Rare disease cohorts funding

Mito-omics approach to investigate a paediatric cohort of multiple ultra-rare mitochondrial disorders

Mitochondria, tiny structures present inside nearly all human cells, are highly efficient cellular power stations, generating the energy needed for normal cellular function. Mitochondrial diseases arise when the mitochondria do not function properly. With a combined minimum birth prevalence of 1 in 5000, mitochondrial diseases represent one of the most common groups of inherited metabolic disorders, and are comprised of severe complex multi-systemic disorders with high clinical, biochemical and genetic variability among patients. To date, we and others have contributed to a knowledge base of >350 disease genes, spanning two genomes, for mitochondrial diseases. Indeed, diagnostic rates have increased from <5% up to >60% over the latest twenty years of research and advancing technology. Yet, despite these diagnostic advances there are no currently available curative therapies.

We now aim to utilize the latest ‘multi-omics’ technologies to improve outcomes for children affected by mitochondrial diseases. At Great Ormond Street, we have a unique collection of samples from a large cohort of well-characterised paediatric patients with multiple ultra-rare mitochondrial diseases. We aim to generate ‘transcriptomic’ and ‘proteomic’ datasets from these samples by RNA sequencing and mass spectrometry, respectively. We will then integrate these datasets with ‘phenomic’ data comprised of clinical, biochemical and radiological data and interrogate using sophisticated computational analyses to elucidate potential diagnostic biomarkers and targets for novel therapies. We aim to increase our impact further by being one of the first to integrate our data into the Great Ormond Street Hospital digital research environment (GOSH DRE) to enhance the quality of patient care in real-time.

Thus, this research project provides a unique opportunity to generate mitochondrial multi-omic (‘Mito-omic’) signatures of a paediatric cohort of multiple ultra-rare mitochondrial diseases to aid in the discovery of underlying disease mechanisms, diagnostic biomarkers, and therapeutic targets for future clinical application.

Defining mitochondrial dysfunction in dermatomyositis: towards new treatment targets

Juvenile dermatomyositis (JDM) is a rare, severe disease, typically affecting muscle and skin, which is thought to be caused by the immune system malfunctioning. JDM is currently treated with drugs that suppress the immune system, such as steroids, which can have bad side effects. Some patients respond to treatment, but many patients do not and can develop long-term severe complications. This means we need new, more effective treatments, but in order to develop these, we need a better understanding of abnormal biological processes in JDM.

We recently analysed genes that are switched on or off in JDM patient blood cells. Unexpectedly, we found genes involved with mitochondria, the ‘power house’ of the cell responsible for producing energy, were abnormally switched on/off in samples from patients treated for 1 year using immune-suppressing drugs. These results suggest that mitochondrial abnormalities are an underlying problem that is not corrected by current treatment. In preparing this proposal, we discussed our findings with patients and parents of those with JDM who felt this is an exciting and important new avenue.

For this project we have access to large numbers of JDM patient samples.

We will analyse:

- Problems with mitochondria and energy metabolism in blood cells and muscle samples from JDM patients;

- Whether markers of mitochondrial problems found in patients’ blood can predict how they respond to treatment;

- Whether mitochondrial energy problems cause inflammation, and whether antioxidant drugs which treat problems with mitochondria can reduce inflammation.

This study is important because mitochondrial dysfunction is a completely novel area to investigate in JDM, and

could bridge the gaps in our understanding of what causes the disease. Knowledge from this project could open the

door to developing new treatments like antioxidant drugs, to use in combination with immune-targeting drugs.

Developing a gene editing therapy for XIAP deficiency

XIAP deficiency is a rare and devastating genetic condition affecting boys, usually in early childhood. Symptoms vary, but most boys develop a life threatening, overactive immune response to infection and many have inflammation of the gut leading to severe colitis. Currently we can offer treatment to control symptoms and damp down the immune system before undertaking a bone marrow transplant to try to cure the disease. However, survival for XIAP patients receiving a transplant is worse than we see in other conditions, with less than half surviving in the long term. We believe that gene therapy, where we insert a normal copy of the defective gene into the patients’ blood stem cells, may offer patients with XIAP deficiency a safer and better treatment. We have developed gene therapy for several immune system diseases and know that it can be a feasible and safe treatment.

We have already done research showing that inserting a normal copy of the defective XIAP gene into blood stem cells improves the condition. Using this type of conventional gene therapy, the gene is inserted into the patient’s genome at random. This could lead to abnormal immune cell function if the gene is not activated as it would be in a healthy person. We believe by using newer targeted gene editing techniques (such as CRISPR/Cas) we can correct the gene defect at its natural location in the genome so it will function as it does in a healthy person. We now want to apply this approach to blood stem cells to see if we can develop an alternative curative treatment option for patients with XIAP deficiency.

We will also try to understand in more detail the immune cell defects in this disease which may lead to other treatments, utilising drugs already used in patients with other conditions.

Genetic discovery in ILVEN leads to patient treatment

ILVEN (inflammatory linear verrucous epidermal naevi) is a rare disease. It causes red scaly lines on the skin, which appear in the first year of life and start to spread, eventually covering the whole body in the worst cases. It is impossible to stop the lines appearing once they start, which is very distressing for parents. Unfortunately, this is not just a major cosmetic issue, the red skin is extremely itchy, leading to sleepless nights for everyone. School attendance can be a problem with decreased sleep, and severe itchiness leads to poor attention in the classroom. When the red lines are all over the body the children do not grow properly, as their bodies are too busy fighting the inflammation. Worse still, this condition is entirely untreatable. It is actually defined by its unresponsiveness to treatments.

We started to study this condition a few years ago, to find out what causes it with a view to finding new treatments. We are just publishing the first two cases we have solved (in press, Journal of the American Medical Association, Dermatology). In these cases we found a faulty gene in the red scaly lines, and because of knowing the gene, we identified a potential treatment already on the market for a different condition. Having treated the first case with the approval of GOSH drug and therapeutics committee, it was amazingly successful, causing rapid improvement in itch, decrease in redness and scale, and catch-up growth. It has been life-changing for the family. We now want to do the same thing for the other cases, who do not have the same faulty gene when we checked, but must have something similar. We have proved the research concept, and with the right funding we can make this a reality for more patients and their families.

Establishing a birth cohort for population-based follow-up of children with rare diseases

What are we doing?

We are setting up a new cohort study to research rare diseases in children.

Why are we doing this?

A rising number of children are living with rare diseases, conditions that affect fewer than 1 in 2000 people. Because each of these diseases only affect a relatively small number of children, it has proved challenging to carry out research about how these conditions affect health and development as children grow up.

How are we going to do it?

We will link information that is routinely collected through the Newborn Screening Programme in North London and surrounding counties, with clinical and genomic information. We will link the information securely, and protect the identities of mothers and babies. We will discuss our plans with parents and patient support groups to understand how we can improve the study so that it best meets the needs of children with rare diseases. We will focus on a disease called ‘congenital hypothyroidism with gland in situ’, which means that children with the condition don’t grow or develop typically. Using the linked information, we will look at what causes this condition, and genetic and other factors to work out what type of treatment a child requires, and for how long.

What will the results lead to?

In the future, we plan to also combine the information we are going to link in this study with information from hospitals and schools. We want to be able to describe long-term health and education of children with congenital hypothyroidism or other rare diseases, and compare those to children without these conditions.

How will we make parents aware of the research?

We will work with a number of charities, including the British Thyroid Foundation and the Genetic Alliance, to speak to parents about the research.

Congenital Hypothyroidism: Prevalence and Risk Factors

Who are we?

We are researchers at University College London (UCL) Great Ormond Street Institute of Child Health.

What is congenital hypothyroidism?

Hypothyroidism is the name given to the condition resulting from an underactive thyroid gland; this means that the thyroid is not producing enough thyroid hormone for the body’s healthy growth and development. Children who are born with congenital hypothyroidism are born without a thyroid gland, a thyroid gland that has not developed properly, or is in the wrong position, or a thyroid gland that is not producing enough thyroid hormones. Without early detection and treatment, congenital hypothyroidism can result in severe learning disability.

Why are we doing this project?

All children in the UK are offered screening for several rare conditions at five days of age. One of these conditions is congenital hypothyroidism. Since the start of newborn screening for congenital hypothyroidism 40 years ago, there has been an increase in the proportion of babies born with this condition, particularly a type called congenital hypothyroidism with gland in situ (CH-GIS). We do not know why CH-GIS is becoming more common, or how it affects health, development and learning as children grow up. We want to know why more babies are being diagnosed with CH-GIS, and what health and development is like for children living with this condition.

The data used in this project

This study will include data from babies born in the North Thames region (including North London, Bedfordshire, Hertfordshire and Essex) and whose newborn screening blood spot samples were tested at the Great Ormond Street Hospital (GOSH) newborn screening laboratory between January 2000 and December 2020.

The following data sources will be used to create the study dataset:

>North Thames Newborn Screening Database. This database contains demographic data and screening test results.

>GOSH Congenital Hypothyroidism Database. This dataset contains information on 1800 children who have screened positive for congenital hypothyroidism through the North Thames newborn screening programme since 2006. The database also contains genetic data for ~50 children with congenital hypothyroidism.

>Hospital Episode Statistics (HES). HES contains data on all admissions to NHS hospitals, Accident and Emergency (A&E) attendances and outpatient bookings.

>Births and Death registration data from the Office of National Statistics (ONS).

>Department for Education (DfE) National Pupil Database (NPD). This database holds data on demographics, phonics and key stage results, and special educational needs provision for all children in state primary and secondary schools; 93% of all school children in England.

>NHS Business Service Authority (NHSBSA) community dispensing data, which contains data on medicines dispensed in community (non-hospital) pharmacies.

The study dataset will be de-personalised, meaning researchers analysing the dataset will not be able to see identifying information such as NHS numbers, names, or addresses.

Where do I find more information about the study?

You can find more information about this research study on our website (https://www.ucl.ac.uk/child-health/research/population-policy-and-practice/child-health-informatics-group) where you will also find a Privacy Notice (https://www.ucl.ac.uk/child-health/research/population-policy-and-practice-research-and-teaching-department/cenb-clinical-4) with more information on how we comply with general data protection regulations (GDPR).

How do I contact the Research team?

If you would like to know more about the project and how we use your data, please contact the principal investigator, Dr Pia Hardelid via email, or by phone or post, via the UCL Great Ormond Street Institute of Child Health:

UCL Great Ormond Street Institute of Child Health

30 Guilford Street

London

WC1N 1EH

Telephone: 020 7242 9789/020 7905 2000

Email: p.hardelid@ucl.ac.uk

What if I do not want my data (or child’s data) to be used in this study?

You are entitled to object to your data, or your child’s data (if you are their legal guardian), being used for this study. The UCL research team will not be able to identify you and cannot remove your records from the study directly at your request. However, if you do not wish your, or your child’s, data to be used for this study, please contact us, using the contact details above.

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