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

早期抗肌生长抑制素治疗成骨不全症的临床前测试

基本信息

批准号：
10840238
负责人：
CHARLOTTE L PHILLIPS
金额：
$ 21.74万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10840238
关键词：
Adult Adverse effects Affect Age Age Months Antibody Therapy Biology Biomechanics Birth Blastocyst Transfer Body Composition Bone Growth Brain Breeding COL1A1 gene COL1A2 gene Cessation of life Child Clinical Collagen Gene Collagen Type I Congenital Disorders Connective Tissue Diseases Deformity Development Early Diagnosis Early treatment Embryo Transfer Environment Exposure to Female Fiber GDF8 gene Gene Mutation Genetic Heterogeneity Growth Health Heart Diseases Hyperplasia Hypertrophy Innovative Therapy Knock-out Lactation Life Metabolic Metabolic Diseases Metabolism Molecular Monoclonal Antibodies Mothers Mus Muscle Muscle Weakness Musculoskeletal Musculoskeletal Development Mutation Operative Surgical Procedures Osteogenesis Imperfecta Outcome Outcome Measure Partner in relationship Pathogenesis Persons Pharmacologic Substance Physicians Preclinical Testing Pregnancy Production Property Puberty Respiratory distress Rod Severity of illness Skeletal Muscle Spinal Curvatures Testing Therapeutic United States Uterus Variant Weaning Wild Type Mouse Woman autosome bisphosphonate bone bone geometry bone health bone loss bone mass cell free DNA clinical heterogeneity conditional knockout critical developmental period critical period effective therapy efficacy evaluation efficacy testing emerging adult experimental study fetal hearing impairment high risk improved inhibitor innovation male maternal serum mouse model muscle form muscle hypertrophy neonatal period new technology novel offspring pharmacologic postnatal preclinical evaluation prenatal prenatal testing primary outcome public health relevance response screening sex skeletal success tool treatment effect ultrasound

项目摘要

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.

摘要：成骨不完美（OI）是一种遗传和临床异质结缔组织障碍导致肌肉无力，骨畸形和脆弱性增加，主要是由于I型胶原基因突变。遗传和临床异质性（> 1500个突变）和越来越多的突变特异性发病机理的证据挑战治疗策略。可以通过无细胞的无细胞DNA筛选测试检测OI突变通常在妊娠10周进行的母体血清，并且最常通过标准检测到严重的OI 超声检查在18-20周。但是，当前的治疗仅限于手术杆或双膦酸盐大孩子。无法治愈。以前，我们通过药理学抑制肌抑制素显示（阴性肌肉质量的调节剂在5周龄开始的OI小鼠模型中改善了骨参数。但是，当OI小鼠在遗传上缺乏Myostatin时，可以实现更大的改善，暗示产前和/或早期生命肌抑制素抑制对于最大程度的疗效至关重要。此外，三个独立的方法，我们证明了怀孕期间孕产妇肌生抑制素的减少改善了骨几何形状和后代的生物力学完整性：1）野生型（WT）后代是大坝出生的，肌生抑素降低（+/MSTN）骨头比wt大坝出生的wt后代更坚固。 2）具有成骨的小鼠Imperfecta（+/OIM）的强度更强出生于 +/mstn大坝的骨骼比出生于 +/oim大坝时； 3） +/OIM胚泡转移到 +/MSTN 受体大坝的骨头比转移到 +/OIM大坝的骨骼更强。重要的是，最后的方法通过胚胎转移实验证明了母体 +/MSTN对后代骨的影响怀孕期间的子宫门环境。根据这些发现，我们将测试在怀孕或泌乳期间或整个孕产妇和胎儿肌生抑制素的药理抑制作用通过抗神经毒素单克隆抗体治疗的妊娠，泌乳和成年早期，两种分子上的抗体治疗 OI鼠标模型。功效的主要结果指标和指标是改善肌肉骨骼健康（骨骼肌，骨骼质量和力量）在出生前，四个星期大，在峰值骨骼质量（4个月大），以及怀孕期间的母体代谢和肌肉骨骼健康哺乳。拟议的项目将对成骨的创新疗法提供临床前评估终身肌肉骨骼健康的两个关键发育时期内的Imperfecta。