Lead Investigator: Professor Jerry Turnbull
Institution: University of Liverpool
Grant type: Project grant
Duration: 24 months
Scientific Title: Synthetic Heparins as Safe Disease-modifying Drugs for Early-Stage Treatment of AD via Inhibition of Beta-Secretase: Evaluation in a Transgenic Mouse Model
Why did we fund this project?
Comments from members of our Research Network:
'The research team has worked hard and overcome significant problems in order to develop, what appears to be, a very valid product to manage a key central process - the growth of plaques.'
'Non toxicity of any drug is very important. Alzheimer's disease causes enough problems without drug side effects.'
'The research proposal is very well presented and absolutely inspiring in that the outcomes could prevent or at least reduce the development of amyloid in Alzheimer's disease, if early diagnosis and treatment are achieved.'
What do we already know?
A major issue is that current Alzheimer's disease treatments only treat the symptoms, and there is a pressing need for treatments that address the underlying disease. A key enzyme called beta-secretase (BACE1) is involved in the key step of creating toxic amyloid peptide fragments that accumulate in Alzheimer's disease. It is a key target for pharmaceutical companies, however it is has been difficult to produce suitable drugs due to problems with side effects and its distribution in the body.
Professor Turnbull and his team have discovered that a class of natural complex sugars similar to the safe blood-thinning drug heparin control the activity of BACE1. Their heparin-based sugars can reduce the activity of BACE1, have very low toxicity, no blood-thinning activity and can be given orally, giving them distinct advantages over other drugs that aim to reduce levels of amyloid peptides. The safety record of heparins for over 70 years suggests that these compounds will have excellent safety and tolerability characteristics, a factor that could be crucial in developing a therapy that would be expected to be delivered for many years to delay onset or slow the progression of the disease.
What does this project involve?
The ultimate goal of this proposal is to test the effectiveness of early-stage treatment with two BACE1 inhibitor candidate drug compounds in genetically-altered mice that mimic signs of Alzheimer's disease. This would tell us whether the compounds should be taken forward into clinical trials for patients with presymptomatic or mild disease.
The researchers aim to screen a small library of compounds to see how well they inhibit the activity of BACE1 and the likelihood of side effects. Based on these tests they will select the best two compounds to take forwards for further testing.
The drugs will be profiled for safety, metabolism and measure the changes in their levels with time after dosing. They will be tested for their effects in mice mimicking the early stages of Alzheimer's disease. These mice develop amyloid plaques, show disruption in brain cells, and develop memory impairments similar to people with Alzheimer's.
The researchers will test the effects of the drugs on memory formation, signalling between brain cells, plaque formation in the brain, reduction in inflammation, activation of stem cells and the development of new neurons in the brain of the mice. This information will give a clear picture of the effectiveness of the compounds in alleviating the damage to brain functions in Alzheimer's disease, and the potential to clinical testing of these compounds.
How will this benefit people with dementia?
This study aims to gain proof that these compounds have real potential to slow down or prevent amyloid formation and thus act to modify the course of Alzheimer's disease. A treatment that prevents or at least reduces the development of amyloid will be of great help to people, potentially giving increased years of higher quality of life, and delaying the onset of the worst symptoms. As there are no drugs currently on the market that actually stop the progression of the disease, a new treatment that can treat the underlying causes of Alzheimer's disease would be an extremely welcome advance. Since the preliminary evidence is that the compounds have low toxicity, they could be used to treat patients with early-stage disease, identified through increasing improvements in early diagnosis.