Developmental timeline


AVGN7 is currently being developed to treat inclusion body myositis, cancer cachexia and Duchenne muscular dystrophy, although additional disease indications are being considered.  The status of the development path for each indication is shown in the figure above.  Completed stages of development are indicated by solid blue arrows, on-going stages by hollow arrows.

Smad signaling2

Smad7 and muscle hypertrophy

Various hormones or ligands (A) bind myostatin/activin receptors (ActRIIb). The serine-threonine kinase ALK4/5 is then recruited to ActRIIb and phosphorylates Smad2 and Smad3 (B). These transcription factors separately form complexes with Smad4 to activate gene expression of the E3 ubiquitin ligases MuRF1 and MAFbx. These factors then stimulate protein degradation and as a result, muscle wasting.

Smad7 expression is also stimulated by this pathway. This "inhibitory Smad" targets ActRIIb for ubiquitination (C) and ultimately degradation (D). Thus, overexpressing Smad7 suppresses Smad2/3 signaling, promotes muscle hypertrophy and prevents muscle wasting.

Mechanisms of muscle enhancement

AVGN7 increases levels of Smad7 in muscle. This blocks the actions of myostatin (MSTN) and other hormones that inhibit muscle growth. Because Smad2 and Smad3 aren't active, neither are the biochemical pathways that degrade muscle protein or cause fibrosis (gray).

Smad2 and Smad3 normally inhibit expression of miR-29 and miR-486, which block an inhibitor of the PI3K-Akt-mTOR pathway. Smad2/3 also inhibit PGC1a. Thus, Smad7's inhibition of Smad2/3 activates pathways that increase muscle protein synthesis, muscle growth and mitochondrial biogenesis.

Smad7 antagonism

Combinatorial therapy

Muscle wasting occurs in many disease states and is activated by similar biochemical events in each. AVGN7 attenuates these events and has the potential to treat a wide variety of disease indications, either by itself or in combination with other drugs (e.g. exon-skipping, gene replacement, etc). Click the link to the right to learn more about muscle wasting diseases.