A Comprehensive Newborn Screening Solution for Duchenne and Congenital Muscular Dystrophies

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 Baebiesandapos; 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.