Fundraising 

The Challenge

 

HNRNPU- related disorder is a rare genetic condition which affects approximately 300 patients worldwide. Although individually uncommon, collectively, rare diseases affect a huge number of people - roughly 350-400 million people worldwide, or between 5-10 per cent of the world’s population. Most rare diseases affect children, and many are fatal or severely disabling.

 

One of the biggest challenges is that there are currently no standardized treatments for most of these complex conditions. Funding is also a major challenge; because rare diseases affect a small number of people relative to cancer or cardiovascular disease for example, they areoften considered lower priorities when it comes to allocating research funding. A new approach is urgently needed to help the patients and families who are in search of better treatments. However, there is great hope. Medicine is evolving and innovations in gene therapies show outstanding potential for treating rare genetic conditions such as HNRNPU-related disease.
 

Gene therapy is the introduction of a new gene to a patient’s cell to replace, silence or manipulate the faulty one. The goal of gene therapy is to restore normal function in affected tissues or cells, potentially enabling a patient to live without the need for ongoing treatments. This would be life- changing for the individuals and families affected by rare genetic conditions.

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Gene Therapy – the future for treating HNRNPU-related disorder

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The underlying problem in HNRNPU-related disorders is that patients produce insufficient HNRNPU protein. Traditional gene therapies use a viral vector to insert new genes into cells to try to treat diseases. We will use a custom-made adeno-associated virus (AAV) vector to deliver the HNRNPU gene into patients' cells with the aim of restoring HNRNPU protein levels in patients.

 

Specifically, Sheffield University's ongoing project currently supported by the LifeArc Pathfinder Award, we are using cellular models of HNRNPU syndrome in the laboratory to test whether the AAV is effective in restoring normal HNRNPU levels and cellular functions. This is an essential first step in the pathway towards developing a gene therapy treatment for HNRNPU-related disease.
 

Why Sheffield?

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The UK has a world-class genetics research base and the University of Sheffield is a leading player. We are the first site in the UK delivering both stem cell transplantation for multiple sclerosis and genetic therapies for Amyotrophic Lateral Sclerosis (ALS) clinical trials. We are renowned for our translational neuroscience research through the Sheffield Institute for Translational Neuroscience (SITraN) and the Neuroscience Research Institute. Sheffield is home to the only National Institute for Health Research (NIHR) funded Biomedical Research Centre in the UK – a collaboration between the University and the Sheffield Teaching Hospitals NHS Foundation Trust, which is one of the UK’s largest and most successful hospitals within the UK National Health Service (NHS).

 

In this study we will build on our considerable local expertise by unifying all the international HNRNPU collaborations we have developed. Dr Balasubramanian in Sheffield is considered the world-leading clinician on HNRNPU-related disorder and has published the largest cohort of patients with HNRNPU syndrome. Dr Balasubramanian has an ongoing natural history study on HNRNPU-related disorder collating longitudinal data on national and international participants with this condition.

 

More recently, we have been working with the HNRNP Research Foundation in the USA to collate clinical data and tissue samples for further analysis and the generation of induced pluripotent stem cells (iPSCs) and relevant neuronal cells. Induced pluripotent stem cells are derived from patient’s own skin or blood cells and reprogrammed in the lab into a stem cell-like state. These iPSCs can then become any cell type in the human body which gives us a powerful tool for investigating and modeling diseases. We will be developing patient iPSC- derived neurons which is the closest model of human disease we can get.

 

The team at the University of Sheffield also includes Professor Stuart Wilson who has been working on HNRNPU for the last two decades and Dr Elizabeth Seward who has expertise in characterizing the electrical activity and communication (electrophysiology) of iPSC-derived neurons. Our work so far has resulted in detailed understanding of the molecular mechanisms of these proteins. Importantly, in addition to the molecular insights, we also have a method for measuring the effectiveness of the gene therapy approach with patient-derived neurons, using both protein expression tests and electrophysiology.

 

Our project will also benefit from the new Gene Therapy Innovation and Manufacturing Centre (GTIMC) which has just been completed in Sheffield. The GTIMC is part of a pioneering network of Gene Therapy Innovation Hubs in the UK dedicated to the clinical development of genetic medicines. The GTIMC will manufacture the viral vectors required for gene therapeutics and provide the critical expertise to swiftly move potential new treatments through early phase clinical trials to commercialization, helping the most innovative research to reach patients.