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

摘要：成骨不全(OI)是一种遗传性和临床异质性的结缔组织疾病。 导致肌肉无力、骨骼畸形和脆性增加，主要是由于I型胶原基因突变。 遗传和临床异质性(&gt；1500突变)和越来越多的证据表明突变特定的致病机制进一步 挑战治疗策略。OI突变可以通过商业无细胞DNA筛查测试检测到 孕妇血清通常在怀孕10周时进行检测，严重的OI最常按标准检测 18-20周时进行超声检查。然而，目前的治疗仅限于外科棒状或双膦酸类药物。 年龄较大的孩子。没有治愈的方法。此前，我们通过药物抑制Myostatin(阴性 肌肉质量调节剂)在5周龄时开始改善两种OI小鼠模型的骨参数。 然而，当OI小鼠也是肌肉生长抑素基因缺陷时，取得了更显著的改善， 提示产前和/或早期抑制肌肉生长抑素是获得最大疗效的关键。此外，到三个月前 独立的方法，我们证明了在怀孕期间减少母亲的肌肉抑制素改善了骨几何形状 和子代的生物力学完整性：1)野生型(Wt)子代出生于肌肉生长抑素降低(+/MSTN)的母鼠 比Wt Dam所生的Wt后代骨骼更强壮；2)成骨不全(+/OIM)的小鼠更强壮 +/MSTN母鸡出生时的骨骼比+/OIM母羊出生时的骨骼；3)+/OIM囊胚转移到+/MSTN 成年后，接受移植的水坝比转移到+/OIM水坝的人骨骼更坚固。重要的是，最后一种方法 通过胚胎移植实验证明，母体+/MSTN对子代骨骼的影响是通过以下方式实现的 妊娠期间的子宫胎盘环境。基于这些发现，我们将测试 妊娠、哺乳期或整个过程中母体和胎儿肌肉生长抑素的药理抑制 抗肌生长抑素单抗治疗妊娠、哺乳和成年早期在两个分子水平上的差异 OI小鼠模型。疗效的主要结果衡量标准和指标是改善肌肉骨骼健康。 (骨骼肌、骨量和力量)Wt和Oi子代在出生前、四周龄和 峰值骨量(4个月大)，以及孕期母体代谢和肌肉骨骼健康 哺乳。拟议的项目将为成骨的创新疗法提供临床前评估。 在终生肌肉骨骼健康的两个关键发育期内不完美。

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.