Career Development Academy awards

Clinician Coders - Learn the basics of programming.

Awarded to Britt Hanson for £350.

12th Congress of the International Paediatric Transplantation Association.

Awarded to Ji Soo Kim for £571.

Advances in Neuroblastoma Research (ANR) 2023.

Awarded to Marta Barisa for £500.

European Alliance of Associations for Rheumatology.

Awarded to Lucy Nguyen for £482.

International Society for Stem Cell Research (ISSCR) 2023.

Awarded to Max Beesley for £365.

Organisation for Human Brain Mapping (OHBM) 2023.

Awarded to Mathilde Ripart for £480.

PReS 2023 European Paediatric Rheumatology Congress.

Awarded to Sarah Francis for £500.

Physiology 2023 at Harrogate Convention Centre.

Awarded to Tereza Masonou for £250.

European Society of Biomechanics 2023.

Awarded to Lara Deliege for £320.

Project: Low intensity, transdiagnostic psychological treatment for children and young people with eating disorders: development and evaluation.

Awarded to Emily Davey for £3,980.

Also part of the accelerating novel therapies theme.

Access to care for children and young people (CYP) with eating disorders has long been challenging, and has worsened since the COVID-19 pandemic. Within the UK, child and adolescent eating disorder services have seen a doubling in the number of referrals. Services have struggled to meet this increased demand and CYP are now facing a longer wait for treatment.

One way to increase access to psychological support for CYP with eating disorders is through an online guided self-help intervention, which is brief in nature and requires less therapist input than specialist treatment. The National Institute for Health and Care Excellence (NICE) recommend guided self-help interventions for adults with bulimia nervosa and binge eating disorder. They are also widely used in the treatment of anxiety and depression in CYP. However, child and adolescent eating disorder services in the UK do not routinely use guided self-help interventions as they have not been sufficiently researched.

Focus groups conducted with key stakeholders (CYP with eating disorders, their parents/carers and clinicians) have highlighted the importance of delivering self-help through an online platform. As such, the aim of this project is to develop an online, guided self-help intervention for CYP with impairing eating disorder symptoms.

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 genomic medicine theme.

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 genomic medicine theme.

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: Optimizing peptide conjugated antisense oligonucleotide therapy for collagen VI-related congenital muscular dystrophy.

Awarded to Shuzhi Cheng for £4,467.

Also part of the accelerating novel therapies theme.

Collagen VI is a protein that acts as a 'glue' in muscle fibers, forming a network within, to ensure their function. Collagen VI-related congenital muscular dystrophies (COL6-CMDs) are rare inherited diseases with no cure. In these diseases, muscles cannot function because genetic mutations lead to faulty collagen VI. Patients develop weakness at birth or shortly after. Some patients never develop the ability to walk and most die from breathing difficulties.

Antisense oligonucleotides (ASOs) are short strands of DNA or RNA designed to correct target genetic mutations. We have identified ASO sequences successful in correcting mutations in patients-derived cells in the lab. However, delivering these ASOs to the right cells in the body, specifically muscle interstitial fibroblasts (MIFs), has proven to be challenging.

My research aims to link ASOs to peptides (short fragment of proteins) that can specifically target and enter MIFs. This approach ensures that ASOs reach the target cells and correct the mutation, increasing their effectiveness. Initial tests showed the ASO-peptide compounds worked in MIF culture. However, further optimization is still needed to overcome the issue of endosome entrapment, where the compounds get trapped inside the cellular compartments. I discovered that modifying these peptides by adding certain amino acids could help them escape from cellular compartments and further enhance their function in correcting mutation.

With additional support, I plan to refine the ASO-peptide compounds to enhance their efficiency in correcting mutations. I will conduct further studies to track the localization and migration of the compounds within the cells. The goal is to develop a highly effective treatment for COL6-CMDs that can correct the genetic mutations and restore normal muscle function. This research not only holds promise for treating COL6-CMDs but also offers a model for developing similar therapies for other genetic disorders, potentially transforming the lives of many patients.

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

Awarded to Krishshan Gobalakrishnan for £4,000.

Also part of the gene, stem and cellular therapies theme theme.

Keratitis Ichthyosis Deafness (KID) syndrome is a rare genetic disease caused by dominant mutations in the gene called GJB2, resulting in its corresponding protein connexin 26 (Cx26) dysfunction. Cx26 is involved in the formation of channels within and between cells for cell-cell communication. Patients with KID suffer from dry, red, thick, inflamed, itchy skin, blindness, and deafness. Furthermore, there is an increased risk of development of skin cancers, resulting in premature death in KID patients.

There is no curative treatment for KID syndrome, only symptomatic control, which leads to the main aim of my project to develop a gene correction therapy for KID syndrome. CRISPR-Cas9 is a gene-editing technique that allows for genome correction. I wanted to use the technology to revert the mutated GJB2, and thus restore Cx26 normal function. I have developed a promising CRISPR gene-editing toolbox that can correct the mutation in GJB2 with high efficiency and observed restoration of Cx26 function.

I am thinking about how to deliver the gene-editing toolbox to patients. The current approach is the use of viral vectors. The downside of viral vectors is that the virus genome can integrate into humans. In the last two years, a new delivery vehicle called virus-like particles (VLPs) has been developed. The big advantage of VLPs is that it does not contain viral genome which reduces the risk of virus genome integration into the human genome.

I propose to adopt this technique in gene therapy for KID syndrome. I believe this vehicle has the potential to deliver gene-editing to patients with minimal risk. Therefore, I would like to ask for support from the Doctoral Training Support Fund, allowing me to perform a preliminary study on VLPs in gene therapy during my PhD study.

Project: Investigating the effects of adrenomedullin on human glomerular function.

Awarded to Emily Moore for £4,981.

Also part of the accelerating novel therapies theme.

Denys Drash Syndrome (DDS) is a rare, severe and incurable childhood kidney disease. DDS is characterised by irreversible scarring to glomeruli – tiny units within the kidney responsible for removing toxins from the blood. We have studied mice with the same genetic problem as patients which DDS and have identified a promising therapeutic target: a molecule called adrenomedullin (AM).

AM is a naturally occurring protein which is involved in the growth and support of new blood vessels. In the early stages of our mouse model of DDS, loss of blood vessels in the glomerulus occurs before irreversible kidney damage sets in. Previous work has shown that treating blood vessels with AM can encourage their repair. This suggests that if we can modulate levels of AM, we may be able to prevent the damage seen in the glomerular blood vessels in DDS and slow down the progressive kidney damage in this untreatable disease. However, this idea has not been explored in a human system, a vital step to translate these findings to patients.

In my project I will diversify the current work, by investigating how AM affects blood vessel cells isolated from human kidneys. Specifically, I will investigate the potential benefits of AM on blood vessel cells isolated from the human glomerulus, using the naturally occurring protein, as well as additional drugs that work by modulating AM. As studying human blood vessels in a laboratory setting is difficult, I will overcome this using a new technique developed by my laboratory, that allows us to grow the blood vessels and cells of the human kidney glomerulus in a 3D system. Through testing AM, I will determine how it influences the human glomerulus, potentially validating a new therapeutic target in DDS.

Project: Characterising monogenic thymic stromal cell defects resulting in T-lymphocytopaenia.

Awarded to Grace Evans for £2,409.

Also part of the gene, stem and cellular therapies theme.

The thymus is an organ that functions as a school, educating cells know as T-cells which allow our body to fight infections. If a child is born without a thymus, a rare condition known as congenital athymia, these T-cells are not produced and so they are unable to clear infections. These patients can be treated with thymus transplantation, a procedure offered at Great Ormond Street Hospital. As the thymus is important in early life, it is important this treatment is given as soon as possible and before they catch infections.

Doctors may struggle to tell the difference between babies with athymia and infants who instead have a problem in their bone marrow. These patients also have no T-cells but have a healthy thymus, meaning they require a different treatment to athymic patients. There are different genes responsible for bone marrow defects compared to athymia but sometimes the genetic cause of a patients low T-cell count is unknown, making it difficult to decide whether the patient has a problem with their thymus or bone marrow and which treatment they need.

We are developing new tests to better help distinguish these two types of patients, ensuring they get their required treatment for survival. This funding would specifically enable us to grow cells from the thymus in a dish to help us better understand how these cells educate T-cells. If we are unsure how a mutation in a gene effects the bone marrow or thymus, we can study thymic cells with these mutations with special equipment to see how these cells differ from healthy thymic cells, this is known as disease modelling. We hope better understanding these genes and how these cells work will mean patients can be diagnosed more quickly and can therefore receive treatment before they obtain infections.

Project: Testing RNA therapies for epilepsy with microelectrode arrays: targeting the GABA switch.

Awarded to Barbora Cerna for £4,994.

Also part of the accelerating novel therapies theme.

In childhood epilepsies, children experience repeated seizures due to abnormal changes in brain cell communication. Normally, brain cells use electrical signals to talk to each other. These signals help build networks in the brain and guide healthy brain development. Early in life, these signals are very active to support brain growth and build connections. As the brain matures, it introduces signals to slow down this electrical activity, creating more organised communication. This developmental shift is a key part of healthy brain development.

In children with epilepsy, this shift is disrupted. Their brains may stay in an overly active state, which can trigger seizures and interfere with normal brain maturation. Current medications are often ineffective for many children, resulting in poor outcomes and an increased risk of early death.

My research focuses on developing a targeted therapy which will reduce the activity of a key player in this imbalance, with the goal of bringing brain activity back to a healthier level.

To study the disrupted shift, I use 3D brain-like models made from patient or healthy donor skin cells that are turned into stem cells. Stem cells can become any type of cell in the human body, including brain cells. From stem cells, I grow simplified human brain-like networks to compare when the developmental shift happens in both healthy and epileptic brains, and to find the best time to give the therapy.

To monitor how brain cells communicate in real time, I use microelectrode arrays, small devices with thousands of tiny sensors that detect signals from many brain cells within my model.

After applying the therapy to the models, I will use these arrays to check whether patient brain-like models mirror the healthy brain-like models, which would suggest that the therapy is restoring brain function and potentially reducing seizure activity.

Project: From liver to blood: mapping liver endothelial dysfunction to circulating biomarkers in AAV gene therapy (part of broader thesis: Investigating the effects of gene therapy with viral vectors on the human liver).

Awarded to Rebecca Jeyaraj for £4,958.

Also part of the gene, stem and cellular therapies theme.

Liver side-effects are common after gene therapy and in some cases, can be severe or even life-threatening. We don’t know why some people develop severe side-effects or how to predict who is most at risk. Until now, researchers have thought that liver problems are mainly caused by the body’s immune system reacting to the gene therapy and accidentally attacking the liver. However, there were only a few immune cells in the livers of two teenagers who died from liver failure after gene therapy in 2025. This has led researchers to consider other causes of liver damage.

One possibility is damage to the cells lining the liver’s blood vessels. This has been observed in monkeys after gene therapy, and I have generated initial results using human liver samples that support investigating this further. Additional funding will allow me to answer two key questions. First, how does damage to the liver’s blood vessels contribute to liver problems? Second, can we detect signs of this damage in patients’ blood early enough to start specific treatment?

I will first study how liver blood vessel cells respond to gene therapy by looking at changes in the genes they switch on and off. I will next infuse gene therapy into human liver samples in the lab and measure proteins released by the liver. This will be compared to proteins in the blood of patients receiving gene therapy. This could identify signals in the blood that provide an early warning of liver damage, helping doctors to identify patients at risk and decide when to start treatment. Ultimately, I hope this will improve our understanding of the causes of liver damage and make gene therapy safer for patients.

Project: Mass spectrometry analysis of blood plasma to identify non-invasive biomarkers of neuroblastoma: a pilot study.

Awarded to Jonathan Neville for £3,574.

Also part of the accelerating novel therapies theme.

Neuroblastoma is the most common cancer of early childhood that develops outside the brain. It grows from immature nerve cells and can behave very differently from child to child. Some tumours resolve on their own, while others need intensive treatment, and even after successful treatment some children relapse.

Keeping track of how a child's neuroblastoma is behaving currently relies on invasive tests: biopsies, bone marrow samples taken under general anaesthetic, and scans that use radioactive tracers. These tests are stressful for children and families, carry their own risks, and cannot always be repeated as often as doctors would like.

In earlier work, we studied tumour tissue removed during surgery using a technique called mass spectrometry, which can identify the fats (lipids) that make up cells. We found that neuroblastoma tissue contains a distinctive pattern of lipids, called ceramides, that differs from the normal tissue nearby – a chemical "fingerprint" of the disease.

This project asks whether the same fingerprint can be picked up in a simple blood sample, rather than needing a piece of tumour tissue. We will analyse small volumes of blood taken from children with neuroblastoma at diagnosis, after surgery, and if their disease returns. Using the same mass spectrometry approach, we will look for lipid patterns that mark the presence of neuroblastoma, and whether these differ between children with lower-risk and higher-risk disease.

If successful, this pilot study will provide early evidence for a blood test that could one day complement, or reduce the need for, more invasive monitoring. This will make it easier and kinder for doctors to track how children with neuroblastoma are responding to treatment, and to detect relapse earlier.

Project: A multiplex digital PCR panel for rapid antibiotic resistance surveillance in paediatric intensive care wastewater.

Awarded to Oliver Giles for £4,795.

Also part of the accelerating novel therapies theme.

Antimicrobial resistance (AMR) is one of the biggest threats to modern healthcare(1). When bacteria become resistant, infections once simple to treat can become difficult or impossible to manage. This matters most in a children's hospital such as Great Ormond Street Hospital (GOSH), where many patients have rare diseases or weakened immune systems and spend long periods in intensive care. Carbapenem-resistant bacteria are especially concerning because carbapenems are among our last-resort antibiotics(2).

Hospital microbiology teams routinely test individual patients, but this cannot show what is happening across a whole intensive care unit (ICU) or identify emerging hotspots.

Wastewater from an ICU carries genetic material shed by patients, staff and the bacteria around them. During the COVID-19 pandemic, wastewater surveillance became an important way of monitoring infection across communities. Applying the same principle to antibiotic resistance could give a unit-wide picture alongside patient testing and identify rising resistance earlier(3).

My PhD is investigating metagenomic sequencing, which reads all the DNA in a sample to search for resistance genes. However, our preliminary results show that clinically important resistance genes are often too rare to detect reliably against the background of unrelated DNA. It is like searching for a needle in a haystack by examining every piece of straw.

This has led us to digital PCR (dPCR), which searches directly for specific resistance genes rather than reading everything in the sample. Early results suggest dPCR can detect genes missed by sequencing, rapidly and at substantially lower cost. This funding will develop and validate a dPCR panel for five carbapenem resistance genes in wastewater from the GOSH intensive care units and compare it with metagenomic sequencing.

The aim is a rapid, affordable tool that helps infection control teams see where resistance is circulating in a children's hospital and act earlier to protect vulnerable patients.

Project: RNA therapy including antisense oligonucleotides for neurological disorders.

Awarded to Barbora Cerna for £96,669.

Also part of the accelerating novel therapies theme.

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

Awarded to Flavia Matos Santo for £96,669.

Also part of the genomic medicine theme.

Project: Building mini organs for disease modelling.

Awarded to Lucy Holland for £96,699.

Also part of the tissue engineering and regenerative medicine theme.

Project: Liver-directed lentiviral gene therapy for progressive familial intrahepatic cholestasis type 2 (PFIC2).

Awarded to Ziyu Jiang for £96,669.

Also part of the gene, stem and cellular therapies theme.

Project: Rescuing B cell development in patients affected by X-linked agammaglobulinemia.

Awarded to Stefano Gritti for £96,669.

Also part of the gene, stem and cellular therapies theme.

Project: A Patient-derived 3D humanized model of ADCY5-related disease to accelerate therapeutic approaches for patients.

Awarded to Scarlett Yeadon for £90,993.

Also part of the accelerating novel therapies theme.

Project: Vascularising human mini-brains in a dish.

Awarded to Imogen Smith for £99,281.

Also part of the tissue engineering and regenerative medicine theme.

Project: Role of mechanical signals in a 3D human model of alveolar differentiation.

Awarded to Ziming Shao for £90,993.

Also part of the tissue engineering and regenerative medicine theme.

Project: Using artificial intelligence and machine learning techniques to improve diagnosis and predict outcomes in children with heart muscle disease.

Awarded to Cameron Taylor for £90,993.

Also part of the applied child health informatics theme.

Project: Health and development outcomes and their interaction for children with chronic liver disease: a population-based cohort using novel linkage between health and education records.

Awarded to Qing Zhang for £90,993.

Also part of the applied child health informatics theme.

Project: Developing an implantable hepatic patch to treat a range of inborn liver diseases.

Awarded to Hassan Rashidi for £128,242.

Also part of the tissue engineering and regenerative medicine theme.

The liver is essential to life as it produces proteins that are involved in key metabolic pathways and removes harmful toxins from the blood. Babies born with deficiencies in key metabolic pathways may die unless they receive an organ transplant. However, liver transplantation is far from an ideal therapy due to the shortage of donor organs, the high risk of the surgery especially in babies/children (mortality about 5%), the life-long problem of rejection, need for immunosuppression and the high risk of developing cancer and/or kidney failure.

Cell therapy is an attractive alternative to whole organ transplant as it avoids the need for an organ donor, major life-threatening surgery and the morbidity of post-surgery complications. However, cell therapies have yet to impact on clinical care due to the difficulty in producing, delivering, and maintaining sufficient numbers of cells to reverse the metabolic liver disease.

Human pluripotent stem cells (hPSCs) are cells with an unlimited ability for self-renewal, which can develop into functional liver cells, known as hepatocytes. I developed a novel approach to generate functional liver cells from hPSCs under the stringent conditions required for human cell therapies and these remained functional when transplanted into a mouse model of inborn liver failure.

I also developed two novel approaches to:

1- Encapsulate cells in a layer of gel making them suitable for transplantation to anybody without risk of rejection by the immune system.

2- Fabricate a polymeric patch to retain cells at the site of implantation for ease of removal/replacement if required.

The Hepatic Patch was implanted successfully in a model of inborn liver disease and achieved normal physiological level of a toxic metabolite within a month. In this project, I will move this technology forwards towards implementation, for the benefit of children with inborn liver disease.

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

Awarded to Louise Gregory.

Also part of the genomic medicine theme.

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 genomic medicine theme.

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.

Project: Machine Learning to Improve the Identification and Treatment of Low Cardiac Output Syndrome after Paediatric Cardiac Surgery.

Awarded to Timothy Dawes for £84,468.

Also part of the applied child health informatics theme.

Background

Heart abnormalities affect 1 in 100 babies born in the UK. Some of these abnormalities are managed with medication or a minor procedure, but one third need open-heart surgery involving a heart-lung bypass machine. This bruises the heart, making it harder to pump blood and oxygen to other organs causing possible damage. Despite frequent checking and testing, it is difficult for doctors to work out which children will develop organ damage after surgery. Doctors have different treatments to support heart function and oxygenation, but the best choice, dose, and timing of these drugs is still uncertain. We want to help children to recover as quickly as possible so they can get home and stay well in the longer term too.

Aims

1. To look at information recorded from monitors and blood tests taken during and after heart surgery to see if patterns of information show us which children are at higher risk of poor heart function after surgery.
2. To look at which treatments allow children to recover best in hospital and afterwards.

Methods

We will access anonymised health information from around 3,000 children who have already undergone heart surgery. We will use computer software to analyse these large datasets and examine how factors such as general health, heart function, surgery details, and treatments affect a child’s recovery in intensive care and beyond. The work will use an ongoing patient and participant involvement and engagement collaboration with GOSH Young Person’s Advisory Group and GOSH Parents and Carers Advisory Group for research.

Expected Outcomes

We hope to support medical teams to personalise care, spot issues early, and use treatments in the best possible way. This will improve recovery times and long-term health outcomes for children while reducing hospital costs.

Project: Investigation of circulating factors that drive paediatric glomerular disease

Awarded to Will Mason for £53,689.

Also part of the tissue engineering and regenerative medicine theme.

The kidneys clean blood through a special filter, called the glomerulus. The glomerulus is like a coffee filter, which retains important blood molecules, and excretes waste. Some children are born with a damaged filter and can’t clean their blood. This means they require dialysis or a kidney transplant. There is an urgent need to understand why this happens and develop new treatments. One idea is that damage to the kidney filter is caused by harmful substances circulating in the blood. If we find these, we will get better treatments for children with kidney diseases.

I will use a new laboratory technique to grow a human child’s kidney filter. The filter will be grown in three dimensions in a laboratory dish. I will expose this kidney filter to blood donated by children with glomerular diseases. This will show if the blood is harmful to the kidney filter. Next, I will use a special machine to try to find the harmful substances in the children’s blood by comparing them with healthy children’s blood. Finally, I will determine which cells in the filter are damaged and how they respond using a microscope.

This project has the potential to identify harmful substances in the blood of children with kidney disease. The project will tell me how these substances affect the kidney filter. In future work, I will try to protect the kidney filter by reducing these harmful substances. This will put me on track to my career goal of finding new treatments for kidney disease. Patients with kidney disease have been involved in the design of the experiments leading up to this project. I will continue to discuss my results with patients as the project progresses. The findings will be communicated by our website, scientific publications, and conference presentations.

Project: A panel of sequencing solutions for fetal cells in maternal blood: advancing non-invasive mutation screening for unborn children.

Awarded to Jose Moreno-Villena for £104,827

Also part of the genomic medicine theme.

Non-Invasive Prenatal Diagnosis (NIPD) methods are used to diagnose diseases in unborn children without needing invasive procedures, like cutting or puncturing the mother’s womb to obtain cells from the baby, which can lead the loss of the unborn child. Currently, NIPD relies on small fragments of the baby’s DNA (baby’s genetic code) found in the mother's blood to screen for common chromosomal abnormalities, such as Down syndrome. However, a positive diagnosis often requires invasive procedures to confirm it. Also, because the circulating baby’s DNA is broken into small pieces, it is impossible to get a complete picture of the baby’s genetic code and diagnosis of many diseases may be missed.

To improve NIPD, we have identified intact cells from the baby in the mother's blood containing the entire and unbroken baby’s DNA. Using novel technologies, I have collected hundreds of cells from the baby in the mother’s blood. We discovered that these include cells from the placenta and cells from the baby’s blood, both carrying the baby's DNA. We have read some of the genes (part of the DNA that specifies proteins) from these cells and now aim to read their complete genomes (entire baby’s DNA) to look for genetic changes that may cause disease.

Thus, if awarded this fellowship, I will not only look at the unborn baby’s genes but at all of the information in the baby’s DNA, obtaining the complete genome from the baby’s cells circulating in the mother’s blood. This would allow for unimpeded screening of genetic changes in unborn children, comparable to genetic tests done after birth today. If successful, this could revolutionize prenatal diagnosis, making it accessible to all parents without risk.

Project: A Novel Model of the Human Growth Plate for Studying Skeletal Diseases.

Awarded to Oliver Gardner for £107,036

Also part of the accelerated novel therapies theme.

Background

As children and adolescents our bones both support our weight and lengthen as we grow because of specialised regions made of cartilage called growth plates. A number of diseases, including acrodysostosis, stop the growth plates functioning properly and so prevent bones growing correctly. Acrodysostosis is a rare and incurable genetic condition which causes a range of symptoms. Most prominently patients have underdeveloped hands and feet, as a result of changes at the growth plate, which severely impact their quality of life.

Aims of the Research

The goal of this project is to make growth plates from human stem cells in the laboratory that can then be used to understand how they are affected by disease and for testing potential treatments. Initially I will look at acrodysostosis before studying other diseases in the future.

Design and Methods

To study the growth plate I will replicate its multi-layered structure by generating different pieces of cartilage in the laboratory and then assembling them together to form an “assembloid”, a more complex structure which will closely mimic the organisation and behaviour of the growth plate. This will allow me to study the growth plate in a totally new way and provide a platform for testing drugs to treat acrodysostosis and other diseases where the growth plate is affected.

Public and Patient Involvement

Through my work on acrodysostosis I have forged a close relationship with the parent led charity Acrodysostosis Support and Research (ASR). My interaction with ASR has shaped the direction of this work towards methods for testing new treatments and I will further develop this relationship with the community over the course of this fellowship.

Dissemination

The results of this work will be submitted for publication in a peer-reviewed journal, presented at scientific conferences and to ASR through regular meetings.

Project: Improving Outcomes for Children with Paediatric Low-Grade Glioma: Translating Clinical and Molecular Research into Practice.

Awarded to Katherine Green for £85,000.

Also part of the accelerating novel therapies theme.

Dr Green is a children’s doctor completing specialist training to treat children and young people with cancers, including brain tumours. She has already completed a research project studying the commonest type of children’s brain tumour, Paediatric Low-Grade Glioma(PLGG), and wants to use this data to help develop better treatments and to improve the future lives of patients with PLGG.

There are approximately 200 new PLGG cases in the UK every year, with 90% patients surviving long-term, but with some children still dying from PLGG. Dr Green’s previous research looked at 814 PLGG patients treated at GOSH and identified that many survivors face difficult consequences of their tumour and treatments in terms of life-long reduced health, function and quality-of-life. Therefore, improving treatments, preventing disability and better supporting patients is critically important for patients and their families.

Dr Green will use the BRC Catalyst fellowship to further develop and study the large group of PLGG patients she collected by completing a comprehensive genetic analysis to better understand the different subtypes of PLGG and what causes and drives these tumours to grow. This will allow her to look at the 10% of children who die from PLGG to try and identify better treatments for these patients, and to perform the first-ever evaluation between PLGG tumour genetics, survivor function and quality-of-life outcomes to develop better treatments and interventions which reduce the risk of disability and improve quality-of-life after a PLGG.

Dr Green previously worked with PLGG patients and families to better understand the impact of PLGG on daily life and will take this research forward by meeting with PLGG survivors in focus groups/workshops to determine what research priorities are most important to them. She will work with major US Children’s Hospitals to link her findings in a new international study of PLGG survivorship outcomes.

Project: CylindAIR: A Biomimetic Airway Model That Replicates Helical Mucociliary Clearance to Advance Respiratory Therapeutics For Rare Disease.

Awarded to Maximillian Woodall for £80,577.

Also part of the gene, stem and cellular therapies theme.

Our lungs are constantly working to keep themselves clean, moving mucus and trapped germs out of the airways like an invisible conveyor belt. In healthy lungs, special airway cells beat in a spiral pattern to sweep away mucus — which traps dust and bacteria — using a screw-like motion from bottom to top. But in children with rare genetic conditions like cystic fibrosis (CF) or primary ciliary dyskinesia (PCD), this system breaks down. Mucus gets stuck, infections build up, and over time, serious lung damage can occur.

Researchers are trying to develop new treatments, including gene therapy, to help fix this. But progress has been slow. One big reason is that current lab models are too simple. They grow airway cells on flat surfaces, which can’t copy the natural upward spiral of mucus clearance. This means they often can’t show whether a new therapy will work in real lungs — or whether it might be cleared too quickly or get stuck in mucus blockages.

This project, called cylindAIR, will build the first lab model shaped like a real airway tube. Using ultra-thin, specialised plastics and donated nasal cells from children with rare respiratory diseases, we will grow living models that behave like real human airways. These models will let us study how mucus moves — or gets blocked — and how new treatments might help.

We are working with clinicians, engineers, and digital health experts — and will also engage patients and families — to ensure this model is relevant, accessible, and impactful. Our aim is to speed up the development of new inhaled medicines and gene therapies that could help thousands of children breathe more easily and live healthier lives.

Project: Assessing the impact of Hirschsprung disease on the development of the gut brain axis.

Awarded to Benjamin Jevans for £121,280

Also part of the tissue engineering and regenerative medicine theme.

Our brain talks constantly to our stomach and intestines, getting updates about digesting food and any problems that are happening. This is known as the gut-brain axis: a series of nerves connecting the gut and brain. Scientists now think that the gut-brain axis is involved in many diseases, such as Parkinson’s disease, which may begin in the gut and travel to the brain. However, there is a lot we don’t understand about the gut-brain axis, including how it develops and the cells involved. We also don’t know whether the gut-brain axis is affected by childhood diseases. Here, we will study how the gut-brain axis is affected in Hirschsprung disease.

Hirschsprung disease happens when the gut nervous system doesn’t develop. Affected children can’t poo, leading their large intestine to swell and burst unless the children undergo surgery. This removes the piece of intestine without the nervous system. However, even after surgery, children suffer lifelong symptoms, often more severely than doctors expected. We believe this is because Hirschsprung disease also affects the gut-brain axis. There is already evidence for this: nerves from the brain look swollen and twisted in the intestines of children with Hirschsprung disease.

We will use the tissue surgically removed from children with Hirschsprung disease to map the brain nerves spreading through the intestine, comparing this to tissue from healthy children. We will also use Hirschsprung disease stem cells to make nerve cells in a dish and see if these form strange nerves compared to healthy cells. These results will help us develop holistic treatments for Hirschsprung disease to reduce the lifelong symptoms these children suffer. This project was developed with feedback from a focus group of families with Hirschsprung disease. We will keep the focus group updated as this project progresses and be guided by their feedback.

Project: Designing better gene therapies with high-throughput diversified HDRT screening.

Awarded to Tom Whittaker for £113,610.

Also part of the gene, stem and cellular therapies theme.

DNA is a molecule inside every cell of your body, made of a long chain of four slightly different smaller molecules. Like how a sentence is made out of letters, their sequence makes up instructions (“genes”) for how your cells should work. Changes to this sequence (“mutations”) stop the instructions making sense, causing disability or disease. Gene therapies correct these mutations.

One way to do this is by making a cut in the cell’s DNA chain near the mutation. The cell notices that the DNA has been cut and will look for another piece of DNA that matches one side to use it as a bridge to try to find the second side and repair the gap. If we add this bridging DNA ourselves, we can put the right sequence back in the middle.

• If a healthy person has a gene with this instruction: “This sentence means something”
• And a sick person has this mutation: “This senteans something”
• We cut their DNA: “This sent/ /eans something”
• And add our bridge: “sentence means”
• The cell repairs it to make: “This sentence means something”

You can write the same instructions with different DNA sequences. The sequence of the bridging DNA affects how effectively the cell uses it for this repair. There are too many different options to test one-by-one. To evaluate many at once:

• We will use many cells and give a mix of bridges: “This sent/ /eans something” “sentence means”
  “sentence means”
  “sentence means”
• And see which are incorporated most often: “This sentence means something”

The bridges compete to be used. Like how the fastest runners win a race, the best bridge sequences will be incorporated into cell DNA most often. We are initially applying this to the disease XLA, in which you can’t make antibody-producing cells to protect from infection.

Project: Targeting blood brain barrier permeability to enhance systemic cerebral drug delivery.

Awarded to Sonam Gurung for £128,331.

Also part of the accelerating novel therapies theme.

Did you know?

• There are more than 7000 rare diseases known
• Over 50% of these affect the brain, causing severe brain disability and reducing life expectancy.
• Less than 5% have approved treatments.

The brain is protected by the blood brain barrier (BBB), a cell layer acting as a ‘gatekeeper’ that acts to maintain stable brain environment. The BBB is a special filter that prevents harmful substances from reaching the brain through the bloodstream and allow necessary substances pass through. However, the filter stops most oral treatments or treatment given through the blood system to treat the brain cells. Ways to overcome this barrier currently includes risky surgical procedures or giving high treatment doses. My aim is to design a new strategy to increase passage of these treatments so they can reach the brain.

The BBB is made of “endothelium” cells that line the blood vessels in the brain. They are packed very tightly together, giving the BBB it’s filtering properties. I will for a short time loosen the tightness of the cells and increase the size of the filters to provide passage for larger, long-lasting brain treatments.

For this, I will increase the amount of a key protein in the BBB “endothelium” layer, using messenger RNA (mRNA) strategy. mRNA provides the blueprint to the cells to make required protein but is short-term.

Steps:

1. To deliver the treatment I will use a packaging system, lipid nanoparticles (LNPs). The LNPs will have a specific navigation signal, that can direct them specifically to the barrier cells from the blood.
2. I will test the mRNA packaged in the LNP in a 3D ‘BBB-in-a-dish’ system and in a mouse model.
3. I will test the power of this treatment to increase effectiveness of a long-term brain directed treatment given through the blood system.

Project: EMPOWER (tackling Ethnic inequity in Maternal and Paediatric health Outcomes and Wellbeing using Electronic health Records).

Awarded to Selina Nath for £130,098

Also part of the applied child health informatics theme.

Babies born to Black and South Asian mothers in the UK have worse health outcomes than those born to White mothers. For example, Black babies are almost three times more likely to die in their first year compared to White babies. These differences are unjust and need urgent attention.

One possible reason may relate to variations in the health and wellbeing of Black and South Asian mothers, influenced by structural barriers and unequal access to care. However, we have lacked long-term data that follow families before, during, and after pregnancy to fully understand how a mother’s wellbeing affects her baby’s health.

EMPOWER (Ethnic inequity in Maternal and Paediatric health Outcomes and Wellbeing using Electronic health Records) is a research programme led by a survivor and shaped by Black and South Asian parents. It will use large-scale linked data from NHS hospitals, maternity services, mental health services, health visiting, and education to explore why babies born to Black and South Asian mothers are more likely to have poor health outcomes. In the future, we will explore children’s education.

The research will use a national dataset called ECHILD, which links health, education, and social care records for over 8 million children and their mothers in England. The main aim is to understand how ethnic inequalities and mothers’ wellbeing during pregnancy affect children’s health.

EMPOWER will be co-produced with Black and South Asian parents and supported by experts. It will include:

• Working charities and parents to shape research questions and plans.
• Reviewing existing policies and research with the NHS Race and Health Observatory to ensure findings translate into policy and practice.

This research will help build foundations for bigger studies and future funding applications. Ultimately, I hope the findings will inform better policies and services for all mothers and babies, regardless of ethnicity.

Project: Engineering vascularised small intestine.

Awarded to Lucinda Tullie for £91,332

Also part of the tissue engineering and regenerative medicine theme.

Children with short bowel syndrome (SBS) don’t have enough working small intestine to absorb water and nutrients essential for health and growth. This can happen if part or all their small intestine is missing from birth or removed during surgery as a baby.

At the moment, there are two ways to help patients with SBS:

1. Feeding through a vein (called parenteral nutrition) can help patients to survive but can cause serious problems such as infection and liver problems.
2. Surgery, such as intestinal transplant. Donor intestines are rare, especially for children, and patients need life-long strong medicines which have serious side-effects.

These treatments come with significant lifelong problems for patients and high cost for the NHS. This is why we urgently need new treatments.

Our research in regenerative medicine is exploring a new solution for treating SBS. We can grow intestinal tissue from human cells. This “engineered” intestine could be used to replace the missing part of the intestine and restore its function. Instead of the entire intestine (which can be expensive and complex), we can successfully engineer the inner lining of the small intestine using patient’s own cells and a supportive structure, called a “scaffold”.

A key problem is that these engineered pieces need a blood supply to survive in a patient after transplantation. During this Fellowship, I will look at ways to improve the blood supply in lab-grown intestines. I plan to do this by adding cells that form blood vessels, to lab-grown intestines, and look at ways to encourage them to form blood vessels. This could supply the nutrients needed to keep larger pieces of engineered small intestine tissue healthy and help them survive after being transplanted into patients.

I will also work closely with SBS patients and families, to feedback project progress in accessible ways.

Applications are currently under review.

Project: Investigating spatial and temporal tumour heterogeneity in neuroblastoma to improve surgical clearance and develop novel techniques for loco-regional control.

Awarded to Jonathon Neville.

Also part of the tissue engineering and regenerative medicine theme.

Neuroblastoma is a paediatric cancer arising from neural tissue during embryonic development. It has varied clinical outcomes, from spontaneous remission to aggressive disease. Neuroblastoma causes 15% of all childhood cancer deaths and five-year survival rates for high-risk disease is 40 – 50%. Certain genetic mutations, changes in gene expression and altered interactions with the immune system are associate with poor outcomes in neuroblastoma. However, these changes vary significantly across a single tumour and this tumour heterogeneity changes over time.

Surgery is an important part of neuroblastoma treatment, but it can be difficult. The tumour often adheres to important structures, and it can be hard to differentiate tumour from healthy tissue. Fluorescence-guided surgery (FGS) uses probes that label tumour tissue to illuminate neuroblastoma intra-operatively. This makes it easier for surgeons to identify tumour tissue, enables complete resection and reduces complications. Some FGS probes under development for neuroblastoma have shown promise in pre-clinical studies, however the utility of these probes is limited by tumour heterogeneity and the effects of treatments prior to surgery (chemotherapy and immunotherapy).

There is little evidence investigating and linking the genetic, gene expression and immune system profiles in neuroblastoma over time. In this study, we will perform imaging-guided, multiple-site biopsies from diagnostic and post-treatment tumours. These samples will undergo genetic, gene expression, and immune system analysis. We will integrate these results to identify characteristics associated with poor outcomes. Tumour tissues will be analysed to identify new targets for FGS probes. By comprehensively mapping tumour heterogeneity we will develop FGS probes which can identify particular subgroups of the tumour (for example, more aggressive areas). Multiple probes will also overcome some of the known issues with tumour heterogeneity and downregulation of targets. These probes would allow surgeons to better tumour intra-operatively and improve outcomes.