A phase I/II clinical study to evaluate the tolerance, safety and efficacy of VGN-R08b intracerebroventricular injection in patients with type III Gaucher's disease

This is an open-label, dose-escalation clinical trial, consisting of dose escalation and dose expansion. A total of 12 subjects are expected to be enrolled.

Dose escalation: Initially, three doses of 6×10^10 vg/g, 1.2×10^11 vg/g, and 1.8×10^11 vg/g (per unit brain weight) are planned to be explored . Three subjects will be enrolled in each dose group. The second and third subjects in the same dose group must be confirmed to be safe and tolerable after at least a 4-week safety assessment of the first subject before receiving the drug. For the high-dose group (1.8×10^11 vg/g), subjects will be enrolled one by one.

Dose expansion: After the dose escalation is completed, the SRC will comprehensively evaluate the data on efficacy, safety, and immunogenicity, etc., to select the optimal effective dose and expand the enrollment by 3 cases.

Inclusion Criteria:

1. The signing of the informed consent form should be completed when the subject is at least 2 years old but less than 18 years old.
2. The subject has a documented medical history of Gaucher disease confirmed by GCase enzyme activity testing, and has a double GBA1 gene mutation.
3. According to the investigator's assessment, the neurological signs and/or symptoms are consistent with type III Gaucher disease.
4. At the time of enrollment, the subject has horizontal eye movement disorders (including gaze paralysis, or delayed or absent saccades), but there is no severe motor dysfunction resulting in bedridden status.
5. The subject is currently receiving substrate reduction therapy (SRT) and/or high-dose ambroxol for Gaucher disease treatment. The subject is required to have been on stable treatment for at least 2 months before enrollment and the investigator determines that the treatment is ineffective for neurological symptoms, or is willing to discontinue the treatment at the time of enrollment (discontinuation 1 week before administration).
6. The subject is currently receiving and willing to continue stable peripheral treatment (including imiglucerase or other ERT, or SRT), and the peripheral symptoms of Gaucher disease are stable at the time of screening, that is, all of the following conditions are met: hemoglobin level ≥ 11.0 g/dL (female) or ≥ 12.0 g/dL (male), platelet count ≥ 100×109/L, spleen volume < 10 times the normal value (MN), liver volume < 1.5 MN, and no bone crisis or asymptomatic bone disease (such as bone necrosis and/or pathological fractures causing bone pain) within 3 months before screening.
7. (Applicable) Male and female subjects with reproductive potential must continue to use an effective contraceptive method (including abstinence) correctly from the screening period until at least 1 year after the start of treatment, and not donate sperm or eggs.
8. The subject (applicable) and their parents/guardians must understand the trial information, purpose and risks described in the informed consent form, and authorize the use of the subject's health information and provide an informed consent form with the signature and date of signing.
9. The subject (applicable) and their parents/guardians are willing to participate in the study as information providers, providing the subject's health status, cognition and physical ability (including providing information for rating scales).

Exclusion Criteria:

1. There are other serious neurological disorders that may cause symptoms of Gaucher disease or interfere with the research objectives;

2. There are severe internal organ damages caused by Gaucher disease, which, after evaluation by the researchers, are considered to pose unacceptable risks to the subjects, or interfere with the subjects' research compliance, or interfere with the execution of the trial;

3. Long-term ventilation or long-term nasogastric feeding (long-term ventilation is defined as: requiring tracheotomy for respiratory assistance, or continuous 14 days or more of non-invasive respiratory assistance for ≥ 16 hours per day, excluding acute reversible diseases that require assisted ventilation and perioperative ventilation. Long-term nasogastric feeding refers to the use of a nasogastric tube for feeding due to severe loss of swallowing function);

4. There are severe immunodeficiencies or autoimmune diseases;

5. There is active infection (including viral infections such as HIV, HBV, HCV or syphilis);

   The following medication and treatment situations exist:

6. Currently using drugs, herbs, or over-the-counter medications that have strong inhibitory or inducing effects on CYP3A4 or P-gp;

7. Having received bone marrow or organ transplantation, or any gene or cell therapy;

8. Having undergone immunization (live vaccines) within 4 weeks;

9. Undergoing systemic immunosuppressive therapy or corticosteroid therapy other than that required by the protocol (local preparations for skin diseases can be used);