Researchers at the Drug Discovery Alliance (DDA) have developed several lead molecules that could help restore the function of the blood brain barrier. One of them has led to a patent application.
Notum and the blood brain barrier
The blood brain barrier is a layer of protection that prevents harmful molecules moving from the blood into the brain. Over the course of Alzheimer’s disease and other neurodegenerative disorders, the blood brain barrier starts to break down and allow harmful substances to pass through.
Changes to the Wnt signalling pathway, of which the protein called Notum is a regulator, can lead to blood brain barrier disruption and other pathological hallmarks of Alzheimer’s disease.
In search for a drug to target Notum
Scientists at our University College London Drug Discovery Institute (UDDI) are working on a project to test whether Notum plays an important role in Alzheimer’s disease. The aim is to look for drugs that interact with Notum and help restore the normal functioning of the blood brain barrier, limiting the harmful features of Alzheimer’s disease.
So what?
Leveraging further funding and collaborations
This project has spurred significant interest in the field and has led to collaboration agreements with multiple research groups, including the formation of a Notum Consortium. The Consortium is formed by researchers from the University College London, University of Oxford, and the Francis Crick Institute.
The institute obtained further funding from various sources to conduct safety studies. Prof Paul Fish, the Head of Chemistry at the UDDI, received a $600k ADDF-Harrington Scholar award for the project. This provides funding, as well as a panel of drug discovery experts from the Harrington Institute to provide guidance in areas such as drug formulation, toxicology and safety studies.
Alongside this work, the UDDI team collaborated with Cancer Research UK Beatson. They found that inhibiting Notum prevents the formation of intestinal adenomas, resulting in a publication in Nature.
Making, testing and refining the lead molecule
The UDDI have been developing ways to show that the lead molecule is having the desired effect on specific cells in the brain. They have developed techniques to measure the changes in Notum expression specifically in the cells of the blood brain barrier.
Testing the lead molecule in vivo
The project is now at the in vivo stage to test the safety and efficacy of the drug in mice with features of Alzheimer’s disease.
Alongside this, the UDDI will work with Prof Henrik Zetterberg, a leading expert in developing biomarkers for Alzheimer's disease and other brain disorders. This collaboration will identify possible biomarkers in mouse plasma that indicate whether the lead molecule is having a positive effect on Alzheimer’s pathology by helping to maintain a healthy blood brain barrier.
Once the lead molecule has been proven to be safe and effective in mice, it can be taken forward to be tested in patients in clinical trials.
To learn more about collaborating with the Drug Discovery Alliance, contact DDAenquiries@alzheimersresearchuk.org to kick-start discussions with the Chief Scientific Officers of all three institutes.