Genetically tailored splice-modulating therapy for A-T

Dr Timothy Yu

Research Project information

Principal researcher: Dr Timothy Yu
Institute: Harvard and Boston Children’s Hospital
Cost: $518,000 over 12 months in partnership with A-TCP
Completion date: Still ongoing

Action for A-T provided $23,000 towards the initial “Design and Test” stage of a new ASO study developed by the US based A-T Children’s Project.

Project Overview

Several ASO drugs have already been approved by the FDA for other rare diseases such as Duchenne muscular dystrophy, spinal muscular atrophy and cytomegalovirus retinitis and Dr Yu and his team have recently developed an ASO therapeutic for a neurodegenerative disorder named Batten disease.

Dr Yu and his team aimed to develop and then deploy an ASO-based splice modulating therapy for Ataxia Telangiectasia.

There are currently no effective treatments for A-T, and the size of the ATM gene poses challenges to traditional gene replacement therapy approaches. Antisense oligonucleotide (ASO) therapies have recently come to the fore as a promising therapeutic strategy for genetic disorders of the central nervous system and as ASO drugs are already in existence for other rare conditions, there is a possibility that one could be developed for A-T.

Research Methods and Outcome

Initially, the Boston based team screened A-T patients with clinically and molecularly confirmed diagnoses to identify at least three patients who bear molecular mutations that may be treatable via splice modulating ASOs. They will then designed and tested ASOs both in vitro and in animal models, to block abnormal splicing. Dr Yu then sought FDA permission to launch and conduct an N-of-1 clinical trial.

Applying ASO therapy to A-T involved making a drug that contains a short strand of RNA that will bind to the mutated site in the A-T child’s RNA so that the child’s cells avoid incorrect “RNA splicing” caused by the mutation. This drug was injected into the child’s spinal fluid to reach the brain.

What next?

Yu and his colleagues were able to perform systematic analyses to not only identify all the genetic mutations that contributed to A-T in this population, but also to assess which mutations would be amenable to treatment with ASOs.  They concluded that up to 15% of children with A-T had favourable mutations. From this 15%, Yu and his team selected one mutation that had a high likelihood of responding favourably to ASOs, then chose to develop a therapy for a young girl.  Yu’s team began testing ASOs on the girl’s cells to see if they could restore function of the faulty DNA damage repair enzyme. Within a year, they had developed a therapy ready for administration and received FDA approval. The child has been receiving her bespoke medicine since 2020, starting treatment at just age 2.  The team will follow up on the girls’ process over the coming years.

ASO therapy could potentially produce the functional ATM protein that is missing within the cells of children with A-T. Initially, only the youngest A-T kids who have lost the fewest brain cells and who carry a certain type of mutation would be treated with this approach, using personalised drugs for each mutation.


Kim, J., Woo, S., de Gusmao, C.M. et al. A framework for individualized splice-switching oligonucleotide therapy. Nature 619, 828–836 (2023).