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)

Официальное название

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

Обзор

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.

Вмешательства

• Генная терапия HG204
  The study will enroll up to 2 cohorts, evaluating a starting dose plus a higher or lower dose

Первичные конечные точки

• Incidence and severity of systemic adverse events [Срок оценки: 52 weeks]

Вторичные конечные точки (5)

• Change from baseline in Clinical Global Impression Scale [Срок оценки: 52 weeks]
• Change from baseline in Griffiths Developmental Assessment Scale [Срок оценки: 52 weeks]
• Change from baseline in Peabody Developmental Assessment Scale [Срок оценки: 52 weeks]
• Change from baseline in Wechsler (toddler/child) Intelligence Scale (fourth version) score [Срок оценки: 52 weeks]
• Adaptive Behavior Rating Scale [Срок оценки: 52 weeks]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Peking University First Hospital — Пекин

Идентификаторы

NCT: NCT06615206 · HG20401

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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