UCL Great Ormond Street Institute of Child Health


Great Ormond Street Institute of Child Health


Identifying and assessing RNA targets for paediatric neurogenetic disorders

Supervisors: Dr Mina Ryten, Dr Haiyan Zhou

Despite amazing progress in the understanding of paediatric neurogenetic disorders, the vast majority of these conditions have no effective disease-modifying treatments. However, this could change with the growing recognition of the therapeutic importance of antisense oligonucleotide (ASO) therapies particularly in the context of rare diseases1. ASOs, which target RNA species rather than proteins, have already been used to successfully treat both Huntington’s disease2 and spinal muscular atrophy3. This progress in therapeutics is occurring at the same time as basic neuroscience is uncovering the complexity of neurons and their transcriptomes4,5. Human neurons can have axonal arbors, which give rise to ~100,000‐240,000 synapses/neuron and which depend on the decentralisation of core elements of the cellular machinery to link extrinsic signals and spatially‐specific protein production5. This adaptable link is often RNA-dependent and requires precise RNA localization, regulation, and translation, to ensure synaptic maintenance and plasticity. While our understanding of these transcriptomic networks is incomplete, in this project we will leverage information on the expression and function of natural antisense transcripts and other types of long non-coding RNAs (lncRNAs) to identify novel therapeutic targets for the treatment of paediatric neurogenetic disorders.

1. Systematic identification of natural antisense and other lncRNAs which regulate the expression of known disease genes.
2. Assessment of their relevance to human disease through rare variant burden analysis using WGS data generated by the 100,000 Genomes Project.
3. Use of cell model systems to assess the functional significance of natural antisense and other lncRNAs.


  • Systematic identification of disease-relevant natural antisense and regulatory long non-coding transcripts: The student will combine a range of existing resources provided by OMIM, Ensembl, PsychENCODE and the Allen Institute to i) identify pairs of disease genes and potential regulatory lncRNAs; ii) study the correlation in expression of these genes across the human brain and during development, and iii) assess each locus of interest for regulatory marks.
  • Rare variant burden analyses in novel transcripts amongst children recruited to the 100,000 Genomes project with neurological conditions: The student will use SKAT-O analyses to calculate the burden of rare potentially pathogenic variants in the lncRNAs of interest amongst paediatric patients with neurological disease in order to identify specific gene pairs of interest.
  • Use of iPSC-derived models of brain development to investigate the functional significance of specific lncRNAs: The student will use established iPSC models of neuronal development and maturation to study the functional significance of specific lncRNAs. Combining functional assays with a range of approaches to knockdown/over-express lncRNAs, as well as replicate their function using synthetic ASOs, the student will identify therapeutic targets of interest.


Ryten timeline

1. Drew L. Why rare genetic diseases are a logical focus for RNA therapies. Nature. 2019.
2. Tabrizi SJ, et al. Targeting Huntingtin Expression in Patients with Huntington's Disease [published correction appears in N Engl J Med. 2019.
3. Finkel RS, et al. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med. 2017.
4. Zhang D et al. Incomplete annotation of OMIM genes is likely to be limiting the diagnostic yield of genetic testing, particularly for neurogenetic disorders. Science Adv. 2020.
5. Holt CE et al. Local translation in neurons: visualization and function. Nat Struct Mol Biol. 2019.