Developing targeted treatments for HNRNPU-related neurodevelopmental disorder using drug repurposing strategies

Project Title: Developing targeted treatments for HNRNPU-related neurodevelopmental disorder using drug repurposing strategies.

Rare diseases affect over 3.5 million people in the UK and recent medical advances have provided the means to generate potential treatments for several rare diseases that have been studied to-date but have no treatment. Importantly, a large proportion (80%) of these diseases are caused by specific alterations (mistakes) in the genetic building blocks or DNA of affected patients. New scientific methodologies, such as gene therapy, have been developed which could enable us to replace or repair DNA mistakes, but such treatments are extremely expensive. Gene therapies also take time to develop and may not be an option for all rare disease patients. Hence, there is a need for having a multi-pronged approach including drug repurposing to find novel therapies for rare neurodevelopmental disorders (RNDDs). The focus of this proposal is drug repurposing for HNRNPU.

Heterogeneous nuclear ribonucleoprotein U (HNRNPU) syndrome is one such RNDD which leads to developmental delay and seizures. We will harness significant local expertise including ongoing work on developing AAV-9 gene therapy for HNRNPU-related disorder in this proposal. The underlying problem is that patients produce insufficient HNRNPU protein. Our overall goal is to develop new treatments to make this condition better. Specifically in this project, we will test the approach of drug repurposing using patient cellular models of HNRNPU syndrome to identify candidate drugs, to check if we are able to restore normal cellular functions. This is an essential first step in the pathway towards developing new treatments for HNRNPU syndrome.

Current modalities of treatment include supportive care for the developmental delay and attaining seizure control through use of multiple medications. This may or may not achieve good seizure control and hence, there is a real and urgent need to do better. HNRNPs including HNRNPU are linked to various diseases and knowledge gained from this proposal will be more widely applicable to all RNDDs.

Entry Requirements:

Candidates must have a first or upper second class honours degree or significant research experience. A real motivation and passion to transform the care and treatment provided for patients with rare diseases is an essential criterion for this application. In addition, candidates must be self-motivated, have the ability to think independently, use own initiative, have good communications skills and be well-organised including good time management. An MSc or experience in bioinformation, molecular genetics, including data mining, cell culture and in vivo studies would be desirable but not essential.

How to apply:

Please complete a University Postgraduate Research Application form available here: https://www.sheffield.ac.uk/postgraduate/phd/apply/applying

Please clearly state the prospective main supervisor in the respective box and select School of Medicine & Population Health (Oncology & Metabolism) as the department.

Enquiries:

Interested candidates should in the first instance contact Dr Meena Balasubramanian (m.balasubramanian@sheffield.ac.uk).