Phase 1/2 Study of MZ-1866, an AAV-9 Gene Therapy Delivered by Intracerebroventricular Injection to Participants With Pitt Hopkins Syndrome

Phase 1/2 First-in-Human Study to Evaluate the Safety, Tolerability, and Efficacy of MZ-1866, an AAV-9 Gene Therapy Delivered by Intracerebroventricular Injection to Participants With Pitt Hopkins Syndrome

The goal of this clinical trial is to learn if MZ-1866 is a safe and tolerable treatment for children and adults with Pitt Hopkins Syndrome.

To evaluate the safety of MZ-1866, the following will be evaluated:

• frequency and severity of adverse events
• physical exam, laboratory results and electrocardiogram findings

Participants will:

• receive a single dose of MZ-1866 by intracerebroventricular injection
• be seen by the study physician and site staff periodically to assess changes to their health status
• be periodically evaluated using neurodevelopmental tools

Caregivers will:

• be interviewed periodically about the health status and development of the participant
• keep diaries and complete periodic questionnaires regarding participant symptoms

Study Overview

• Status: Recruiting
• Conditions: Pitt Hopkins Syndrome
• Intervention / Treatment: Genetic: MZ-1866

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Emily Radomile; Phone Number: 1-844-446-2494; Email: clinicaltrials@mahzi.com

Study Locations

• Israel
  • Tel Litwinsky, Israel
    • Recruiting
    • Sheba Medical Center
    • Contact: Ester Frank; Phone Number: 972-52-629-0473; Email: Ester.Frank@sheba.health.gov.il
    • Principal Investigator: Gali Heimer, M.D., Ph.D.
• United States
  • California
    • Oakland, California, United States, 94609
      • Recruiting
      • UCSF Benioff Children's Hospital Oakland
      • Contact: Matt Thura; Email: matt.thura@ucsf.edu
      • Principal Investigator: Alex Fay, M.D., Ph.D.
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • Children's Hospital Colorado
      • Principal Investigator: Diana Walleigh, MD
      • Contact: Sky Gould; Phone Number: 750-777-1583; Email: sky.gould@childrenscolorado.org
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Not yet recruiting
      • Rush University Medical Center
      • Principal Investigator: Elizabeth Berry-Kravis, M.D., Ph.D.
      • Contact: Tara Khandelwal; Email: Mehr_Khandelwal@rush.edu

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• The participant has a TCF4 gene mutation confirmed as "pathogenic" or "likely pathogenic" by whole exome sequencing, whole genome sequencing, gene panel, single gene testing, or microarray, performed at an accredited laboratory
• Clinical phenotype consistent with Pitt Hopkins Syndrome, in the opinion of the investigator
• The participant, or the participant's parent or legal guardian, is willing to provide access to prior medical records for the collection of demographics and diagnostic and treatment history

Exclusion Criteria:

• A deletion that includes the TCF4 gene that is over 12 Mbp in size
• Another genetic mutation or clinical comorbidity not associated with Pitt Hopkins Syndrome that could potentially confound interpretation of the study data
• A central nervous system structural or vascular abnormality that is a contraindication to the ICV administration procedure, including but not limited to: signs or symptoms of increased intracranial pressure, history of a space-occupying lesion, or presence of a ventricular shunt that would preclude ICV procedures or safety assessments, or increase risk to the participant
• Not able to receive prophylactic corticosteroids due to a medical contraindication or participant has a history of a condition that could worsen with corticosteroid therapy as assessed and determined by the Investigator
• Not able to undergo MRI procedures
• Cannot be anesthetized for the ICV injection

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: Cohort 1 (MZ-1866); Participants ages 12-25 years	Genetic: MZ-1866; AAV-9 gene therapy delivered by intracerebroventricular injection
Experimental: Cohort 2 (MZ-1866); Participants aged 2-11 years	Genetic: MZ-1866; AAV-9 gene therapy delivered by intracerebroventricular injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate the safety and tolerability of MZ-1866 in participants with Pitt Hopkins Syndrome	Frequency and severity of adverse events of special interest	Week 104

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate the safety and tolerability of MZ-1866 in participants with Pitt Hopkins Syndrome	Frequency and severity of adverse events	Week 104
To further assess the safety and tolerability of MZ-1866 in participants with Pitt Hopkins Syndrome	Frequency of clinically significant physical examination findings, vital signs, laboratory tests and electrocardiograms that are considered outside normal range.	Week 104

Collaborators and Investigators

• Sponsor: Mahzi Therapeutics
• Collaborators: California Institute for Regenerative Medicine (CIRM)

Study record dates

Study Major Dates

• Study Start (Actual): December 19, 2025
• Primary Completion (Estimated): March 1, 2029
• Study Completion (Estimated): July 1, 2029

Study Registration Dates

• First Submitted: August 4, 2025
• First Submitted That Met QC Criteria: August 13, 2025
• First Posted (Actual): August 21, 2025

Study Record Updates

• Last Update Posted (Actual): May 11, 2026
• Last Update Submitted That Met QC Criteria: May 7, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Gene Therapy; Intracerebroventricular; ICV; PTHS; MZ-1866; AAV9 Gene Therapy; TCF4
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Pathologic Processes; Disease Attributes; Respiratory Tract Diseases; Disease; Neurobehavioral Manifestations; Respiration Disorders; Signs and Symptoms, Respiratory; Neurodevelopmental Disorders; Pitt-Hopkins syndrome
• Other Study ID Numbers: MZ1866-CL101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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