Dr. Roger Reeves, a professor in the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins University School of Medicine, has devoted his career to studying genetic intellectual disabilities.
In September, Reeves and his colleagues published a study in Science Translational Medicine that detailed a compound capable of normalizing the development of the cerebellum in a mouse model of Down syndrome with a single injection. Abnormalities in the cerebellum are thought to have some connection to the disease.
Down syndrome occurs when people have three--rather than the normal two--copies of chromosome 21. The result is a condition known as "trisomy," which gives people with Down syndrome extra copies of the genes housed on that chromosome. The extra genes are what cause physical and mental disabilities in people with Down syndrome.
"Most people with Down syndrome have a cerebellum that's about 60% of the normal size," Reeves said in a previous statement.
Most physical manifestations of Down syndrome can now be treated, but no approved therapies exist to improve cognitive function in patients. One of the major challenges of finding drugs to treat Down syndrome is that the condition is incredibly complex. There are anywhere from 300 to 500 genes affected by Down syndrome that cause 80% to 90% of symptoms.
Using mouse models of the disease, which include the smaller cerebellum, Reeves' team of Johns Hopkins and NIH scientists administered a one-time dose of a drug to supercharge a biochemical chain of events known as the sonic hedgehog pathway, which triggers growth and development. They injected the compound, a sonic hedgehog pathway agonist, at birth while the rodents' cerebellums were still developing.
In people with Down syndrome, a smaller cerebellum arises because cells in the cerebellum don't divide for a short period of time during development. Scientists noted that cells in the cerebellums of mice with Down syndrome don't see as much of a growth factor as non-Down syndrome mice. The sonic hedgehog pathway agonist acts by mimicking the growth factor.
The single injection normalized the growth of the cerebellum through adulthood and boosted learning and memory in mice. Animals treated with the compound performed just as well in behavioral tests as normal mice.
Reeves' work has gained international attention. The French Fondation Jérôme Lejeune last year awarded Reeves a 2012 Sisley-Jérôme Lejeune International Award for Translational Research in Intellectual Disabilities.
The early research is promising, but altering sonic hedgehog to induce growth could potentially have unintended effects on the body. The next step for Reeves' team is to look for more targeted ways to safely harness the power of sonic hedgehog in the cerebellum.
Compound restores learning deficits in Down syndrome mice