Phelan-McDermid Syndrome, SHANK3 Haploinsufficiency
Conditions
Keywords
SHANK3 Haploinsufficiency, SHANK3, Phelan-McDermid Syndrome
Brief summary
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.
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.
Interventions
GENETICJAG201
Adeno-associated virus 2/9 expressing a miniature version of the human SHANK3 gene (AAV2/9-miniSHANK3)
Sponsors
Jaguar Gene Therapy, LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Multicenter, open-label, first-in-human (FIH), single-dose, dose-escalation, safety, tolerability, and clinical activity of JAG201. A traditional 3+3 design strategy will be implemented for dose escalation from the 1st cohort to the 2nd cohort.
Eligibility
Sex/Gender
ALL
Age
2 Years to 9 Years
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events (AEs) | Enrollment to Month 60 | Incidence, type, severity, and frequency of AEs |
| Incidence of Serious Adverse Events (SAEs) | Enrollment to Month 60 | Incidence, type, severity, and frequency of SAEs |
| Clinically significant abnormalities in laboratory values | Enrollment to Month 60 | Changes in clinically significant abnormalities in laboratory values |
| Incidence of immunogenicity response abnormalities | Enrollment to Month 60 | Incidence of anti-AAV9 antibodies, anti-transgene antibodies, and T-cell reactivity to transgene over time |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change from Baseline in SAND | Enrollment to Month 60 | To characterize the preliminary disease response to JAG201 by assessing the change from baseline in SAND (Sensory Assessment for Neurodevelopmental Disorders) |
Countries
United States
Contacts
CONTACTJaguar Gene Therapy
STUDY_DIRECTORDan Gallo, PhD
Jaguar Gene Therapy
Outcome results
None listed