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Genome Sequencing Study Reveals Targets for Splice-Switching Antisense Oligonucleotide Therapy

NEW YORK — Researchers in the US and South Korea have created a system to identify rare disease patients with certain genetic variants who may be best suited for splice-switching antisense oligonucleotide (ASO) therapy, using ataxia telangiectasia (A-T) as a model.

Splice-switching ASOs are short, synthetic antisense nucleic acids that bind to pre-messenger RNA and interfere with the splicing process. While previous studies have shown the benefits of such therapy to restore functional protein levels in certain rare diseases, identifying patients who will likely respond has been challenging. 

In a paper published in Nature on Wednesday, the authors described a strategy to identify patients with A-T, a rare neurological disorder, who could be treated with splice-switching oligonucleotide therapy. The framework could be used for other rare genetic disorders as well, they noted.

"Our study unlocks a new category of patients who could benefit from ASO therapy," co-corresponding author Timothy Yu, a researcher in the division of genetics and genomics at Boston Children's Hospital, told GenomeWeb.

For their study, Yu, co-corresponding author Jinkuk Kim, a researcher at Korea's Advanced Institute of Science and Technology, and colleagues analyzed whole-genome sequencing (WGS) data from 235 individuals who were clinically or genetically diagnosed with A-T. The data was gathered from the Children’s Project Global A-T Family Data Platform, an international initiative led by family advocates that is mainly funded by the A-T Children’s Project.

A-T is an autosomal recessive disease with a prevalence of 1 in 40,000 to 1 in 100,000 live births worldwide. Patients with the condition undergo progressive cerebellar degeneration and immunodeficiency, and are prone to developing cancer. The disease is caused by a loss of function of the ATM gene.

While the WGS analysis revealed several A-T-causing genetic variants in the ATM gene, the researchers were particularly interested in the ones that could be targeted with ASOs. This led to the development of a taxonomy to classify the disease-causing variants based on their predicted amenability to splice-switching ASO therapy.

They found that 9 percent of patients had at least one variant that would probably respond to splice-switching ASOs, and an additional 6 percent who would possibly benefit from the therapy, totaling 15 percent of the cohort. Most of the ASO-amenable mutational events were in deep intronic regions that were more than 20 nucleotides away from an exon and would not have been found with an exon-focused sequencing approach.

They calculated that WGS provided a 3.5-fold to 7-fold higher "ASO therapeutic yield" than whole-exome sequencing would have. "I hope our findings serve as an impetus for wider and earlier adoption of WGS," said Yu.

Next, the authors shortlisted two recurrent genetic variants that could be targeted by ASOs and developed oligonucleotides that were capable of rescuing functional ATM deficits in patient cell lines. One of these is currently being tested in a pilot clinical trial, which has been underway for the past 36 months, the authors wrote.

The researchers said they believe that 70 percent of the 35 A-T patients with ASO-amenable variants in the study could be treated with as few as five splice-switching ASOs, whereas treating all 35 individuals would require 15 distinct drugs.

Meanwhile, through a meta-analysis on literature of other diseases, the authors found inherited retinal disease caused by recessive ABCA4 deficiency that is likely to have ASO-amenable variants in similar proportions as A-T.

Although the findings take the field of genetic therapy forward, the authors cautioned that ASO therapy remains investigational and contains uncertainty and risk that must be weighed carefully in a clinical context. "Continued study of patient-customized ASO therapies in serious genetic illness, facilitated by this framework, will be important to gather the body of evidence necessary to support the viability of this approach," they wrote.