A Phase I/II, First-In-Human Trial to Evaluate the Safety, Tolerability, and Pharmacokinetic Activity to Prevent or Treat Neuropsychiatric Symptoms in Pediatric Subjects With Timothy Syndrome (TS1-ASO)

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

Study Overview

• Status: Not yet recruiting
• Conditions: CACNA1C
• Intervention / Treatment: Drug: TS1-ASO

Detailed Description

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 currently no disease-modifying therapies targeting the neurologic and developmental features of TS1, representing a critical unmet medical need.

This first-in-human Phase I/II study evaluates TS1-ASO, an investigational antisense oligonucleotide designed to modulate pre-Messenger RNA (mRNA) splicing of CACNA1C by reducing inclusion of exon 8A and promoting expression of exon 8. This targeted approach aims to correct the underlying molecular mechanism driving abnormal calcium signaling. Preclinical studies in human induced pluripotent stem cell-derived neural organoids, assembloids, and in vivo transplantation models have demonstrated that TS1-ASO achieves target engagement, normalizes calcium channel function, and rescues disease-relevant cellular phenotypes. Toxicology studies in rodents and juvenile nonhuman primates support a favorable safety profile with no dose-limiting toxicities observed at clinically relevant exposures.

The study employs a non-randomized, open-label, sequential dose-escalation design in a small cohort of pediatric participants with genetically confirmed TS1. Dosing is administered intrathecally via lumbar puncture to achieve direct central nervous system exposure, consistent with established delivery approaches for antisense oligonucleotide therapies in neurologic disorders. Dose selection and escalation are guided by cerebrospinal fluid (CSF) volume-based scaling from nonclinical models, incorporating a conservative, stepwise approach to achieve pharmacologically active Central Nervous System (CNS) concentrations while maintaining safety margins.

Participants undergo intensive safety monitoring, including continuous cardiac telemetry during dosing periods, serial electrocardiograms, neurologic assessments, and comprehensive laboratory evaluations. Pharmacokinetic sampling in CSF and plasma is conducted to characterize drug distribution and exposure. Pharmacodynamic assessments include measurement of CACNA1C exon 8/8A splicing in CSF as a marker of target engagement. Clinical outcome assessments span multiple domains of neurodevelopment and function, including adaptive behavior, motor skills, communication, seizure frequency (where applicable), and caregiver- and clinician-reported measures.

Given the ultra-rare nature of TS1 and limited patient population, the study is designed to generate descriptive safety, pharmacokinetic, and exploratory efficacy data to inform future development. The study includes a staged enrollment approach with interim safety reviews to ensure appropriate risk mitigation. Longitudinal follow-up allows for assessment of durability of response and continued safety evaluation over time.

This trial represents a precision medicine approach targeting the molecular basis of TS1 and is intended to establish foundational clinical data for a novel therapeutic strategy addressing neurodevelopmental disease in this population.

• Study Type: Interventional
• Enrollment (Estimated): 5
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Sergiu Pasca, MD; Phone Number: (650) 497-5922; Email: spasca@stanford.edu
• Study Contact Backup: Name: Grant Wells; Phone Number: 650-714-4344; Email: gwells2@stanford.edu

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University
      • Contact: Rebecca Levy, MD, PhD; Phone Number: (650) 497-5922; Email: rjlevy@stanford.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 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.
• Inability to complete required procedures including anesthesia, magnetic resonance imaging brain, and lumbar puncture (LP).
• Participation in another investigational trial within the 90 days prior to first dose, including any gene therapy within the participant's lifetime.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TS1-ASO Arm; TS1-ASO Drug Administration	Drug: TS1-ASO; Antisense oligonucleotide targeting CACNA1C exon 8A/8 splicing

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From the first dose through 12 months of treatment and follow-up.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	From first dose through 12 months of treatment
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).	From first dose through 12 months of treatment
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.	From Baseline through 12 months.
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.	From Baseline through 12 months.
Change in adaptive behavior (Vineland Adaptive Behavior Scales Third Edition - Vineland-3)	Adaptive functioning will be measured using the Vineland Adaptive Behavior Scales Third Edition (Vineland-3). Changes in composite and domain scores (communication, daily living skills, socialization, and motor skills) will be assessed to evaluate developmental progress.	From Baseline through 12 months.
Change in gross motor function (Gross Motor Function Classification System - Expanded & Revised)	Gross motor function will be evaluated using the Gross Motor Function Classification System Expanded & Revised (GMFCS-E&R). Changes in classification level over time will be used to assess motor development and functional mobility.	From Baseline through 12 months.
Change in communication function (Communication Function Classification System)	Communication abilities will be assessed using the Communication Function Classification System (CFCS). Changes in classification level will be evaluated to assess expressive and receptive communication function.	From Baseline through 12 months.
Change in early language development - MacArthur-Bates Communicative Development Inventories (MB-CDIs)	In younger participants or those with communication delays, language development will be assessed using the MacArthur-Bates Communicative Development Inventories (MB-CDIs). Changes from baseline will be used to evaluate early communication and language acquisition.	From Baseline through 12 months

Collaborators and Investigators

• Sponsor: Stanford University
• Investigators: Principal Investigator: Sergiu Pasca, MD, Stanford University

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 1, 2030

Study Registration Dates

• First Submitted: May 4, 2026
• First Submitted That Met QC Criteria: May 15, 2026
• First Posted (Actual): May 22, 2026

Study Record Updates

• Last Update Posted (Actual): May 29, 2026
• Last Update Submitted That Met QC Criteria: May 27, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Antisense oligonucleotide; Timothy Syndrome
• Additional Relevant MeSH Terms: Timothy syndrome
• Other Study ID Numbers: 86899

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (IPD) that underlie the results reported in publications will be shared. This includes safety data (adverse events, laboratory results, and clinical assessments), pharmacokinetic data (CSF and plasma concentrations), pharmacodynamic data (CACNA1C splicing measures), and key clinical outcome measures (e.g., neurodevelopmental, behavioral, and seizure assessments). Data will be shared in a de-identified format to protect participant privacy and in accordance with applicable regulatory and institutional requirements. Access will be provided to qualified researchers upon reasonable request and following approval of a data use agreement.
• IPD Sharing Time Frame: De-identified individual participant data will be made available beginning 6 months after publication of the primary study results and will remain available for a period of 5 years following publication.

IPD Sharing Access Criteria

Access to de-identified individual participant data (IPD) and supporting documentation will be granted to qualified researchers, including academic investigators and collaborators, who submit a methodologically sound research proposal that is aligned with the scientific objectives of the study and approved by the study sponsor.

Researchers will be able to access de-identified datasets underlying published results, including safety data (adverse events, laboratory values), pharmacokinetic and pharmacodynamic data, and key clinical outcome measures, along with supporting materials such as the study protocol, statistical analysis plan, and data dictionaries.

Access will be provided through a secure data-sharing mechanism following execution of a data use agreement (DUA) that outlines conditions for data protection, confidentiality, and appropriate use.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No