Genomic medicine awards

Awarded to Meredyth Wilkinson for £19,116 as part of the new projects call 2026.

Juvenile dermatomyositis (JDM) is a rare childhood disease that causes inflammation in muscles and skin, leading to weakness, pain and long-term symptoms. Although treatments are available, they do not work well for all patients, and it can take months or years to find the right treatment for each child. There is a clear need to better understand how this disease works, so that treatments can be improved and more personalised. Our previous research has shown that, in addition to inflammation, problems with the parts of cells that produce energy, called mitochondria, which do not function properly, play an important role in JDM. However, we do not yet know where in the muscle tissue these problems occur, or which types of cells are most affected. In this project, we will use a new state-of-the-art method called spatial transcriptomics, which allows us to study gene activity directly within tissue samples while preserving their structure. This means we can define not only which genes are turned on or off, but also exactly where this occurs within the muscle. We will analyse muscle biopsy samples from children with JDM and compare them to healthy samples. This will allow us to map how mitochondrial problems and inflammation are organised within the tissue, and how this differs between patients. The results of this study will help us better understand how JDM affects muscle at the individual cell level. Knowing this will help inform which drugs might be effective to reverse this problem. In the future, this could support the development of new tests to classify patients more accurately and guide treatment decisions. It will also help identify new ways to target disease mechanisms, particularly those related to mitochondrial function.

Awarded to Judy Breuer for £19,420 as part of the new projects call 2026.

In children with rare genetic disorders, a faulty gene can cause life-threatening problems. Gene therapies offer a revolutionary approach: a healthy copy of the gene is delivered into the patient’s body using specially modified viruses called Adeno-Associated Viruses (AAVs). AAVs transport the healthy gene to the cells where it is needed.

While gene therapy has transformed lives, liver problems are a known risk. In rare but serious cases these can be fatal, including three deaths from liver failure in 2025. We do not understand why some children experience severe liver damage while others do not. One possibility is that the immune system attacks the AAVs and accidentally injures the liver. As more gene therapies reach patients, understanding and preventing these liver problems is vital. From talking to patients and parents, we know that understanding what is happening in the liver will help families make informed treatment decisions.

We have worked with hospitals across the UK and a pioneering clinical trial to collect liver samples from children who received gene therapy, including those with and without liver complications. By comparing these two groups, we aim to identify what is different in their livers, and, crucially, how to prevent serious complications.

The centrepiece of this project is spatial transcriptomics, a powerful new technology that allows us to map, cell by cell, which genes are switched on or off across the liver. This provides an unprecedented, detailed picture of the liver after gene therapy, and where exactly the problems are. Working with a biotechnology company, we are also developing custom tools to detect the AAVs directly within liver samples, which has not been done before.

Ultimately, we want to make gene therapies as safe as possible, using these rare and precious samples donated by patients and their families.

Awarded to Louis Grandjean for £23,710 as part of the new projects call 2023.

In an infectious diseases outbreak it is important to identify the source case (where the outbreak came from) in order to implement appropriate treatment and preventive measures. This project will use high resolution whole genome DNA sequencing to improve identification of the source case in an infectious diseases outbreak. This new technology will help us to understand the origins of infectious diseases outbreaks and even potentially to identify superspreaders of infectious disease in the future. Identifying superspreaders (those individuals that give rise to many secondary cases) could allow us to target infection control interventions to have greater impact.

Awarded to Emil Gustavsson for £8,700 as part of the new projects call 2023.

Niemann-Pick Disease Type C (NPC) is a rare genetic condition that affects children. It arises due to changes in the NPC1 gene, leading to an accumulation of fatty substances inside the cells. This buildup results in complications in the brain, nerves, and other organs as time progresses. Unfortunately, there is no cure for NPC. The existing approaches focus on supportive therapies and targeted symptom management. However, there is hope for a new kind of treatment called antisense oligonucleotide (ASO) therapy, which can be used to target and reduce abnormal molecules produced because of changes in NPC1. Nevertheless, it is important to maintain normal gene function while reducing the abnormal molecules. Also, there might be other molecules produced due to these gene changes that we do not completely understand. Understanding these molecules can help make the therapy work better and avoid unexpected issues. Our project is all about filling in these gaps in knowledge.

To achieve this, we will use a state-of-the-art technique known as long-read sequencing. This advanced method allows us to thoroughly analyse all the molecules produced by the NPC1 gene. Our investigation will focus on cells obtained from a patient with NPC caused by NPC1 gene changes. Subsequently, we will subject these cells to a novel ASO treatment and compare them to normal cells. This approach will enable us to elucidate how genetic changes impact these molecules and identify those that the new treatment can rectify. Notably, this research extends beyond the realm of improving NPC treatments; it highlights the potential of long-read sequencing as a valuable tool for exploring other genetic conditions.

In conclusion, our study, which delves into the complete spectrum of molecules generated by the NPC1 gene, holds the promise of advancing NPC treatments. Furthermore, it underscores the broader applicability of this analysis technique in investigating a range of genetic diseases.

Awarded to Natalie Chandler for £25,000 as part of the new projects call 2023.

Our genome codes for what diseases we have as well as features such as eye and hair colour. Rare diseases occur in 1/17 people and can be very serious. These are caused by changes in our genomes. New treatments are being developed that can treat conditions with particular genomic changes, but in the past, it could take years and required many tests to identify the causal genetic change.

Whole genome sequencing (WGS) is a test that is now available in the NHS, and which looks for changes across nearly all of the genome in one go. However, the test currently used, called “short read” sequencing, still leaves gaps in sequencing meaning we may fail to find the cause of the condition. New technologies called “long-read” sequencing can examine these gaps and early studies have shown this can make a diagnosis in an extra 4% of patients.

We plan to compare the two WGS tests by using this new technology on a group of patients where current testing failed to find the cause of their condition, to see if this can increase the rate of diagnoses. If we find that it looks useful, we will also look at how difficult this is to do and how much it might cost, and other aspects needed to bring this from research to a clinical service for routine use. We will also look at whether it might replace the short read test or if the two should be used together.

Our team is based in the North Thames Genomics Laboratory Hub, and we work alongside the scientists doing the clinical service testing. This means we understand what is required to bring new tests into service and how to make this happen quickly if things look promising. In this project we will be testing patients with epilepsy and prenatal cases where we don’t have a diagnosis but where we know a quick diagnosis is vital. Developing these tests is costly and the companies who make these tests are helping by offering substantial discounts to do this work.

Awarded to Michelle Lowe for £2,000. Also under the PPIE theme.

Some Black and Asian women do not readily access maternity care and so may face worse maternal outcomes. Women from these groups are also often not included in research studies. This means that we know little about their experiences of maternity care – especially their feelings towards genetic testing during pregnancy. Better understanding the needs that might be unique to these communities could prevent racial inequalities in maternal care and improve outcomes. By working together with parents from these communities, this work will guide future research on maternity care, including a project looking at the experiences of Black and Asian parents who are offered genetic testing in pregnancy. In the study described here Black and Asian parents will be asked to join a discussion group where they will watch a video about prenatal sequencing (a genetic test offered in pregnancy) before sharing their views on this test with the group. They will also be asked for their views on a future research project, and their thoughts on what might encourage or put people off taking part in genetic research studies. Working together will make sure that the future project reflects the needs of these communities and sharing the results from these sessions will help researchers understand the issues that are important when planning studies with people from these backgrounds. Parents will also be sent a summary of the results and will be invited to an online event showcasing these results where they can see the role their input had in the research. Importantly, this work will help researchers build relationships with parents from Black and Asian communities and let them know about organisations like Antenatal Results and Choices (ARC) who support all parents making decisions about testing during pregnancy but who might be less well known to these groups.

Project: Application of Bioinformatics methods for clinical metagenomics to blood transfusion safety and an outbreak of unexplained acute hepatitis in children.

Awarded to Sarah Buddle for £2,693.

Also part of the Career Development Academy.

My PhD focuses on developing methods for clinical metagenomics, a powerful technique that involves sequencing all the DNA in a sample from a patient with a suspected infectious disease. This allows us to pinpoint the potential cause of the illness.

We used metagenomics to investigate a recent outbreak of unexplained hepatitis in children. Our study revealed that a virus called adeno-associated virus 2 (AAV2) was present more frequently and at higher levels in these hepatitis patients than in healthy control subjects. Moreover, we discovered that the genome structure of AAV2 in liver samples from these patients was complex and unusual. We also analysed the gene expression at both the RNA and protein level to give insight into the mechanism of the hepatitis.

Adeno-associated viruses (AAVs) are often used in gene therapy to deliver a functional gene to a patient. Unfortunately, hepatitis is a common side effect of AAV gene therapy, and we suspect that it may be similar to the hepatitis in the outbreak. To provide proof of concept, we are obtaining ethical approval to analyse DNA, RNA and protein sequence data from samples from a patient who developed severe hepatitis following AAV gene therapy.

Project: Genomic differences in SARS-CoV-2 between children and elderly: implications for disease severity and transmission dynamics

Awarded to Tereza Masonou for £3,302.

Also part of the Career Development Academy.

The COVID-19 pandemic has claimed the lives of over 6.5 million people, in particular the elderly. But why do infected children seem to be spared from severe disease, and what role do they play in spreading the virus?

This project seeks to determine whether the virus produced by nasal cells of children under 11 is different from that produced by elderly adults over 70. Our preliminary results show that the viral genome produced by children is shorter, has more mutations, and is associated with lower infectivity compared to the virus produced by elderly nasal cells. This suggests that children may produce more defective viral genomes, which could activate the immune response to fight the virus more effectively. However, it may also mean that viral variants may have a higher likelihood of emerging from infected children.

To gain a more comprehensive understanding of how the virus replicates in different age groups, we aim to use advanced technology called ultra-deep long-read nanopore sequencing. We will analyse stored samples from our experimental epithelial infection model, as well as samples collected from COVID-19+ children and elderly people.

This information will help us develop more effective infection control strategies and antiviral therapies that protect vulnerable populations.

Project: The mosaic brain: a new diagnostic approach in focal epilepsies.

Awarded to Flavia Matos Santo for £96,669.

Also part of the Career Development Academy.

Project: How do ciliary genes contribute to the aetiology of congenital hypopituitarism and related disorders?

Awarded to Louise Gregory.

Also part of the Career Development Academy.

Congenital hypopituitarism (CH) is a highly variable and debilitating disorder affecting 1:3000 - 1:4000 live births, with accompanying phenotypes such as eye, midline brain, and facial abnormalities. I have access to a large cohort of patient samples with CH and related disorders (n=>1,900); however pathogenic variants have only been identified in ~10% of patients. Next generation sequencing (NGS) has recently uncovered variants in 6 genes implicated in ciliary function and disorders in our CH cohort. Data suggests interactions between ciliopathy genes and the critical Sonic Hedgehog (Shh) pathway, which is known to be important for hypothalamo-pituitary (HP) development. My project aims to characterise these genes in a HP developmental context, which has not been previously investigated. I will perform multiple studies on patient fibroblasts, and on suitable cell-lines using CRISPR-Cas9/base editing, as well as using other techniques to evaluate expression and function. I will continue to analyse DNA from more patients on my new targeted-gene panel and through NGS to uncover further novel genes of interest, both ciliary and non-ciliary, which I will consider for functional analysis. My research will help patients by diagnosing their molecular mechanism, which in turn will assist in personalised medicine and optimising their treatment, improve their quality of life, and the lives of their families.

Project: Understanding cell-to-cell communication in the tumour microenvironment of arteriovenous malformation.

Awarded to Maanasa Polubothu.

Also part of the Career Development Academy.

Arteriovenous malformation (AVM) is a vascular tumour which presents in children in the first few years of life. It grows progressively and relentlessly over time leading to pain, deformity, spontaneous bleeding, heart failure and can lead to death. At present there is no cure. We recently discovered that the cause of AVM is genetic mutations (mistakes in the DNA code) which happen at some point during fetal development in known cancer genes. By using cancer drugs that directly target these mutations in children with AVM we can reduce the size of the tumour slightly in some patients, although not completely, and many patients have no response. Interestingly, the genetic mutations in AVM are only present in ~5% of the cells of the whole tumour, so ~95% of cells do not have the genetic mutation but are still growing aggressively. In order to treat the whole tumour we need to understand what signals the mutant cells are sending out to cause surrounding “normal’ cells to keep growing. To do this we will use innovative technology to look at how genes are expressed in each individual cell throughout the whole tumour in samples from children with AVM. This will allow us to understand which signalling pathways have been switched “on” or “off” in each individual cell and identify which pathways are responsible for tumour growth and therefore which we need to target with drugs stop AVMs growing. We will then create mini-AVMs in a dish to study how tumours develop over time. If successful, this research will directly benefit children with AVM by shedding light on the underlying processes that drive AVM growth and by identifying new “druggable” targets. Finally, mini-AVMs in a dish can be used in the future to rapidly screen new drugs thus accelerating the path to medical treatments.