A new method has been established for classifying genetic mutations from whole genome sequencing (WGS) data amenable to therapy with splice-switching antisense oligonucleotides (ASOs). Researchers from the Korea Advanced Institute of Science and Technology (KAIST) and Boston Children’s Hospital used this framework to identify a molecular diagnosis targetable by custom ASOs for 235 people with ataxia-telangiectasia (A-T), a fatal and debilitating genetic disorder passed down from parent to child. In a pilot clinical study, one of these ASOs was used to treat a child diagnosed with A-T shortly after birth, and it demonstrated good tolerability with no serious adverse events for three years.

This study sets up a way to find people with genetic diseases who might benefit from a therapy that uses splice-switching ASOs in the future. It also shows how ASOs can be used to reduce the effects of splice-switching genetic variants in a general way and on a large scale. Conducted in collaboration with the patient advocacy foundation A-T Children’s Project (ATCP), the study, titled “A framework for individualized splice-switching oligonucleotide therapy,” was published in Nature.

Ninety-five percent of rare diseases have no treatments, and many of them are due to splice-altering variants that prevent protein expression. In this context, custom ASOs represent a class of therapeutic agents that can be used to create variant-targeted therapies, even those applicable to a single patient. However, it is unclear how many targetable variants exist or how to locate them.

The Global A-T Family Data Platform is an international initiative led by family advocates and primarily funded by ATCP that has systematically collected clinical information and genomic DNA from people who have been clinically or genetically diagnosed with A-T. This work resulted in a WGS dataset containing information from 235 people with A-T through the use of WGS.

Within the A-T cohort of 235 people, 35 were found to have ASO-amenable variants, and a small-scale ASO screening for several possibly amenable variants was successful. The authors pointed out that while treating all 35 patients would require 15 different medications, it may be possible to treat around 70% of them with as few as five splice-switching ASOs. Each of the tested variants had its mis-splicing corrected by ASOs, demonstrating the usefulness of the predictive framework. For two common variants of ATM, splice-switching ASOs were developed and shown to be effective at reversing functional deficits in patient cell lines. For the past 36 months, one of these has been tested in a pilot first-in-human investigative trial and has shown promising safety.

Applying the framework to a meta-analysis of the published literature yielded the finding that people with inherited retinal disease due to recessive ABCA4 deficiency (Stargardt disease or cone rod dystrophy) are likely to have ASO-amenable variants in similar proportions, indicating that 15% is a reasonable first estimate for other recessive genetic conditions. However, spinal muscular atrophy (SMA) stands out due to its peculiar genetic architecture. All patients with SMA have a pathogenic splice “variant” in SMN2, a gene that can substitute for SMN1, which means that ASO- or small-molecule-mediated splice modulation can be used to treat the disease even though it is caused by recessive variants in SMN1.

By proving the viability of rapid WGS and analysis to identify variants that may be amenable to splice-switching intervention, this study lays the groundwork for personalized genetic therapy and allows for the timely design, testing, and deployment of an appropriate ASO. However, it should be stressed that this method is still in the early stages of research and comes with some degree of uncertainty and risk that must be carefully weighed in a clinical setting. There are still important practical, legal, financial, and moral questions to be answered. In order to gather the body of evidence required to support the viability of this approach, it will be crucial to continue studying patient-customized ASO therapies in severe genetic illnesses using this framework.

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