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.
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;
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;
Single group
HG204
GeneticThe study will enroll up to 2 cohorts, evaluating a starting dose plus a higher or lower dose
Incidence and severity of systemic adverse events
Number of adverse events (AEs), serious adverse events (SAEs), and dose-limiting toxicities (DLTs)
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.
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.
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.
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.
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HuidaGene Therapeutics Co., Ltd.
Lead sponsor
Peking University First Hospital
Collaborator
