JAG201 Gene Therapy Study in Children & Adults With SHANK3 Haploinsufficiency

A Phase 1/2, Multicenter, Open-Label, Dose-Escalation, Safety, Tolerability, and Clinical Activity Study of a Single Dose of JAG201 Gene Therapy Delivered Via Intracerebroventricular Administration in Participants With SHANK3 Haploinsufficiency

This is a Phase 1/2, first in human, open-label, dose-escalation study to evaluate the safety, tolerability, and clinical activity of a single dose of JAG201 administered via intracerebroventricular (ICV) injection in pediatric and adult participants with SHANK3 haploinsufficiency resulting from SHANK3 loss of function mutations and chromosomal deletions encompassing the SHANK3 gene. Clinical data will be evaluated for safety, tolerability, and preliminary clinical activity of JAG201 in pediatric and adult participants with SHANK3 haploinsufficiency. The pediatric cohorts will start enrolling first and the enrollment for adult cohorts may be initiated at a later timepoint in the study.

Study Overview

• Status: Recruiting
• Conditions: Phelan-McDermid Syndrome; SHANK3 Haploinsufficiency
• Intervention / Treatment: Genetic: JAG201

Detailed Description

A target of 6 pediatric participants aged 2 to 9 years will be treated in Cohorts 1 and 2. In total, all participants will be followed for safety and tolerability for at least 5 years after the date of treatment with JAG201. The study will include 5 periods: Pre-Screening, Screening, Gene Therapy Administration and Perioperative Management, Initial Follow-Up, and Long-Term Follow-Up. Study participants will be evaluated for treatment eligibility during the Pre-Screening and Screening Periods. The Pre-Screening/Screening Period may be up to 90 days before treatment with JAG201 (Day 1). On Day 1, treatment-eligible participants will receive a one-time ICV injection of JAG201. Participant safety will be monitored closely after JAG201 administration in a hospital setting. During the Initial Follow-Up Period, up to Year 2, participants will return at regularly scheduled intervals for safety and clinical activity assessments. Participants will continue the study in the Long-Term Follow-Up Period through Year 5.

• Study Type: Interventional
• Enrollment (Estimated): 6
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Jaguar Gene Therapy; Phone Number: 224-303-0701; Email: medinfo@jaguargenetherapy.com

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Recruiting
      • Rush University
      • Principal Investigator: Elizabeth B Kravis, MD, PhD
      • Contact: Giulia DeMarco; Phone Number: 312-942-9841; Email: Giulia_DiMarco@rush.edu
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Boston Children's Hospital
      • Contact: Anna Cronin; Phone Number: (617)-919-3499; Email: anna.cronin@childrens.harvard.edu
      • Principal Investigator: Siddharth Srivastava, MD
  • New York
    • New York, New York, United States, 10029
      • Recruiting
      • Seaver Autism Center at Mount Sinai
      • Contact: Serena Cai; Phone Number: 212-241-6231; Email: serena.cai@mssm.edu
      • Principal Investigator: Alex Kolevzon, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Is male or female, and 2 to 9 years of age at the time of JAG201 administration
2. Has a molecular confirmation of a loss of function mutation in SHANK3 or a 22q13.3 deletion classified as a Class I deletion
3. Has evidence of developmental/cognitive delay of at least 2 standard deviations (SD) below the mean (i.e., ≤ 70) via either Intelligence Quotient (IQ) OR Developmental Quotient (DQ) assessment (as applicable)
4. Has an overall Phelan-McDermid Syndrome (PMS) Assessment of Severity (PMSA-S) Score of 3 or greater at Screening
5. Willing to initiate structured therapies and continue for the duration of the study as determined by the specific therapist (structured therapies may include, at a minimum, physical therapy, occupational therapy, speech therapy, and applied behavior analysis)
6. Is stable on any medication regimens (if being administered to control the signs and symptoms of underlying disease) for at least 3 months prior to the planned JAG201 study treatment
7. If undergoing any kind of behavioral or therapeutic intervention, then the level of intervention must have remained stable for at least 3 months prior to the planned JAG201 study treatment (exclusive of school vacations/illness).
8. Is a permanent legal resident of the U.S. residing within the continental U.S.

Key Exclusion Criteria:

A pediatric participant who meets any of the following criteria will be excluded from this study:

1. Has history of developmental regression defined in this study as a prolonged loss of previously acquired skills (defined as skills maintained for at least 3 months) with loss of skills persisting for at least 3 months
2. Has known or suspected prion disease (e.g., Creutzfeldt-Jakob Disease)
3. Has poorly-controlled epilepsy (defined as an increase in the dose or addition of new anti-epileptic medications within the past 3 months) or any history of status epilepticus or seizure-induced hospitalizations within the last 12 months
4. Has history of acute cerebrovascular episodes
5. Has active autoimmune disease or prior treatment with immunomodulatory therapy, immunotherapy, and/or immunosuppressive drugs within 3 months prior to study enrollment (Note: Inhaled or topical steroids are permitted in the absence of active autoimmune disease)
6. Has infection (viral, bacterial, or fungal) that requires treatment < 6 weeks before JAG201 administration (Note: JAG201 administration may be postponed until the infection has resolved and the participant is clinically stable)
7. Has medical illness or other concern that would cause the Investigator to conclude that the participant will not be able to perform the study procedures or assessments or would confound interpretation of data obtained during assessments
8. Has known allergy or hypersensitivity to prednisolone or other glucocorticosteroids, or their excipients
9. Has received any vaccine < 6 weeks before JAG201 administration
10. Has received any gene therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pediatric Cohort 1; Starting Dose	Genetic: JAG201; Adeno-associated virus 2/9 expressing a miniature version of the human SHANK3 gene (AAV2/9-miniSHANK3)
Experimental: Pediatric Cohort 2; Escalated Dose	Genetic: JAG201; Adeno-associated virus 2/9 expressing a miniature version of the human SHANK3 gene (AAV2/9-miniSHANK3)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Adverse Events (AEs)	Incidence, type, severity, and frequency of AEs	Enrollment to Month 60
Incidence of Serious Adverse Events (SAEs)	Incidence, type, severity, and frequency of SAEs	Enrollment to Month 60
Clinically significant abnormalities in laboratory values	Changes in clinically significant abnormalities in laboratory values	Enrollment to Month 60
Incidence of immunogenicity response abnormalities	Incidence of anti-AAV9 antibodies, anti-transgene antibodies, and T-cell reactivity to transgene over time	Enrollment to Month 60

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in SAND	To characterize the preliminary disease response to JAG201 by assessing the change from baseline in SAND (Sensory Assessment for Neurodevelopmental Disorders)	Enrollment to Month 60

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in Vineland Adaptive Behavior Scales	To characterize further the preliminary clinical activity of JAG201 by assessing change from baseline in Vineland Adaptive Behavior Scales, Third Edition	Enrollment to Month 60

Collaborators and Investigators

• Sponsor: Jaguar Gene Therapy, LLC
• Investigators: Study Director: Dan Gallo, PhD, Jaguar Gene Therapy

Study record dates

Study Major Dates

• Study Start (Actual): January 7, 2024
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2031

Study Registration Dates

• First Submitted: October 16, 2024
• First Submitted That Met QC Criteria: October 25, 2024
• First Posted (Actual): October 28, 2024

Study Record Updates

• Last Update Posted (Actual): February 9, 2026
• Last Update Submitted That Met QC Criteria: February 5, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Phelan-McDermid Syndrome; SHANK3; SHANK3 Haploinsufficiency
• Additional Relevant MeSH Terms: Telomeric 22q13 Monosomy Syndrome
• Other Study ID Numbers: JAG-201-CL-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No