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Developing gene therapy for treatment of epilepsy using HNRNPU-related neurodevelopmental disorder as an exemplar

   Department of Oncology and Metabolism

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  Dr M Balasubramanian, Dr E Seward, Prof S A Wilson, Prof Laura Ferraiuolo  No more applications being accepted  Funded PhD Project (UK Students Only)

About the Project

HNRNPU syndrome is a neurodevelopmental disorder where patients suffer from epilepsy along with developmental delay and intellectual disability. We have shown that patients have reduced levels of the HNRNPU protein which leads to alterations in pre-mRNA splicing. In this project we aim to (1) identify and characterize the alterations in gene expression that arise in neurons derived from HNRNPU patient-derived induced pluripotent stem cells (iPSCs) using single cell RNA seq and proteomics, (2) examine the consequences of altered gene expression on neuronal function using patch clamp electrophysiology, and (3) develop a gene therapy approach to provide a treatment for this syndrome. We will use Adeno associated virus (AAV) to deliver HNRNPU protein to restore normal HNRNPU levels in patient cells and confirm that normal neuronal functions are restored. The project will provide multidisciplinary training in modern molecular, cell and physiological technologies including the generation and use of patient derived stem cells and gene therapy strategies involving AAV. The project offers the opportunity to pioneer the development of the first ever treatment for HNRNPU syndrome. The project supervisory team listed above have a broad range of expertise across the disciplines.

Writing up period/publishing. (Year 3-3.5).

Student training:

The student will acquire expertise in iPSC maintenance and differentiation, gene therapy approaches, molecular biology and electrophysiology. They will engage in laboratory meetings across the 4 P.I.s laboratories on a weekly basis. They will be working in well-funded laboratories with a broad range of expertise on hand in the form of PhD students and post-docs to provide direct training in relevant techniques. They will be encouraged to attend relevant training courses for example in bioinformatics analysis of RNAseq data and given multiple opportunities to present their work at both local national and international meetings when appropriate. 

Entry Requirements:

Candidates must have a first or upper second class honors degree or significant research experience. In addition, candidates must be self-motivated, have the ability to think independently, use own initiative, have good communications skills and be well-organized 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.


Interested candidates should in the first instance contact (Dr Balasubramanian, [Email Address Removed])

How to apply:

Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply

Please clearly state the prospective main supervisor in the respective box and select Oncology & Metabolism as the department.

Interview Date: Early Feb 2023

Proposed start date: 1/03/23

Funding Notes

University of Sheffield funded project, only home students to apply; Overseas candidates are welcome to apply, however they will need to fund the fee difference from elsewhere.


[1] Yates TM, et al., Balasubramanian M. (2017) De novo mutations in HNRNPU result in a neurodevelopmental syndrome. Am J Med Genet A. v173: 3003-3012.
[2] Durkin A, Albaba S, Fry AE, Morton JE, Douglas A, Beleza A,Williams D, Volker-Touw CML, Lynch8 SA,Canham N,Clowes V, StraubV, Lachlan K, Gibbon F, Gamal ME, Varghese V, Parker MJ, Newbury-Ecob R, TurnpennyPE, Gardham A, Ghali N, Balasubramanian M. Clinical findings of 21 previously unreported probands with HNRNPU-related syndrome and comprehensive literature. Am Journal of Med Genet A, 2020;182(7):1637-1654.
[3] Dugger SA, et al., Goldstein, D.B. (2020) Neurodevelopmental deficits and cell-type-specific transcriptomic perturbations in a mouse model of HNRNPU haploinsufficiency. BioRXiV doi: https://doi.org/10.1101/2020.05.01.072512
[4] Xu XX and Luo, JH (2018) Mutations of N-Methyl-D-Aspartate Receptor Subunits in Epilepsy. Neurosci. Bull. 34:549-565.
[5] Paoletti, P et al, Zhou, Q. (2013) NMDA receptor subunit diversity:impact on receptor properties, synaptic plasticity and disease. Nat Rev. Neuro 14:383-400
[6] Hansen, K.B., et al, Traynelis, S.F. (2018). Structure, function, and allosteric modulation of NMDA receptors. J Gen Physiol 150: 1081-1105.
[7] Yoon, SY et al, Wolfe, JH (2020) Global CNS correction in a large brain model of human alpha-mannosidosis by intravascular gene therapy. Brain 143:2058-2072 [8]. Mendell, J.R. et al, Kaspar, B.K. (2017) Single-dose Gene-replacement therapy for spinal muscular atrophy. N Engl J Med 377:1713-1722.
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