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

• 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
• 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

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（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型胶原基因突变。 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， 挑战治疗策略。OI突变可以通过商业化的无细胞DNA筛选试验检测， 通常在妊娠10周时进行母体血清检测，并且最常通过标准 在18-20周时进行超声筛查。然而，目前的治疗仅限于手术棒或双膦酸盐， 年龄较大的孩子。没有解药。以前，我们通过药理学抑制肌肉生长抑制素（阴性 肌肉质量调节剂）改善了两种OI小鼠模型的骨参数。 然而，当OI小鼠也是肌生长抑制素遗传缺陷时， 这表明产前和/或生命早期肌肉生长抑制素抑制对于最大功效是关键的。此外，三 通过独立的方法，我们证明了在怀孕期间减少母体肌生长抑制素可以改善骨几何形状 1）由肌生长抑制素降低的母鼠所生的野生型（Wt）后代（+/μ g） 具有比Wt母鼠所生的Wt后代更强的骨骼; 2）具有成骨能力缺失（+/oim）的小鼠具有更强的 当出生于+/01 m母鼠时，骨骼比出生于+/01 m母鼠时更少;和3）+/01 m囊胚转移到+/01 m母鼠 与转移到+/OIM母鼠的母鼠相比，受体母鼠在成年时具有更强的骨骼。重要的是，最后一种方法 通过胚胎移植实验证明，母体+/mglutamine对后代骨骼的影响是由以下因素引起的： 怀孕期间的子宫胎盘环境。基于这些发现，我们将测试 在妊娠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 通过抗肌生长抑制素单克隆抗体治疗， OI小鼠模型。主要疗效指标和指标是改善肌肉骨骼健康 （骨骼肌和骨量和强度）的Wt和OI后代出生前，在4周龄和 峰值骨量（4个月大），以及怀孕期间的母体代谢和肌肉骨骼健康， 哺乳期拟议的项目将提供临床前评估的创新疗法的骨生成 在两个关键的发展时期，终身肌肉骨骼健康的。