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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
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Long-Term Liver-Targeted AAV8 Gene Therapy for Mucopolysaccharidosis IVA
Shaukat A Khan1, Eliana Benincore-Florez1,2, Fnu Nidhi1,3
1Department of Biomedical Research, Nemours Children's Health, Wilmington, DE 19803, USA.
Current Issues in Molecular Biology
|November 26, 2025
Summary
Gene therapy using AAV8 vectors improved biochemical markers and bone pathology in a mouse model of Mucopolysaccharidosis IVA (MPS IVA). Male mice showed greater therapeutic benefits than female mice, highlighting potential sex-based differences in treatment efficacy.
Area of Science:
- Biochemistry
- Genetics
- Medical Science
Background:
- Mucopolysaccharidosis IVA (MPS IVA) is a genetic lysosomal storage disorder caused by GALNS enzyme deficiency.
- This deficiency leads to the accumulation of GAGs, impacting cartilage and bone development, causing skeletal dysplasia.
- Current treatments like ERT and HSCT have limited efficacy on bone lesions.
Purpose of the Study:
- To evaluate the long-term efficacy of liver-specific AAV8 gene therapy in an MPS IVA mouse model.
- To assess the impact of gene therapy on biochemical markers and bone pathology.
- To investigate potential sex-based differences in therapeutic response.
Main Methods:
- Administration of liver-specific AAV8 vectors with a thyroxine-binding globulin promoter in MPS IVA mice.
- Long-term monitoring (24 weeks in males, 48 weeks in females) of biochemical markers and bone pathology.
- Measurement of GALNS enzyme activity and keratan sulfate levels in plasma and tissues.
Main Results:
- Supraphysiological GALNS enzyme activity was observed in plasma and multiple tissues in treated mice.
- Keratan sulfate levels were normalized in plasma, liver, and bone in male mice.
- Treated male mice showed reduced vacuolated cells and improved bone pathology, while female mice had less pronounced improvements.
Conclusions:
- Liver-specific AAV8 gene therapy demonstrates long-term therapeutic potential for MPS IVA.
- Significant improvements in biochemical markers and bone pathology were observed, particularly in male mice.
- The study suggests potential sex-based differences in gene therapy efficacy for MPS IVA.
