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Research and Development jo testing new list

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.

 

Understanding and correcting glucose metabolism defects in AT

 Research Project information

Principal researcher: Associate Professor Vincenzo Costanzo
Institute:   IFOM – The FIRC Institute of Molecular Oncology, Milan, Italy
Cost: £125.820,50 over 36 months in partnership with the Action for A-T (UK), AEFAT (Spain) and BrAshA-T (Australia)
Start Date: 1st of April 2023

What are the researchers proposing to do?
Costanzo and team will test the hypothesis that ATM (the protein which is missing or not functioning completely in AT) controls chemical reactions required for the correct use of glucose. Glucose usage defects could lead to glycogen accumulation*, which might be toxic for brain cells.  They will study the molecular reactions controlled by ATM that promote the correct usage of glucose and assess possible toxicity of glycogen accumulation to understand how these defects occur and how they could be corrected.

*Glycogen is the body’s stored form of glucose.

Why?

AT is caused by the lack of functional ATM protein. ATM regulates the activation of chemical reactions that promote cell survival. The details of ATM function in the control of these reactions are poorly understood. Preliminary experiments indicate the presence of defects in glucose usage, leading to the discovery that AT patients’ cells accumulate glycogen.

How will the research be done?

The team will study the mechanisms leading to inefficient glucose processing and glycogen accumulation in AT cells and the impact of glycogen accumulation on AT cell survival. They will monitor glucose metabolism in primary AT cells. They will directly measure the activity of enzymes controlling key regulatory reactions in glucose processing. To understand whether glucose usage defects are linked to mitochondrial impairments they will also measure mitochondrial function. To identify possible alterations in pathways controlling energy metabolism in AT cells they will explore the impact of known enzymes involved in glycogen accumulation and AT cell survival. Finally, to validate the impact of the alterations linked to impaired glucose metabolism they will use Purkinje neurons derived from both healthy and AT human reprogrammed cells in the lab.

How could it make a difference to the lives of those affected by AT?
The researchers expect that these studies on isolated cells will provide fundamental clues on glucose metabolism impairment that will be useful for clinicians to design therapeutic interventions with drugs, compounds and enzymes to prevent neuronal cell death during the early phase of AT, and at later stages, to improve general well-being of AT patients by improving AT cells fitness.

 

Trial REadiness in Ataxia Telangiectasia (TREAT-AT)                       

Research Project information

Principal researchers: Dr Rita Horvath and Dr Anke Hensiek
Institute:  University of Cambridge, UK
Cost: £250,000 over 36 months co-funding in partnership with Action for A-T (UK), AEFAT (Spain) and BrAshA-T (Australia)
Start Date: 1st of January 2023

What are the researchers proposing to do?

There are several challenges to assess the effectiveness of drugs in clinical trials aiming to treat the neurological manifestations in AT:

  • Individuals with AT have unique features which can differ between people and may not progress predictably
  • There is currently no established test in AT, such as a blood test or brain scan to track changes in the neurological symptoms
  • Human samples are needed to better evaluate the effectiveness of an intervention, as the animal models do not present neurodegeneration

The team at Cambridge have identified a particular mutation (the ‘UK mutation’) that causes a type of AT and may be treatable with a new genetic treatment called antisense oligonucleotide (ASO) therapy. Their study will use 10 years of existing data tracking people with AT and gather a further 2 years of new data in people with the UK mutation.

Why?
This robust and extensive study into the progression of neurological symptoms in AT aims to establish optimal biomarkers in preparation for clinical trials in AT. Biomarkers are biological molecules found in blood, other body fluids, or tissues that are indicators of the disease condition. They can be measured easily and can be used to monitor the disease. Specifically, the team are preparing for a future trial of an antisense oligonucleotide therapy in patients with the UK mutation.

 How will the research be done?

The team will study the clinical symptoms, blood biomarkers and brain imaging findings in a subgroup of AT caused by the so called “UK mutation”. Team members are experts in all aspects of this study including translational research, state-of-the-art imaging and eye assessment. They will involve AT patients and their family members in the research and also in the design of a future clinical trial. They will also actively engage with AT charities to enable a better distribution of information to patients.

How could it make a difference to the lives of those affected by AT?
This study will help us to understand the natural history of AT and aims to allow rapid progression to trial-readiness, vital to the delivery of clinical trials, such as a novel ASO therapy to a cohort of AT patients. They will ensure the most thorough methods to fairly assess therapy effectiveness, which will benefit any future clinical trial in AT. They will involve AT patients and their family members in the design of a future clinical trial.

Data-driven drug discovery for AT – interrogation of dysfunctional pathways at single-cell resolution in cerebellar organoids

Research Project information

Principal researcher: Dr Sam Nayler
Institute:  QIMR Berghofer Medical Research Institute, Queensland, Australia
Cost: £149,690.39 co-funding in partnership with Action for A-T (UK), AEFAT (Spain) and BrAshA-T (Australia)
Start Date
: 1st of December 2022

What are the researchers proposing to do?

In a previous study, Dr Sam Nayler and his team performed genetic sequencing on single cells from mini-brains made from AT patient cells. They have predicted from this data which genes are disrupted in the absence of ATM (the gene missing or not functioning completely in AT), with a focus on key genes which could be targeted with drugs. However, further analysis is required to understand how the different cell types of the brain are affected, and as a result which drugs might elicit restorative effects, while minimizing side effects.  They will now perform a much deeper analysis of this data aiming to classify the cell types at the highest resolution possible using the latest statistical advances, relevant data in the field and best-current practice. This will enable fine-grained analysis of specific cell types (i.e. astrocyte, granule, Purkinje neuron) between AT patients and controls. The team will share these with other interested researchers.  Three major pathways have been identified as being disrupted in AT minibrains which the team will confirm by establishing cerebellar organoid technology. They will validate these pathways using a variety of biochemical approaches which will form the basis of a testing pipeline for drugs computationally-predicted to restore these pathways. In addition to this work they will also functionally characterize neuronal activity. They will examine the contribution of an important immune cell, the microglia, which has not previously been possible.

Why?

There are currently no effective drugs for treating the neurological symptoms of AT. This is in part due to a lack of understanding in precisely how cells of the cerebellum degenerate. Through studying the patterns in which genes are expressed in AT mini-brains in comparison to those made from control donors, it should be possible to determine which malfunctioning parts of the cell cause symptoms in AT and thus might be targetable with drugs.

How will the research be done?

Using a dataset comprising of more than 20,000 cells from four AT patients, the team will perform different types of analysis to classify transcriptionally-distinct cell types which comprise cerebellar organoid tissue. Iterative clustering and biomarker enrichment will be performed in addition to curation of biomarkers known to mark specific cell types of the cerebellum. Once cell types have been precisely outlined, statistical testing will be used to derive a list of genes per cell type which are affected in the absence of ATM. These genes will be grouped together to rebuild a picture of the malfunctioning genetic pathways and be used to computationally predict drugs which may help.

How could it make a difference in the lives of those affected by AT?

The team aim to uncover how specific cell types are affected in AT and build a model that has discovery and pre-clinical testing capability. Testing of drugs in their cerebellar organoids would provide the first step in exploring the use of drugs which could translate to therapeutic options for AT patients. Additionally, it is hoped that their system could be used to supplement ongoing clinical trials of a supplement called Triheptanoin in AT patients.

PROJECT: Study of natural killer cells in AT pathogenesis and their therapeutic implications

Principal researchers: Dr Margherita Doria (right) and Dr. Maria Giovanna Desimio

Institute:  Tor Vergata University of Rome, Italy

Cost: £91,000 over 24 months in partnership with Action for A-T (UK), AEFAT (Spain) and BrAshA-T (Australia)
Start Date: 1st of November 2022

 What are the researchers proposing to do?

The aim of this project is to identify alterations in blood immune cells of people with AT that could serve as predictors of cancer development and targets of novel anti-cancer immunotherapies. By studying a small group of AT patients, the team at the Bambino Gesù Children’s Hospital (Rome, Italy) recently identified some defects in cells of the innate immune defence against tumours and viruses that are called ‘natural killer’ (NK) cells. Specifically, AT NK cells showed features that are typical of ‘exhausted’ cells and displayed reduced expression and function of the activating NKG2D receptor correlated with the increase of its ligands (NKG2DLs) in the plasma of patients. The expression of NKG2DLs, normally absent, is induced by tumorigenic transformation, infection and, in general, when cells undergo a ‘stress’, a condition that typically occur in AT due to genetic defects of the ATM enzyme. The present study aims to verify the hypothesis that persistent engagement of stress-induced NKG2DLs may result overtime in NKG2D down-regulation and, consequently, in the loss of anti-tumor and anti-viral efficacy of NK cells during AT disease progression

Why?

Individuals with AT are at higher risk of developing leukemias and lymphomas in the first two decades of life and of solid organ malignancies as they get older. In AT, the loss of several distinct ATM functions beyond maintenance of genome stability has been linked to cancer development, though results are controversial. There is currently no way to predict which patient will develop a malignancy and treatment of cancer is challenging due to patient’s increased sensitivity to chemo/radiotherapy. Therefore, a greater understanding of cancer pathogenesis and its biomarkers as well as new therapeutic treatments are urgently required.

How will the research be done?

The team will perform a 2-years longitudinal study in AT patients and in control healthy individuals, using blood samples to analyze NK-cell phenotype and function, NKG2DL expression, as well as the presence of immunomodulatory, inflammatory, and oxidative stress factors. The NKG2D/NKG2DL axis will be investigated in a specific ATM-deficient mouse. Finally, NK-cell enhancing products will be tested on NK cells of AT patients.

How could it make a difference to the lives of those affected by AT?
There will be no immediate benefits to patients with AT, but results of this study may help the development of cancer predictive tests and provide an important building block for the design of innovative strategies to lengthen and improve lives. A major goal of this study is to identify non-invasive markers (measured in a blood sample) that could predict the risk of cancer, thereby functioning as indicators for malignancy screening without delay and, eventually, for early cancer treatment. Novel biomarkers integrating those already put forward can be of great use for the clinician in the management of AT patients and help the identification of individuals at highest risk of cancer to be frequently monitored and considered for emerging treatment options. In addition, the proposed definition of NK cell defects in AT may pave the way to novel NK-cell therapeutic approaches against cancer in AT patients.

 

Research Project information

Project Brain-penetrating ATM gene therapy

Principal researcher: Dr James Dixon
Institute: University of Nottingham, UK
Cost: £147,304.37 over 24 months in partnership with Action for A-T (UK), AEFAT (Spain) and BrAshA-T (Australia)
Start Date: 5th of September 2022

What are the researchers proposing to do?
Dr James Dixon and team propose to combine gene therapy and editing to engineer an effective therapy to treat AT in the brain. Their focus is to combine novel nanoparticle chemistry with state-of-the-art gene editing technology to replace faulty AT genes and ‘molecularly cure’ any AT mutation as a medicine for all patients.

In their lab, they have demonstrated that delivering genes to AT patient cells can correct aspects of the disease, and that their gene therapy is effective when injected into healthy mouse brains. They now aim to improve how the medicine penetrates through brain tissue. In parallel they will use the most advanced gene editing technologies to replace defective AT genes, or to provide extra ‘active’ copies.

AT patient cells will be used to determine if their proposed treatment corrects the disease permanently. With success they will progress to deliver the therapy to brain slices and then into healthy mice. This research is in its infancy but if successful will pave the way for future trials of their technology.

Why?

There is no effective treatment targeted at the genetic defect in AT patients, that being the lack of a functioning copy of the ATM gene. Therefore, new therapeutic approaches are required, and using genetics to provide new copies or edit the faulty copies offers a potential route to a cure.

How will the research be done?

The team will employ testing of their systems in AT patient cells and then move to test the delivery of genes into the brains of mice. They will use modern molecular techniques to confirm how effective the therapy is and show how wide-spread the therapy can treat the entire section of the brain needed to treat AT brains. This will be done in collaboration with colleagues at Johns Hopkins University in the USA.

How could it make a difference to the lives of those affected by AT?
This research is early stage so will not immediately impact AT patients. However, development of this approach in the future could help to permanently correct the gene deficiency in AT patients, with the aim to deliver a medicine that will cure the disease. Even though the researchers are not testing the therapy within patients in this proposal, it is hoped that this will be the start of a road that will lead to treatments that will be more acceptably administered, ideally only once, to prolong life in children affected by AT.

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)

Research Project information

Principal researchers:  Dr William Whitehouse & Dr Emily Petley
Institute:  University of Nottingham
Cost:  £177,865.96 over 24 months in partnership with the A-T Society and BrAshA-T
Project Completion Date: 30th of August 2022

Project Overview

Dr William Whitehouse, along with Dr Emily Petley and professionals from the two UK national A-T clinics, aimed to document the natural history of A-T. The NHS set-up in the UK provides a unique opportunity to do such a study.


Research Methods

Dr Petley reviewed the clinical notes of everyone with A-T seen in the adult and paediatric A-T clinics since 2001, extracting data on infections; immune deficiencies; cancers; lung disease; brain and nervous system disorders; growth; nutritional status; mortality; and genetics. The data was statistically analysed to determine links between signs and symptoms and describe how A-T progresses.

Project Outcome

The project has documented the pattern of disease of ataxia-telangiectasia (A-T) in 173 people.  The outcome has determined at what age manifestations of the disease occur in the UK A-T population, and how common each manifestation of the disease is. This will help doctors and healthcare professionals pre-empt complications of the condition, so that they can aim to treat them early. It is hoped that this will result in a better outcome for people with A-T, for example detecting cancer earlier. This study will also find links between manifestations of the condition.

This study has raised questions and theories that clinicians are currently unable to answer without further research. However, raising these questions and theories will enable further research to be carried out, potentially finding treatments or in the long term a cure for the condition.

By understanding the condition in more detail, the team behind the study hope to help people with A-T and their families to have a greater understanding of what to expect at what age. This will help them to plan their future, for example education, housing, and careers.

Most of the aims of this project were met successfully. COVID-19 did have an impact on meeting with families and the development of focus groups. A plan to approach this in 2023 has been made.

Publications

  • Petley E, Yule A, Alexander S, Ojha S, Whitehouse WP. The natural history of ataxia-telangiectasia (A-T): A systematic review. PLoS One. 2022 Mar 15;17(3):e0264177. doi: 10.1371/journal.pone.0264177. PMID: 35290391; PMCID: PMC9049793.
  • Currently preparing manuscript of descriptive data on natural history of ataxia-telangiectasia.


What next?
Focus groups with people with A-T and their families will be held in 2023 to discuss the results and consult people with A-T and their families about their priorities in A-T research.

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: 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 AT specific patient-held record we are initially calling ‘My A-Team Pack’ for children and young people with AT. 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 AT using the best available evidence.
This project has been funded by the charity ‘Action for A-T’ and is supported by ‘The AT Society’. At the start of this project, parents with children with AT told us that healthcare professionals and school teachers are often uncertain about what AT 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 AT to several different professional groups.

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

Study advertisement

Information for parents/carers

Information sheet for children aged 11-16yrs

PROJECT:  Exploring effectiveness, feasibility, and acceptability of a novel home-based complex intervention for children with ataxia telangiectasia: a pilot randomised controlled trial

Study advertisement

Information for parents/carers

Information for children

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

 

PROJECT: AT cerebellar neurodegeneration and inositol phosphate signalling

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

LENGTH: Concluded

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

This project has now completed. The proposal was based on a previous finding from the Paull laboratory that the cerebellum obtained from deceased AT individuals has reduced levels of expression of proteins that are involved in calcium signalling, which is known to be important for cerebellar function. Similar protein expression changes have been observed in other patients with progressive ataxia. One goal of this proposal was to examine whether this was also observed at the mRNA level (that is the transcript level), with mRNA being the cellular molecule used to make proteins.  This would help to provide insight into the basis underlying such changes.  A second goal was to examine how loss of ATM affects calcium signalling using human neurons in culture.

For the first goal, mRNA expression was examined in normal and age-matched cerebella from normal and AT individuals. In parallel, mRNA expression was also examined in the cortex, a brain region less affected in AT, to determine if the changes were cerebellum-specific.  Results from this analysis showed that mRNA expression in AT individuals is very different from normal individuals, although there is significant heterogeneity among the AT individuals. The differences were most extreme in the cerebellum tissue, with fewer changes observed in the cortex. Of the mRNAs that were strongly reduced, 13 genes were known to be associated with ataxia in other familial disorders, including those involved in calcium signalling. These findings suggest that ATM loss affects gene expression in multiple pathways that are necessary for normal cerebellum function, not only calcium signalling.

To investigate the mechanisms underlying ATM loss and altered gene expression, a neuronal cell model was used. From previous work, Paull had observed that DNA damage and RNA-containing structures called called R-loops arise at sites of active transcription in the absence of ATM. In the neuronal cells, loss of ATM caused higher levels of DNA damage and higher levels of R-loops at certain sites. Interestingly, treatment with an anti-oxidant reduced the level of R-loops specifically in AT cells.

These findings demonstrate that ATM has a unique role in the cerebellum and are consistent with the notion that loss of ATM affects the expression of genes that are critical for cerebella function. They suggest that oxidative damage may have an additive impact on impairing ATM function in the cerebellum. Although further studies are required to gain insight into the precise mechanism, they suggest that agents that prevent oxidation-induced DNA damage have the potential to diminish the impact of ATM loss. They provide important insight into the unique or special function of ATM in the cerebellum, which, if clearly understood, could help target treatment.

The Global Search for a Cure

As AT is such a rare disease, it is critical that our valuable resources committed to finding a cure for AT 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 AT 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 AT, 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 AT 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/