Newly identified compound normalizes brain development in mice with Down syndrome

Investigators from Kyoto University and Tokyo Medical and Dental University have found a compound that normalizes brain structure and function in mice with Down syndrome.

Down syndrome (DS), or trisomy 21, is a genetic disorder resulting from the presence of an extra partial or full copy of chromosome 21. In other words, DS patients have three copies of chromosome 21, unlike healthy people who have two copies of chromosome 21. DS always cause physical and intellectual disabilities that may severely affect the longevity and life quality of patients.

The estimated DS incidence is between 1 in 1,000 to 1 in 1,100 live births worldwide. Currently, screening tests are available for prenatal diagnosis of DS. A pregnant woman carrying a fetus diagnosed with DS may choose to terminate the pregnancy to avoid giving birth to a baby with a genetic defect. So far, there is no effective treatment to rescue DS-associated neurocognitive impairment.

In the present study, the investigators identified a compound, named ALGERNON, in their screen of neural stem cells. The compound has potent inhibitory activity against the enzyme DYRK1A which has been suggested to function in cell proliferation and brain development. DYRK1A is localized in the DS critical region of chromosome 21, and is thought to be a critical gene for understanding DS-associated defects.

The investigators tested the effect of ALGERNON on DS development. ALGERNON was orally administrated to a pregnant mouse carrying a DS mouse embryo. The investigators found that ALGERNON administration normalized the formation of the cerebral cortex in the brain of DS mouse embryos. Generally, DS mice have a thinned cerebral cortex. Furthermore, the investigators discovered that after birth, the DS offspring did not show abnormal behaviors.

The investigators also tested ALGERNON in human neural stem cells derived from patients with DS and found that it rescued proliferative deficits -- the cells grew normally.

Collectively, the results demonstrate that ALGERNON helps normalize brain structure and function in DS mice. The compound might be able to reverse neurodevelopmental abnormalities in human embryos with DS. However, studies are still needed to verify the safety and efficacy of ALGERNON. If there are drugs that could normalize the development of a DS fetus, parents may not give up the DS fetus.

Findings of the study are published online before print 5 September 2017 in the journal PNAS.

The corresponding author Dr. Masatoshi Hagiwara is a professor in the Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University.
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