GGC Researchers Rescue Rare Heart Defect in Zebrafish Model

10.15.20

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

Greenwood, SC – A research team at the Greenwood Genetic Center (GGC) has successfully used small molecules to restore normal heart and valve development
in an animal model for Mucolipidosis II (ML II), a rare genetic disorder. Progressive heart disease is commonly associated with ML II. The study is
reported in this month’s JCI Insight.

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.

This work was supported by funding from the National MPS Society, ISMRD, and the Yash Gandhi Foundation, as well as through an R01 grant from the NIH National
Institute of General Medical Sciences.

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

Meet Ella

We will remember February 26th for the rest of our lives. On that day, we received the call from the Greenwood Genetic Center that they had discovered our daughter, Ella Marie, has Kleefstra syndrome. Very early on, my wife, Kelly, observed Ella being delayed in some of her milestones. Kelly monitored Ella’s progression and sought out testing in an effort to get Ella some assistance. Along the way, we were sent to GGC and met with LEARN MORE

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