Authors :
Presenting Author: Olivia Kim-McManus, MD – Rady Children's Institute for Genomic Medicine
Laurence Mignon, PhD – n-Lorem Foundation
He Pu, PhD – n-Lorem Foundation
Julie Douville, PhD – n-Lorem Foundation
Sarah Glass, PhD – n-Lorem Foundation
Catherine Parisien, MSc – n-Lorem Foundation
Janelle Celso, BS – UC San Diego
Kendall Robbins, BS – Rush University Medical Center
Stephen Kingsmore, MD – Rady Children's Institute for Genomic Medicine
Joseph Gleeson, MD – UC San Diego Rady Children's Institute for Genomic Medicine
Elizabeth Berry-Kravis, MD – Rush University Medical Center
Rationale:
SRD is a rare genetic disease characterized by intractable seizures, developmental delay, autism, and movement disorders, with no approved treatments. We created an individualized ASO for each patient specifically targeting their unique pathogenic variant with the aim of slowing disease progression by alleviating symptoms and improving quality of life. Patients have been treated for 23 and 16 months. We report long-term safety and efficacy results of individualized ASO therapy in two n=1 clinical trials for SCN2A-related disorders (SRD).
Methods:
FDA-authorized research INDs have allowed for investigational intrathecal dosing. The treatment endpoints for patient nL00333, a 10-year-old male with a dominant gain-of-function variant (c.5645 G >A, p.Arg1882Gln), include frequency of refractory seizures, changes in adaptive behavior, sensory sensitivity, cognition, and language. This patient has received 11 intrathecal ASO doses over 23 months. Treatment endpoints for patient nL00001, a 15-year-old male with a mixed gain/loss of function variant (c.2558G >A, p.Arg853Gln), include frequency of refractory seizures, changes in gastrointestinal symptoms, and neurodevelopment including motor function. This patient has received 7 intrathecal ASO doses over 16 months.
Results:
Long term data reveal no ASO-related safety concerns and confirm clinical benefit as defined by prolonged seizure-free periods and reduction in concomitant seizure medications including sodium channel blockers, among other neurodevelopmental endpoints meaningful to each individual’s phenotype.
Conclusions:
Long-term investigational therapy with individualized ASOs is supported by an excellent safety profile, along with important clinical benefits observed early in treatment, at low doses, and with sustained efficacy. Experience to date suggests that SCN2A related disorders due to gain of function and mixed gain and loss of function related disorders appear to be good targets for ASOs, and extension to additional SRD patients and genetic variants is warranted.
Funding:
California Institute for Regenerative Medicine, CIRM CLIN2-15085 (Kim-McManus)