Study on the Safety, Tolerability, and Preliminary Efficacy of Single Intrathecal Injection of AAV-MECP2 in the Treatment of Rett Syndrome

Research background:

Rett syndrome (RTT) is a congenital neurodevelopmental disorder that mainly affects women. Its typical clinical manifestations include cessation or even regression of neural development from 6-18 months after birth, loss of acquired skills such as cognition, language ability, and hand function, often accompanied by stereotyped hand movements, abnormal respiratory rhythms, seizures, and anxiety disorders. RTT is a rare disease with a incidence rate of about 1/10000-15000, which is estimated to account for more than 10% of female intellectual disability. It has a great impact on patients and their families, with severe damage to their social functioning and a very poor quality of life.

Approximately 90-95% of typical RTT patients and 40-50% of atypical RTT patients have detected abnormalities in the methylation CpG binding protein 2 (MeCP2) encoding gene, as well as mutations or deletions in the MECP2 gene. The human MECP2 gene is located at Xq28, and its encoded protein methylated CpG binding protein 2 is a member of the methylation domain family. It is a transcription inhibitory factor that regulates RNA splicing and is a key epigenetic regulator in the brain, affecting neural function. In animal experiments, it was found that Mecp2 deficient mice showed significant improvement in RTT symptoms after receiving Mecp2 protein supplementation through genetic engineering technology.

In recent years, the success of gene therapy in neuromuscular diseases such as spinal muscular atrophy (SMA) has demonstrated the feasibility of applying gene therapy technology in the human body. Since 2023, TAYSHA (intrathecal administration) and Neurogene (intracerebroventricular administration) have respectively initiated gene therapy clinical trials for Rett syndrome. Currently, 2 adult RTT patients and several pediatric RTT patients have completed dosing. At doses ≤1.0×10^15 vg/person, the treatment continues to demonstrate a favorable safety profile with no serious treatment-related adverse events reported. No signs or symptoms indicative of MECP2 overexpression induced toxicity have been observed. Neurogene reported a serious adverse event (SAE) in the 3rd subject receiving a higher dose (3×10^15 vg/person) via intracerebroventricular administration, resulting in patient death. This suggests that excessive dosing may lead to severe adverse reactions.

Professor Qiu Zilong, a senior researcher at the Songjiang Research Institute of Shanghai Jiao Tong University School of Medicine, has been conducting long-term research on RTT. In 2012, it was discovered that MECP2 regulates neuronal synaptic homeostasis plasticity; In 2014, it was discovered that MECP2 regulates microRNA splicing processing; Established MECP2 transgenic crab eating monkey animal model in 2016; In 2019, the neural mechanism of MECP2 mice was identified and gene editing intervention therapy was attempted; Establish a MECP2 mutant mouse AAV gene therapy technology roadmap in 2022 and apply for an invention patent. The independently developed AAV-MECP2 significantly prolonged the lifespan of MECP2 knockout mice in lateral ventricle injection experiments, and the therapeutic effect of AAV-MECP2 with CAG promoter was significantly better than similar products. The safety and efficacy of intrathecal administration in monkey have been tested for 3 months, and blood routine, blood biochemistry, and immune factor indicators have all shown good safety.