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A framework for identifying treatable targets in rare genetic diseases

Written by Charlotte Harrison, Science Writer

The rarity of many genetic conditions means that the traditional model of drug discovery and development for such disorders is not economically practical. A new study published in Nature describes a system that classifies genetic mutations into those that are, and are not, likely treatable by therapy that uses splice-switching antisense oligonucleotides (ASOs).

Splice-switching ASOs can restore functional protein levels; for example, in rare neurogenerative disorders. But for splice-switching ASOs to realise their full potential, those people most likely to benefit need to be identified. With this aim in mind, the researchers analysed whole-genome sequencing data of 235 individuals with ataxia-telangiectasia. This rare genetic disorder affects motor control and speech and is caused by defects in the ATM gene.

Variation classification

The researchers analysed data for various kinds of genetic variation, which produced complete genetic diagnoses for 99% of the individuals. A computational taxonomy was then designed to categorize variants as ‘probably’, ‘possibly’ or ‘unlikely’ amenable to correction by ASO-mediated splice-switching.

This system classified 9% of people with ataxia–telangiectasia as having genetic variants that were probably amenable, 6% as having possibly amenable variants, and the majority — 85% —as having variants that were unlikely amenable.

These predictions were then validated experimentally in cell lines derived from the individuals and/or in assays with fragments of the affected gene. Two ATM variants were then selected for further study, with an eye on possible therapeutic potential. The researchers showed that the ASOs corrected mis-splicing in patient-derived fibroblasts. Further studies tested off-target effects, the dose–response relationship and if ATM function was restored.

Clinical trial

The researchers then progressed one ASO to clinical-grade manufacturing and toxicology studies; following positive results this ASO was termed atipeksen. A clinical trial of atipeksen was started for a person diagnosed with ataxia–telangiectasia soon after birth to determine if the ASO prevents or slows disease progression.

The results of this trial are not known yet, as the neurological decline in ataxia–telangiectasia occurs in children aged 5–10 years. Nevertheless, the authors note that atipeksen has not caused any serious adverse events over the past 3 years.

Proof of concept

Overall, this study provides the proof of concept that it is possible to estimate the proportion of people with recessive genetic diseases that could be treated through splice modulation.

“Our study provides a framework for how individualized genetic therapy might work, using genome sequencing and analysis to efficiently identify variants that might be amenable to splice-switching intervention, in time to design, test and deploy an appropriate ASO,” said the authors. “If successful, these approaches could someday encourage a re-evaluation of which genetic findings are considered ‘actionable’,” they concluded.