The 3-month follow-up results of the first sentinel patient in the RDGT-101 clinical study (ChiCTR2600121466), led by Professor Feng Zhichun’s team at the Seventh Medical Center of Chinese PLA General Hospital, have been officially announced. This is the world’s first human clinical study of AAV9-NAGLU for mucopolysaccharidosis type IIIB (MPS IIIB) administered via intracerebroventricular (ICV) injection, marking landmark preliminary evidence for this innovative therapy.
- Favorable safety profile: No dose-related toxicity, no serious adverse events (SAEs), and no abnormalities in liver or kidney function were observed. Only two grade 1 adverse events were reported, both assessed as unrelated to the study drug.
- Promising efficacy: Serum NAGLU enzyme activity approached the level of healthy controls; urinary heparan sulfate decreased by 58.4%; complete extension of contracted hand and foot joints was achieved. Multiple indicators of the pediatric patient, including speech clarity, logical conversation ability, eye contact, skin texture and appetite, were significantly improved. Concurrent improvement in hematological indicators suggested systemic benefits.
Mucopolysaccharidosis Type IIIB (MPS IIIB, also known as Sanfilippo Syndrome Type B) is an autosomal recessive lysosomal storage disorder caused by pathogenic variants in theNAGLUgene. Due to the deficiency of α-N-acetylglucosaminidase (NAGLU) activity, heparan sulfate cannot be effectively degraded in patients and gradually accumulates in tissues including the central nervous system (CNS), ultimately leading to neurological damage characterized by progressive degeneration of language, cognition, behavior and motor function. MPS III mainly affects the brain and spinal cord, with MPS IIIB specifically caused byNAGLUgene variants. Currently, there remains no approved therapy that can definitively modify the disease course for this condition.
Over the past decade, global exploration of treatments for MPS IIIB has continued, and key issues in the therapeutic development of this disease have been gradually clarified: whether drugs or therapeutic genes can reach the CNS effectively, stably and safely, and form replicable and generalizable clinical pathways in pediatric patients. For example, the ABO-101 program developed by Abeona, which delivers AAV9-NAGLU via intravenous administration, observed safety and biological activity signals in early studies. The study design also included neurocognitive development, cerebrospinal fluid (CSF) heparan sulfate, peripheral glycosaminoglycans (GAGs), and liver and spleen volume as key observational endpoints. On the other hand, the rAAV2/5-hNAGLU program conducted by uniQure/Institut Pasteur adopted multi-site intraparenchymal injection, completed administration in 4 children, and conducted follow-up for up to 66 months, providing important clinical experience for the feasibility and long-term observation of local CNS delivery in MPS IIIB.
These international studies have jointly advanced the field of MPS IIIB gene therapy, and also highlighted the core challenges in clinical translation: the key to MPS IIIB treatment lies in striking a balance among CNS delivery efficiency, intracerebral distribution coverage, perioperative safety, tolerability in pediatric patients, and accessibility of clinical pathways. For patient families, the most urgent demand is to access a disease-modifying treatment that can intervene in CNS neurodegeneration as early as possible, has clear biological evidence, and is implementable in real clinical settings.
Against this background, RDGT-101 selects the ICV route for CNS delivery, with clear medical rationale: this route can bypass the blood-brain barrier (BBB) and allow therapeutic vectors to directly enter the CSF circulation. Meanwhile, compared with multi-site intraparenchymal injection, ICV administration has higher route recognizability and greater potential for standardized operation within the collaboration system of pediatric neurosurgery and critical care medicine. For MPS IIIB, which is characterized by widespread CNS involvement, this route is expected to achieve a better balance among delivery efficiency, procedural safety and future clinical scalability.
Currently, 3 patients with MPS IIIB have completed administration in the RDGT-101 study. The research team will continue to advance the 52-week follow-up in accordance with the protocol, systematically evaluate multi-dimensional indicators including safety, CSF and peripheral biomarkers, neurocognitive development, behavior and imaging findings, and advance subsequent clinical development on the basis of rigorous medical evidence. For pediatric rare diseases such as MPS IIIB, where irreversible neurodegeneration is the major threat, the clinical advancement of RDGT-101 represents a treatment direction closer to the real needs of patients: delivering therapeutic genes to the CNS effectively within the earliest possible disease window, and striving for the possibility of modifying the disease course for affected children and their families in a sustainable, verifiable and scalable manner. It will also provide reusable clinical pathways and technical foundations for the development of gene therapies for more CNS genetic diseases.