Exciting Developments in Research - Winter 2015

Drug Development

The Jerome Lejeune Foundation has partnered with a biotech company, ManRos Therapeutics, on an ambitious project to bring new drug candidates for the treatment of intellectual disability in Down syndrome to phase 1 clinical trial in two years. Most cell processes (like cell division) are controlled by something called “phosphorylation” which is the process of adding a phosphate group to a molecule. The enzymes that regulate these phosphate groups are called protein kinases.

Research has shown clearly that many human diseases are characterized by abnormal phosphorylation, so searching for ways to regulate these kinases provides one of the most promising fields of medical research, as evidenced by the award of three Nobel prizes for research on the subject in 1992, 2000, and 2001.

DYRK1A is protein kinase that is produced on the 21st chromosome and therefore overexpressed in individuals with Down syndrome. Investigations on mouse models for Down syndrome have strongly implicated DYRK1A as a likely cause of intellectual disability.

Dr. Laurent Meijer, one of the CEOs of ManRos is one of the few specialists on kinase who has worked and published with all three of the Nobel laureates. With his business partner and co-CEO Hervé Galons, two lead molecular candidates for investigation have been identified. One is derived from a marine sponge, and the other from an Asian plant. The latter molecule is probably the most selective inhibitor of DYRK1A ever described in the scientific literature.

The 21st chromosome carries both the APP and DYRK1A genes, and many researchers suspect that these two proteins together play an important role in the development of Alzheimer’s disease. The program at ManRos, therefore, is called the TRIAD program to reflect the dual targets of Trisomy 21 and Alzheimer’s disease. The TRIAD program provides an innovative and exciting new avenue for understanding, and potentially treating both Alzheimer’s and Down syndrome.

Recognizing the extraordinary opportunity the TRIAD program offers to potentially improve the lives of those living with Down syndrome, the board of the Jerome Lejeune Foundation has agreed to offer substantial support to ManRos Therapeutics over the next two years.

The Foundation’s considerable financial investment in this project shows that the Jerome Lejeune Foundation is committed to those living with Down syndrome, and to investing our donors’ gifts in the best way in order to rapidly advance treatments to improve quality of life.

A New Tool for Research

While no animal model can replace a human, the availability of several varieties of genetically modified mice has been essential to researchers who are working to better understand Down syndrome. Mice, however, offer limited opportunities, especially in the area of behavioral testing and in depth neurological analysis.

Scientific research in Down syndrome is moving quickly, and researchers’ need for tools that more closely resemble humans is critical. The Jerome Lejeune Foundation has responded by applying for and receiving matching funds from the Betancourt Foundation. Work has begun to develop 7 models of genetically engineered rats that will mimic Down syndrome and provide researchers new tools to study 3 critical gene targets: APP, DRK1A, and CBS. This new rat will make possible new opportunities to study behavioral changes and cognitive status, reinforcing the understanding of these genetic pathways altered by Down syndrome.

A rat will also make more advanced testing possible to researchers than are currently possible with mice. Rats provide a remarkable advantage in the study of the physiology of the central nervous system, and for conducting neuropharmacological studies leading to drug treatments to improve the lives of those living with Down syndrome.

(Rat photo By AlexK100 [CC BY-SA 2.0 (http://creativecommons.org/licenses/by-sa/2.0)], via Wikimedia Commons)

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