UCL Great Ormond Street Institute of Child Health


Great Ormond Street Institute of Child Health


Using ‘omics to understand disease progression and monitor the efficacy of gene therapy for inherite

Supervisors: Professor Sara Mole, Dr Wendy Heywood

Using ‘omics to understand disease progression and monitor the efficacy of gene therapy for inherited paediatric neurodegenerative diseases

There are life-limiting inherited neurodegenerative disorders of children that are autosomal recessive lysosomal storage diseases (LSDs, combined incidence ~1:50 000). There is no treatment for most children such as those affected by the neuronal ceroid lipofuscinoses (NCL, Batten disease) and there is a desperate need to develop and follow the effectiveness of novel gene and other therapies. Treatment is needed for the CNS, the eye and some peripheral organs. There is a need to monitor early disease and the effect of treatment before first symptoms present.


(1) To ‘omically profile two NCL mouse disease models (such as CLN5, CLN2), currently held at UCL, that are models for disease that begins in late infancy. (2) To use ‘omics to monitor the efficacy of ongoing drug and gene therapy targeting the brain and periphery for these mouse models. 
CLN5 and CLN2 proteins are located in the lysosome matrix. Drug repurposing and gene therapy is underway for both at UCL – that for CLN5 disease is at an early stage of development; CLN2 is a severe mouse disease model.


1. Comprehensively profile fluids and tissues from mouse disease models (held at UCL School of Pharmacy) from birth through early disease, to identify proteins whose expression changes, and detect lipids typically altered in LSDs. Fluids would be blood, urine (if it can be collected easily) and CSF occasionally. Use multi-omic technologies (proteomics, metabolomics and lipidomics) and specialised bioinformatics with machine learning to integrate findings for disease prediction and candidate biomarkers to monitor disease status at tissue level and for clinical development. Drawing on the expertise of the lab, develop high throughput targeted multiplex assay(s) to measure candidate biomarker proteins and lipids; Use assay(s) to monitor both toxicology and efficacy of gene or other therapies.

2. For each mouse model perform in depth studies to understand and assess the effect of disease on the CNS and peripheral organs, and to do the same for mice being treated by gene therapy from birth and later in the disease. To define the treatment window by integrating these results and show efficacy of treatment (e.g. delay in the appearance of brain pathology). Vector backbone being used for CNS gene therapy is AAV9, which has a wide distribution in the brain and spinal cord, targeting both neurons and astrocytes. Vectors currently in use in NCL mouse models have already shown to be efficacious can be further optimised or adapted using different promoters to drive cell-specific expression as required. Two drugs are currently being compared for repurposing.

Timeline (if applicable):

‘omic discovery up to12 mo, targeted assay development 6-18 mo, organ pathology, efficacy 13 mo onwards.


1.    Iwan K, Patel N, Heslegrave A, Borisova M, Lee L, Bower R, Mole SE, Mills PB, Zetterberg H, Mills K, Gissen P, Heywood WE (2021) Cerebrospinal fluid neurofilament light levels in CLN2 disease patients treated with enzyme replacement therapy normalise after two years on treatment. F1000Research 10(614). doi: 10.12688/f1000research.54556.1
2.    K Iwan, R Clayton, P Mills, B Csanyi, P Gissen, S E Mole, D N Palmer, K Mills, W E Heywood. (2021). Urine proteomics analysis of patients with Neuronal Ceroid Lipofuscinoses. Iscience 24(2) 102020 doi: 10.1016/j.isci.2020.102020
3.    SM kleine Holthaus, S Herranz-Martin, G Massaro, M Aristorena, J Hoke, MP Hughes, R Maswood, O Semenyuk, M Basche, AZ Shah, IP Klaska, AJ Smith, SE Mole, AA Rahim, RR Ali (2019). Neonatal brain-directed gene therapy rescues a mouse model of neurodegenerative CLN6 Batten disease. Hum Mol Genet. 28(23) 3867-3879. doi: 10.1093/hmg/ddz210
4.    Hughes MP, Smith DA, Morris L, Fletcher C, Colaco A, Huebecker M, Tordo J, Palomar N, Massaro G, Henckaerts E, Waddington SN, Platt FM, Rahim AA. AAV9 intracerebroventricular gene therapy improves lifespan, locomotor function and pathology in a mouse model of Niemann-Pick type C1 disease. Hum Mol Genet. 2018; 27(17):3079-3098
5.    Heywood WE, Galimberti D, Bliss E, Sirka E, Paterson RW, Magdalinou NK, Carecchio M, Reid E, Heslegrave A, Fenoglio C, Scarpini E, Schott JM, Fox NC, Hardy J, Bahtia K, Heales S, Sebire NJ, Zetterburg H, Mills K. Identification of novel CSF biomarkers for neurodegeneration and their validation by a high-throughput multiplexed targeted proteomic assay. Mol Neurodegener. 2015;10(1):64