- Gene therapeutic for different muscle wasting disease states
- AAV:Smad7 - enhances muscle mass/strength, prevents muscle wasting
- Gene therapeutic for limb girdle muscular dystrophy (LGMD) 2i
- AAV:FKRP - restores functional FKRP, ameliorates many pathologies in mouse models of LGMD2i
- Combinatorial approach to restore muscle structure, function and strength
The stages of developmental for AVGN7, AVGNF and the combo-therapy are illustrated on the timeline above. Completed stages for each therapeutic are indicated by intact images whereas silhouettes represent stages that are currently being performed.
Smad7 and muscle hypertrophy
Various ligands bind the activin receptors including ActRIIb, which in turn recruits ALK4/5, a serine-threonine kinase that phosphorylates Smad2 and Smad3 (A). 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 activin receptors for ubiquitination (B) and ultimately degradation (C). Thus, overexpressing Smad7 suppresses Smad2/3 signaling, promotes muscle hypertrophy and prevents muscle wasting.
FKRP and the DGC
Dystrophin links the intracellular contractile machinery to the muscle cell's membrane by binding to F-Actin and, on the opposite end, to different components of the dystrophin-associated glycoprotein complex or "DGC". Carbohydrates are attached to several DGC proteins, some by Fukutin-related protein (FKRP), and without such attachments, muscle cells become poorly anchored and are susceptible to contraction-induced injury. This is what occurs in patients with LGMD2i.
Animal studies indicate that restoring expression of a functioning FKRP stabilizes muscle structure, prevents future degeneration and partially restores muscle function and exercise capacity.
Muscle wasting occurs in many disease states and is activated by similar biochemical events in each. AVGN7 attenuates these events and thus, has the potential to treat a wide variety of disease indications, either as a single therapeutic or in combination with others (e.g. AVGNF). Click the link to the right to learn more about muscle wasting diseases.