UCL Great Ormond Street Institute of Child Health


Great Ormond Street Institute of Child Health


Oligonucleotide therapy for treatment of rare metabolic disorders

Supervisors: Dr Wendy Heywood, Dr Haiyan Zhou


The inherited metabolic disorders of glycosphingolipid (GSL) metabolism are a relatively rare group of diseases that have diverse and often neurodegenerative phenotypes. Typically, a deficiency in catabolic enzyme activity leads to lysosomal storage of GSL substrates. The most common glycosphingolipidoses are Fabry disease which accumulates globotriasylceramide (Gb3) and Gaucher disease which accumulates glucosylceramide (Gb1). GSLs typically consist of sphingosine, fatty acid and carbohydrate functional groups. When GSLs accumulate in disease a side reaction occurs where non-specific action of a deacylase enzyme removes the fatty acid group creating a lyso-lipid. These lyso-lipids are toxic and considered more disease causing than the accumulated GSL1,2. Inhibitors of AC exist and are used as chemotherapeutic agents but they have off target effects. This project would aim to create a gene silencing treatment for the deacylase. If this gene expression could be suppressed thereby reducing the generation of the toxic lyso-lipids then this would create a treatment that could be applied to all of the GSL disorders. Novel therapies using other strategies are hence needed.
RNA-targeted therapeutics, including Antisense oligonucleotide (AON) and small interfering RNA (siRNA) technologies offer great potential as a therapeutic strategy for conditions that cannot be treated by traditional drugs. These short synthetic single stranded nucleotides can regulate the target gene’s expression in a gene-specific manner. This technology has been approved to be successful in a number of neuromuscular and metabolic diseases, as exemplified by the FDA approvals of a number of antisense drugs in the last decade.3 This RNA technology also provides a new pathway for drug discovery and development for personalized medicine by correcting the specific genetic defect. The Zhou’s laboratory has been substantially involved in the preclinical development of RNA drugs in a number of neuromuscular disorders, neurological and metabolic diseases in areas of new target identification, novel approach development and the in vivo validations in murine models.4,5
The overarching aim of this project is to develop a novel RNA therapy for children with rare metabolic disorders. In this 3-year PhD program, we will focus on developing AON/siRNA approaches to target the GSL metabolism pathway and using Gaucher disease type II as the disease model.

1. Design and validation of various RNA therapeutic approaches in targeting the deacylase and GSL metabolism cascade. AONs and siRNAs will be designed to target the key genes involved in GSL metabolism.
2. Skin fibroblasts cultured from patients affected by GD or Fabry disease, available in our laboratories or commercially available from cell repositories, will be used as the cellular model for the in vitro validation.
3. Outcome measures on the effects of AONs or siRNAs on the target gene will be measured at mRNA and protein levels and functional activity suppression of the target gene will be monitored by GSL,ceramide, lyso-lipid and sphingosine measurement.
The student is expected to gain a broad experience in the following fields and techniques: understanding different mechanism of action of RNA therapies, the design principle of gene silencing approach and the usage of various bioinformatics in silicon assay; the in vitro validating system of RNA therapies; expression analyses at the RNA and protein levels (quantitative RT-PCR, immunochemistry, mRNA next generation sequencing) and mass spectrometry studies in metabolic disorders; preclinical RNA drug development for metabolic disorders.

1. Nowak A, et al. Mol Genet Metab. 2018 Feb;123(2):148-153.
2. Lelieveld LT. J Lipid Res. 2022 Mar 18;63(5):100199.
3. Sardone V et al. Molecules. 2017 Apr 5;22(4) pii: E563.
4. Zhou H et al. Nuc Acid Res. 2011;39:7194-208
5. Marrosu E et al. Mol Ther Nuc Acid. 2017;8:416-427