Therapeutic and diagnostic methods involving biglycan and utrophin
The present disclosure provides methods for predicting a patient's response to biglycan therapy for diseases or conditions associated with an abnormal level or activity of biglycan; disorders associated with an unstable cytoplasmic membrane, for example, due to an unstable dystrophin associated protein complex (DAPC); disorders associated with abnormal synapses or neuromuscular junctions, including those resulting from an abnormal MuSK activation or acetylcholine receptor (AChR) aggregation. Examples of such diseases include muscular dystrophies, such as Duchenne's Muscular Dystrophy, Becker's Muscular Dystrophy, neuromuscular disorders and neurological disorders. This application also provides combination therapeutics, such as a biglycan therapeutic and a utrophin therapeutic.
1. A method of treating a muscular dystrophy in a patient in need thereof, the method comprising:
(i) determining that a patient has a utrophin deficiency by measuring a level of membrane-associated utrophin at the sarcolemma in a sample of muscle cells from the patient and comparing with a reference value, wherein the utrophin deficiency is characterized by a decreased level of utrophin protein or activity;
(ii) administering a first dose of a biglycan polypeptide to the patient, wherein the biglycan polypeptide comprises an amino acid sequence corresponding to amino acids 38-365 of SEQ ID NO: 11; and
(iii) measuring the level of membrane-associated utrophin at the sarcolemma in a sample of muscle cells from the patient; and if the level of utrophin measured in (iii) is increased relative to the level of utrophin determined in (i), then
(iv) administering a second dose of the biglycan polypeptide.
2. A method of treating a muscular dystrophy in a patient in need thereof, the method comprising:
(i) determining that a patient has a utrophin deficiency by measuring the level of membrane-associated utrophin at the sarcolemma in a sample of muscle cells from the patient and comparing with a reference value, wherein the utrophin deficiency is characterized by a decreased level of utrophin protein or activity;
(ii) administering a dose of a biglycan polypeptide to the patient to increase the level of utrophin at the sarcolemma in a patient in need thereof, wherein the biglycan polypeptide comprises an amino acid sequence corresponding to amino acids 38-365 of SEQ ID NO: 11; and
(iii) measuring the level of membrane-associated utrophin at the sarcolemma in another sample of muscle cells from the patient.
3. A method of treating a muscular dystrophy in a patient in whom a utrophin deficiency characterized by a decreased level of utrophin protein or activity has been determined by measuring the level of membrane-associated utrophin at the sarcolemma in a sample of muscle cells from the patient and comparing with a reference value, comprising administering a dose of a biglycan polypeptide to the patient, wherein the biglycan polypeptide comprises an amino acid sequence corresponding to amino acids 38-365 of SEQ ID NO: 11, wherein the level of membrane-associated utrophin at the sarcolemma of muscle cells in the patient is increased after administration of the biglycan polypeptide.