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)

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.

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.