Translational Research
Rare Neurodevelopmental Disorders
HNRNPU-related neurodevelopmental disorder (HNRNPU-NDD)
Complementary to our clinical research on HNRNPU-NDD, we are working to understand the underlying disease mechanism. We are identifying and characterising 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. We are examining the consequences of altered gene expression on neuronal function using patch clamp electrophysiology. We are engineering therapeutic interventions for HNRNPU-NDD and aim to develop the first in-human gene therapy for this condition. Knowledge gained from this can act as a model for similar loss-of-function rare neurodevelopmental disorders and establish Sheffield as a pioneer for this therapeutic approach.
Characterisation of HNRNPU missense variants
Loss of function variant are the most likely observed molecular diagnosis in HNRNPU-related disorder. We are systematically exploring the contribution of missense variants to the phenotype in HNRNPU-related disorder through cutting-edge molecular approaches in the laboratory.
Rare Bone Disorders
Osteogenesis Imperfecta
Through deep phenotyping of rare bone disorders like Osteogenesis Imperfecta, we are establishing adjuvant findings to aid in the diagnosis of rare bone disorders. Here is an example of electron microscopy image from patients with OI with collagen flowers caused due to an amalgamation of abnormal collagen fibrils seen in type 1 collagen defects commonly associated with OI.
Developing advanced gene therapies in rare diseases
We are at the forefront of improving understanding of the molecular defects that underpin OI which is predominantly caused due to a defect in the production, processing or secretion of type 1 collagen and other rare done disorders making use of patient-derived cells. Leading on from this, we want to establish ways to correct the molecular defect in OI and work towards personalised gene therapies for OI and other rare genetic disorders.
Similarly, our work on rare neurodevelopmental disorders such as HNRNPU are focused on developing gene-directed therapies to reverse the phenotype and make the lives of children and families living with this devastating condition better.
