For nearly 40 years, the couple has carefully choreographed experiments in the Infectious Diseases department at St. Jude Children’s Research Hospital. Their recent work mobilized four labs in three departments to create a new medication for a devastating neurological disorder that strikes only three of every 1 million people.
Known as PKAN, or pantothenate kinase-associated neurodegeneration, the progressive, life-threatening disease has had no effective treatment. The disorder typically develops in toddlers and can be misdiagnosed as epilepsy or muscular dystrophy.
Rock and Jackowski doggedly characterized the enzymes that are key to triggering PKAN and discovered how they are regulated.
Inspirations for the research
Jackowski paints a poignant picture of young PKAN patients she’s met through advocacy groups and clinical centers in the U.S. and Europe.
“They continue to smile through their disabilities,” she says. “They keep trying to participate even when they can’t say the words they try to vocalize. When they raise their hands, they can’t control their arms.
“Many of these children have a hard time telling jokes but still laugh at their own jokes,” she continues. “They’re not shy; they’re just like the kids at St. Jude. Their positive attitude is amazing.”
Discovery leads to treatment
Moved by the plight of young patients struggling to walk, speak and swallow, Jackowski, Rock and their collaborators have developed a treatment that raises hopes of easing symptoms and extending the lives of PKAN patients.
“It’s a brand-new mechanism of action that’s never before been described,” says Jackowski, who, like Rock, joined St. Jude in the early 1980s.
“We really like the project because it blazes new ground, but in the end, getting something to help kids is wonderful,” Rock says. “We think it’s a significant achievement, and everyone on the team is really pumped.”
Thought to occur when nerve cells lack enough coenzyme A (CoA), PKAN results from mutations in the PANK2 gene. The shortage of CoA in the body is a problem that can’t be overstated, according to the scientists.
“It’s so intertwined with central energy metabolism,” Jackowski explains.
“It’s the universal oil that lubricates the engine of life,” Rock adds.
Search for the perfect drug
The team, which included Stephen White, DPhil, and Richard Lee, PhD, developed a class of small molecules called pantazines. The molecules activate the other PANK proteins to compensate for the missing CoA. But first, the researchers spent several years weeding out medications that weren’t good candidates. The team scoured the St. Jude library of more than 500,000 drug-like molecules to find those that might be effective.
To qualify, a drug had to check several key boxes: be able to cross the blood-brain barrier to reach affected nerve cells, work in pill form and cause few side effects. The drug also needed to activate enzymes instead of inhibiting them — which happens to be the opposite effect of most available drugs, Rock says.
“It was a big chore,” he recalls. “This isn’t a cure that corrects the genetic defect; this is a bypass of that genetic defect. The plan from the beginning was for patients to be on this drug for the rest of their lives.”
High hopes for helping kids
Structural biologists at St. Jude showed that compound PZ-2891 temporarily locks PANK in the “on” position to promote CoA production in cells.
St. Jude patented the pantazines for use in treating CoA disorders, and planning has begun for clinical safety trials.
Rock and Jackowski say they’re gratified their work may help PKAN patients and their families desperately hoping for successful treatments,
“We were provided the resources here at St. Jude to pursue this work and try to make a difference in their lives,” Jackowski says. “Hopefully we’ll be able to help a lot of kids.”