Biglycan is a small, naturally occurring extracellular matrix protein naturally found in muscle. It is a 37kD polypeptide chain and is a member of the Small Leucine-Rich Repeat Proteoglycan (SLRP) family of proteins. In immature muscle, Biglycan regulates the expression of a key ensemble of cell surface proteins including utrophin, alpha and gamma sarcoglycan, and the NODS complex of nNOS, dystrobrevin and syntrophin.
DMD and BMD are X-linked genetic disorders of muscle resulting from mutations of the gene encoding the protein dystrophin. Biglycan, a natural component of muscle, activates a utrophin-based compensatory pathway that can potentially overcome the damaging effects of dystrophin loss in DMD and BMD patients. Utrophin is a dystrophin homolog that is highly expressed at the muscle cell membrane during development and is up-regulated by Biglycan. Systemically-administered recombinant Biglycan improves muscle health, structure and function in dystrophin-deficient mice (mdx, the standard animal model in DMD) with no signs of toxicity. These results indicate that Biglycan treated mice have healthier, better functioning skeletal muscle that undergoes less death and degeneration.
Biglycan is widely expressed in the body as a proteoglycan (PG). However, in muscle, Biglycan is also naturally expressed as a non-glycanated (NG) form that lacks GAG side chains seen in the PG form. The NG Biglycan is a component of the dystrophin/utrophin associated protein complex and is the only form efficacious in countering muscular dystrophy. Tivorsan’s product candidate, TVN-102, is derived from the NG form of Biglycan. TVN-102 completely lacks GAG side chains and can be manufactured in homogenous NG preparations, facilitating manufacture and mitigating off-target effects.
Biglycan has a strongly competitive and differentiated profile that has the potential to: (1) reverse or delay the progression of DMD and BMD in children and adults by addressing the primary pathological defect with these disorders; (2) be effective in all forms of the disorders, regardless of mutation; and (3) be non-conflicting (or synergistic) with other current or emerging therapies.