For the 2020 AGM the technical presentations were held digitally via the Zoom platform, and each one was held on a different day. This blog post covers the first, A Eureka Moment, presented by Professor Andrew Crosby and Dr Emma Baple from Exeter University. They presented together, alternating between sections of the presentation.
Andrew began by explaining that his interest in HSP stems from his belief that its later onset and slower progression make it the kind of condition where it is possible to slow or prevent progression.
HSP
Emma gave an overview of HSP, noting that the differences between the types of HSP is very large. The common feature is progressive lower limb stiffness and weakness, but beyond that it is difficult to draw conclusions about how a person is affected. HSP is a condition which affects the upper motor neurons, which sit in the spine and provide the connection between the brain and the lower motor neurons which then connect to muscles. The symptoms of HSP are progressive because of the gradual deterioration of the upper motor neurons over time.
Over 80 different genes have been identified for HSP. Overall we have some 22,000 genes in our DNA, each making a protein which is responsible for the development or function of an aspect of us. A spelling mistake in a gene can cause it not to function, and HSP is often associated with spelling mistakes in the genes which are part of the operation of the upper motor neurons.
The team at Exeter have been responsible for identifying 15 different HSP genes to date. They are also looking into commonalities between types of HSP.
When they see someone in clinic with HSP that person often wants to know if they will develop HSP or not. Particularly people want to know when they will develop symptoms, how HSP and symptoms will develop over time, and what will the effect of HSP be on their lives. A genetic test can answer if someone will get HSP, but it is only the first step.
Fat Processing
The function of most of the genes which are affected in HSP are not know. However, the function of the gene which is responsible for SPG5 is well known. SPG5 was discovered by the Exeter team. The function of the gene is known to process fats within a cell in a specific particular way. From this, we can be sure that this fat processing pathway is important in the way that upper motor neurons work, and that disruptions in the pathway can cause HSP.
The next step was then to see if the other HSP genes were also involved with the same or similar fat processing pathways. It was found that many of the other HSP genes are responsible for the same or similar pathways as SPG5, and this hypothesis has been published in Brain: https://academic.oup.com/brain/article/143/4/1073/5679762
Additionally, there are similarities and overlaps with HSP and other degenerative motor neuron conditions - which means that if a treatment can be developed for HSP it may also benefit those with other similar conditions.
Various work is being undertaken which is showing that the hypothesis is most likely correct. The work has involved cellular models and new methods to analyse fat processing pathways so that the effects of each HSP gene in the fat processing pathway can be investigated.
Future Plans
Their future plans are to allow a completely different approach to testing. At the moment tests are looking for the specific known HSP genes, whereas the new understanding allows the test to look at the fat processing pathways instead, which avoids the uncertainties with interpreting genetic test results. They are hoping to be able to do this from a standard 10ml blood sample.
The approach to potential treatments also varies. The aim is to look for treatments which have potential to alter the affected fat processing pathway. Any that are found can be tested in a clinical trial. The crux of these two things is that they would expect to see an improvement in the fat processing pathway with a treatment, and that improvement should be detectable from the blood test. The detection of the improvement from the blood test should be more certain than seeing a change in how HSP afffects a person with their day-to-day symptom variation. Essentially the fat processing pathway is a biomarker for HSP.
Q&A
From the Q&A at the end there were some interesting questions.
A question was asked around gene editing - this is a lab-based technique for editing one cell. These techniques cannot be used in the bodies, so it is a tool for studying rather than a tool for altering someones DNA in the body.
Although this presentation talks about fat processing, this is not the same as the levels of fat in your diet. The management of fat/cholesterol in the blood is not the same as the processing of fats/cholesterols in the cells. There is no evidence which links levels of fat/cholesterol's in the body with HSP, although there are several with HSP who also have issues with digestion. This is an area where further investigation is needed.
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