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Published on: May 16, 2025
Intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome: an uncontrolled phase 1/2
Marc Tardieu1, Michel Zérah2, Marie-Lise Gougeon3
1Paediatric Neurology Department, Université Paris Sud and Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Sud, Le Kremlin-Bicêtre, France.
Insights
This gene therapy trial for Sanfilippo type B syndrome showed improved neurocognitive progression in children. Early treatment in the youngest patient yielded the best results, suggesting a potential window of opportunity for intervention.
Area of Science:
- Neuroscience
- Genetics
- Pediatrics
Background:
- Mucopolysaccharidosis type IIIB (Sanfilippo type B) is a rare genetic disorder causing progressive cognitive decline.
- Currently, no treatments exist for the neurological aspects of this lysosomal storage disease.
- This study investigates a novel intracerebral gene therapy approach.
Purpose of the Study:
- To evaluate the safety and efficacy of intracerebral gene therapy using a recombinant adenoassociated viral vector (rAAV2/5) in children with Sanfilippo type B syndrome.
- To assess neurocognitive progression, brain growth, enzyme activity, and immune response post-treatment.
Main Methods:
- Phase 1/2 clinical trial involving four young children with Sanfilippo type B syndrome.
- Treatment involved intraparenchymal delivery of rAAV2/5 encoding human α-N-acetylglucosaminidase (NAGLU) with immunosuppression.
- Safety and efficacy outcomes were monitored for 30 months, including adverse events, cognitive development, and NAGLU enzyme levels in cerebrospinal fluid (CSF).
Main Results:
- The gene therapy was well-tolerated, with manageable adverse events and no unexpected serious reactions.
- All patients demonstrated improved neurocognitive progression compared to the natural disease course.
- Sustained NAGLU enzyme activity was detected in CSF, and an initial immune response subsided, suggesting acquired tolerance.
Conclusions:
- Intracerebral rAAV2/5 gene therapy is a potentially safe and effective treatment for Sanfilippo type B syndrome.
- Early intervention, particularly in younger patients, may offer the most significant benefits.
- Further long-term follow-up is necessary to confirm sustained efficacy and safety outcomes.
Background:
Mucopolysaccharidosis type IIIB syndrome (also known as Sanfilippo type B syndrome) is a lysosomal storage disease resulting in progressive deterioration of cognitive acquisition after age 2-4 years. No treatment is available for the neurological manifestations of the disease. We sought to assess the safety and efficacy of a novel intracerebral gene therapy.
Methods:
Local regulatory authorities in France allowed inclusion of up to four children in this phase 1/2 study. Treatment was 16 intraparenchymal deposits (four in the cerebellum) of a recombinant adenoassociated viral vector serotype 2/5 (rAAV2/5) encoding human α-N-acetylglucosaminidase (NAGLU) plus immunosuppressive therapy. We assessed tolerance, neurocognitive progression, brain growth, NAGLU enzymatic activity in CSF, and specific anti-NAGLU immune response for 30 months after surgery. This trial is registered with EudraCT, number 2012-000856-33, and the International Standard Clinical Trial Registry, number ISRCTN19853672.
Findings:
Of seven eligible children, the four youngest, from France (n=2), Italy (n=1), and Greece (n=1), aged 20, 26, 30, and 53 months, were included between February, 2012, and February, 2014. 125 adverse events were recorded, of which 117 were treatment emergent and included six classified as severe, but no suspected unexpected serious adverse drug reactions were seen. Vector genomes were detected in blood for 2 days after surgery. Compared with the natural history of mucopolysaccharidosis type III syndromes, neurocognitive progression was improved in all patients, with the youngest patient having function close to that in healthy children. Decrease in developmental quotient was -11·0 points in patient one, -23·0 in patient two, -29·0 in patient three, and -17·0 in patient four, compared with -37·7 in the natural history of the disease. NAGLU activity was detected in lumbar CSF and was 15-20% of that in unaffected children. Circulating T lymphocytes that proliferated and produced tumour necrosis factor α upon ex-vivo exposure to NAGLU antigens were detectable at 1-12 months and 3-12 months, respectively, but not at 30 months in three of four patients.
Interpretation:
Intracerebral rAVV2/5 was well tolerated and induced sustained enzyme production in the brain. The initial specific anti-NAGLU immune response that later subsided suggested acquired immunological tolerance. The best results being obtained in the youngest patient implies a potential window of opportunity. Longer follow-up is needed to further assess safety outcomes and persistence of improved cognitive development.
Funding:
Association Française Contre les Myopathies, Vaincre les Maladies Lysosomales, Institut Pasteur, and UniQure.
