CACNA1CPhase 1/2TS1-ASONCT07600658
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
A Phase 1/2 study testing TS1-ASO in people with CACNA1C, run by Stanford University at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 2 months and older
- Conditions the study is for
- CACNA1C
- What is being tested?
- TS1-ASO
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 5 participants
- Where
- 1 siteUnited States
- Study dates
- Sep 2026to Dec 2030
- Phase
- Phase 1/2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 months and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site
Stanford University
Stanford, California, 94305
Rebecca Levy, MD, PhD, (650) 497-5922, rjlevy@stanford.edu
About this study
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:
Read more
- Is TS1-ASO safe and well tolerated when administered intrathecally in children with TS1?
- 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:
- Receive intrathecal injections of TS1-ASO via lumbar puncture using a stepwise dose-escalation approach
- Undergo safety monitoring including neurologic exams, cardiac monitoring, laboratory testing, and adverse event assessments
- Provide cerebrospinal fluid (CSF) and blood samples for pharmacokinetic and biomarker analyses
- Complete neurodevelopmental, behavioral, and functional assessments (e.g., adaptive behavior, motor function, communication, seizure tracking) over time
Read the 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.
- Conditions
- CACNA1C
- Being tested
- TS1-ASO
- Keywords
- Antisense oligonucleotide, Timothy Syndrome
- Medical subject headings
- Timothy syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TS1-ASODrug
Antisense oligonucleotide targeting CACNA1C exon 8A/8 splicing
| Study group | Role | What they receive |
|---|---|---|
| TS1-ASO Arm | Experimental | TS1-ASO Drug Administration Receives: Drug: TS1-ASO |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: From the first dose through 12 months of treatment and follow-up.
Secondary outcomes (8)
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).
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: From Baseline through 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 May 2026
- Study startSep 2026 (estimated)
- Primary completionDec 2029 (estimated)
- Study completionDec 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for CACNA1CStudies of the same condition, open and under way.
- More trials run by Stanford UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 5 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Stanford University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Sergiu Pasca, Stanford University
- Investigators
- Sergiu Pasca, MD, Principal investigator, Stanford University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07600658
- Sponsor's protocol ID
- 86899
- Acronym
- TS1-ASO
- Status last verified
- May 2026
- First submitted
- 4 May 2026
- Last updated
- 29 May 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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.
Study at a glance
From the registry record, last updated by the sponsor on 29 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT07600658
- Acronym / sponsor ID
- TS1-ASO / 86899
- Conditions
- CACNA1C
- Keywords
- Antisense oligonucleotide, Timothy Syndrome
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 5 participants (estimated)
- Lead sponsor
- Stanford UniversityUniversity, hospital or other
- Study start
- Sep 2026 (estimated)
- Primary completion
- Dec 2029 (estimated)
- Study completion
- Dec 2030 (estimated)
- First posted
- 22 May 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- Is TS1-ASO safe and well tolerated when administered intrathecally in children with TS1?
- 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:
- Receive intrathecal injections of TS1-ASO via lumbar puncture using a stepwise dose-escalation approach
- Undergo safety monitoring including neurologic exams, cardiac monitoring, laboratory testing, and adverse event assessments
- Provide cerebrospinal fluid (CSF) and blood samples for pharmacokinetic and biomarker analyses
- Complete neurodevelopmental, behavioral, and functional assessments (e.g., adaptive behavior, motor function, communication, seizure tracking) over time
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 design
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| TS1-ASO Arm | Experimental | Drug: TS1-ASOTS1-ASO Drug Administration |
Who may qualify
- Ages
- 2 months and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (2 listed)
- 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.
Key exclusion criteria (6 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TS1-ASOAntisense oligonucleotide targeting CACNA1C exon 8A/8 splicing | Drug | TS1-ASO Arm |
Primary outcome
Incidence, frequency, and severity of adverse events (AEs) and serious adverse events (SAEs) from first dose through 12 months of treatment and follow-up.
Time frame: From the 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.
8 secondary outcomes
Pharmacokinetic (PK) profile of TS1-ASO in cerebrospinal fluid (CSF).
Time frame: From first dose through 12 months of treatment
Pharmacokinetic (PK) profile of TS1-ASO in plasma.
Time frame: From first dose through 12 months of treatment
Change in CACNA1C exon 8/8A splicing in CSF
Time frame: From Baseline through 12 months.
Seizure frequency (in participants with epilepsy)
Time frame: From Baseline through 12 months.
Change in adaptive behavior (Vineland Adaptive Behavior Scales Third Edition - Vineland-3)
Time frame: From Baseline through 12 months.
Change in gross motor function (Gross Motor Function Classification System - Expanded & Revised)
Time frame: From Baseline through 12 months.
Change in communication function (Communication Function Classification System)
Time frame: From Baseline through 12 months.
Change in early language development - MacArthur-Bates Communicative Development Inventories (MB-CDIs)
Time frame: From Baseline through 12 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 May 2026.
- Individual participant dataSharing planned: Yes. 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Sergiu Pasca, MD principal investigator
Stanford University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing TS1-ASO in people with CACNA1C, run by Stanford University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 29 May 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Sergiu Pasca, MD ((650) 497-5922, spasca@stanford.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence, frequency, and severity of adverse events (AEs) and serious adverse events (SAEs) from first dose through 12 months of treatment and follow-up. (time frame: From the first dose through 12 months of treatment and follow-up.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 May 2026; AzTrials last refreshed its copy on 30 Oct 2026.