METHODS OF TREATMENT OF MUSCULAR DYSTROPHIES
The invention relates to methods and agents useful for treating muscular dystrophies (MDs), in particular, Duchenne muscular dystrophy (DMD). Methods and agents for treating various physiological and pathological features associated with muscular dystrophies are also provided.
1 . A method of improving pulmonary function in a subject with a muscular dystrophy, the method comprising administering to a subject in need thereof an effective amount of an agent that inhibits connective tissue growth factor (CTGF), thereby improving the subject's pulmonary function.
2 . The method of claim 1 , wherein the muscular dystrophy is selected from the group consisting of Duchenne muscular dystrophy, Becker's muscular dystrophy, congenital muscular dystrophy, distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophy, myotonic muscular dystrophy, and oculopharyngeal muscular dystrophy.
3 . The method of claim 2 , wherein the muscular dystrophy is Duchenne muscular dystrophy.
4 . The method of claim 1 , wherein the subject is non-ambulatory.
5 . The method of claim 1 , wherein the improvement in pulmonary function is a reduction in the rate of decline, a stabilization in the rate of decline or a reversal (improvement) in the rate of decline of the subject's forced vital capacity % predicted (FVCpp), forced expiratory volume % predicted at 1 second (FEV1 pp), peak expiratory flow rate % predicted (PEFRpp), maximum static inspiratory pressure % predicted (MIPpp) or maximum static expiratory pressure % predicted (MEPpp).
6 . The method of claim 1 , wherein the anti-CTGF agent is selected from group consisting of anti-CTGF antibodies, anti-CTGF antibody fragments, anti-CTGF antibody mimetics and anti-CTGF oligonucleotides.
7 . The method of claim 6 , wherein the anti-CTGF agent is an anti-CTGF antibody.
8 . The method of claim 7 , wherein the anti-CTGF antibody is a human or humanized antibody.
9 . The method of claim 7 , wherein the anti-CTGF antibody is pamrevlumab.
10 . The method of claim 7 , wherein the anti-CTGF antibody binds to CTGF competitively with pamrevulmab.
11 . The method of claim 7 , wherein the effective amount of an anti-CTGF antibody is at least 35 mg/kg.
12 . The method claim 6 , wherein the anti-CTGF oligonucleotide is selected from the group consisting of antisense oligonucleotides, siRNAs, miRNAs and shRNAs.
13 . The method of claim 1 , further comprising the administration of a corticosteroid, ataluren and/or eteplirsen.
14 . A method of improving cardiac function in a subject with a muscular dystrophy, the method comprising administering to a subject in need thereof an effective amount of an agent that inhibits connective tissue growth factor (CTGF), thereby improving the subject's cardiac function.
15 . The method of claim 14 , wherein the improvement in cardiac function is a reduction in the rate of decline, a stabilization in the rate of decline or a reversal (improvement) in the rate of decline of the subject's left ventricular ejection fraction percentage (LVEF %), circumferential peak strain (%), or global circumferential strain (%).
16 . A method of reducing the development of or reducing the progression rate of cardiac fibrosis in a subject with a muscular dystrophy, the method comprising administering to a subject in need thereof an effective amount of an anti-CTGF agent, thereby reducing the development of or reducing the progression rate of cardiac fibrosis in the subject.
17 . The method of claim 16 , wherein the subject's degree of cardiac fibrosis is assessed by mass of late gadolinium enhancement.
18 . A method of increasing the muscle strength of a subject with a muscular dystrophy, the method comprising administering to a subject in need thereof an effective amount of an anti-CTGF agent, thereby increasing the subject's muscle strength.
19 . The method of claim 18 , wherein the increased muscle strength is measured as an increase in the subject's grip strength.
20 . A method for reducing muscle inflammation, muscle edema, fat infiltration or percentage of dystrophic muscle composition in a subject with a muscular dystrophy, the method comprising administering to the subject an effective amount of an anti-CTGF agent, thereby reducing muscle inflammation, muscle edema, fat infiltration or percentage of dystrophic muscle composition in the subject.
21 . The method of any one of claim 1 , 14 , 16 , 18 or 20 , wherein the subject is non-ambulatory.