A Comprehensive Newborn Screening Solution for Duchenne and Congenital Muscular Dystrophies

针对杜氏肌营养不良症和先天性肌营养不良症的新生儿综合筛查解决方案

• 批准号: 9927653
• 负责人: Viren R Amin
• 金额: $ 66.64万
• 依托单位: BAEBIES, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-08 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9927653
• 关键词: Adopted; Affect; Algorithms; Biochemical; Biochemistry; Biological Assay; Blood; Cardiac; Certification; Child; Childhood; Clinic; Clinical; Congenital Disorders; Copy Number Polymorphism; Creatine Kinase; Databases; Detection; Development; Disease; Duchenne muscular dystrophy; Dystrophin; Engineering; Enzymes; Gene Duplication; Genes; Genomics; Goals; Health; Immunoassay; Individual; Infant Care; Isoenzymes; Laboratories; Life; Measurement; Measures; Methods; Microfluidics; Modification; Molecular Abnormality; Molecular Analysis; Morbidity - disease rate; Muscle; Muscular Atrophy; Muscular Dystrophies; Neonatal Screening; Neurology; Newborn Infant; Outcome; Pathogenicity; Patient-Focused Outcomes; Patients; Pediatrics; Phase; Pilot Projects; Protein Isoforms; Public Health; Reagent; Reporting; Research; Risk; Sampling; Sensitivity and Specificity; Services; Small Business Innovation Research Grant; Specimen; Spottings; System; Testing; Thyroid Gland; Universities; Update; Validation; Variant; Wasting Syndrome; assay development; causal variant; clinical Diagnosis; congenital muscular dystrophy; cost; design; digital; enzyme activity; genetic variant; improved; innovation; instrument; interest; male; mortality; next generation sequencing; novel therapeutics; operation; screening; screening panel; screening program

Congenital genetic abnormalities are a leading cause of childhood mortality and morbidity. While routine newborn screening (NBS) has dramatically improved health outcomes, many congenital disorders such as Duchenne muscular dystrophy (DMD) and other congenital muscular dystrophies (CMD) are not currently detected by routine NBS. Presymptomatic identification through NBS is critical to facilitate earlier initiation of therapies and for improved long-term outcomes of patients with DMD or other CMDs. With several new therapies on the horizon, the interest in DMD screening has grown considerably and there is reason to believe testing may be adopted for public health screening in the next five years. The goal of this Fast Track SBIR project is to develop a complete testing solution for efficient newborn screening of DMD and CMDs from dried blood spot (DBS) specimens. The system will consist of automated, low volume biochemical assays for creatine kinase (CK) enzyme activity and CK isoform expression (CK-MM and CK-MB) followed by 2nd-tier targeted next generation sequencing (tNGS) in CK (+) individuals to detect common casual gene variants associated with DMD and CMDs. The proposed 1st-tier biochemical tests will leverage Baebies' proprietary SEEKERTM platform, which is FDA cleared for NBS of lysosomal storage disorders, to provide high throughput, multi-analyte CK testing to the newborn screening market. The biochemical measurements will be combined into a decision algorithm to reduce false positives and eliminate false negatives. A similar strategy is used successfully in some state NBS programs for detection of thyroid conditions, where TSH and T4 are measured simultaneously and correlated to better define disease state. The addition of tNGS for 2nd-tier analysis will provide further precision to our system and has the potential to revolutionize the care of infants and young children with elevated CK levels. After initial validation of the system, the next steps will be to extend the clinical portion of the study to generate evidence for nomination to the Recommended Universal Screening Panel (RUSP), which states use to inform their NBS offerings. We anticipate further validation within a Phase IIB trial concomitant with seeking CLIA certification for the screening service and eventually FDA approval of the biochemical test system. The final product of this research will be differentiated from competing single analyte CK tests for NBS by its use of an automated, multianalyte biochemical assay (at minimal added cost compared to single analyte tests due to the tiny reagent volumes required) and the rapid, small sample tNGS workflow – which combined will enable efficient identification of newborns at risk for DMD/CMDs with lower false positive rates and no false negatives.

先天性遗传异常是儿童死亡率和发病率的主要原因。同时例行 新生儿筛查（NBS）大大改善了健康结果，许多先天性疾病，例如 Duchenne肌肉营养不良（DMD）和其他先天性肌肉营养不良（CMD）目前尚未 通过常规NBS检测。通过NBS识别的鉴定对于促进早期倡议至关重要 DMD或其他CMD患者的疗法和改善的长期结局。有几个新 地平线上的疗法，对DMD筛查的兴趣已经仔细增长，有理由相信 在未来五年内，可以采用测试进行公共卫生筛查。 这个快速轨道SBIR项目的目标是开发一个完整的测试解决方案，以提高新生儿 从干斑（DBS）标本中筛选DMD和CMD。该系统将由自动化组成， 创建激酶（CK）酶活性和CK同工型表达的低体积生化测定（CK-MM） 和CK-MB），然后在CK（+）个体中进行第二层针对的下一代测序（TNG）以检测 与DMD和CMD相关的常见休闲基因变体。提出的第一层生化测试将 利用Baebies的专有Seekertm平台，该平台已清除用于溶酶体存储的NB 为了向新生儿筛查市场提供高吞吐量的多分析型CK测试，疾病。这 生化测量将合并为决策算法，以减少误报并消除 假否定。在某些州NBS程序中成功使用了类似的策略来检测甲状腺 条件，简单地测量TSH和T4以更好地定义疾病状态。 添加用于第二层分析的TNG将为我们的系统提供进一步的精度，并有可能 彻底改变了CK水平升高的婴儿和幼儿的护理。 在对系统进行初始验证之后，下一步将是扩展研究的临床部分以生成 提名提名的推荐通用筛选面板（RUSP）的证据，该面板用于告知 他们的NBS产品。我们预计在IIB阶段试验中会进一步验证与寻求Clia 筛选服务的认证以及最终的FDA批准生化测试系统。决赛 这项研究的产物将通过使用竞争的单个分析物CK测试来区分NB 自动化的多植物生化测定（与单个分析物测试相比，以最少的成本相比 需要的小试剂量）和快速的小样品TNG工作流程 - 合并将启用 有效地识别有较低误报率较低且没有假否定的DMD/CMD风险的新生儿。