Precision ASO therapy for KCNT1 Epilepsy

Last week in Nature Medicine, our team reports on the administration of valeriasen, an investigational KCNT1-targeting antisense oligonucleotide (ASO), to two infants with epilepsy of infancy with migrating focal seizures (EIMFS), the most severe form of KCNT1-related epilepsy. Children with KCNT1-EIMFS suffer from dozens of seizures daily and face a universally poor prognosis with high early mortality.

Experimental therapy was associated with a striking reduction in seizures, which fell by half in one child and ceased in another. However, both children developed hydrocephalus. Following the necessary discontinuation of therapy to study this adverse event, one participant sadly passed away after the focus of her care was shifted to comfort in late 2021. We are profoundly grateful to her family for their partnership and continued belief in this work, despite tragic loss, which has been essential to understanding the risks and potential of this therapeutic class. Importantly, it has led our team to develop safety monitoring protocols that have permitted ongoing safe administration of novel ASOs for many other serious diseases.

We did not abandon this therapeutic approach. After re-evaluating delivery methods, we transitioned our second participant to intracerebroventricular (ICV) dosing. This approach has been well-tolerated to date, and careful dose escalation has been accompanied by a ~75% reduction in seizures.

Bringing this dataset to publication took five years as we developed a safer protocol to present to the field. However, recognizing these safety findings deserved immediate disclosure, we shared these outcomes directly with field leaders, at the 2022 ANA meeting (and other conferences), and with the press. These same considerations underlie our support for the "One to Millions" initiative, launched by the Critical Path Institute (C-Path) and supported by the N=1 Collaborative and others, to facilitate rapid and transparent data sharing in such trials.

We hope these findings help colleagues navigate this complex frontier, laying groundwork to safely treat more children with KCNT1-related epilepsy and other devastating genetic conditions.