SUPERCHARGING DISCOVERIES

GOSH Charity’s and Sparks’ National Call continues in its bid to support researchers across the UK as they investigate causes of rare diseases in children. Two researchers awarded grants tell Pioneer what they hope to achieve.

As part of its ambition to help unlock breakthroughs in child medicine, Great Ormond Street Hospital Children’s Charity (GOSH Charity) has awarded a £2.5 million investment into 11 pioneering child health research projects to researchers based as six institutions across the country. Funding from the GOSH Charity and Sparks National Call (the children’s medical research charity Sparks merged with GOSH Charity at the end of March 2021) is the UK’s largest charitable grant-making scheme of its kind dedicated to paediatric rare disease research.

Professor Siddharth Banka, University of Manchester Grant awarded to identify treatments for KMT2 chromatin disorders.

Q: What are chromatin disorders?

A: Chromatin disorders are a group of rare genetic conditions affecting brain development, which can result in neurodevelopmental disorders (NDD) such as intellectual disability and problems with other body systems.

There’s no set definition of what chromatin disorders are, but we think there are around 200 known chromatin disorders and maybe one in 2,000 children will have one. We have little knowledge of how and why chromatin disorders cause NDD but recent findings suggest certain disorders may be treatable.

Q: What’s your plan for the grant?

A: Over the last few years we’ve been trying to work out the underlying mechanisms causing intellectual and neurological problems in a particular chromatin disorder called Kabuki syndrome type 1. So far there is no treatment for this condition.

The current grant proposal from GOSH Charity is an extension of our previous work in Kabuki syndrome type 1, which is caused by changes in a gene called KMT2D. We’ll study another chromatin disorder, Kleefstra syndrome type 2, caused by changes in the KMT2C gene. We suspect because these two genes are quite closely related, the similar approaches might help understand both the disorders.

We’ll conduct experiments to see how these genetic changes affect the development and function of brain cells. The final part of the research would be to identify potential therapies.

Q: What impact do you hope your research will make?

A: We hope our research to improve the understanding of these disorders leads to the identification of new treatments for them and increase the awareness of these diseases among clinicians, scientists and the general public. The lessons we learn for these conditions may have wider applications in several other disorders..

Q: Why is charity funding so important to your work?

A: Research funding for rare disorders affecting children is challenging to obtain. Funding from GOSH Charity, therefore, is crucial.

I’m enormously grateful to the charity’s supporters. It’s their donations that will lead to real changes in people’s lives.

Dr Paula Alexandre, ICH Grant awarded to investigate the underlying causes of cerebellar developmental disorders.

Q: Why did you apply for the National Call?

A: I dedicated the last two decades to studying brain development and understanding the mechanisms that regulate neurogenesis, a process that generates new nerve cells (neurons) in the brain. My group and wide network of collaborators want to understand the underlying causes of cerebellar malformations. The cerebellum is a region at the back of the brain that plays a major role in movement, cognition, language and emotional processing. Problems in this region are generally associated with cognitive and speech impairment, epilepsy and movement disorders.

Q: Why is more research required into the underlying causes of human developmental brain disorders?

A: To understand the causes, one needs to understand human brain development, but most of the current knowledge in cerebellum development and malformations is based in animal studies. We’ve already shown that some critical developmental mechanisms aren’t shared between humans and animals. The developing human cerebellum contains specific zones that are expanded compared to other mammalian species. We want to know whether these zones are disrupted in diseases characterised by smaller cerebellums.

Q: What will the grant allow you to do?

A: Financing will allow us to establish the first human cellular model at ICH to study cerebellum development, investigate the cellular and molecular causes of the cerebellar hypoplasia, a developmental malformation characterised by a reduced cerebellum volume, and test potential therapies. Initially, we’re planning to focus on Down’s syndrome and Non-Ketotic Hyperglycinemia (NKH), two conditions that can present cerebellum hypoplasia.

Q: Why is this grant essential to your work?

A: New funds are crucial to develop a new line of research in the lab, supported by an interdisciplinary group of local and international researchers, world leaders in their fields.

This project involves cerebellum development experts in the US, Professor Kathleen Millen and Dr Parthiv Haldipur, and ICH researchers Professor Nick Green, an authority in NKH, and Professor Patrizia Ferretti and Professor Rick Livesey, specialists in neuro stem cells. GOSH Charity is one of the few organisations sponsoring child health research. Supporting child health research is an investment into a better future for many children and their families.

FIND OUT WHERE THE GRANTS HAVE BEEN AWARDED

1 University of Warwick

• Developing a clinical checklist to ensure causes of poor behavioural outcomes in children with intellectual disability are routinely considered. 2 UCL Great Ormond Street Institute of

Child Health

• See this page. • Generating human models of acrodysostosis – a group of rare genetic disorders causing abnormal skeletal growth and can also affect neural development – for testing mechanisms and pharmacological intervention. • Leveraging transcriptomics to improve the diagnostic rate and understanding of neurometabolic disorders.

3 University College London

• Targeting amino acid metabolism as a novel treatment avenue for DiamondBlackfan anaemia, an inherited condition caused by errors in genes coding for ribosomal proteins. • Dissecting the role of mechanical lung compression in congenital diaphragmatic hernia on a single cell level. 4 University of Southampton

• Developing and validating a paediatric pain assessment tool for children with cancer and life-limiting conditions. 5 University of Cambridge

• Identification of pathways that protect against beta-propeller protein-associated neurodegeneration. 6 University of Manchester

• See page 10. 7 University of Oxford

• The treatment of Dravet syndrome. • Reversing zeta-globin transcriptional silencing: towards embryonic globin induction in patients with severe alphathalassemia.

Two grants were part-funded by condition-specific partner charities (Acrodysostosis Support & Research and Dravet Syndrome UK) to help co-fund research into these diseases.