UF Health scientist lands grant for rare disease

A team led by a UF Health scientist last month landed what it believes is the first National Institutes of Health grant ever awarded specifically to study a rare neurological disease that can devastate the lives of children and their families.

UF Health biochemist and molecular geneticist Dr. Andrew Liu and his collaborators were awarded a $2.4 million, five-year grant in January to investigate the genetic underpinnings of Smith-Kingsmore syndrome, or SKS.

The funds will enable the scientists to embark on the largest study ever undertaken to unravel the mysteries of a poorly understood disorder that is currently diagnosed in just 100 patients in the United States, almost all children, Liu said.

The hope is that the study might lead to the eventual development of a drug therapy to lessen some of the symptoms of the disease. SKS causes severe intellectual disability, developmental delay, large brain and head size, seizures and, often, profound sleep disruption.

“I am just so thrilled for the SKS community that has been working tirelessly to raise awareness of the disease and to attract funding,” said Liu, an associate professor in the UF College of Medicine’s department of physiology and aging. “This grant would not have been possible without the parents of children with SKS.”

Scientists only recognized SKS as a distinct disease in 2013. Like other rare disorders, often called “orphan diseases,” SKS has attracted the interest of relatively few researchers and, until now, most funding had been raised by families with a loved one affected by SKS.

“This grant is just really incredible,” said Kristen Groseclose, president and co-founder of the Smith-Kingsmore Syndrome Foundation, an association of family members with loved ones who have SKS. “Dr. Liu and everyone he works with give our families hope. He took an interest in our community when few scientists were working on understanding SKS.”

The foundation previously raised $178,000 to help fund Liu’s work.

Groseclose’s son Jack, now 20, was diagnosed with severe autism as an infant, long before SKS was discovered. His sleep deprivation was especially difficult for a family that had to monitor him constantly. Jack had slept only a couple of hours a night since birth.

A few years ago, Jack’s sleep doctor in Cincinnati read a paper by Liu on circadian rhythms and knew immediately this was someone who might offer the family answers.

Liu’s work focuses on the circadian clocks keeping human cells in tune with the cycle of night and day. The clocks affect blood pressure, heart health and the sleep/wake cycle, among many impacts.

In 2018, Liu was a senior member of a research team that showed how the gene mTOR helped regulate the circadian clock. A disease-causing variant of mTOR can interrupt the clock’s operation.

Liu then knew little about SKS. But he quickly realized his work might alleviate SKS symptoms, including hyperactivity, aggression and self-harm. By stabilizing their cellular clock, Liu said, doctors might reduce the severity of symptoms influenced by irregular sleep patterns.

“Sleep impacts everything, including cognitive function,” Liu said. “If we address sleep, can we improve learning skills? Can we improve verbal interactions with others?”

The NIH grant will enable Liu and collaborators to systematically analyze numerous variants of the mTOR gene and how they might alter a key protein expressed by the gene. Does a particular gene variant lead to a change in the protein that then puts the clock out of kilter? Or is it harmless?

Liu, who has gotten to know families of children with SKS, said the study’s last stage will look at the possibility of developing a drug therapy to help patients. 

“This is the first time in my life to have a cell phone number of the patient’s parents and have direct contact,” he said. “That is a truly remarkable experience for a bench scientist.”

Liu’s key collaborators are Dr. John Hogenesch of Cincinnati Children’s Hospital Medical Center and Dr. Carlos Prada of the Ann and Robert H. Lurie Children’s Hospital of Chicago.