Overview

Study Brief Summary overall design This study explored dose escalation of single-arm, open, single intrathecal injection in female RTT subjects with MECP2 gene mutations. The investigator plans to conduct 2-3 dose groups. It is expected that each dose group will enroll 3 subjects, with a total of 6-9 female RTT subjects aged 2-10 years old due to MECP2 gene mutations.

dose escalation

1. For safety reasons, each subject in the first dose group needs to complete a 30-day safety observation. After the researcher determines that it is safe and tolerable, the next subject can be enrolled in the group;
2. The follow-up dose group adopts a sentinel test design, with the first case of each dose group being a sentinel. The first subject needs to complete a 30-day safety observation, and after the researcher determines that it is safe and tolerable, the remaining subjects can be enrolled in the group;
3. If none of the three subjects in a certain dose group developed DLT, the study will proceed to the next higher dose group;
4. If there are no safety issues and no adverse events of dose escalation termination in dose group 2 (see dose termination escalation rules), the researcher and funding unit (Genecombio) will conduct a comprehensive evaluation of the safety data and efficacy trends of all subjects in dose group 2 to determine whether to escalate to dose group 3;
5. During the DLT observation period, if the subject does not observe DLT and the researcher believes that continuing treatment can bring clinical benefits to the subject, the subject will continue to receive treatment; During the DLT observation period, if there is no occurrence of DLT or ≥ grade 2 adverse events related to the investigational drug, it will be escalated to the next dose group. If the subject experiences grade ≥ 2 adverse events related to the study drug, the dose group will be expanded to 3 subjects for further observation of drug safety, and a "3+3" rule will be applied from this dose group onwards. Each subject in each dose group will be enrolled on a case by case basis.

According to the "Technical Guidelines for Long term Follow up Clinical Research of Gene Therapy Products (Trial)", in clinical studies, subjects can automatically enter the long-term follow-up research stage after the last follow-up (52 weeks after administration), and the follow-up period is 5 years after the initial administration.

Eligibility

Inclusion Criteria:

1. Age range from 2 to 10 years old, female;
2. The clinical diagnosis of the subject is RTT, and after genetic testing, it was found to be a pathogenic variant of the MECP2 gene;
3. The legal guardian is able to understand the requirements and procedures of the research plan, voluntarily participate, and sign an informed consent form.

Exclusion Criteria:

1. Has participated in or is currently participating in other RTT drug clinical trials or other AAV gene therapy clinical studies;
2. The subject has a history of head injuries that can cause neurological disorders such as epilepsy, physical disabilities, etc;
3. The subject has MECP2 gene mutation but does not cause RTT;
4. Subjects with allergic constitution, including those allergic or hypersensitive to prednisolone, other glucocorticoids, their excipients, and local anesthetics;
5. The subjects had status epilepticus in the 3 months prior to enrollment;
6. Subjects require invasive or non-invasive ventilation support;
7. Serum anti AAV9 neutralizing antibody titer\>1:200;
8. During the screening visit, subjects with the following abnormal findings: ALT, AST, and γ-glutamyl transferase (GGT) levels all ≥1.0×ULN, TBIL ≥1.0×ULN; serum creatinine (Scr) \>1.0×ULN; activated partial thromboplastin time (APTT) prolonged \>1.5×ULN / INR \>1.5; platelet count (PLT) \<100×10\^9/L or investigator judgment that PLT results are abnormal and clinically significant;
9. Contraindications for lumbar puncture or intrathecal therapy exist;
10. Positive for human immunodeficiency virus antibody, or hepatitis B surface antigen, or hepatitis C antibody, or Treponema pallidum antibody, or current TORCH viral infection, or current Epstein-Barr virus infection;
11. Combination use of any of the following drugs within 90 days prior to administration, and planned immunotherapy therapy (cyclosporine, tacrolimus, methotrexate, cyclophosphamide, intravenous immunoglobulin, rituximab) other than prophylactic medication as specified in the protocol within 3 months after the start of the trial;
12. The researchers believe that it is not suitable to participate in this study.