MSA is a difficult disease. It affects areas – several of them – which are deep inside the brain and can hardly be examined. Signs and symptoms are similar, in the early stages, to other diseases and it is comparatively rare. Getting adequate information about it is difficult. The PROSPECT study was set up to address this.
The basic idea is to collect biological samples, brain scans and other objective information and clinical assessments from as many patients as possible who are believed to have MSA. All this material and information is stored permanently to provide a solid resource – a Bio Bank – that can be freely accessed by MSA researchers. Regular updating of samples and information for all patients will provide a consistent record of disease progression – a massive asset that will augment the existing brain bank of post-mortem tissue.
Blood samples, Cerebrospinal fluid (CSF) and skin samples all contain loads of biological substances that reflect the body’s metabolism and there is growing success in finding the right signals to show that a person definitely has MSA rather than something else. Determining these biomarkers is vital because diagnosis at present is so difficult.
The new funding
The funding agreed this year will support the longitudinal aspect of the study. A cross-sectional study is when one set of samples and measurements per patient is taken at one point in time. A longitudinal study is when a series of sets of samples and measurements are taken regularly over time. The benefit of the latter is that changes can be seen that are associated with the progression of the disease.
So what? If the research has already provided tests to show that you have MSA for sure, why would you want to know how far you are down the line if nothing can be done about it?
Here is where there is some tentative good news. Research into finding the causes of MSA and to look for clues for how to slow or stop its progress has been going on for decades. This has begun to yield fruit so that right now at least three treatment approaches have got as far as clinical trials.
The reliability of clinical trials depends on knowing firstly that each patient actually has the disease and not something masquerading as it. The biomarker aspect of the PROSPECT study has made much progress in providing this. Secondly, you need a way of knowing with certainty whether the treatment is having a measurable effect on modifying the progress. The forthcoming clinical trials will use assessment in the clinic to measure whether the treatments are having a tangible effect in slowing the disease down. But this is a blunt instrument – we all know that symptoms can vary so much from day to day. So this longitudinal study is timely – although not quite soon enough to provide the definitive method for measuring disease progression in the trial participants.
Much of the funding will support recruiting 100 patients from four centres in the UK a “large, biomarker-confirmed, trial-ready cohort” for rapid enrolment into MSA trials. This is no trivial task because of the comparatively low numbers of patients with probable MSA. Biosamples will be taken from these recruits on a yearly basis along with brain scans and clinical assessments.
The collection of samples, the establishment of the joint biobank and the determination of useful biomarkers is being done in collaboration with other research centres in France, Spain, Germany and Russia.
The story continues…..
Neurofilament Light Chain (NfL)
Various biomarkers are actively being established which, when taken together, can provide a profile for indicating a high probability of MSA. Another marker: the measured level of neurofilament light chain (NfL) in blood and CSF though not specific to MSA, seems to correlate well with the severity of this condition. If other markers indicate that a person does have MSA, measuring the changes in NfL can give a good indication of how the MSA is progressing. The project will work on confirming the reliability of this measure.
The trials provide an opportunity to demonstrate how good NfL is as a measure of disease progression. Measured changes in the levels of NfL in patients given the treatments and those not given them, will be compared with the normal estimations of disease progression through clinical assessment and brain scans. This could establish NfL measurement as an important tool for the routine assessment of disease severity and progression. NfL measurement could be used to back up conclusions about whether treatments actually work.
The three types of trial
Exenatide – This is a drug already in use for the treatment of diabetes. There are indications that it can slow Parkinson’s and possibly MSA.
Alpha-synuclein antibodies – As several neurodegenerative diseases result in inclusions of aggregated alpha-synulein in cells, much work has been going on to see whether anti-bodies can be used to remove this protein so that its propensity to aggregate harmfully is eliminated.
Anti-sense Oligonucleotide Therapy (ASO) is a way of interfering with the molecular mechanism of producing a protein and so could be used to suppress the production of alpha-synuclein which in a misfolded, aggregated form is believed to be a major toxin that causes the cells to degenerate in MSA.
As trials of these potential treatments get under way, it is expected that PROSPECT participants can be offered for enrolment because they are collectively on the point of becoming the “large, biomarker-confirmed, trial-ready cohort” envisaged.