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Updated: Aug 31, 2025
Intravenous Injections in Neonatal Mice
Published on: November 11, 2014
Disease correction in mucopolysaccharidosis type IIIB mice by intraparenchymal or cisternal delivery of a capsid
Courtney J Rouse1,2, Kimberley Hawkins1, Nadia Kabbej1
1Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA.
Abstract:
Mucopolysaccharidosis type IIIB (MPS IIIB) is an autosomal recessive lysosomal storage disease caused by mutations in the gene that encodes the protein N-acetyl-glucosaminidase (NAGLU). Defective NAGLU activity results in aberrant retention of heparan sulfate within lysosomes leading to progressive central nervous system (CNS) degeneration. Intravenous treatment options are limited by the need to overcome the blood-brain barrier and gain successful entry into the CNS. Additionally, we have demonstrated that AAV8 provides a broader transduction area in the MPS IIIB mouse brain compared with AAV5, 9 or rh10. A triple-capsid mutant (tcm) modification of AAV8 further enhanced GFP reporter expression and distribution. Using the MPS IIIB mouse model, we performed a study using either intracranial six site or intracisterna magna injection of AAVtcm8-codon-optimized (co)-NAGLU using untreated MPS IIIB mice as controls to assess disease correction. Disease correction was evaluated based on enzyme activity, heparan sulfate storage levels, CNS lysosomal signal intensity, coordination, activity level, hearing and survival. Both histologic and enzymatic assessments show that each injection method results in supranormal levels of NAGLU expression in the brain. In this study, we have shown correction of lifespan and auditory deficits, increased CNS NAGLU activity and reduced lysosomal storage levels of heparan sulfate following AAVtcm8-coNAGLU administration and partial correction of NAGLU activity in several peripheral organs in the murine model of MPS IIIB.
Insights
Gene therapy using AAVtcm8-coNAGLU in MPS IIIB mice corrected lifespan and auditory deficits. This treatment increased N-acetyl-glucosaminidase (NAGLU) activity in the central nervous system and reduced harmful heparan sulfate storage.
Area of Science:
- Genetics
- Neurology
- Biochemistry
Background:
- Mucopolysaccharidosis type IIIB (MPS IIIB) is a genetic lysosomal storage disease.
- Defective N-acetyl-glucosaminidase (NAGLU) causes heparan sulfate buildup and central nervous system (CNS) degeneration.
- Current treatments face challenges in crossing the blood-brain barrier.
Purpose of the Study:
- To evaluate the efficacy of AAVtcm8-coNAGLU gene therapy for MPS IIIB.
- To assess the impact of intracranial and intracisternal magna injections of AAVtcm8-coNAGLU.
- To determine if this gene therapy can correct CNS and peripheral organ pathology in MPS IIIB mice.
Main Methods:
- Utilized the MPS IIIB mouse model.
- Administered AAVtcm8-codon-optimized (co)-NAGLU via intracranial or intracisterna magna injection.
- Evaluated disease correction through enzyme activity, heparan sulfate levels, CNS lysosomal signals, motor function, hearing, and survival.
Main Results:
- Both injection methods led to supranormal NAGLU expression in the brain.
- Significant correction of lifespan and auditory deficits was observed.
- Reduced heparan sulfate storage and increased CNS NAGLU activity were confirmed.
- Partial correction of NAGLU activity was noted in peripheral organs.
Conclusions:
- AAVtcm8-coNAGLU gene therapy effectively corrects key pathological features of MPS IIIB in mice.
- Intracranial and intracisterna magna delivery methods show promise for CNS gene therapy in MPS IIIB.
- This approach offers a potential therapeutic strategy for MPS IIIB by restoring NAGLU function and mitigating CNS damage.
