Scholars

Timothy Yu, MD, PhD

Boston Children’s Hospital

Disease Areas

Rare / Orphan, Neuroscience

Focus

ASO Treatment for KCNT1-Associated Developmental Epileptic Encephalopathy

Scholar Profile

2024 Oxford-Harrington Rare Disease Scholar

Harrington Discovery Institute has been supporting Dr. Yu’s research since 2020 in multiple projects, including personalized antisense oligonucleotide (ASO) therapy for developmental epileptic encephalopathy (DEE) caused by genetic changes in the KCNT1 gene. KCNT1- related DEE is an ultra-rare, infant-onset seizure disorder caused by mutations in brain-expressed potassium channels. Severe forms of KCNT1-related DEE can cause dozens of seizures per day, with devastating neurodevelopmental consequences.

Dr. Yu’s KCNT1-targeting ASO program demonstrated target engagement and disease rescue in cultured patient-derived neurons, as well as a mouse model of disease. Dr. Yu was able to obtain FDA permission to advance the program into the clinic for two KCNT1-related DEE patients. In this pilot trial, the treatment initially elicited remarkable seizure reductions in both individuals, demonstrating the promise of this approach. However, both patients subsequently developed hydrocephalus, leading one family to make the difficult decision to withdraw from the trial and seek comfort measures.

Despite this setback, the trial was able to continue, leading to a pivotal innovation: Dr. Yu’s team successfully switched from intrathecal to intracerebroventricular (ICV) dosing. This has allowed for safe use of the drug at lower doses and has elicited a 75% reduction in seizures.

Dr. Yu’s pioneering research into ASOs and the ongoing support from Harrington Discovery Institute and the Oxford-Harrington Rare Disease Centre are creating a roadmap for researchers developing therapeutics for other ultra-rare diseases.

“Oxford-Harrington’s steadfast commitment to research into all genetic diseases, not just the handful that are highly prevalent, is so important,” Dr. Yu said.

"The Oxford-Harrington Rare Disease Centre is helping us advance new models that can work for all children with genetic disease."