Accelerating novel therapies awards

Awarded to Sara Mole for £24,399 as part of the new projects call 2023.

Batten disease is a group of rare inherited life-limiting diseases in children where brain cells die. The most common is juvenile CLN3 disease which begins with rapid loss of sight at about age 6 years. It takes time to confirm the diagnosis because this requires using a specially designed panel to test for all the genes that cause similar symptoms, or a single gene test in a family already known to have the disease. There are no simple tests using a blood sample that allow doctors to diagnose before symptoms present. Nor are there tests to monitor how the disease is progressing through following substances in the body that change with disease (a biomarker). This study aims to develop a specialised test for a group of promising biomarker molecules, and involve GOSH patients to help test these.

A new test will be set up and first used to check which samples from patients are best to use (blood plasma, urine or even a dried bloodspot). This biomarker test will then be used with more patients to check that it is reliable. If so, it will be developed for use in the GOSH diagnostic lab. We have years of experience of developing specialist tests for rare diseases and providing them to patients. GOSH ICH would be the first centre in the UK (and to our knowledge in Europe) to offer this new specialist test for faster and earlier diagnosis of CLN3 disease patients.

We will also investigate whether the biomarker is useful for monitoring whether new drugs currently being developed are effective at stopping or slowing down the disease. If so, this will support continued development of these treatments towards eventual clinical trials for testing in patients.

Together, these findings will show that this new biomarker is useful for both diagnosis and for monitoring disease progression.

Awarded to Chris O'Callaghan for £17,500 as part of the new projects call 2023.

Hundreds of millions of microscopic hairs called cilia line the airways of the lungs, nasal passages, and sinuses. They are packed full of two types of motors allowing them to beat a million times a day in a coordinated fashion, transporting mucus, inhaled particles, and pathogens out of the lungs and nasal passages forming the first line of defence against infection. In the disease Primary Ciliary Dyskinesia (PCD) protein defects in the cilia cause them to either be static or to beat in a way that does not transport mucus, leading to chronic upper and lower respiratory infection and progressive severe lung damage. Worryingly young children with PCD have significantly worse lung function than children with cystic fibrosis, and early diagnosis is essential to reduce lung damage.

PCD is a rare disease affects around 1 in 8,000 newborn children and more than 50 causative gene mutations have been discovered that result in protein abnormalities. The clinical features are very variable and the main diagnostic test to determine ciliary protein abnormalities is transmission electron microscopy (TEM). Unfortunately, TEM can only detect the abnormal protein in 70% of cases and is very expensive to perform, relying on specialist expertise that is very limited. Genetic testing is available, but similarly can only detect 70% of cases and mostly those with clearcut ciliary abnormalities. This is one of the main reasons PCD is so underdiagnosed. We aim to develop a new diagnostic test for ciliary proteins in PCD using a method called targeted proteomics. This allows identification of the proteins in cilia from patients with PCD, with the potential of detecting all the abnormal proteins in PCD, 30% of which are currently missed by TEM and genetics. A major advantage of the targeted proteomics approach is the potential to markedly reduce expense and time taken. If successful the test will be integrated into the PCD national diagnostic pathway and markedly increase availability for PCD diagnostic testing, particularly in countries that struggle to afford TEM.

Awarded to Christian Hedrich for £24,958 as part of the new projects call 2023.

Chronic nonbacterial osteomyelitis (CNO) is a rare bone condition, that most frequently affects children and young people. The bone becomes swollen (inflamed) and it can cause significant pain, deformity and can cause bones to break. The disease is difficult to diagnose and treat because there are no good tests and no good treatments.

This project will investigate a gene called “P2X7R”. We recently found abnormalities (mutations) in this gene in a large group of people affected by CNO. We suspect this gene affects a particular type of cell (“osteoclast”) whose normal role is to eat bone to keep bone healthy. To further investigate how this gene affects human bones, we have made modified human cells that have the abnormal genes with the aim to investigate bone eating cells in the laboratory. This replaces the need to use animals to research this further.

We will use our genetically modified osteoclasts on pieces of human bones that are collected during routine bone surgery (i.e. surgery where pieces of bone are routinely removed and would otherwise be disposed of). We will compare inflammation and bone resorption caused by modified osteoclasts when compared to cells without CNO-associated gene mutations. Results will then be confirmed comparing cells from blood taken from CNO patients with healthy individuals. Finally, we will look at the effects of different anti-inflammatory medications on osteoclasts’ bone eating capacity in this tissue culture model to build a foundation for future treatment studies.

This project will improve our understanding of the causes of CNO and accelerate the development of new treatments. Our findings may also benefit other inflammatory diseases, which are associated with this abnormal genetic problem, such as rheumatoid arthritis, systemic lupus, etc. A key aim is to establish state-of-the-art techniques to replace the need to use animals in bone immunology research.

Awarded to Mehul Dattani for £14,500 as part of the new projects call 2023.

Congenital adrenal hyperplasia (CAH) is a group of conditions that cause ill health and sometimes death. In CAH the body is missing a chemical substance (enzyme), which stimulates the adrenal glands to release hormones, including cortisol. Without cortisol, the body is less able to cope with illness, which can be life-threatening. Children with CAH need to take lifelong hormone replacement multiple times each day. They need regular blood tests to monitor hormone concentrations in the body and need regular dose adjustments.

At Great Ormond Street Hospital (GOSH) we look after ~200 children with CAH and admit them yearly to monitor their hormone concentrations over 24 hours. A cannula (a thin, plastic tube) is inserted into a vein, so that blood samples can be taken every 2 hours. This can be uncomfortable/painful. Hospital admission can also impact on a patient’s/carer’s quality of life. It is also costly to the NHS, involving an overnight stay for the patient and intensive nursing involvement.

We aim to improve patient and parent/carer experience by testing a minimally invasive method of blood sampling, which involves ‘dried blood spot’ (DBS) samples that can be taken at home.

We will take DBS samples from 50 children with CAH. We will use blood taken from their cannula at the same time as their planned hormone test - only one drop of blood will be needed per DBS sample. We will develop a new test to analyse DBS samples and compare these hormone results to current standard hospital laboratory tests which require cannula blood samples.

This work will lead to a new at-home test being developed, to see how well hormone replacement treatment works. This will be more convenient for patients/families and should lead to better CAH disease control. It will also save the NHS money and may benefit other patient groups.

Awarded to Jinhong Meng for £24,808 as part of the new projects call 2023.

Duchenne Muscular Dystrophy (DMD) is a rare genetic disorder affecting 1:5000 boys at birth. Patients suffer from progressive muscle weakness and dysfunction due to the changes of a protein called dystrophin, which helps to keep the muscle fibres intact. 15-30% of the cases are caused by a single nucleotide change in the DMD gene, which can be corrected by RNA base editing, a novel technology that has the potential to correct certain errors or mutations in the RNA of intact cells.

Adenosine Deaminase Acting on RNA (ADAR) is an enzyme which can correct the single nucleotide change in the RNA strand, to restore normal protein expression. ADAR and its guidance RNA (gRNA) can be delivered in a format of antisense oligonucleotides (AONs), or via an adenovirus-associated virus (AAV) system to reach its targeting site. However, it is not known which delivery strategy is more effective.

We aim to develop an optimal RNA editing approach, to correct the single nucleotide alteration in DMD muscle cells, by comparing the efficiency of these two delivery methods, and evaluating the potential side-effects caused by these treatments.

Both the AONs and the AAV vectors have been proven clinically safe, thus the optimal method identified in this research could be readily moved to next level of translational application.

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

We aim to address our lack of knowledge of how genetic changes lead to epilepsy in babies and how we can use this knowledge to design better treatments.

We suspect that some babies with epilepsy have low chloride levels in nerve cells which affects the ability of GABA, a chemical in the brain, to calm excitable neurons down. We also suspect that this process may be happening in other types of epilepsy. If we can identify the cause of the brain excitability in these epilepsies, we can find more targeted treatments which work for many different types of epilepsy.

We will do this by creating a lab model which very closely mimics what is going on in patient's brains. Patients with epilepsy who consented to take part in this research have donated skin samples, allowing us to make brain cells, or neurons, from patient skin cells. In addition, we are able to use skin cells donated for research by individuals without epilepsy. The "brain cells in a dish" give us a window into understanding the effects of genetic changes that lead to epilepsy, including the ability to check chloride levels and electrical activity.

We will make neurons from patients with the same epilepsy but caused by 2 different genes. This will allow us to look for shared disease processes which could be targeted by new treatments.
Potential impacts of this project will include new understanding about why seizures occur, particularly in early life epilepsies. We will also test a new form of treatment which blocks a chloride transporter, returning chloride levels to normal. This would have a significant impact as babies with this type of epilepsy have seizures which do not respond well to currently available treatments.

Awarded to Elena Marrosu and Serena Barral for £24,882 as part of the new projects call 2023.

Diseases affecting the human brain are often very difficult to study. This has previously limited our scientific understanding, which has hindered the development of better treatments for our patients. Recent scientific advances mean that we can now make brain organoids, or “brains in a dish”, where we convert a patient’s skin cells into brain cells. We can use these brain organoids to study biological processes that cause brain disease.

In this project, we will make complex brain organoids, for a rare childhood disease known as KMT2B-dystonia. This is a genetic condition that leads to twisting postures of the arms, legs and body and affected children have progressive difficulties in walking and talking. Our brain organoid model will allow us to better understand disease processes and to develop better precision treatments for this condition. An effective treatment for KMT2B-dystonia may also be translated to a broader range of both rare and common brain disorders.

iMDbio - An Inherited Metabolic Disease Bioresource.

Awarded to Philippa Mills for £52,961.

We have collected almost 2000 blood and urine samples from approximately 1500 individuals including:

- patients with an inherited metabolic disease (IMD) that has been confirmed by looking for changes in their DNA

- individuals believed to have an IMD because of the symptoms they have

- family members of patients with an IMD or believed to have an IMD

IMDs arise when a change in an individual’s DNA occurs that affects how they metabolise key nutrients in their food, such as proteins, fats and carbohydrates. This can cause too much, or not enough of important chemicals called metabolites needed for health, growth and energy. There are very few effective treatments for many of these ‘inherited metabolic disorders’ which can present in various ways depending on the disorder. Most of these disorders present early in life and can have severe health consequences. This may include neurological abnormalities, loss of developmental milestones, movement difficulties and seizures. Sadly, many of these disorders often result in early death. We need to find better ways of understanding these disorders so that new treatments can be developed.

We will use the samples we have collected to create a bioresource that researchers can use to better understand IMDs. We will call this bioresource ‘iMDBio’. iMDBio will be a repository linking patient’s clinical data to information that we get from analysing the important molecules such as proteins, metabolites and fats present in their samples, and to their DNA sequence. Knowing how these important molecules change with disease will provide us with a disease ‘signature’ for each IMD. These ‘signatures’ will not only allow us to better understand IMDs and help us to diagnose future patients but will also help to guide design of more effective treatments.

Promoting the use of patient relevant tissue and samples for novel therapeutic development.

Awarded to Claire Smith for £47,959.

This project will combine the resources of two existing UCL biobanks, to form an umbrella resource to simplify the supply of patient relevant samples, the aim of which is two-fold. Firstly, to improve access to human tissue for use as models of human disease for therapeutic development, particularly patients with rare diseases. Secondly, to improve access to human diagnostic samples to find new targets for disease.

Both existing biobanks have seen a surge in interest following the COVID-19 pandemic. We have supported projects studying drug resistance in CMV infections in children undergoing anti-viral therapy, clinical trials (INHALE), developing new anti-virals against respiratory pathogens, and projects that are developing genetic therapies for rare airway and skin diseases (EB, PCD and CF).

However, due to a lack of designated staff, we are effectively limited in our ability to support researchers, particularly those unfamiliar with handling these samples. This funding will enable us to provide a designated Research Assistant who will be responsible for processing/supplying samples and providing training to new users. In addition to this, the funding will also support outreach efforts to increase awareness of the biobank's services and expand its use to new researchers. We will build on our current platform to expand the range of tissues we provide, including the generation of iPSC from the primary tissue, and run a cost-recovery business model to extend the life of the biobank beyond this initial 2-year term.

By facilitating the use of tissues from individual patients, we will create more accurate models for testing new treatments, particularly patients with rare disease that cannot be easily replicated using other models. The merging of these two biobanks will encourage collaboration between researchers working in different fields to revolutionise the way we develop and test therapeutics.

Neuromuscular diseases highly specialised biobank.

Awarded to Francesso Muntoni for £59,538.

Project: RNA therapy including antisense oligonucleotides for neurological disorders.

Awarded to Barbora Cerna for £96,669.

Also part of the Career Development Academy.

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 Career Development Academy.

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.