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
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.
Critical illness including cardiac arrhythmia that is unstable, invasive ventilatory support, sustained hypoglycemia, or active infection.
Diagnosis of a secondary genetic disorder in addition to TS1.
Hypoxic-ischemic injury to >25% of the brain from prior cardiac arrest.
Age > 5 years old with absence of any neurologic, developmental, or psychiatric diagnoses, or symptoms on physical exam and intake assessment scales as there would unlikely be a benefit to treatment in the setting of normal cognition and development and lack of epilepsy or other neuropsychiatric diagnoses.
Single group
TS1-ASO
DrugAntisense oligonucleotide targeting CACNA1C exon 8A/8 splicing
Incidence, frequency, and severity of adverse events (AEs) and serious adverse events (SAEs) from first dose through 12 months of treatment and follow-up.
Safety and tolerability of TS1-ASO will be evaluated by systematic collection and analysis of AEs and SAEs following intrathecal administration. Events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and assessed for severity, seriousness, and relationship to study drug and procedure. Safety assessments include continuous cardiac monitoring (telemetry), serial electrocardiograms, neurologic examinations, and routine laboratory evaluations (hematology, chemistry, coagulation, and urinalysis). Procedure-related safety (e.g., lumbar puncture complications), neurologic status, and potential class-related effects of antisense oligonucleotides will be closely monitored. Data will be summarized descriptively to characterize the overall safety profile of TS1-ASO in this population.
Pharmacokinetic (PK) profile of TS1-ASO in cerebrospinal fluid (CSF).
Pharmacokinetic parameters of TS1-ASO will be characterized using serial CSF samples collected at predefined time points following intrathecal administration. Parameters include maximum concentration (Cmax).
Pharmacokinetic (PK) profile of TS1-ASO in plasma.
Pharmacokinetic parameters of TS1-ASO will be characterized using plasma samples collected at predefined time points following intrathecal administration. Parameters include time to maximum concentration (Tmax).
Change in CACNA1C exon 8/8A splicing in CSF
Pharmacodynamic activity will be assessed by measuring the ratio of exon 8 to exon 8A transcripts in CSF using quantitative polymerase chain reaction (qPCR). Changes from baseline will be used to evaluate target engagement and biological activity of TS1-ASO in modulating RNA splicing.
Seizure frequency (in participants with epilepsy)
Seizure frequency will be assessed using caregiver-reported daily seizure logs. Changes in seizure frequency over time will be evaluated to explore potential treatment effects on neurologic outcomes.
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