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：成骨不全症 (OI) 是一种遗传和临床异质性结缔组织疾病导致肌肉无力、骨骼畸形和脆弱性增加，这主要是由于 I 型胶原蛋白基因突变造成的。遗传和临床异质性（> 1500 个突变）以及越来越多的突变特异性发病机制的证据进一步挑战治疗策略。 OI 突变可以通过商业游离 DNA 筛选测试来检测母体血清检查通常在妊娠 10 周时进行，严重 OI 最常通过标准检测 18-20周时进行超声检查。然而，目前的治疗仅限于手术棒扎或双磷酸盐年龄较大的孩子。没有治愈方法。之前，我们通过药物抑制肌肉生长抑制素（阴性从 5 周龄开始，两个成骨不全小鼠模型的骨骼参数得到改善。然而，当 OI 小鼠也存在肌肉生长抑制素基因缺陷时，获得了更显着的改善。表明产前和/或生命早期的肌生长抑制素抑制对于最大功效至关重要。此外，通过三独立的方法，我们证明怀孕期间减少母体肌生长抑制素可以改善骨骼几何形状和后代的生物力学完整性：1) 肌肉生长抑制素减少 (+/mstn) 的母鼠所生的野生型 (Wt) 后代拥有比 Wt 母亲所生的 Wt 后代更强的骨骼； 2）患有成骨不全症（+/oim）的小鼠具有更强的 +/mstn 水坝出生的骨头比 +/oim 水坝出生的骨头多； 3) +/oim 囊胚转移至 +/mstn 接受母体成年后的骨骼比转移到+/oim母体的母体更坚固。重要的是，最后一种方法通过胚胎移植实验证明母体+/mstn对后代骨骼的影响是由怀孕期间的子宫胎盘环境。根据这些发现，我们将测试其功效在怀孕或哺乳期间或整个过程中对母体和胎儿肌生长抑制素的药理学抑制怀孕、哺乳期和成年早期通过抗肌生长抑制素单克隆抗体治疗两种不同分子 OI 鼠标模型。主要结果指标和功效指标是改善肌肉骨骼健康 Wt 和 OI 后代在出生前、四周龄和出生时的（骨骼肌和骨量和强度）峰值骨量（4 个月大），以及孕期和孕期的母亲代谢和肌肉骨骼健康哺乳期。拟议的项目将为成骨创新疗法提供临床前评估终生肌肉骨骼健康的两个关键发育时期的不完美。