MICA: HD-CSF: Studying cerebrospinal fluid to understand key CNS pathobiological targets in Huntington's disease.
Funded Period:May 15 - Apr 19
Huntington's disease (HD) is a fatal, incurable inherited disease that causes brain degeneration and dementia. It is one of the commonest inherited causes of neurodegeneration and causes complex disability lasting around twenty years from onset to death. HD is always caused by a mutation that causes cells to produce a harmful protein called mutant huntingtin (mHTT).
The most promising experimental treatments being developed are drugs to reduce production of the mHTT protein that causes HD. This is called 'gene silencing' or 'huntingtin lowering'. Another promising approach is to develop drugs to restore the balance of protective and toxic chemicals produced by the brain's immune cells. These are known as kynurenine pathway or 'KP' metabolites and we know from animal models and post-mortem human brains that their balance is altered in HD in a way that seems to make the disease worse.
Cerebrospinal fluid (CSF) is a clear fluid, produced by the brain, which surrounds the brain and spinal cord, contains chemicals derived from the brain, and can be collected from living patients by a relatively straightforward procedure called lumbar puncture.
Developing huntingtin-lowering drugs would happen faster if we could measure how much mHTT is in the nervous system - then we would know if we have successfully lowered it. The same is true for KP metabolites and drugs to alter them. But nobody has ever measured CSF huntingtin levels, because the concentration is too low; and KP metabolites have never been accurately measured in HD patients.
We have developed an ultra-sensitive test to measure mutant huntingtin levels, using laser-activated counting of single huntingtin molecules labelled with newly-developed antibodies. Our pilot data show that this test can measure mHTT for the first time, in CSF from two different populations. What's more, the level of mHTT seems to increase as the disease progresses, meaning that it potentially serve as a 'biomarker' to predict progression or decide on the best time to treat patients with drugs in the future. We are working to develop tests that will mention the different chopped-up lengths of mHTT, to help figure out which are the most harmful ones.
We have also developed sensitive and reliable tests for KP metabolites, and we need good quality CSF to measure them in.
The 'HD-CSF' study will collect CSF and clinical data from 80 HD gene carriers and controls, twice each, two years apart, using methods designed to ensure the CSF is as pure and useful as possible. Poor quality CSF, and inconsistencies in handling and processing it, has been a problem with previous studies trying to use CSF to study HD.
Importantly, as well as CSF collection, HD-CSF participants will undergo detailed clinical and cognitive assessment, and MRI scanning to measure the rate
Project completion date : 2019-04-30 12:00:00
Major organization : UNIVERSITY COLLEGE LONDON
Address : Gower Street,
Country :United Kingdom
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