Grant to Support Probe of Rare, Deadly Disorder in Infants

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November 22, 2024

Nick Burgis (right) and co-principal investigator Yao Houndonougbo in Burgis' Science Building laboratory.

The ITPA protein plays an essential role in several metabolic processes that are essential to human life. Severe defects in ITPA are uncommon, but the results can be devastating.

Infants born with a rare ITPA abnormality face the risk of a lethal neurological condition known as Developmental and Epileptic Encephalopathy 35. Few diagnosed with the disorder live past their third birthday. Even patients with less severe ITPA deficiencies can experience dangerous side-effects to medications prescribed for other conditions - including conditions that are life-threatening.

Nick Burgis, professor and chair of chemistry, biochemistry and physics at EWU, is perhaps the nation's leading authority on the ITPA protein and the genetic processes it regulates. Together with his colleague Yao Houndonougbo, himself a professor of chemistry and biochemistry at Eastern, Burgis is using that knowledge to pursue development of the first generation of molecular-level treatments for ITPA-related disorders.

Burgis' and Houndonougbo's efforts recently received an important boost from the National Institutes of Health, which last month announced a three-year, $350,000 "research enhancement" award that will extend the agency's previous support for the two scientists and their students.

The focus of the work supported by the grant, says Burgis, is to identify a molecule that can restore the ITPA's proper functionality. To do this, he, Houndonougbo and their students will deploy a battery of digital and biochemical tools to look for promising molecule among a "virtual and physical library" of 300,000 molecules housed at UCLA.

What our work together has already shown is that there is one variant that quite a few people have - the P32T - in which a portion of the protein is destabilized," Burgis says. "We've established that this destabilization produces basically the same result as one of the other mutants which causes the infantile encephalopathy."

As part of this effort, Burgis - along with two, yet-to-be-named Eastern undergraduate researchers - will eventually travel to Southern California to conduct the molecular hunt with Robert Damoiseaux, a professor of molecular and medical pharmacology who directs UCLA's Molecular Screening Shared Resources laboratory.

Like the NIH award, Houndonougbo sees the partnership with the UCLA as a validation of the work being done at EWU: "I think he [Damoiseaux] is really interested because our research combines computational and biochemical methods like we are doing," says Houndonougbo.

And, in fact, Houndonougbo's use of these methods, particularly molecular docking, is poised to yield important clues as to which "drug-like" molecules in UCLA's library to target.

"What our work together has already shown is that there is one variant that quite a few people have - the P32T - in which a portion of the protein is destabilized," Burgis says. "We've established that this destabilization produces basically the same result as one of the other mutants which causes the infantile encephalopathy."

The hope, he continues, is that addressing this particular destabilization could lead to drug therapies that would benefit all at-risk populations: both infants with encephalopathyas well as older populations with less severe forms of ITPA deficiency.

Though work on the project began back in 2015, and Burgis and Houndonougbo acknowledge there remains much left to be done, both say progress so far has been nothing short of extraordinary.

"The work so far has given us a single pathway to address deficiencies in both populations, which was just amazing," Burgis says. "We were kind of surprised at the results, but it was as clear as it could be."

The project, "Computational and biochemical screening for the discovery of molecules that stabilize ITPA clinical variants" was funded by the NIH's National Institute of General Medical Sciences. The funding runs through August 2027.

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