Follistatin Gene Delivery Enhances Muscle Growth and Strength in Nonhuman Primates

Abstract

Antagonists of myostatin, a blood-borne negative regulator of muscle growth produced in muscle cells, have shown considerable promise for enhancing muscle mass and strength in rodent studies and could serve as potential therapeutic agents for human muscle diseases. One of the most potent of these agents, follistatin, is both safe and effective in mice, but similar tests have not been performed in nonhuman primates. To assess this important criterion for clinical translation, we tested an alternatively spliced form of human follistatin that affects skeletal muscle but that has only minimal effects on nonmuscle cells. When injected into the quadriceps of cynomolgus macaque monkeys, a follistatin isoform expressed from an adeno-associated virus serotype 1 vector, AAV1-FS344, induced pronounced and durable increases in muscle size and strength. Long-term expression of the transgene did not produce any abnormal changes in the morphology or function of key organs, indicating the safety of gene delivery by intramuscular injection of an AAV1 vector. Our results, together with the findings in mice, suggest that therapy with AAV1-FS344 may improve muscle mass and function in patients with certain degenerative muscle disorders.

An Engineered Human Follistatin Variant: Insights into the Pharmacokinetic and Pharmocodynamic Relationships of a Novel Molecule with Broad Therapeutic Potential

“…Many studies of the biologic activity of this protein have been limited to gene therapy approaches using adeno-associated viral delivery (Takabe et al, 2003;Kota et al, 2009;Medina et al, 2009;Foley et al, 2010). These investigations have shown that follistatin has potent antiinflammatory activities, wound-healing properties, and muscle hypertrophy and hyperplasia-stimulating effects in rodents and nonhuman primates (Kogure et al, 1995;Wankell et al, 2001;Fuwii et al, 2005;Fumagalli et al, 2007;Tsuchida, 2008;Zimber et al, 2011;de Kretser et al, 2012).…”

“…Several groups have reported potent beneficial effects of follistatin administration in various indications, such as inflammation, liver repair, fibrosis, wound healing, hair regrowth, and muscle disorders, including muscular dystrophy (Kogure et al, 1995;Wankell et al, 2001;Fuwii et al, 2005;Fumagalli et al, 2007;Tsuchida, 2008;Zimber et al, 2011;de Kretser et al, 2012). Many of these disorders require systemic wide pharmacological effects, and as a result, several groups have focused on the use of gene therapy in the form of adeno-associated virus to obtain protein exposure levels required for activity in animal models of disease (Takabe et al, 2003;Kota et al, 2009;Medina et al, 2009;Foley et al, 2010). These studies have yielded promising proof-ofconcept data for the therapeutic potential for follistatin; however, from a practical perspective, the use of follistatinadeno-associated virus as a bona fide human therapeutic is squelched by a tenuous clinical and regulatory path.…”

Development of a Small-Molecule Screening Method for Inhibitors of Cellular Response to Myostatin and Activin A

“…Therefore, recent strategies have focused on blocking myostatin signaling specifically by neutralizing the ligand with various binding proteins such as monoclonal antibodies, receptor decoys, and extracellular antagonists (e.g., follistatin). 7,8 However, specifically targeting myostatin over other TGF-β ligands is still difficult due to the similarity in structure between the ligands. This is especially true for the close family member of myostatin, activin A, which shares high affinity for the same type II receptors and naturally occurring antagonist proteins.…”

Insights into the Impact of Heterogeneous Glycosylation on the Pharmacokinetic Behavior of Follistatin-Fc–Based Biotherapeutics

“…Follistatin (FST) is a regulatory glycoprotein with a myriad of biologic functions in humans (Ueno et al, 1987;Kogure et al, 1995Kogure et al, , 1996Fuwii et al, 2005;Fumagalli et al, 2007;Kota et al, 2009). It is involved in the regulation of early fetal development and cellular differentiation, regulating follicle-stimulating hormone and luteinizing hormone release and action (Carroll et al, 1991;Barakat et al, 2008;Aroua et al, 2012), wound healing (Fumagalli et al, 2007), tissue regeneration and repair, including bone, muscle, and skin (Inoue et al, 1994;Funaba et al, 1996;Gajos-Michniewicz et al, 2010, and limiting cancer cellular proliferation (Ogino et al, 2008;Tumminello et al, 2010;Karve et al, 2012;Ren et al, 2012;Sepporta et al, 2013).…”