CROSS-REFERENCE TO RELATED APPLICATIONS

This application is U.S. National Phase of International Application PCT/FR2016/053289, filed Dec. 9, 2016 designating the U.S., and published in English as WO 2017/098173 A2 on Jun. 15, 2017, which claims priority to French Patent Application No. 15 62040 filed Dec. 9, 2015.

FIELD

The present invention relates to the field of medicine. It relates more particularly to the use of compounds for preventing and/or treating, in a subject, myopathy, typically muscular dystrophy or cardiomyopathy, or muscle trauma. The invention also relates to compositions, in particular pharmaceutical compositions comprising such compounds, and corresponding kits, as well as their uses for preventing and/or treating muscular myopathy or trauma. The compounds and compositions according to the invention may typically be advantageously used to prevent and/or treat muscular dystrophy, cardiomyopathy or muscular trauma, preferably Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (BMD) and/or or a symptom or abnormality characteristic of DMD or BMD.

BACKGROUND

Muscular dystrophies are a group of diseases characterized by weakness and progressive degeneration of the body's muscles and inflammation. They atrophy little by little, i.e. they lose their strength and volume. These are genetic diseases that may begin at birth, during childhood or in adulthood. About forty different genes are involved in muscular dystrophies. It is difficult to know the frequency of all dystrophies, but some studies estimate that about 1 in 3,500 people have DMD. Dystrophies may affect anyone and appear at any age. There are more than 30 forms, which differ by the age of onset, the muscles affected, and the severity. These are diseases that progressively worsen and for which there is no treatment. The muscles affected in the event of muscular dystrophy are mainly those that allow voluntary movements, especially the muscles of the legs and arms. The respiratory muscles and the heart may sometimes be affected. This is the case in DMD. Unfortunately, most people with muscular dystrophy gradually lose the ability to walk. Other symptoms may include muscle weakness, including heart, gastrointestinal, eye, and inflammatory disorders.

Usually two major groups of muscular dystrophies are differentiated:congenital muscular dystrophies (CMD), which begin in the first 6 months of life. There are about 10 forms of variable severity, including CMD with primary merosin deficiency (a constituent of the muscle cell membrane), Ullrich's CMD, rigid spine syndrome, and Walker-Warburg's syndrome; andmuscular dystrophies beginning later in childhood or adulthood such as Duchenne muscular dystrophy (DMD); Becker muscular dystrophy (BMD); Emery-Dreyfuss muscular dystrophy (there are several forms); fascio-scapulo-humeral muscular dystrophy, also called Landouzy-Dejerine myopathy; limb girdle muscular myopathies, so called because they affect, in particular, the muscles around the shoulders and hips; myotonic dystrophies (types I and II), which include Steinert's dystrophy that is characterized by myotonia (i.e. the muscles fail to relax normally after contraction); and oculopharyngeal muscular dystrophy.

The best known and most common type of muscular dystrophy is Duchenne muscular dystrophy (DMD), also known as Duchenne muscular myopathy. It originates from the loss of function of a gene carried by the X chromosome in the p21 region coding for dystrophin, a protein located under the membrane and playing a role in the contraction of the muscle. DMD is a fairly common disease in the world, affecting only the male sex. Its incidence is one in 3,500. At birth, no symptoms are observed, but during development, there is a gradual loss of motility. The disease manifests itself by a progressive degeneration of the skeletal, smooth and cardiac muscles as well as by cognitive and behavioral deficits. This degeneration is partly related to an excessive increase of calcium which leads to the activation of proteases at the origin of cell death. At the age of 12, these children lose the ability to walk and more than half do not live beyond 20-30 years old. The causes of death are either muscular respiratory failure or cardiomyopathy. There is no effective treatment against DMD today.

The symptoms of Becker muscular dystrophy are comparable to those of Duchenne muscular dystrophy, but they are less marked and the evolution is less rapid. Symptoms begin around 5 to 15 years of age, sometimes later, and are characterized by a progressive loss of muscle strength in the limbs and trunk. In more than half of the cases, walking remains possible until the age of about 40 years of age. On the other hand, a heart attack is frequent and may appear from the beginning.

Currently the only treatments used against myopathies, especially against muscular dystrophies, aim to reduce inflammation and progression of the disease using glucocorticoids (prednisone and prednisolone). These treatments have modest beneficial effects but may cause many side effects that may lead to complications, especially in the case of long-term treatments. Side effects include weight gain that may compromise mobility, reduced bone mineral density with increased risk of fractures, cataract development, and increased intraocular pressure. β-blockers, phosphodiesterase inhibitors, and angiotensin-converting enzyme inhibitors are specifically used to improve the cardiac function, in particular to reduce the development of cardiac hypertrophy and arrhythmia observed in the patient. However, these treatments have no effect on cardiac or skeletal muscle degeneration. Moreover, they are used later for healing purposes in order to reduce the symptoms that have appeared, but can not be used in a preventive manner.

The inventors now describe molecules or compounds, and compositions comprising such molecules or compounds, wherein the compounds, active throughout the musculature (skeletal, cardiac and smooth muscles), are able not only to treat a diagnosed myopathy, or muscle trauma, but also to prevent the occurrence of myopathy. In particular, these compounds are capable of reducing the necrotic disorders observed in the heart, diaphragm and skeletal muscles of subjects suffering from DMD and BMD, and of preventing such damage in subjects at risk of developing myopathy, typically muscular dystrophy.

SUMMARY

The invention relates to molecules (also referred to herein as “compounds”) for the prevention or treatment of myopathies, typically muscular dystrophies and cardiomyopathies, and muscular trauma. In the context of the present invention, the terms “myopathy” or “myopathies” do not designate and do not cover uremic myopathy.

The molecules of the invention are preferably for the prevention or treatment of Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) or a symptom or abnormality characteristic of DMD or BMD.

In a preferred embodiment of the invention, the compound according to the invention: i) reduces or inhibits the activity of calcium channels and reduces the functional impairments of skeletal, smooth and/or cardiac muscle cells, ii) reduces muscle necrosis possibly present in skeletal, smooth and/or cardiac muscle cells and preferably, iii) reduces muscular inflammation.

A particular compound according to the invention for use in preventing or treating myopathy in a subject is an ADP ribosylcyclase antagonist compound (CD38 being an example of ADP ribosylcyclase), a cyclic ADP ribose antagonist compound (“cADPR” or “ADPRc”). and/or a nicotinic acid adenine dinucleotide phosphate antagonist compound (“NAADP” or “nicotinic acid adenine dinucleotide phosphate”).

The invention furthermore relates to a compound or a mixture of compounds as described herein for use in treating muscular trauma or for preventing or treating myopathy in a subject, typically muscular dystrophy and/or cardiomyopathy, or at least one symptom, or at least one characteristic anomaly of the preferably several characteristic symptoms or anomalies (for example 2, 3, 4 or 5).

The invention furthermore relates to a composition, in the form of a pharmaceutical composition, comprising at least one compound according to the invention and a pharmaceutically acceptable carrier. One particular object typically relates to a pharmaceutical composition comprising, in addition to the at least one compound according to the invention, at least one other compound (different from the compounds according to the invention) that is therapeutically active (and recognized as such by those skilled in the art).

The invention also relates to the use of such a composition for preventing or treating myopathy or for treating muscular trauma in a subject. It also relates to the use of such a composition for treating muscular trauma or for preventing or treating muscular dystrophy or cardiomyopathy in a subject, typically at least one symptom or one anomaly that is characteristic of muscular dystrophy, preferably several symptoms (for example 2, 3, 4 or 5); preferably to prevent or treat DMD or BMD. The described uses may also be advantageously implemented in combination with at least one other therapeutically active compound (recognized as such by those skilled in the art and different from the compounds according to the invention), in particular in the treatment of muscular dystrophies or cardiomyopathies, typically at least one characteristic symptom or anomaly of DMD and/or BMD.

Finally, the invention relates to a prophylactic or therapeutic kit comprising a compound (or a mixture of at least two, for example three, compounds according to the invention), and/or a composition according to the invention, and at least one other therapeutically active compound (recognized as such by those skilled in the art and different from the compounds according to the invention), in particular in the treatment of muscular dystrophies, typically at least one characteristic symptom or anomaly of the DMD and/or BMD, cardiomyopathy or muscular trauma, wherein the compounds are preferably in separate containers.

