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: 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: 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: 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.