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Research and Development

Research and Development

We believe in the power of research to change the future and are passionate about investing in innovative research to drive us towards better treatments and move us closer to a cure for AT. By bringing top scientists together and exploring the latest advances in technology, we are proud that our funding and support of world-leading medical science has already advanced our understanding of the condition.

 

PROJECT: Functional and metabolomic analysis of iPSC-derived Purkinje neurons from A-T patients 

SCIENTIFIC LEAD: Dr Marco Foiani & Dr Domenico Delia: FIRC Institute of Molecular Oncology, Milan, Italy

LENGTH: Due to conclude 2022

COSTS: £80,000

STUDY: This project really is cutting-edge science. We know that the cells of people with AT are missing the ATM protein. What we don’t know, is why some brain-cells die off in the absence of the ATM protein, particularly the Purkinje cells and granule neurons. This is arguably the biggest question in AT research. Purkinje cells are large neurons with many branching extensions found in the cortex of the cerebellum of the brain and they play a fundamental role in controlling motor skills. Before answering the question, as it is impossible to remove Purkinje cells from the brains of living people, the scientists first had to focus on growing Purkinje cells in the laboratory from induced pluripotent stem cells, developed from the cells of people with AT, and turn them into Purkinje cells. Once achieved, they will carry out a series of analyses of the metabolic processes at work in the cells, to determine what factors and alterations make these cells hypersensitive to the absence of ATM.

PROGRESS: The team have succeeded in creating the first ATM-deficient Purkinje cells, a significant development in itself. They have obtained mature Purkinje neurons without needing to involve coculture with mouse cerebellar granule cells. It is the first time this has ever been achieved with cells from people with AT. The cells are now being produced in sufficient numbers so they can then be used to screen potential drugs and in further experiments to understand why it is that these cells die off when other neurons don’t. So far, imaging analysis has been performed in order to compare the mitochondrial content, structure and activity, and an analysis undertaken to determine the response to drugs that induce metabolic stress by targeting the glycolysis pathway. Mitochondria are the powerhouse of the cell. They produce the energy required for the cell’s function but can produce by-products that can damage cellular components. An assessment of the expression of certain mitochondrial proteins which are defective as a consequence of ATM-deficiency, on cerebellar biopsies from AT patients, is also being undertaken.

 

PROJECT: Natural History of AtaxiaTelangiectasia (N-HAT)

SCIENTIFIC LEAD: Dr William Whitehouse & Dr Emily Petley: University of Nottingham, UK

LENGTH: Due to conclude 2022

COSTS: £177,866 in partnership with BrAshA-T and Action for A-T

STUDY: A Natural History is a detailed description of a condition based on extensive data, and is a vital document for any rare condition.
Until now there has been no Natural History of AT. It was essential for us to address that. The project will provide information about the progression of AT to help families better understand and manage the condition. It will also be invaluable for designing clinical trials and shaping clinical guidance so that the most suitable treatments and services for patients are provided, and enabling education, housing, mobility and wellbeing needs to be better understood. Dr Whitehouse and Dr Petley, with the help of professionals from the two AT specialist clinics in Nottingham and Cambridge, are using data collected over 20 years for their study. It is the first study of its kind, not only in the UK, but across the world and will therefore have far-reaching, international impact when completed.

PROGRESS: Whilst COVID delayed data collection, the three year project is nonetheless progressing well and a large systematic review on the natural history of AT has been completed. Some of the results from the review were presented at the British Paediatric Neurology Association (BPNA) Annual Conference 2020 in Belfast, and were highly commended by the BPNA committee. The database was constructed with the help of the study statistician and we are pleased that data collection will be finalised in 2021, reviewed and submitted for publication to a peer-reviewed journal in 2021.

 

PROJECT: Modulation of RELB/p52-dependent NF-KB activities to improve neurodegenerative symptoms of AT

SCIENTIFIC LEAD: Dr Svetlana Khorenenkova, Cambridge University, UK

LENGTH: The study will commence in 2021

COSTS: £90,000

STUDY: Over the course of the year, we invited scientists from around the world, to submit proposals exploring the areas of neurodegeneration or cancer in AT, our priority research areas. It was a lengthy but rewarding process as the year culminated with our Scientific Advisory Board, and additional external scientists, shortlisting 5 high calibre applications for funding. Following further rounds of presentations and interviews, the Review Panel, joined by three AT family members, were unanimous in selecting Dr Khoronenkova to receive the funding. Dr Khoronenkova’s study will research the underlying explanation of why neurodegeneration in AT involves loss of cerebellar neurons, particularly the Purkinje cells and granule neurons. Microglia are a form of immune cell present in the cerebellum, which are becoming increasingly implicated in neurodegenerative disorders. Dr Khoronenkova has evidence that when AT microglia are aberrantly activated, they can destroy undamaged neurons. The Cambridge University team will be seeking to confirm that microglia are abnormally activated when ATM is lost. This work is exciting as there is a strong possibility of therapeutic intervention since drugs already exist that can dampen microglial activation.

 

PROJECT: AT cerebellar neurodegeneration and inositol phosphate signalling

SCIENTIFIC LEAD: Professor Tanya Paull: University of Texas, Austin, USA

LENGTH: Due to conclude 2022

COSTS: £90,000 co-funded by the AT Society, BrAshA-T (Australia), AEFAT (Spain), Action for A-T

STUDY: Our Scientific Advisory Board identified another project worthy of investment and we are proud to now be funding this exciting new project in collaboration with other international AT organisations. The study will explore a link between AT cerebellar neurodegeneration and inositol phosphate signalling. Inositol phosphate regulates calcium signalling, which is well established to be a major signalling pathway required for neuronal function. Professor Paull has discovered that components for this pathway are reduced in samples derived from human AT cerebellar material. Her working model is that loss of ATM causes toxic protein aggregation at the sites of DNA damage, leading to aberrant inositol-phosphateregulated calcium signalling, which is the critical event conferring neurodegeneration in AT patients. Professor Paull aims to establish the differences in expression of genes in the brain material of AT patient and controls to consolidate her finding that there might be abnormal calcium signalling and to investigate the underlying mechanism. This excellent proposal used valuable brain material from deceased AT and control individuals coupled with high quality scientific analysis.

 

PROJECT: CoIN Study, Covid-19 impact on wellbeing in families of children with rare neurogenetic disorders

SCIENTIFIC LEAD: Dr. Charlotte Tye (King’s College London)

Are you the parent of a child aged 0-16 with AT or other rare genetic and/or neurodevelopmental disorder?

Can you help us understand the impact of Covid-19 on the wellbeing of families of children with rare genetic and neurodevelopmental disorders?

If you are, we invite you to take part in a regular online survey being led by King’s College London and involving a UK-wide team of researchers (CoIN Study).

The CoIN Study will track changes in wellbeing during and after the pandemic in order to understand the specific challenges facing families of children with rare disorders. Your responses will be rapidly fed back to The AT Society, and used to identify and provide better ways of supporting you both now and in the future.

The survey will take up to 40 minutes to complete the first time you do it and about 15 minutes to complete thereafter. We will ask you to complete the survey once per month until children are back in their usual education.

Please click here for more information: www.coinstudy.co.uk

 

PROJECT:  Designing ‘My A-Team Pack’ for children and young people with Ataxia Telangiectasia

SCIENTIFIC LEAD:  Munira Khan & Dr Lisa Bunn (University of Plymouth)

COSTS: £89,862.48 over 36 months by Action for A-T

This study aims to undertake coproduction of an A-T specific patient-held record we are initially calling ‘My A-Team Pack’ for children and young people with A-T. By co-production we mean that all participants will work together to produce the design of the pack. This study is part of a wider project which ultimately aims to improve the care and management of children and young people with A-T using the best available evidence.
This project has been funded by the charity ‘Action for A-T’ and is supported by ‘The A-T Society’. At the start of this project, parents with children with A-T told us that healthcare professionals and school teachers are often uncertain about what A-T is and how it affects the life of the child and the wider family. Parents also told us that is was difficult to keep track of information and often found themselves repeating information about A-T to several different professional groups.

For more information about this study please contact [email protected] 

 

Information sheet for parents or carers
Information sheet for children aged 11-16yrs

The Global Search for a Cure

As A-T is such a rare disease, it is critical that our valuable resources committed to finding a cure for A-T are fully maximised. This can only be achieved through a coordinated effort by all of the major stakeholders across the globe including patients and their families/supporters, researchers, clinicians and charitable organisations.

Consequently, we have developed the A-T Global Alliance,  a group of international AT charities, who all believe passionately that we are stronger together. Our collective goal is to speed up the search for a cure, or at least treatments and therapies that minimise the effects of this degenerative disease and allow a better quality of life for those affected. We meet to share findings, strategies and expertise and to facilitate information on A-T for researchers, health professionals, patients and families.

An important output of this group has been the creation of the cureat.org.website in 2021 which provides a useful source of international information on A-T, including information about the latest research projects, publications and clinical trials, patient care, support and registries, related meetings and conferences and various engagement opportunities.

Members of the alliance have also co-funded a research event in March 2022, organised by Action for A-T. “Spotlight on A-T” was a family focussed webinar to highlight some of the current A-T research projects which are taking place around the world. It was hosted by Broadcaster and Journalist, Naga Munchetty, and researchers from around the world provided a concise overview of their current research studies and answered questions from the audience. The presentations were broadcast live in English and a recording of the full webinar is available to view below.

https://player.vimeo.com/video/681314292?h=ddde3b5ad6

Additional research areas

We are proactive in our support of other global research, whether by conducting surveys for them, guiding project design, or liaising with families. Some examples
of this include: supporting Professor Malcolm Taylor’s cancer study of AT patients (The University of Birmingham); and Dr May Yung Tiet’s exploration of cognitive function in AT (Cambridge University).

We have also continued to support various clinical trials through the year. More information can be found here: https://atsociety.org.uk/research/clinical-trials/