Preclinical Testing of Early Life Anti-Myostatin Therapy for Osteogenesis - PROJECT 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. Severe OI is detected by standard American College of Obstetricians and Gynecologists (ACOG) recommended ultrasound screening (18-22 weeks). Additionally, paternal OI and de novo mutations can be detected by commercial cell-free DNA screening in maternal serum as early as 10 weeks gestation- demonstrating efficacy of early screening technologies. Although OI can be diagnosed before birth, physicians currently lack tools for in utero intervention. The goal of this proposal is to evaluate an innovative in utero pharmacological approach to building bone and muscle strength during development and throughout the lifespan. Previously, we demonstrated that 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 genetically deficient for myostatin, suggesting prenatal and/or early life myostatin inhibition is critical for maximum efficacy. Furthermore, we demonstrated that reduced maternal myostatin during pregnancy improved bone geometry and biomechanical integrity offspring with unaltered myostatin levels. Together these results indicate that inhibiting maternal myostatin during pregnancy is an innovative strategy to improve bone and muscle strength in offspring with OI. Here, we will test the efficacy of pharmacological inhibition of maternal and fetal myostatin via anti-myostatin monoclonal antibody therapy in two molecularly distinct OI mouse models initiated at two critical developmental time frames equivalent to 1) prenatal screening/diagnoses at 18-22 months (ACOG recommended) ultrasound (mouse E14.5); 2) pre-conception planning by a couple affected by OI. Maternal anti-myostatin monoclonal antibody treatment will be continued throughout lactation, followed by direct delivery to the offspring from the time of weaning into adulthood. Aim 2 will begin to elucidate the mechanism by which inhibiting myostatin in the maternal environment alters pregnancy health, maternal-fetal transport, and fetal musculoskeletal development using multiomic single nucleus sequencing. Finally, maternal health is a key outcome for in utero therapeutic development and is paramount for clinical consideration. Therefore, Aim 3 will evaluate maternal safety, metabolic and musculoskeletal health during pregnancy and lactation in wildtype and OI mice. The proposed project will provide preclinical evaluation of innovative in utero therapies for OI during critical developmental windows to maximize lifelong musculoskeletal health. Finaly, the project deliverables will provide key evidence for early therapeutic intervention as a strong rationale for implementing early first-trimester screening for OI.
