A Comprehensive Newborn Screening Solution for Duchenne and Congenital Muscular Dystrophies

先天性遗传异常是儿童死亡和发病的主要原因。虽然例行 新生儿筛查（NBS）极大地改善了健康状况，许多先天性疾病，如 杜氏肌营养不良症（DMD）和其他先天性肌营养不良症（CMD）目前没有 通过常规NBS检测。通过NBS进行症状前识别对于促进早期启动 治疗和改善DMD或其他CMD患者的长期结局。与几个新的 随着治疗方法的出现，对DMD筛查的兴趣已经大大增加，有理由相信， 在未来五年内，可能会采用测试作为公众健康检查。 这个快速通道SBIR项目的目标是为高效的新生儿开发一个完整的测试解决方案。 从干血斑（DBS）标本中筛选DMD和CMD。该系统将包括自动化、 肌酸激酶（CK）酶活性和CK亚型表达（CK-MM）的低容量生化测定 和CK-MB），然后在CK（+）个体中进行二级靶向下一代测序（tNGS），以检测 与DMD和CMD相关的常见偶然基因变异。建议的第一级生化测试将 利用Baebies专有的SEEKERTM平台，该平台已获得FDA批准用于NBS的溶酶体储存 疾病，提供高通量，多分析物CK测试新生儿筛查市场。的 生物化学测量将被组合到决策算法中，以减少假阳性并消除 假阴性类似的策略在一些国家统计局的甲状腺检测项目中得到了成功的应用。 TSH和T4被同时测量并关联以更好地定义疾病状态。的 为第二层分析增加tNGS将为我们的系统提供更高的精度，并有可能 彻底改变CK水平升高的婴幼儿护理。 在对系统进行初步确认后，下一步将扩展研究的临床部分， 推荐的通用筛选小组（RUSP）提名的证据，各州使用该证据通知 NBS的报价我们期待在IIB期试验中进一步验证，同时寻求CLIA 筛选服务的认证和最终FDA批准的生化测试系统。最终 这项研究的产品将通过使用一种 自动化、多分析物生化分析（与单一分析物测试相比，由于 所需的试剂体积很小）和快速、小样本tNGS工作流程-两者相结合， 有效识别DMD/CMD风险新生儿，假阳性率较低，无假阴性。

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.