Autosomal dominant optic atrophy (DOA) and Leber hereditary optic neuropathy (LHON) are the commonest forms of inherited optic neuropathies. They cause irreversible blindness in children and young adults, which results in high socioeconomic burden and psychological distress. Intriguingly, some LHON carriers and patients with DOA experience rapidly progressive visual loss, whereas others do not. We do not fully understand the factors underlying this phenotypic variability.
We aim to discover new therapeutic targets for DOA and LHON by exploring the factors underlying this phenotypic variability. We will perform whole genome and RNA sequencing on blood samples obtained from patients with a confirmed molecular diagnosis of LHON and DOA. Unaffected individuals will be recruited, as well as those with mild, moderate and severe visual loss. Genome sequencing will reveal associations between genetic variants and disease severity, whilst RNA sequencing will show sets of genes that are differentially expressed between patient subgroups. These results will inform experiments using existing in vitro disease models to understand the biological pathways affected.
This will be of major relevance to clinicians in terms of prognostication and stratification for future clinical trials. Furthermore, it will inform future efforts to design new gene therapies to treat these devastating blinding conditions.
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