Down syndrome is due to a genetic alteration due to the presence of an extra copy of chromosome 21, which is why it is also known as trisomy of chromosome 21, and it is estimated that it affects one in every 1,000 newborns worldwide. People with this syndrome are generally more likely to have health problems, and about half of babies born with the syndrome have heart disease, such as the inability of the heart to separate into four chambers, leaving a “hole.” ” in the heart.
Researchers at the Francis Crick Institute and University College London (UCL) have identified a gene that causes heart disease in Down syndrome. The researchers found that overactivity of this gene partially reversed these defects in mice, which opens new possibilities for developing therapies to treat heart conditions in people with Down syndrome. The results of the work have been published in Science Translational Medicine.
If the heart disease is very severe, the baby may need to undergo high-risk surgery soon after birth, and those affected often require continuous heart monitoring for the rest of their lives. Therefore, it is necessary to find better treatment options and this must be guided by knowledge of which of the 230 additional genes on chromosome 21 are responsible for heart disease. But before this study, the identity of these causal genes was not known.
The Crick and UCL team studied human fetal hearts with Down syndrome, as well as embryonic hearts from a mouse model of Down syndrome. The researchers used genetic mapping to identify a gene on human chromosome 21 called Dyrk1a, which causes heart disease when present in three copies in the mouse model of Down syndrome. This gene had previously been linked to cognitive impairment and facial changes in Down syndrome, but its role in heart development was unknown.
New therapeutic approach to reverse heart defects
An extra copy of Dyrk1a turned down the activity of genes needed for cell division in the developing heart and the function of mitochondria, which produce energy for cells. These changes correlated with the inability to correctly separate the chambers of the heart. The team found that while three copies of Dyrk1a are needed to cause heart defects in mice, it was not enough on its own. Therefore, another unknown gene must also be involved in the origin of heart defects in Down syndrome. The team is currently searching for this second gene.
The researchers tested a Dyrk1a inhibitor in mice pregnant with pups that were a model of the heart defects in Down syndrome while their hearts were forming. When Dyrk1a was inhibited, the genetic changes were partially reversed and the heart defects in the puppies were less severe.
Victor Tybulewicz, Group Leader of the Immune Cell Biology Laboratory and Down Syndrome Laboratory, said: “Our research shows that inhibiting Dyrk1a can partially reverse the changes in mouse hearts, suggesting that this may be a useful therapeutic approach.” “However, in humans the heart forms in the first 8 weeks of pregnancy, probably before a baby can be tested for Down syndrome, so it would be too early for treatment. The hope is that a Dyrk1a inhibitor will have an effect on the heart later in pregnancy, or even better after birth. “These are possibilities we are currently investigating.”
“It was significant that simply restoring the copy number of a gene from 3 to 2 reversed the heart defects in the mouse model for Down syndrome.”
Eva Lana-Elola, senior laboratory research scientist at the Crick, and co-first author, said: “It was significant that simply restoring the copy number of a gene from 3 to 2 reversed the heart defects in the mouse model for Alzheimer’s syndrome. Down. We now aim to understand which of the other genes on this additional chromosome are involved. “Although Dyrk1a is not the only gene involved, it is clearly an important player in many different aspects of Down syndrome.”
Rifdat Aoidi, Postdoctoral Project Research Scientist at the Crick and co-first author, said: “We still don’t know why changes in cell division and mitochondria mean the heart can properly form chambers. Dysfunction in mitochondria has also been linked to cognitive impairment in Down syndrome, so increasing mitochondrial function could be another promising avenue for therapy.” The researchers worked with Perha Pharmaceuticals to test the DYRK1A inhibitor. The company is testing the drug in a clinical trial for cognitive disorders associated with Down syndrome and Alzheimer’s disease.
Jeanne Lawrence, Professor of Neurology and Pediatrics at the University of Massachusetts, who was not involved in the study, said: “This study shows that a DYRK1A inhibitor given to a mother mouse very early in pregnancy reduces heart defects in the descendants. However, it is important to note that the drug is administered before the heart develops, very early in pregnancy. The development of the human heart occurs in the first 8 weeks of pregnancy, before the early detection of trisomy 21 (around 10 weeks). Therefore, the treatment in this study provides more evidence of the involvement of DYRK1A, but I do not believe that the potential effectiveness of this drug in preventing human congenital heart disease was intended to be demonstrated,” he told SMC Spain.
