The Jerome Lejeune Foundation has been intensely involved in supporting the development of therapeutic treatments related to the overexpression of the gene Dryk1A for those living with Down syndrome.
•We have funded a clinical trial conducted by Drs. Mara Dierssen and Rafael de la Torre in Barcelona Spain on the use of EGCG, a natural substance found in green tea, as an inhibitor of Dryk1A, and
•We are currently partnering with Manros Therapeutics to develop a new drug from a powerful molecule that has been described in scientific literature as the most powerful inhibitor of Dryk1A ever discovered.
Dryk1A is a gene found on the 21st chromosome that produces a category of protein called a kinase, and this type of protein works like a "master switch" to turn cell processes on and off. It does this through something called phosphorylation.
All those living with Down syndrome have three copies of Dryk1A, and the resulting overexpression of this protein has been strongly implicated in intellectual disability, at least because of it’s impact on neurogenesis, or the formation of neurons in the cerebral cortex. As Dr. Dierssen states: "Changes in the cellular architecture of neurons in the cerebral cortex, in Down syndrome animal models had already been detected in the past.” This new research just published in The Journal of Neuroscience adds to the existing understanding of the role of Dryk1A by suggesting that it also affects the delicate balance between excitation (controlled by glutamate) and inhibition (controlled by GABA) of neurons. This synchronization between GABA and glutamate receptors is critical to behavior and the processing of information.
So, it appears that Dryk1A is responsible for more that just the proliferation and deformation of neurons. In fact, a lot more.
For example, we know that one of the targets that Dryk1A turns on and off is another gene on chromosome 21, APP, or the amyloid precursor protein. Overexpression of that gene results in the accumulation of neuritic plaques associated with Alzheimer's disease, a great concern for those who are living with Down syndrome, especially as longevity increases. Research has also been done on diabetic mice to show that inhibiting Dryk1A along with another protein, GSK3B can induce the proliferation of beta cells increasing beta cell mass and improving glycemic control for those with diabetes. Diabetes is most likely caused by other genetic factors, but it is up to 4 – 6 times more prevalent in those living with Down syndrome than in the general population. Perhaps inhibiting Dryk1A could have a positive effect on diabetic control for those with Down syndrome.
The delicate balance between excitation and inhibition in Down syndrome has been a therapeutic target for researchers for some time. In fact, at least two of the current clinical trials being conducted on Down syndrome are on drugs that inhibit GABA. It’s a little confusing, but if you use a drug to inhibit the neurotransmitters responsible for inhibition, you have less inhibition and are therefore moving toward restoring the delicate synchronization that must exist between inhibition and excitation.
Using a mouse with three copies of the Dryk1A gene, this new research claims to have discovered a link between the overexpression of Dryk1A and the balance between inhibition and excitation in the cerebral cortex. Pretty exciting! Possibly, then, this new research has pointed out a connection between two very active target areas of research, namely research into inhibiting the overexpression of Dryk1A, and the regulation of GABA.
As Dr. Dierssen states, “studying the physiology, or the function of this cerebral cortex, [we] found that those cellular alterations and slight changes in inhibitory connectivity translate into a deficit of activation of this region and of its neuronal activity rhythm and synchronization." She goes on to state that “the study that we've published explains some of these cellular alterations and offers for the first time an in vivo study of the physiology of the cerebral cortex, a key structure in executive functions such as concentration, learning or problem-solving."
What the team of researchers in Barcelona suggest is that overexpression of Dryk1A results in a loss in synchronization between excitation and inhibition in neurotransmission. The effect is a decrease in the firing rate of neurons and consequently how those neurons communicate within the cerebral cortex itself, and between the different regions of the brain.
The practical result of this research for those living with Down syndrome and their families is a possible explanation for several compromised cognitive processes they experience including attention, decision making, learning, and working memory. Additionally, this research supports intensified investigations on how to reduce overexpression of the Dryk1A kinase and additional work to validate the connection between overexpression of Dryk1A and inhibitory neurotransmission.
Very exciting for the us, this research validates the considerable investment the Jerome Lejeune Foundation has made into research on targeted treatments that address the overexpression of Dryk1A. We look forward to continued investigations and to new and expanded clinical trials that will soon bring these treatments to individuals who desire them.