Maternal Anti-myostatin (GDF8) Therapy to Enhance Offspring Musculoskeletal Health in Mouse Models of Osteogenesis Imperfecta

母体抗肌生长抑制素 (GDF8) 疗法可增强成骨不全小鼠模型后代的肌肉骨骼健康

• 批准号: 10041912
• 负责人: CHARLOTTE L PHILLIPS
• 金额: $ 20.37万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10041912
• 关键词: Adult; Adult Children; Adverse effects; Age; Age-Months; Alleles; Antibodies; Antibody Therapy; Architecture; Biochemistry; Biomechanics; Blastocyst Transfer; Blocking Antibodies; Body Weight; Bone Density; Bone Resorption; Cellular biology; Clinic; Clinical; Clinical Trials; Collagen; Collagen Gene; Collagen Type I; Connective Tissue Diseases; Cysteine; Deformity; Development; Dominant-Negative Mutation; Embryo Transfer; Environment; Environmental Risk Factor; Exhibits; Fracture; GDF8 gene; Gene Mutation; Genetic; Genetic Heterogeneity; Genotype; Glycine; Goals; Growth; Health; Heterozygote; Human; Hyperplasia; Hypertrophy; Knockout Mice; Modality; Molecular; Monoclonal Antibodies; Mus; Muscle; Muscle Weakness; Musculoskeletal; Musculoskeletal Diseases; Mutation; Operative Surgical Procedures; Osteoblasts; Osteoclasts; Osteogenesis; Osteogenesis Imperfecta; Outcome Measure; Pathogenesis; Patients; Perinatal; Perinatal mortality demographics; Pharmacologic Substance; Pharmacology; Phenotype; Physiological; Physiology; Play; Pregnancy; Prenatal Diagnosis; Property; Role; Severity of illness; Skeletal Muscle; Skeleton; Testing; Therapeutic; Therapeutic Intervention; Ultrasonography; Variant; Work; base; bone; bone fragility; bone geometry; bone health; bone mass; bone quality; bone strength; clinical heterogeneity; congenic; drug discovery; efficacy testing; experimental study; fetal; heritable connective tissue disorder; high risk; improved; innovation; mouse model; muscle form; muscle strength; novel; offspring; perinatal period; postnatal; prenatal; prenatal testing; primary outcome; programs; skeletal; success

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. Currently there is no cure. Genetic and clinical heterogeneity (> 1500 mutations) and growing evidence of mutation specific pathogenesis further challenges drug discovery. Deficiency in myostatin, a circulating negative regulator of muscle growth, results in increased muscle mass and physiological loading on the skeleton with concomitant increases in bone mass and biomechanical integrity. Developmental programming by the prenatal environment is hypothesized to play a significant role in lifelong bone health and promises to provide a novel modality for therapeutic intervention. Congenital myostatin null mice demonstrate both myofiber hyperplasia and hypertrophy, while mice with postnatal myostatin deficiency exhibit only hypertrophy, indicating some aspects of adult physiology are irreversibly determined during prenatal development. Previously, by three independent approaches we demonstrated that reduced maternal myostatin during pregnancy improves 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 through embryo transfer experiments demonstrated that the maternal +/mstn effect on offspring bone was 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 pregnancy via maternal anti-myostatin (GDF8) monoclonal antibody treatment as a prenatal therapeutic approach for OI using two molecularly distinct OI mouse models. The primary outcomes measures and indicators of efficacy are improved musculoskeletal health (skeletal muscle and bone mass and function) of Wt and OI offspring at the age of peak bone mass (4 month old). OI can be diagnosed prenatally, whether genetically or by ultrasound, yet we have no prenatal treatment options and, are thus missing a critical therapeutic window. This high risk study represents a more than incremental leap towards establishing the translational potential of a prenatal treatment for OI, it is a paradigm shift in understanding and treating OI; a shift from believing only genetic and postnatal factors control bone health, to the inclusion of the prenatal/perinatal period as an important and modifiable window for controlling adult bone health.

总结 成骨不全（OI）是一种遗传和临床异质性结缔组织疾病 导致肌肉无力、骨畸形和脆性增加，主要是由于I型胶原蛋白 基因突变目前没有治愈方法。遗传和临床异质性（> 1500个突变）和 突变特异性发病机制的证据越来越多，进一步挑战了药物发现。缺乏 肌肉生长抑制素是肌肉生长的循环负调节剂，导致肌肉质量增加， 骨骼上的生理负荷伴随着骨量和生物力学的增加 完整产前环境的发育编程被假设为在胎儿发育过程中起重要作用。 在终身骨骼健康中的作用，并有望提供一种新的治疗干预方式。 先天性肌生长抑制素缺失小鼠表现出肌纤维增生和肥大，而小鼠 出生后肌肉生长抑制素缺乏症患者仅表现出肥大，表明成人生理学的某些方面 是在产前发育过程中不可逆转地决定的。此前，通过三种独立的方法， 我们证明了在怀孕期间减少母体肌肉生长抑制素可以改善骨的几何形状， 后代中的生物力学完整性：1）肌生长抑制素减少的母鼠所生的野生型（Wt）后代 （+/m3）比Wt母鼠所生的Wt后代具有更强的骨骼; 2）具有成骨能力的小鼠 （+/oim）出生于+/martum母鼠时比出生于+/oim母鼠时具有更强的骨骼;和3）+/oim 转移到+/mGly受体母鼠的囊胚在成年时比转移到 +/oim大坝。重要的是，通过胚胎移植实验的最后一种方法证明， 母体+/孕激素对后代骨的影响是由子宫胎盘环境在 怀孕基于这些发现，我们将测试药物抑制母体 通过母体抗肌肉生长抑制素（GDF 8）单克隆抗体在妊娠期间与胎儿肌肉生长抑制素 使用两种分子上不同的OI小鼠模型作为OI的产前治疗方法。的 疗效的主要结果测量和指标是改善的肌肉骨骼健康（骨骼 肌肉和骨量和功能）的Wt和OI后代在峰值骨量年龄（4月龄）。 OI可以在产前诊断，无论是遗传学还是超声波，但我们没有产前诊断。 治疗选择，因此错过了关键的治疗窗口。这项高风险研究代表了 在建立产前治疗的转化潜力方面， 这是理解和治疗OI的一个范式转变;从只相信遗传和 出生后因素控制骨骼健康，纳入产前/围产期作为重要的 以及用于控制成人骨骼健康的可变窗口。