Victoria Suslovitch

Abstract Splice-switching antisense oligonucleotides (ASOs) could be used to treat a subset of individuals with genetic diseases 1 , but the systematic identification of such individuals remains a challenge. Here we performed whole-genome sequencing analyses to characterize genetic variation in 235 individuals (from 209 families) with ataxia-telangiectasia, a severely debilitating and life-threatening recessive genetic disorder 2,3 , yielding a complete molecular diagnosis in almost all individuals. We developed a predictive taxonomy to assess the amenability of each individual to splice-switching ASO intervention; 9% and 6% of the individuals had variants that were ‘probably’ or ‘possibly’ amenable to ASO splice modulation, respectively. Most amenable variants were in deep intronic regions that are inaccessible to exon-targeted sequencing. We developed ASOs that successfully rescued mis-splicing and ATM cellular signalling in patient fibroblasts for two recurrent variants. In a pilot clinical study, one of these ASOs was used to treat a child who had been diagnosed with ataxia-telangiectasia soon after birth, and showed good tolerability without serious adverse events for three years. Our study provides a framework for the prospective identification of individuals with genetic diseases who might benefit from a therapeutic approach involving splice-switching ASOs.

Antisense oligonucleotides (ASOs) can modulate pre-mRNA splicing. This offers therapeutic opportunities for numerous genetic diseases, often in a mutation-specific and sometimes even individual-specific manner. Developing therapeutic ASOs for as few as even a single patient has been shown feasible with the development of Milasen for an individual with Batten disease. Efforts to develop individualized ASOs for patients with different genetic diseases are ongoing globally. The N = 1 Collaborative (N1C) is an umbrella organization dedicated to supporting the nascent field of individualized medicine. N1C recently organized a workshop to discuss and advance standards for the rigorous design and testing of splice-switching ASOs. In this study, we present guidelines resulting from that meeting and the key recommendations: (1) dissemination of standardized experimental designs, (2) use of standardized reference ASOs, and (3) a commitment to data sharing and exchange.

Ataxia-telangiectasia (A-T) is a rare, childhood-onset, multi-systemic, progressive condition. Parents of children with rare diseases like A-T are emotionally, socially, and psychologically impacted by the diagnosis. To examine the parental perspective of having a child with A-T, and to better understand how parents cope with an A-T diagnosis, we conducted 10 semistructured interviews. Thematic analysis using a phenomenological approach resulted in five themes: (1) Parental responsibilities change as the result of an A-T diagnosis, (2) An A-T diagnosis brings about shifts in identity for all family members, (3) Parental coping changes over time, (4) A-T parents experience continuous uncertainty and a lack of stability, and (5) A-T parents receive support from various people, places, and resources. Many parents fostered resilience by adopting a present-centered and positive mindset about the impacts of the diagnosis. Parents also became A-T experts and used their knowledge to advocate for their children and help mentor other parents. Responses from parents indicated a need for providers to incorporate parental mental well-being check-ins to pediatric rare disease appointments and welcome parents as respected members of their children's care team. Genetic counselors are in a unique position to help coordinate complex care for children with A-T (and other rare diseases) and provide support to family members using the framework of family-centered care. This paper offers suggestions for expanding support and learning to cope with a difficult diagnosis for parents of children with rare diseases, specifically A-T, based on stories from parents of children with A-T.