A First-in-Human Clinical Trial to Evaluate the Safety, Tolerability, and Efficacy of a Novel CRISPR RNA-editing Therapy in Patients with Mecp2 Duplication Syndrome, a Rare Orphan Disease (HERO) (HERO)

An Open-label, Multiple-dose Clinical Study to Evaluating the Safety, Tolerability and Preliminary Efficacy of a Single Intracerebroventricular Injection of HG204 for the Treatment of MECP2 Duplication Syndrome

Methyl-CpG binding protein 2 (MECP2) is a dosage-sensitive, X-linked gene critical for central nervous system development and functional maintenance, which gain-of-function causes MECP2 duplication syndrome (MDS). Affecting primarily in males, this disorder is characterized by severe intellectual disability, motor dysfunction, infantile hypotonia, epilepsy, respiratory tract infections, and premature death before 25 years of age with no curative therapy.

HG204 is a CRISPR RNA-editing therapy packaging novel high-fidelity Cas13Y (hfCas13Y) technology, using one single adeno-associated virus (AAV) vector to target and knock down MECP2 mRNA in the brain. Preclinical studies showed that a single intracerebroventricular injection of HG204 persistently decreased MECP2 mRNA and MECP2 protein in the cortex of the MDS mice, reversed the abnormal motor and social phenotypes, and significantly prolonged survival in MDS mouse models.

Study Overview

• Status: Recruiting
• Conditions: MECP2 Duplication Syndrome
• Intervention / Treatment: Genetic: HG204

• Study Type: Interventional
• Enrollment (Estimated): 6
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Study Director; Phone Number: 732-318-9873; Email: HG20401@huidagene.com

Study Locations

• China
  • Beijing
    • Peking, Beijing, China
      • Recruiting
      • Peking University First Hospital
      • Contact: Study Director; Email: HG20401@huidagene.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Males ≥ 2 and ≤18 years at the time of signing informed consent;
• Genetic test and clinical confirmed diagnosis of MDS;
• Stable pattern of seizures, or has had no seizures while currently receiving medical treatment (including antiepileptics) and physical therapy are stable for at least 2 months before screening;
• Willing to adhere to protocol, including biological samples collection and hospitalization for intracerebroventricular injection surgery;
• Acceptable hematology, clinical chemistry, and urine laboratory parameters.

Exclusion Criteria:

• MECP2 gene triplication;
• Concurrent genetic syndromes other than MDS;
• Significant brain or cerebellar atrophy, or other significant degenerative changes as shown in cranial MRI at screening;
• Prior or current hypertension, cardiomyopathy, myocardial ischemia or atrial fibrillation and other cardiovascular diseases;
• Prior central nervous system surgery within 6 months before enrolment;
• Systemic use of immunosuppressive drugs within 3 months before enrolment;
• Prior gene therapy or oligonucleotide therapy treatments;
• Any other conditions that would not allow the potential subject to complete follow-up examinations during the study and would, in the opinion of the investigator, make the potential subject unsuitable for the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• 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: HG204; Once intracerebroventricular injection; The duration of the study is about 60 weeks for each subject, including a 8 weeks screening period, enrollment visit, treatment visit and 52 weeks follow-up period.	Genetic: HG204; The study will enroll up to 2 cohorts, evaluating a starting dose plus a higher or lower dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence and severity of systemic adverse events	Number of adverse events (AEs), serious adverse events (SAEs), and dose-limiting toxicities (DLTs)	52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in Clinical Global Impression Scale	Clinical Global Impression Scale is a scale to evaluate mental disorder severity, with a score range from 1-7, the higher scrore means worse mental disorder.	52 weeks
Change from baseline in Griffiths Developmental Assessment Scale	Griffiths Developmental Assessment Scale is a scale to evaluate mental development function of children aged 0-8, including sensory, cognitive and movement, the minimum score is 0, and no maximum limit for the highest score, the higher score means better mental development.	52 weeks
Change from baseline in Peabody Developmental Assessment Scale	Peabody Developmental Assessment Scale is a scale to evaluate motor function of children aged 0-6, with a score range from 0-100, the higher scrore means better motor function.	52 weeks
Change from baseline in Wechsler (toddler/child) Intelligence Scale (fourth version) score	Wechsler (toddler/child) Intelligence Scale (fourth version) score is a scale to assessing the intelligence of children aged 6 to 16, the score range showed a normal distribution, there is no minimum and maximum score, score from 90 to 110 points is normal intelligence result, the higher score means better intelligence.	52 weeks
Adaptive Behavior Rating Scale	Adaptive Behavior Rating Scale is a scale assessing daily living ability of children aged 0-18, with a score range from 0-200, the higher score means better daily living ability	52 weeks

Collaborators and Investigators

• Sponsor: HuidaGene Therapeutics Co., Ltd.
• Collaborators: Peking University First Hospital

Study record dates

Study Major Dates

• Study Start (Actual): October 30, 2024
• Primary Completion (Estimated): October 31, 2026
• Study Completion (Estimated): October 31, 2026

Study Registration Dates

• First Submitted: September 4, 2024
• First Submitted That Met QC Criteria: September 23, 2024
• First Posted (Actual): September 26, 2024

Study Record Updates

• Last Update Posted (Estimated): November 26, 2024
• Last Update Submitted That Met QC Criteria: November 22, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: MDS; CNS; MECP2; CRISPR; dupMECP2; neurodevelopmental disease; Gene-editing; HG204
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Pathologic Processes; Genetic Diseases, Inborn; Disease; Neurobehavioral Manifestations; Heredodegenerative Disorders, Nervous System; Intellectual Disability; Genetic Diseases, X-Linked; Syndrome; Rett Syndrome; Mental Retardation, X-Linked
• Other Study ID Numbers: HG20401

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