Study of Brain Development in Those at Risk for Huntington’s Expands with $18M NIH Grant

Efforts to understand brain development in young people at risk for Huntington’s disease have been given a boost by an $18 million grant awarded by the National Institute of Neurological Disorders and Stroke, a division of the National Institute of Health (NIH).  

The five-year grant was given to Peg Nopoulos, MD, chair of psychiatry and a professor of psychiatry, neurology, and pediatrics at the University of Iowa Carver College of Medicine, to continue a 10-year study on brain development in high-risk children and expand it to include young adults.

The original study, called the Kids-HD, used imaging scans to follow brain growth and development in children with the cytosine-adenine-guanine (CAG) gene expansion in the Huntingtin gene (HTT)  — the root cause of Huntington’s disease — and compare them to those with a normal gene expansion.

The researchers found abnormalities in the striatum — an area of the brain involved in controlling movement that is known to deteriorate in Huntington’s. In children between the ages of 6 and 18, these abnormalities were seen long before symptoms appeared. Nopoulos proposed that the delay in symptoms may be due to the cerebellum, another part of the brain responsible for motor control, compensating for the striatum’s abnormalities.  

“Since this was the only study of its kind, this [grant] renewal will help us repeat the study with a larger sample size and continue to evaluate the beginnings of the disease process,” Nopoulos said in a news release. 

The newly funded project, named the Children to Adult Neurodevelopment in Gene-Expanded Huntington’s Disease (ChANGE-HD) (NCT01860339), will also expand the size and scope of the original program with the addition of four new sites, University of Texas, Houston, University of California, Davis, Children’s Hospital of Philadelphia, and Columbia University. The study is currently recruiting in Iowa with the new sites likely to begin soon; more information can be found here.

Brain structure in children, adolescents, and young adults up to the age of 30 (the time it takes for the brain to fully develop) will be evaluated using magnetic resonance imaging to quantify changes to the entire brain, while brain function will be assessed with cognitive tests, behavioral assessment, and physical and neurological evaluation. 

The analysis will compare the structure and brain function of those at risk for Huntington’s who have CAG repeats of 40 and above to those who have a repeat length of 39 or less.

“Even with the momentum behind finding a treatment for patients in the early stages of disease, it will be important to consider the effects the gene has on necessary brain development,” Nopoulos said. 

Currently, ongoing Phase 3 clinical trials (NCT03761849, NCT03842969) are testing a gene therapy approach that “knocks down” or silences the activity of the HTT gene, limiting the production of the disease-causing huntingtin protein. This strategy may potentially treat all Huntington’s patients, regardless of their individual HTT mutation.

The first of these studies is now enrolling some 900 adults, ages 25 to 65, diagnosed with manifest Huntington’s at sites across the U.S., Europe, Canada and elsewhere. Contact information for these sites can be found here.

“Since the brain takes 30 years to mature, and we know that this gene affects brain development, we really need to understand the impact of ‘knocking down’ a gene that is involved in brain development,” Nopoulos said. 

“If the gene therapy works, people are going to want to give it to young people to prevent disease and we have to know how brain development is being affected in order to do that,” she added.