An Open-label, Single Arm, Dose-Escalation Clinical Study to Evaluating the Safety, Tolerability and Preliminary Efficacy of a Single Intracerebroventricular Injection of RB001 for the Treatment of SHANK3-related Phelan-McDermid Syndrome.
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 8
- 试验地点
- 1
- 主要终点
- To evaluate the safety and tolerability of a single intracerebroventricular injection of RB001 through week 52
研究概览
简要总结
This is an open-label, dose-escalation study to evaluate the safety, tolerability, and clinical activity of a single dose of RB001 administered via intracerebroventricular (ICV) injection in pediatric with SHANK3 related Phelan-McDermid Syndrome. Clinical data will be evaluated for safety, tolerability, and preliminary efficacy of RB001 in participants with SHANK3 related PMS.
详细描述
SHANK3-related Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder primarily caused by a deletion of chromosome 22q13 or a mutation of the SHANK3 gene. The syndrome is characterized by intellectual disability and language impairment. The SHANK3 protein is part of the postsynaptic density complex and participates in postsynaptic signal transduction and synaptic development, serving as a critical structural protein for central nervous system development and functional maintenance. SHANK3 deficiency leads to abnormal neuronal development and is the primary cause of PMS. The estimated global prevalence is approximately 1/15,000. Clinical manifestations include global developmental delay, particularly severe language delay, autism-like behaviors, hypotonia, and potentially epilepsy. Currently, there are no effective treatments for this condition.
RB001 is developed by Shenzhen Reborngene Therapeutics Co., Ltd. for the treating of Phelan-McDermid Syndrome. RB001 utilizes the Adeno-Associated Virus (AAV) vector to deliver an optimized SHANK3-minigene via intracerebroventricular (ICV) injection. Nonclinical studies have demonstrated that a single ICV injection of RB001 could restore SHANK3 mRNA and protein expression in the target region of central nervous system of the SHANK3-mutant mouse models, as well as the restore of motor deficits, stereotypical behaviors, and reduced exploratory behaviors and neuronal function.
A target of 8 pediatric participants aged 3 to 18 years will be treated. All participants will be followed for safety, tolerability and preliminary efficacy after the date of treatment with RB001.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 3 Years 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥3 years and <18 years (at the time of signing informed consent), any gender
- •Genetic test and clinical confirmed diagnosis of SHANK3-related PMS
- •Meets diagnostic criteria for moderate or more severe Autism Spectrum Disorder (ASD)
- •Intelligence Quotient (IQ) score <70 or Developmental Quotient (DQ) (excluding gross motor) average score <70
- •Willing to provide biological samples required for the study (e.g., blood, urine)
- •Consent to hospitalization for intracerebroventricular injection surgery
- •The holders of parental authority who are able to understand and willing to comply with study requirements and procedures, voluntarily participating and signing the informed consent
排除标准
- •A pediatric participant who meets any of the following criteria will be excluded from this study:
- •Previous or current participation in other PMS drug clinical trials or other AAV gene therapy clinical studies
- •Has known allergic constitution, including allergy or hypersensitivity to prednisone acetate, other glucocorticosteroids, their excipients, or local anesthetics
- •Subjects with status epilepticus within 3 months prior to enrollment
- •Subjects requiring invasive or non-invasive ventilatory support
- •Serum anti-AAV neutralizing antibody titer >1:200
- •Significant laboratory abnormalities: alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl transferase (GGT) with any value above the upper limit of normal; total bilirubin above the upper limit of normal; creatinine ≥159 μmol/L; hemoglobin (Hb) <80 g/L; prothrombin time (PT) prolonged by ≥3 seconds; activated partial thromboplastin time (APTT) prolonged by ≥10 seconds; fasting blood glucose ≥7.0 mmol/L; glycated hemoglobin (HbA1c) ≥6.5%; platelets (PLT) <100×10^9/L
- •Subjects with liver disease or history of heart disease that may pose drug-related risks as assessed by the investigator
- •Subjects deemed unsuitable for intracerebroventricular administration or with other special circumstances as assessed by the investigator
- •Positive for human immunodeficiency virus antibody, hepatitis B surface antigen, hepatitis C antibody, syphilis antibody, active TORCH virus infection, or active Epstein-Barr virus infection
- •Concomitant use of any of the following medications within 90 days prior to administration, or planned immunosuppressive treatment within 3 months after starting the trial, except for prophylactic medications specified in the protocol (cyclosporine, tacrolimus, methotrexate, cyclophosphamide, intravenous immunoglobulin, rituximab, etc. )
- •Other conditions deemed unsuitable for participation in this study by the investigator
研究组 & 干预措施
RB001
Once intracerebroventricular injection; The duration of the study is about 14 months for each subject, including a 2-month screening period, an inpatient period from Day 1 (Dosing) to Day 7 post-administration and a subsequent 12-month outpatient follow-up period.
干预措施: RB001 (Genetic)
结局指标
主要结局
To evaluate the safety and tolerability of a single intracerebroventricular injection of RB001 through week 52
时间窗: 52 weeks
Types, severity, and incidence of adverse events (AEs) and serious adverse events (SAEs) within 52 weeks after RB001 injection
次要结局
- To evaluate the changes on Clinical Global Impression Scale - Severity (CGI-S) after a single intracerebroventricular injection of RB001 through week 52(52 weeks)
- To evaluate the changes on Clinical Global Impression Scale - Improvement (CGI-I) after a single intracerebroventricular injection of RB001 through week 52(52 weeks)
- To evaluate the changes on Griffith developmental assessment scale - Chinese (GDS-C) after a single intracerebroventricular injection of RB001 through week 52(52 weeks)
- To evaluate the changes on Wechsler Preschool and Primary Scale of Intelligence (WPPSI) or Wechsler Intelligence Scale for Children (WISC) after a single intracerebroventricular injection of RB001 through week 52(52 weeks)
- To evaluate the changes on Adaptive Behavior Assessment System-Second Edition (ABAS-2) after a single intracerebroventricular injection of RB001 through week 52(52 weeks)
- To evaluate the changes on Social Life Ability Scale For Infant-Junior Middle School Student (S-M) after a single intracerebroventricular injection of RB001 through week 52(52 weeks)
- To evaluate the changes on Child Behavior Checklist (CBCL) after a single intracerebroventricular injection of RB001 through week 52(52 weeks)
- To evaluate AAV viral load after a single intracerebroventricular injection of RB001 through week 52(52 weeks)
- To evaluate AAV viral shedding after a single intracerebroventricular injection of RB001 through week 52(52 weeks)
- To evaluate AAV binding and neutralizing antibodies after a single intracerebroventricular injection of RB001 through week 52(52 weeks)
- To evaluate SHANK3 binding antibody after a single intracerebroventricular injection of RB001 through week 52(52 weeks)
- To evaluate changes in T-cell responses against AAV and SHANK3 after a single intracerebroventricular injection of RB001 through week 52(52 weeks)
- To evaluate the changes on Patient's Global Impressions of Improvement (PGI-I) after a single intracerebroventricular injection of RB001 through week 52(52 weeks)
- To evaluate the changes on Childhood Autism Rating Scale (CARS-2) after a single intracerebroventricular injection of RB001 through week 52(52 weeks)
- To evaluate the changes on Autism Behavior Checklist (ABC) after a single intracerebroventricular injection of RB001 through week 52(52 weeks)
- To evaluate the changes on Peabody developmental motor scales - 2nd Edition (PDMS-2) after a single intracerebroventricular injection of RB001 through week 52(52 weeks)
- To evaluate the changes on Children's sleep habits questionnaire(CSHQ) after a single intracerebroventricular injection of RB001 through week 52(52 weeks)
研究者
Ye Wu
Professor, Chief Physician
Peking University First Hospital