Methods and compositions for improving neuromuscular junction morphology and function
AssigneeThe Board of Trustees of the Leland Stanford Junior University
InventorsHelen M. Blau, Yu Xin Wang, Mohsen Afshar Bakooshli
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Abstract
The present disclosure provides methods of improving, enhancing, and/or rejuvernating neuromuscular junction morphology and/or function in a subject by administering to the subject an amount of a 15-PGDH inhibitor effective to inhibit 15-PGDH activity and/or reduce 15-PGDH levels in the subject. The methods described herein are useful for treating subjects afflicted with neurogenic myopathies, aged-induced loss of muscle mass, genetic neuromuscular wasting disorders, or after trauma or injury, among others.
Claims34
A method of improving, enhancing, and/or rejuvenating neuromuscular junction (NMJ) morphology and/or function, and/or inducing and/or promoting formation of NMJs, in a subject having degeneration of NMJs, the method comprising:
- administering to the subject an amount of a 15-PGDH inhibitor effective to inhibit 15-PGDH activity and/or reduce 15-PGDH levels in the subject, thereby improving, enhancing, and/or rejuvenating NMJ morphology and/or function, and/or inducing and/or promoting formation of NMJs, in the subject.
The method of any one of the preceding claims, wherein the method results in a decreased number of NMJs lacking the presence of motor neurons.
The method of any one of the preceding claims, wherein the method results in decreased blebbing of motor neuron axons.
The method of any one of the preceding claims, wherein the method results in decreased apoptosis of motor neurons.
The method of any one of the preceding claims, wherein the method results in enhanced NMJ morphology, and/or increased conduction of nerve signals to the muscle.
The method of any one of the preceding claims, wherein the method results in a decreased number of AChR-rich vesicles at the NMJ.
The method of any one of the preceding claims, wherein the method results in increased expression and/or localization of AChR at the NMJ.
The method of any one of the preceding claims, wherein the method results in decreased AChR degradation.
The method of any one of the preceding claims, wherein the method results in increased AChR stability.
The method of any one the preceding claims, wherein the method results in improved, enhanced, and/or rejuvenated mitochondrial morphology and/or function in motor neurons.
The method of any one of the preceding claims, wherein the method results in improved, enhanced, and/or rejuvenated motor neuron synaptic terminals at the NMJ.
The method of any one of the preceding claims, wherein the method results in improved, enhanced, and/or rejuvenated skeletal muscle mass and/or neuromuscular function in the subject.
The method of any one of the preceding claims, wherein the subject has muscle denervation and/or partial muscle denervation.
The method of any one of the preceding claims, wherein the subject has a neurogenic myopathy, an aged-induced loss of muscle mass, a genetic neuromuscular wasting disorder, nerve trauma or injury, muscle trauma or injury, or any combination thereof.
The method of any one of the preceding claims, wherein the subject has or has experienced one or more selected from the group consisting of:
- acute peripheral nerve injury, muscle disuse, myopathy with neurogenic and autoimmune involvement with target fibers or tubular aggregate formation, and vascular myopathy.
The method of any one of the preceding claims, wherein the 15-PGDH inhibitor is selected from the group consisting of a small molecule compound, a blocking antibody, a nanobody, and a peptide.
The method of any one of the preceding claims, wherein the 15-PGDH inhibitor is selected from the group consisting of:
- SW033291 and (+)-SW209415.
The method of any one of the preceding claims, wherein the subject is a human.
The method of any one of the preceding claims, wherein the subject is less than 30 years of age.
The method of any one of the preceding claims, wherein the 15-PGDH inhibitor reduces or blocks 15-PGDH expression.
The method of any one of the preceding claims, wherein the 15-PGDH inhibitor reduces or blocks enzymatic activity of 15-PGDH.
The method of any one of the preceding claims, wherein the method is independent of muscle cell proliferation.
The method of any one of the preceding claims, wherein the administering comprises systemic administration or local administration.
Dependencies are inferred from the claim text.