Stanford University
The goal of this clinical trial is to learn if an antisense oligonucleotide (TS1-ASO) can safely treat and potentially prevent neuropsychiatric and neurodevelopmental symptoms in pediatric participants (age \>2 months) with Timothy Syndrome Type 1 (TS1). The main questions it aims to answer are: 1. Is TS1-ASO safe and well tolerated when administered intrathecally in children with TS1? 2. What are the pharmacokinetics and preliminary efficacy of TS1-ASO on neurodevelopmental and neurologic outcomes? This is a single-arm study (no comparison group). Participants will: 1. Receive intrathecal injections of TS1-ASO via lumbar puncture using a stepwise dose-escalation approach 2. Undergo safety monitoring including neurologic exams, cardiac monitoring, laboratory testing, and adverse event assessments 3. Provide cerebrospinal fluid (CSF) and blood samples for pharmacokinetic and biomarker analyses 4. Complete neurodevelopmental, behavioral, and functional assessments (e.g., adaptive behavior, motor function, communication, seizure tracking) over time
Timothy Syndrome Type 1 (TS1) is an ultra-rare, life-threatening autosomal dominant disorder caused by a pathogenic gain-of-function variant (p.G406R) in exon 8A of the CACNA1C gene, which encodes the CaV1.2 L-type calcium channel. The condition is characterized by multisystem involvement, including cardiac arrhythmias (long QT syndrome), syndactyly, hypoglycemia, and a high prevalence of neurodevelopmental and neuropsychiatric manifestations such as autism spectrum disorder, epilepsy, and global developmental delay. While advances in cardiac management have improved survival, there are curren…
Inclusion Criteria: * Confirmed CACNA1C c.1216 G\>A, p.G406R variant in exon 8A (TS1) on exome or genome testing. * Age \> 2 months. Given that neurodevelopmental symptoms start early in TS1 and treatment is predicted to more effectively prevent rather than rescue developmental delay, ASD, and epilepsy, the Sponsor proposes that early treatment is most likely to yield clinical benefit. Exclusion Criteria: * Critical illness including cardiac arrhythmia that is unstable, invasive ventilatory support, sustained hypoglycemia, or active infection. * Diagnosis of a secondary genetic disorder in…
Antisense oligonucleotide targeting CACNA1C exon 8A/8 splicing
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