GGC Researchers Rescue Rare Heart Defect in Zebrafish Model

Small molecule restores normal heart development in model organism with genetic disorder

The small molecules included the cathepsin protease K inhibitor, odanacatib, and an inhibitor of TGFß growth factor signaling. Cathepsin proteases
have been associated with later onset heart disease including atherosclerosis, cardiac hypertrophy, and valvular stenosis, but their role in congenital
heart defects has been unclear. The current study offers new insight into how mislocalizing proteases like cathepsin K alter embryonic heart development
in a zebrafish model of ML II.

“Mutations in GNPTAB, the gene responsible for ML II, alter the localization and increase the activity of cathepsin proteases. This disturbs growth
factor signaling and disrupts heart and valve development in our GNPTAB deficient zebrafish embryos,” said Heather Flanagan-Steet, PhD,
Director of the Hazel and Bill Allin Aquaculture Facility and Director of Functional Studies
at GGC. “By inhibiting this process, normal cardiac development was restored. This finding highlights the potential of small molecules and validates
the need for further studies into their efficacy.”

Flanagan-Steet noted that she hopes the current work with ML II zebrafish will provide the basis to move one step closer to a treatment.

Confocal analyses show that treatment with 50 nM of odanacatib restores normal morphology to MLII zebrafish hearts and valves.