proteins are regulated by specific ligands.
• a typical example is 2-3 DPG which regulates adult hemoglobin.
• the adult protein is absent or mutated, then its specific ligand is found free in the cytoplasm and, therefore, induces, directly or indirectly, the activation of the corresponding fetal gene. This induction is possible only in the case where the histone deacetylase is inhibited, by butyrate for example, that is to say in the situation of a glycolitic metabolism, which is the case of juvenile cells.
• histone slows down the expression of these genes.
• histone deacetylase In the presence of butyrate or other inhibitors of histone deacetylase, this general inhibition is lifted and the selective inducer, activated by the mutation, is then allowed to trigger the silent gene.
• Histone deacetylase inhibitors such as butyrate are used in the treatment of sickle cell anemia.
• SMN1 being mutated, its ligand CH3-SmRNP (methyl, smallribonucleoprotein) would become inductive, if however the butyrate allows it to act by promoting the reacetylation of histones.
• CH3-SmRNP methyl, smallribonucleoprotein
• the expression of SMN2 was thus obtained by the butyrate (Chang et al., 2001). It would also be useful in this case to promote the methylation of SmRNP or to increase its expression. NO donors could be helpful as well as methyl donors.
• the present invention also applies to myopathy of Miyoshi (MM) and to myopathy of the belt or form 2B of the "limbgirdle muscular dystrophy” (LGMD2B) (Bushby K., Acta Myologica, vol. 19, 2000, p. 209-13) which are characterized by the absence of dysferline, a homologous protein, myoferline, which can then serve as a substitute (Davis et al. Hum., Mol. Genêt., 2000, vol. 9, p. 217-226 ).
• LGMD2B limbgirdle muscular dystrophy
• gamma-AchR acetylcholine receptor
• the general ligand is a histone deacetylase inhibitor (HDAC) and the specific ligand a phospholipid for MM and LGMD2B and choline for gamma-Achr syndrome.
• HDAC histone deacetylase inhibitor
• dysferline and myoferline are part of a family of C2 domain molecules which recognize and strongly bind phospholipids. It has been reported in the prior art (Perrine SP et al. EXPERIENTIA, BIRKHAUSER VERLAG. BASEL, CH, vol. 49, no. 2, February 15, 1993 (1993-02-15), pages 133-137) l ' use of a butyrate-based compound to treat beta hemoglobinopathies, sickle cell anemia and beta thalassemia syndromes. It should be noted that this document is not concerned with muscular dystrophies, such as Duchenne dystrophy and that it offers arginine butyrate as a derivative of butyrate to avoid sodium overload for the patient. Thus the active principle which these authors propose to use is butyrate and not arginine.
• the present invention is based on the implementation of a double switch system for removing inhibition of the fetal gene: i) the general switch linked to histone acetylation, and ii) the selective switch, linked to product of the only missing gene (NO in the case of utrophin).
• the histone deacetylase inhibitor opens the general switch and arginine (NO) opens the selective switch.
• a histone deacetylase inhibitor could be used for the preparation of a medicament intended for the treatment or prevention of a disease resulting from the deficiency of an adult gene in an individual by re-expression of the homologous fetal gene.
• This medicament according to the invention is intended to reactivate the expression of at least one fetal gene in adult tissues so as to restore the presence and / or the localization of at least one fetal protein.
• the invention aims to reactivate the fetal gene encoding the embryonic form of the protein encoded by the defective adult gene.
• the invention is particularly interested in the treatment of muscular dystrophies, such as Duchenne or Becker dystrophy where the defective adult gene is the dystrophin gene and the homologous fetal gene is the utrophin gene.
• dystrophin is spatially very close to NOsynthase, and NO produced locally will undoubtedly have essential effects on this protein, the mutation of which is accompanied by a deficit of NOsynthase at the membrane.
• NO then induces the expression of utrophin, the silent counterpart of dystrophin which predominates in fetal life, and which, moreover, only remains in adults in places where the NOsynthase is very high (plaque motor, vessels).
• arginine, substrate of NOsynthase, and NO donors cause an over-expression of utrophin.
• This effect was obtained without lifting the general switch linked to histyl acetylation, because NO also blocks essential stages of the Krebs cycle, which leads to an elevation of acetylCoA and ketone bodies (butyrate).
• NO acts as an inducing ligand but also via butyrate on the histone deacetylase.
• the use of a histone deacetylase inhibitor according to the invention also offers the advantage of having a medicament which can be administered orally.
• the action of L-arginine and its derivatives on the reactivation of the fetal gene is obtained parenterally.
• histone deacetylase inhibitors advantageously administered orally make it possible to maintain the effect during these periods.
• histone deacetylase inhibitors make it possible to maintain during these periods "the general switch" linked to the acetylation of the open histones.
• the main compound used to induce the expression of utrophin is the substrate of NOsynthase: L-arginine.
• L-arginine The inventors have now shown (FIG. 4) that an arginine butyrate salt considerably increases the amount of utrophin in healthy muscles and in mdx mice.
• the histone deacetylase inhibitor can thus be chosen from the group comprising butyrate, phenylbutyrate, isobutyramide, valproate, hydroxamate derivative of butyric acid, apicidin, CBHA (m-carboxycinnamic acid bishydoxyamide) , HC toxin, M344 (4-dimethylamino-N- (6-hydroxycarbamoyl-hexyl) -benzamide), Nullscript (4- (1, 3-dioxo-1H, 3H-benzo [de] isoquinolin-2 - yl) -N-hydroxybutanamide), SAHA (suberoylanil ide hydroxamic acid), Scriptaid (6 - (1.3 -dioxo- 1H, 3H- benzo [de] isoquinolin- 2 -yl) -N-hydroxyhexanamide), trichostatin (TSA; (R- (E, E) -7- [4
• the aim of the present invention is therefore to reexpress this silent copy, using a whole series of combinations of compounds of the type described above.
• these are bifunctional compounds in which the ligand of the absent or abnormal protein is covalently linked to a histone deacetylase inhibitor.
• Such compounds have the capacity to treat the pathologies in which a gene is mutated, by inducing the expression of a homologous gene, mainly the fetal copy of this gene (in the cases where it exists) using a bifunctional compound ional cleavable which will release in the body i) the histone deacetylase inhibitor acting on the general switch, non-specific, linked to the acetylation of histones, and ii) ligand of the mutated protein, activating the specific switch.
• this ligand is not available or is unusable, it is possible, as a replacement, to link its precursor or its product, or even a molecule promoting its action.
• a very particular subject of the invention is therefore the use in combination of a histone deacetylase inhibitor and a compound regulating a protein encoded by an adult gene for the preparation of a medicament intended for the treatment or prevention of 'a disease resulting from the deficiency of said adult gene for which there is a silent homologous gene.
• said compound is capable of binding and regulating the protein encoded by this adult gene.
• said medicament contains the histone deacetylase inhibitor and the compound regulating a protein encoded by an adult gene, separately in the same package.
• said medicament contains the histone deacetylase inhibitor and the compound regulating a protein encoded by an adult gene, in a single pharmaceutical form containing the two ingredients.
• the histone deacetylase inhibitor and the compound regulating a protein encoded by an adult gene are covalently linked optionally via a spacer arm.
• Said link or spacer arm is cleavable in the body so as to release the two active ingredients.
• the histone deacetylase inhibitor is associated with at least one compound chosen from the group comprising NO, a NO donor compound or a compound capable of releasing, promoting or inducing NO formation in cells.
• Said medicament is intended for the treatment or prevention of a disease resulting from the deficiency of the dystrophin gene by allowing the re-expression of the utrophin gene.
• Said disease is Duchenne or Becker's dystrophy.
• a drug comprising histone deacetylase is administered to an individual who has received concomitantly or prior to the administration of the said drug an appropriate amount of at least one compound chosen from the group comprising NO, a NO donor compound or a compound capable of releasing, promoting or inducing the formation of NO in cells.
• the compound capable of inducing the formation of NO is for example L-arginine, or one of its derivatives constituting a substrate for NO-synthase or promoting the availability of the substrate.
• L-arginine or one of its derivatives constituting a substrate for NO-synthase or promoting the availability of the substrate.
• a preferred example of the first embodiment of the invention below relates to a pharmaceutical composition comprising arginine butyrate.
• the NO donor compound is for example molsidomine or one of its derivatives capable, during its transformation in the organism, of releasing NO.
• the invention relates to the treatment of spinal muscular atrophy, where the histone deacetylase inhibitor is combined with a methyl donor compound capable of activating the SmRNP (smallribonucleoprotein) endogenous in methylan.
• CH3-SmRNP is capable of binding the proteins encoded by the SMN1 gene, and when the latter is deficient, it allows the re-expression of the homologous SMN2 gene by combining with the histone deacetylase inhibitor.
• the histone deacetylase inhibitor is associated with one or more phospholipids capable of binding dysferline.
• Said medicament is intended for the treatment or prevention of a disease resulting from the deficiency of the dysferline gene by allowing the re-expression of myoferline.
• Said disease is Miyoshi myopathy (MM) or form 2B of belt myopathy (limb girdle muscular dystrophy) (LGMD2B).
• the histone deacetylase inhibitor is associated with choline or a derivative thereof capable of binding the nicotinic receptor acetylcholine.
• Said medicament is intended for the treatment or prevention of a disease resulting from the deficiency of the gene of the epsilon subunit of said adult receptor by allowing the re-expression of the homologous fetal gene encoding the gamma subunit of said receptor.
• Said disease is a myasthenic syndrome called gamma-AchR.
• the histone deacetylase inhibitor is associated with 2-3diphosphoglycerate, a derivative or precursor (inosine) thereof capable of binding to hemoglobin.
• Said drug is intended for the treatment of sickle cell anemia by allowing the re-expression of fetal hemoglobin.
• the invention aims to offer new bifunctional products in which the histone deacetylase inhibitor and the compound capable of binding to a protein encoded by an adult gene, are covalently linked optionally via a spacer arm.
• the two ingredients are advantageously linked by ester or amide bonds.
• the chemical groups ensuring the covalent bond are, for example, carboxylic ester, carboxylic amide, thiocarboxylic ester or thiocarboxylic amide groups.
• the bifunctional product binds, by an ester or amide bond, a histone deacetylase inhibitor (valproate, butyrate or others) to the allosteric ligand of adult hemoglobin, such as 2-3 diphospho glycerate ( DPG). It is also possible to replace 2-3-DPG with its precursor, 1 inosine.
• a histone deacetylase inhibitor valproate, butyrate or others
• 2-3-DPG with its precursor, 1 inosine.
• the compound Once administered to the patient, the compound will be cleaved by esterases or amidases at the ester or amide link (these enzymes are abundant in cells and blood).
• the released histone deacetylase inhibitor will act nonspecifically on the histone-dependent general switch, while 2-3-DPG, or its precursor, will specifically activate the fetal hemoglobin switch.
• the histones being acetylated in principle any gene should be activated, but 2-3-DPG will activate the fetal hemoglob
• FIG. 6 shows a covalent amide bond binding valproic or butyric acid to the amine of arginine (which is different from a salt obtained by neutralization). Cleavage of the amide bond by amidase in the cells will release the histone deacetylase inhibitor, and the NO precursor.
• Another possibility, described in FIG. 6a, is to form an ester bond between the 30H butyrate or the OH valproate and the carboxyl group of arginine. In each case, the main histone dependent switch is turned on, while the NO signal that is generated will specifically induce the expression of utrophin.
• L-arginine precursor of NO
• cGMP linked to butyrate or valproate by an amino or ester bond
• LGMD2B the compound to be synthesized binds the histone deacetylase inhibitor (butyrate or valproate or others) by an ester bond, to the dysferline ligand.
• the dysferline ligand is probably a phospholipid because dysferline includes a C2 domain, common to other proteins, domain which binds phospholipids.
• FIG. 7 shows an example, again the ester link could be changed to an amino link.
• Another example concerns the congenital syndromes of Myasthenia due to a mutation of the adult ⁇ subunit of the receptor for which it would be necessary to reactivate the expression of the ⁇ subunit which confers its fetal form on the nicotinic receptor.
• the bifunctional compound proposed in this case would associate, via an ester bond, for example, the histone deacetylase inhibitor (butyrate or valproate or others) with a specific ligand of the receptor such as choline (FIG. 8), the cleavage of the bond. ester by esterases releasing butyrate or valproate opening the general switch, and also releasing the specific inducer of the fetal form of the nicotinic receptor, choline.
• the ligand of the SMN1 protein could be directly or indirectly snRNPs which is involved in the splicing of mRNAs. Methylation of the snRNP complex seems necessary for its functioning. It would be dangerous to use snRNPs as a specific inducer (antibodies to snRNPs cause Lupus erythematosus). In this situation, it is only possible to help the functioning of snRNPs by promoting its methylation.
• a methyl donor can be linked by an ester or amino link to a histone deacetylase inhibitor (butyrate, valproate) as we have previously described.
• the objective is to induce the expression of SMN2, the silent copy of the SMN1 gene, including its exon 7.
• the subject of the invention is also pharmaceutical compositions comprising, as active agent, at least one product as defined above.
• FIG. 1 illustrates the possibility of inducing an increase in utrophin in the muscle under the effect of histone deacetylase inhibitors, using butyrate, leader of these inhibitors on mouse myotube cultures
• FIG. 2 represents the immunofluorescence analysis of the utrophin present in the muscles of dystrophic mice dx, the animal model of Duchenne muscular dystrophy, into which were injected butyrate and by way of comparison of L-arginine as NO donor
• FIG. 3 represents the immunofluorescence analysis of the utrophin after application of the same molecules as for FIG. 2 to human myotubes in culture
• FIG. 4 represents the increase in utrophin in healthy mice treated with arginine butyrate.
• FIG. 5 shows examples of bifunctional products that can be used in the case of sickle cell anemia.
• FIG. 6 shows examples of bifunctional products that can be used in the case of Duchenne muscular dystrophy.
• FIG. 7 shows examples of bifunctional products that can be used in the case of Miyoshi myopathy and LGMD2B.
• - Figure 8 shows examples of bifunctional products that can be used in the case of congenital myasthenic syndrome (mutation of the epsilon subunit of the nicotinic receptor).
• - Figure 9 shows examples of bifunctional products that can be used in the case of spinal muscular atrophy.
• Example 1 Increase in the utrophin in myotubes of mdx mice treated with butyrate ( Figurel).
• Myotubes of dystrophic mdx mice (xlt line) are treated with 5 ⁇ l of butyrate for 48 h.
• the increase in utrophin is then quantified in Western Blot.
• the measurement of the intensity of the bands shows an increase in expression of utrophin by a factor of 2 after treatment of the myotubes with butyrate.
• Example 2 Increase in utrophin in mdx mice treated with butyrate ( Figure 2).
• M dx mice are injected daily, ip and for 6 weeks with 200 mg / kg / day either of butyrate, or of L-arginine, or of physiological saline. It is observed that the utrophin is poorly expressed in the muscle of mdx mice injected with physiological saline used as a control. In contrast, in mice injected with butyrate or L-arginine, utrophin appears under the muscle membrane. It should be noted that the increase in utrophin is greater in the case of mice injected with butyrate. The increase in utrophin was quantified in Western Blot. The measurement of the intensity of the bands shows an increase in expression of utrophin by a factor of 2 in the mdx mice treated with butyrate.
• Example 3 Increase in utrophin in human myotubes treated with butyrate ( Figure 3).
• Example 4 Increase in Utrophin in Healthy Mice Treated with Arginine Butyrate (Figure 4).
• OF 1 mice are injected daily, ip and for 6 weeks with 100, 200 or 300 mg / kg / day either of arginine butyrate or of physiological saline.
• mice injected with arginine butyrate utrophin appears very clearly under the muscle membrane. This increase is dose-dependent.
• the induction of utrophin under the muscular membrane is important probably due to an additive effect of arginine via NO and of butyrate via activation of the transcription of the gene for utrophin.
• Patent N ° 99/07442
• Pharmaceutical composition comprising NO or at least one compound capable of releasing or inducing the formation of NO in cells.

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