# US 7,612,038 B2 · Biglycan and related therapeutics and methods of use

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- Number: US 7,612,038 B2
- Document ID: US7612038B2
- Status: Granted
- Kind: B2
- Application number: 10/081,736
- Filed: 2002-02-20
- Published: 2004-04-01
- Granted: 2009-11-03
- Earliest claimed: 1999-11-18
- Assignees: Brown University
- Inventors: Justin R. Fallon; Beth McKechnie; Michael Rafii; Hilliary Creely; Mark A. Bowe; Alison Amenta; Mary Lynn Mercado; Hiroki Hagiwara
- Web page: https://patentgrep.com/patent/US7612038B2

## CPC

- G01N 33/6887: {from muscle, cartilage or connective tissue}
- A61K 38/1709: {from mammals}
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- G01N 2400/12: Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar
- G01N 2500/02: Screening involving studying the effect of compounds C on the interaction between interacting molecules A and B (e.g. A = enzyme and B = substrate for A, or A = receptor and B = ligand for the receptor)
- G01N 2500/04: Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
- G01N 2800/2878: Muscular dystrophy
- G01N 2800/2885: Duchenne dystrophy
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention provides compositions and methods for treating, preventing, and diagnosing diseases or conditions associated with an abnormal level or activity of biglycan; disorders associated with an unstable cytoplasmic membrane, due, e.g., 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. Example of diseases include muscular dystrophies, such as Duchenne's Muscular Dystrophy, Becker's Muscular Dystrophy, neuromuscular disorders and neurological disorders.

## Claims

### Claim 1

A method for activating the cell-surface receptor muscle, skeletal, receptor tyrosine kinase (MuSK) in a cell having an abnormal dystrophin-associated protein complex (DAPC), comprising contacting the cell with a biglycan therapeutic in an amount effective to potentiate agrin-induced phosphorylation of the receptor MuSK, wherein the abnormal DAPC is caused by one or more of (i) a mutation in a DAPC component, or (ii) an abnormally lower level of a DAPC component compared to a control cell, wherein the DAPC component is: a dystroglycan, dystrophin, or a sarcoglycan, and wherein the receptor MuSK is activated thereby.

### Claim 2 (depends on 1)

The method of claim 1, wherein the biglycan therapeutic upregulates utrophin levels.

### Claim 3 (depends on 1)

The method of claim 1, wherein the biglycan therapeutic is a polypeptide including a biglycan amino acid sequence which is at least about 90% identical to SEQ ID NO: 9.

### Claim 4 (depends on 3)

The method of claim 3, wherein the biglycan amino acid sequence includes one or more Leucine Rich Repeats (LRRs) of human biglycan having SEQ ID NO: 9.

### Claim 5 (depends on 3)

The method of claim 3, wherein the polypeptide is derivatized with one or more glycosaminoglycan (GAG) side chains.

### Claim 6 (depends on 1)

The method of claim 1, wherein the biglycan amino acid sequence is at least about 90% identical to amino acids 38-365 of SEQ ID NO: 9.

### Claim 7 (depends on 6)

The method of claim 6, wherein the biglycan amino acid sequence is at least about 95% identical to amino acids 38-365 of SEQ ID NO: 9.

### Claim 8 (depends on 3)

The method of claim 3, wherein the cell is a muscle cell.

### Claim 9 (depends on 1)

The method of claim 1 further comprising assaying activity of the receptor MuSK, wherein the assay for the receptor MuSK activity comprises determining the phosphorylation state of the receptor MuSK.

### Claim 10 (depends on 1)

The method of claim 1, wherein the biglycan therapeutic binds to alpha-sarcoglycan and gamma-sarcoglycan.

### Claim 11 (depends on 1)

The method of claim 1, wherein the biglycan therapeutic stimulates phosphorylation of alpha-sarcoglycan on a cell membrane.

### Claim 12 (depends on 3)

The method of claim 3, wherein the biglycan amino acid sequence is identical to amino acids 38-365 of SEQ ID NO: 9.

### Claim 13 (depends on 3)

The method of claim 3, wherein the biglycan amino acid sequence is encoded by a nucleic acid which hybridizes under stringent conditions of 6.0×sodium chloride/sodium citrate (SSC) at about 45° C. to a complementary strand of SEQ ID NO: 8.