Preclinical testing of early life anti-myostatin therapy for osteogenesis imperfecta

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Summary: Osteogenesis imperfecta (OI) is a genetically and clinically heterogeneous connective tissue disorder resulting in muscle weakness, bone deformity and increased fragility, primarily due to type I collagen gene mutations. Genetic and clinical heterogeneity (> 1500 mutations) and growing evidence of mutation specific pathogenesis further challenges therapeutic strategies. OI mutations can be detected by commercial cell-free DNA screening tests in maternal serum which are generally conducted at 10 weeks gestation, and severe OI is most often detected by standard ultrasound screening at 18-20 weeks. However, current treatment is limited to surgical rodding or bisphosphonates in older children. There is no cure. Previously, we showed by pharmacological inhibition of myostatin (a negative regulator of muscle mass) beginning at 5 weeks of age improved bone parameters in two mouse models of OI. However, more significant improvements were achieved when OI mice were also genetically deficient for myostatin, suggesting prenatal and/or early life myostatin inhibition is critical for maximum efficacy. Furthermore, by three independent approaches, we demonstrated that reduced maternal myostatin during pregnancy improved bone geometry and biomechanical integrity in offspring: 1) Wildtype (Wt) offspring born to dams with reduced myostatin (+/mstn) had stronger bones than Wt offspring born to Wt dams; 2) Mice with osteogenesis imperfecta (+/oim) had stronger bones when born to +/mstn dams than when born to +/oim dams; and 3) +/oim blastocysts transferred to +/mstn recipient dams had stronger bones as adults than those transferred to +/oim dams. Importantly, the last approach demonstrated through embryo transfer experiments that the maternal +/mstn effect on offspring bone is conferred by the uteroplacental environment during pregnancy. Based on these findings, we will test the efficacy of pharmacological inhibition of maternal and fetal myostatin during either pregnancy or lactation or throughout pregnancy, lactation and early adulthood via anti-myostatin monoclonal antibody treatment in two molecularly distinct OI mouse models. The primary outcome measures and indicators of efficacy are improved musculoskeletal health (skeletal muscle and bone mass and strength) of Wt and OI offspring just prior to birth, at four weeks of age and at peak bone mass (4-month-old), as well as maternal metabolic and musculoskeletal health during pregnancy and lactation. The proposed project will provide preclinical evaluation of an innovative therapy for osteogenesis imperfecta during two critical developmental periods for lifelong musculoskeletal health.