rb001 gene therapy study in children with shank3-related phelan mcdermid syndrome (pms)

Conditions: Phelan-McDermid Syndrome; SHANK3 Haploinsufficiency

Summary: this is a first in human, 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.

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.

Eligibility criteria:
inclusion criteria: * 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 exclusion criteria: 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

Keywords: aav shank3 phelan-mecdermid syndrome 22q13.3 deletion syndrome