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Delving Into Glycogen Storage Diseases

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Estimates suggest that glycogen storage diseases (GSD) affect from around one person in 40,000 to less than one person in 1,000,000, making them “ultra-rare” diseases. This results in diluted research efforts and calls for novel approaches to develop personalized diagnosis and treatment strategies. The PoLiMeR (Polymers in the Liver: Metabolism and Regulation) consortium is one initiative working to improve research into GSDs and other metabolic diseases.

As part of this consortium, Gaia Fancellu, of glycoscience specialists Iceni Diagnostics, is developing and implementing analysis tools to assess the structural features of glycogens associated with GSDs. In this interview, Gaia talks about her work in more detail, discusses the challenges of studying GSDs, and highlights the advantages of using a “Systems Medicine” approach to do so.

Anna MacDonald (AM): Can you tell us a little about glycogen storage diseases? Why are they so challenging to study and treat?

Gaia Fancellu (GF):
Glycogen storage diseases, or GSDs, are a collection of rare conditions that are very hard to treat and can be fatal in children. They are based on specific enzyme deficiencies involved in the breakdown or synthesis of glycogen, which is a storage form of glucose. The challenge with metabolic disorders such as GSDs lies in the fact that perturbation of one part of the metabolism network – for instance through the impact of a genetic defect – can give rise to impact at quite a remote part of the network. Trying to pin down cause-and-effect is not trivial, which substantially hampers both diagnosis and therapeutic intervention hence the need to take a holistic approach and study all aspects of the network at once. This is why a “Systems Medicine” approach is being deployed to gain insight into the underlying mechanisms of disease that would not be accessible by conventional research approaches.

AM: What are the advantages of using a “Systems Medicine” perspective to study GSDs?

The complexity of the metabolic network means a simple reductionist approach – looking at specific components in isolation - will not help researchers and medics gain an understanding of all the pathways and their interactions, so the major EU project, PoLiMeR (Polymers in the Liver: Metabolism and Regulation), which I am part of, is taking a “Systems Medicine” approach to the challenge. This requires truly interdisciplinary researchers, trained in the three “pillars of Systems Medicine”; experimental, computational and clinical research. The programme is a training network with PhD students working on different aspects of the challenge. Once fed with patient data, it has the potential to provide the basis for a personalized diagnosis and treatment strategy for each individual.

AM: Can you give us an overview of your work in this area so far?

I’m working on characterisation of glycogen, a branched polymer, in different ways to understand the real structure of glycogen from healthy people, and compare this with the structure found in cells from patients affected by these diseases. I am doing this following a top-down approach. The first step will be based on breaking down glycogen using specific enzymes to determine polymer length, positions and number of branching points at different cleavage points. The results will be analysed by high performance chromatography and mass spectrometry. In the second step, I’ll work with fluorescent probes to detect defects in the structure of glycogen based on changes in fluorescence.

AM: Can you tell us more about the fluorescent probe technology you are using in your work? What benefits does this technology offer?

I first used fluorescent probe methodology in my Masters in Pharmaceutical Chemistry to investigate the activity of some synthesised compounds on amyloid fibril formation in relation to Alzheimer’s disease. In my current work, a similar approach will be used to detect the how GSD mutations impact on glycogen structure, to help understanding of GSDs.

AM: What is the PoLiMer consortium? What were the key themes discussed at the project’s recent meeting in the Netherlands?

I’m one of 15 PhD students taking part in PoLiMeR, a €4 million four-year training network that provides innovative research training in personalized “Systems Medicine” and aims to discover new treatments for GSDs. My work in analytical carbohydrate chemistry is being complemented by fellow researchers across Europe, who are applying mathematical models, genetics and biochemical engineering to the challenge.

Our recent six-monthly consortium get-together in Groningen provided a fantastic opportunity to network with the rest of the team and to learn about their research activities. This was complemented by intensive training sessions in computational methods to produce metabolic models, which are key to informing experimental design and analysis, as well as cover broader issues of data handling and ethics. Overall, it was a really great experience scientifically and socially. I’m looking forward to attending the next meetings to discuss and share the progresses in my research with the rest of the consortium.

Gaia Fancellu was speaking to Anna MacDonald, Science Writer for Technology Networks.