Methods of treating muscular dystrophy
Disclosed herein are α7β1 integrin modulatory agents and methods of using such to treat conditions associated with decreased α7β1 integrin expression or activity, including muscular dystrophy. In one example, methods for treating a subject with muscular dystrophy are disclosed. The methods include administering an effective amount of an α7β1 integrin modulatory agent to the subject with muscular dystrophy, wherein the α7β1 integrin modulatory agent increases α7β1 integrin expression or activity as compared to α7β1 integrin expression or activity prior to treatment, thereby treating the subject with muscular dystrophy. Also disclosed are methods of enhancing muscle regeneration, repair, or maintenance in a subject and methods of enhancing α7β1 integrin expression by use of the disclosed α7β1 integrin modulatory agents. Methods of prospectively preventing or reducing muscle injury or damage in a subject are also disclosed.
1. A method for treating a subject with muscular dystrophy, comprising administering an effective amount of an α7β1 integrin modulatory agent to the subject with muscular dystrophy, wherein the α7β1 integrin modulatory agent comprises ciclopirox ethanolamine, deferoxamine, 2,2-dipyridyl; 5α-cholestan-3β-ol-6-one, N032-0003, N066-0070, N069-0071, N069-0075, N064-0028, N066-0053, N069-0073, 1080-0573, an agent having a formula selected from
wherein each R 1 and R 2 independently is selected from C 1-10 alkyl, substituted C 1-10 alkyl, C 1-10 alkoxy, substituted C 1-10 alkoxy, acyl, acylamino, acyloxy, acylC 1-10 alkyloxy, amino, substituted amino, aminoacyl, aminocarbonylC 1-10 alkyl, aminocarbonylamino, aminodicarbonylamino, aminocarbonyloxy, aminosulfonyl, C 6-15 aryl, substituted C 6-15 aryl, C 6-15 aryloxy, substituted C 6-15 aryloxy, C 6-15 arylthio, substituted C 6-15 arylthio, carboxyl, carboxyester, (carboxyester)amino, (carboxyester)oxy, cyano, C 3-8 cycloalkyl, substituted C 3-8 cycloalkyl, (C 3-8 cycloalkyl)oxy, substituted (C 3-8 cycloalkyl)oxy, (C 3-8 cycloalkyl)thio, substituted (C 3-8 cycloalkyl)thio, halo, hydroxyl, C 1-10 heteroaryl, substituted C 1-10 heteroaryl, C 1-10 heteroaryloxy, substituted C 1-10 heteroaryloxy, C 1-10 heteroarylthio, substituted C 1-10 heteroarylthio, C 2-10 heterocyclyl, C 2-10 substituted heterocyclyl, C 2-10 heterocyclyloxy, substituted C 2-10 heterocyclyloxy, C 2-10 heterocyclylthio, substituted C 2-10 heterocyclylthio, imino, oxo, sulfonyl, sulfonylamino, thiol, C 1-10 alkylthio, and substituted C 1-10 alkylthio, thiocarbonyl; or
two R 1 substituents, together with the atom to which each is bound, may form ring selected from a C 6-15 aryl, substituted C 6-15 aryl, C 3-8 cycloalkyl, substituted C 3-8 cycloalkyl, C 1-10 heteroaryl, substituted C 1-10 heteroaryl, C 2-10 substituted heterocyclyl, and C 2-10 heterocyclyloxy, substituted;
two R 2 substituents, together with the atom to which each is bound, may form ring selected from a C 6-15 aryl, substituted C 6-15 aryl, C 3-8 cycloalkyl, substituted C 3-8 cycloalkyl, C 1-10 heteroaryl, substituted C 1-10 heteroaryl, C 2-10 substituted heterocyclyl, and C 2-10 heterocyclyloxy, substituted;
each of A, B, C, D, E, and F independently may be selected from carbon, nitrogen, oxygen, and sulfur; and
n may be zero, 1, 2, 3, 4, or 5; or
a combination of any of these compounds, wherein the α7β1 integrin modulatory agent increases α7β1 integrin expression or activity as compared to α7β1 integrin expression or activity prior to treatment, thereby treating the subject with muscular dystrophy.
2. The method of claim 1 , wherein the muscular dystrophy is merosin deficient congenital muscular dystrophy Type 1A (MDC1A), merosin deficient congenital muscular dystrophy Type 1D (MDC1D), limb-girdle muscular dystrophy (LGMD), Duchenne muscular dystrophy (DMD), Fukuyama congenital muscular dystrophy (FCMD) or Facioscapulohumeral muscular dystrophy (FHMD).
3. The method of claim 2 , wherein the muscular dystrophy is DMD, MDC1A or FCMD.
4. The method of claim 2 , wherein the muscular dystrophy is DMD.
5. The method of claim 1 , wherein the α7β1 integrin modulatory agent is administered with an additional therapeutic agent.
6. The method of claim 5 , wherein the additional therapeutic agent is a costameric protein, a growth factor, satellite cells, stem cells, myocytes or an additional α7β1 integrin modulatory agent.
7. The method of claim 6 , wherein the additional α7β1 integrin modulatory agent is laminin-111, a laminin-111 fragment, SU9516, valproic acid, or a valproic acid analog.
8. The method of claim 1 , further comprising selecting a subject with muscular dystrophy.
9. The method of claim 8 , wherein selecting a subject with muscular dystrophy comprises diagnosing the subject with muscular dystrophy prior to administering an effective amount of the α7β1 integrin modulatory agent to the subject.
10. A method for treating a subject with muscular dystrophy, comprising administering an effective amount of an α7β1 integrin modulatory agent to the subject with muscular dystrophy, wherein the α7β1 integrin modulatory agent is selected from an agent having a formula of
wherein the α7β1 integrin modulatory agent increases α7β1 integrin expression or activity as compared to α7β1 integrin expression or activity prior to treatment, thereby treating the subject with muscular dystrophy.
11. A method for treating a subject with muscular dystrophy, comprising administering an effective amount of an α7β1 integrin modulatory agent to the subject with muscular dystrophy, wherein the α7β1 integrin modulatory agent is selected from one or more of
wherein the α7β1 integrin modulatory agent increases α7β1 integrin expression or activity as compared to α7β1 integrin expression or activity prior to treatment, thereby treating the subject with muscular dystrophy.
12. A method for treating a subject with muscular dystrophy, comprising administering an effective amount of an α7β1 integrin modulatory agent to the subject with muscular dystrophy, wherein the α7β1 integrin modulatory agent is selected from
wherein the α7β1 integrin modulatory agent increases α7β1 integrin expression or activity as compared to α7β1 integrin expression or activity prior to treatment, thereby treating the subject with muscular dystrophy.