Researchers have identified certain genetic targets that they believe are responsible for intellectual disability in Down syndrome. Understanding research is difficult for those without a background in science, but we have tried here to provide a simplified, brief explanation of three of those targets, including a short description of the research or clinical trials being conducted for each target.

GABA

GABA is short for gamma-Aminoburtrytic acid. It is an inhibitory neurotransmitter, and its role is to suppress the excitability of neurons in the central nervous system. Normal neurotransmission relies on a balance between GABA and an excitatory neurotransmitter called glutamate. In simple terms, GABA helps put the brakes on the communication between neurons (the cells that transmit nerve impulses) so that these processes flow smoothly. You might say that the GABA - glutamate balance is the brains traffic control system.

It has long been thought by researchers that individuals with Down syndrome have an imbalance in the GABAergic system, and therefore too much inhibition (slowness) in neurotransmission. However, recent research funded by the Jerome Lejeune Foundation has challenged that notion and suggests that GABA in those with DS may actually be excitatory, rather than inhibitory. (see Breaking Developments later in this newsletter)

Some researchers believe that rather than looking to specific genes to improve cognition, it would be better to focus on balancing the GABA system. To accomplish this, they are looking at drugs called inverse agonists, or antagonists, that will put the brakes on GABA to reduce its excessive inhibitory effect. Drugs currently being investigated in clinical trials by Roche and Balance Therapeutics are in this family of drugs.

DRK1A

Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1a (isn’t DYRK1A much easier?) is a gene that resides on chromosome 21, and through mouse studies has been shown to contribute to cognitive disability in Down syndrome. The Jerome Lejeune Foundation is deeply involved in supporting research on DYRK1A, and we have written about our supported projects in past newsletters. The Foundation has been supporting Drs. Mara Dierssen and Rafael de la Torre in a clinical trial on the use of EGCG (an antioxidant in green tea), and also the development of a new drug to regulate the gene through our partnership with ManRos Therapeutics.

In investigations on mice, resolving the overdosing of DYRK1A to improve cognitive function is easy. As researchers say, you just “knock out” the extra copy of the gene by removing it through a breeding process. Of course, that is not possible in humans, so drug therapies that regulate DYRK1A are the solution. Our hope is that the Jerome Lejeune Foundation's partnership with ManRos Therapeutics will result in a new drug to regulate DYRK1A being in clinical trial by 2017.

APP

The link between Down syndrome and Alzheimer’s disease has become broadly discussed and is now closely investigated by researchers working in both areas. The way the body processes APP (Amyloid precursor protein) is known to be responsible for the accumulation of beta-amyloid plaques and neurofibrillary tangles within the brain (see the graphic below). Since APP is a gene on the 21st chromosome, those with Down syndrome have three copies of the gene rather than two; and therefore, the problem is exacerbated for these individuals. Researchers claim that all those living with Down syndrome will have the neurological features of Alzheimer’s disease by the time they are 35 or 40 and some 80% will experience dementia later in life!

DRK1A may have a relationship to APP in that DRK1A is a protein kinase, and therefore responsible for something called phosphorylation, a process that turns protein (like APP) on and off. Since DRK1A is over-expressed in those with DS, some believe it plays a role in regulating APP and could be a cause of the excessive accumulation of neurological plaques and tangles that occur in these people. Wouldn't it be amazing if in regulating DRK1A, we found we could impact APP and the production of beta amyloid too!

The TRIAD program being funded by the Jerome Lejeune Foundation is developing a new drug that we believe will regulate DRK1A, and also impede the development of Alzheimer’s disease in those with Down syndrome.

Transition Therapeutics (Elan Corp) completed a phase 2a study of their drug ELND005 on patients with Down syndrome in April 2014. ELND005, or scyllo-inositol, is thought to decrease the accumulation of amyloid.

The Jerome Lejeune Foundation, along with DownSyndrome Achieves, the Alzheimer's Association, LuMind Foundation, and the Global Down Syndrome Foundation recently funded a two-day international conference in Chicago on advancing DS and Alzheimer's disease research. The conference convened 40 of the world's leading researchers who agreed that "the cure for Alzheimer's disease will come through Down syndrome research."