Related Experiment Video
Updated: Jul 4, 2025
Efficient Gene Knockdown in the Liver via Intrasplenic Injection of Adeno-Associated Virus Serotype 8 (AAV8)-Delivered Small Hairpin RNA
Published on: November 1, 2024
Liver-Directed Adeno-Associated Virus-Mediated Gene Therapy for Mucopolysaccharidosis Type VI
Nicola Brunetti-Pierri1,2, Rita Ferla1,2, Virginia Maria Ginocchio1,2
1Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy.
Abstract:
BACKGROUND: Mucopolysaccharidosis type VI (MPS VI) is an inherited multisystem lysosomal disorder due to arylsulfatase B (ARSB) deficiency that leads to widespread accumulation of glycosaminoglycans (GAG), which are excreted in increased amounts in urine. MPS VI is characterized by progressive dysostosis multiplex, connective tissue and cardiac involvement, and hepatosplenomegaly. Enzyme replacement therapy (ERT) is available but requires life-long and costly intravenous infusions; moreover, it has limited efficacy on diseased skeleton and cardiac valves, compromised pulmonary function, and corneal opacities. METHODS: We enrolled nine patients with MPS VI 4 years of age or older in a phase 1/2 open-label gene therapy study. After ERT was interrupted, patients each received a single intravenous infusion of an adeno-associated viral vector serotype 8 expressing ARSB. Participants were sequentially enrolled in one of three dose cohorts: low (three patients), intermediate (two patients), or high (four patients). The primary outcome was safety; biochemical and clinical end points were secondary outcomes. RESULTS: The infusions occurred without severe adverse events attributable to the vector, meeting the prespecified end point. Participants in the low and intermediate dose cohorts displayed stable serum ARSB of approximately 20% of the mean healthy value but returned to ERT by 14 months after gene therapy because of increased urinary GAG. Participants in the high-dose cohort had sustained serum ARSB of 30% to 100% of the mean healthy value and a modest urinary GAG increase that did not reach a concentration at which ERT reintroduction was needed. In the high-dose group, there was no clinical deterioration for up to 2 years after gene therapy. CONCLUSIONS: Liver-directed gene therapy for participants with MPS VI did not have a dose-limiting side-effect and adverse event profile; high-dose treatment resulted in ARSB expression over at least 24 months with preliminary evidence of disease stabilization. (Funded by the Telethon Foundation ETS, the European Commission Seventh Framework Programme, and the Isaac Foundation; ClinicalTrials.gov number, NCT03173521; EudraCT number, 2016-002328-10.)
Insights
Gene therapy shows promise for Mucopolysaccharidosis type VI (MPS VI), a rare genetic disorder. High-dose treatment led to sustained enzyme levels and disease stabilization in patients, with no serious adverse events observed.
Area of Science:
- Genetics and Genetic Disorders
- Lysosomal Storage Diseases
- Gene Therapy
Background:
- Mucopolysaccharidosis type VI (MPS VI) is a genetic lysosomal disorder caused by arylsulfatase B (ARSB) deficiency.
- Accumulation of glycosaminoglycans (GAG) leads to multisystemic complications including skeletal, cardiac, and pulmonary issues.
- Current enzyme replacement therapy (ERT) has limitations in treating skeletal and cardiac manifestations.
Purpose of the Study:
- To evaluate the safety and efficacy of liver-directed gene therapy using an adeno-associated viral vector (AAV8) expressing ARSB in MPS VI patients.
- To determine the optimal dose for sustained therapeutic benefit and disease stabilization.
Main Methods:
- A phase 1/2 open-label gene therapy study enrolled nine MPS VI patients aged 4+.
- Patients received a single intravenous infusion of AAV8-ARSB across low, intermediate, and high dose cohorts after ERT interruption.
- Safety was the primary endpoint; biochemical (serum ARSB, urinary GAG) and clinical outcomes were secondary.
Main Results:
- Gene therapy infusions were safe, with no severe adverse events attributed to the vector.
- High-dose gene therapy resulted in sustained serum ARSB levels (30-100% of healthy mean) for at least 24 months.
- Patients in the high-dose group showed no clinical deterioration, with urinary GAG levels not requiring ERT reintroduction.
Conclusions:
- Liver-directed gene therapy for MPS VI is safe and well-tolerated, with no dose-limiting adverse events.
- High-dose gene therapy demonstrated sustained ARSB expression and preliminary disease stabilization in MPS VI patients.
- Gene therapy offers a potential alternative to lifelong ERT for MPS VI, particularly for skeletal and cardiac manifestations.
