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)

HuidaGene Therapeutics Co., Ltd.6 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

MECP2 Duplication Syndrome

Interventions

Eligibility

Sex: MALEMin age: 2 YearsMax age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Incidence and severity of systemic adverse events

Number of adverse events (AEs), serious adverse events (SAEs), and dose-limiting toxicities (DLTs)

Time frame: 52 weeks

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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

Time frame: 52 weeks

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)

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts