Related Experiment Video
Updated: Jul 17, 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
Systematic gene therapy derived from an investigative study of AAV2/8 vector gene therapy for Fabry disease
Mulan Deng1, Hongyu Zhou1, Shaomei He1
1The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006, Guangdong Province, People's Republic of China.
Background:
Fabry disease (FD) is a progressive multisystemic disease characterized by a lysosomal enzyme deficiency. A lack of α-galactosidase A (α-Gal A) activity results in the progressive systemic accumulation of its substrates, including globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3), which results in renal, cardiac, and/or cerebrovascular disease and early death. Enzyme replacement therapy (ERT) is the current standard of care for FD; however, it has important limitations, including a low half-life, limited distribution, and requirement of lifelong biweekly infusions of recombinant enzymes.
Methods:
Herein, we evaluated a gene therapy approach using an episomal adeno-associated viral 2/8 (AAV2/8) vector that encodes the human GLA cDNA driven by a liver-specific expression cassette in a mouse model of FD that lacks α-Gal A activity and progressively accumulates Gb3 and Lyso-Gb3 in plasma and tissues.
Results:
A pharmacology and toxicology study showed that administration of AAV2/8-hGLA vectors (AAV2/8-hGLA) in FD mice without immunosuppression resulted in significantly increased plasma and tissue α-Gal A activity and substantially normalized Gb3 and Lyso-Gb3 content.
Conclusions:
Moreover, the plasma enzymatic activity of α-Gal A continued to be stably expressed for up to 38 weeks and sometimes even longer, indicating that AAV2/8-hGLA is effective in treating FD mice, and that α-Gal A is continuously and highly expressed in the liver, secreted into plasma, and absorbed by various tissues. These findings provide a basis for the clinical development of AAV2/8-hGLA.
Insights
Gene therapy using AAV2/8 vectors effectively treats Fabry disease (FD) in mice by restoring α-galactosidase A (α-Gal A) activity. This approach offers a promising alternative to enzyme replacement therapy (ERT) for FD.
Area of Science:
- Genetics
- Biochemistry
- Pharmacology
Background:
- Fabry disease (FD) is a genetic lysosomal storage disorder caused by deficient α-galactosidase A (α-Gal A) activity.
- Accumulation of globotriaosylceramide (Gb3) and Lyso-Gb3 leads to severe organ damage and premature death.
- Current enzyme replacement therapy (ERT) has limitations, including short half-life and frequent infusions.
Purpose of the Study:
- To evaluate a novel gene therapy for Fabry disease using adeno-associated viral vectors.
- To assess the efficacy and safety of AAV2/8-hGLA in a preclinical mouse model of FD.
Main Methods:
- An adeno-associated viral 2/8 (AAV2/8) vector encoding human GLA cDNA was developed.
- The vector utilized a liver-specific expression cassette.
- AAV2/8-hGLA was administered to a mouse model of FD lacking α-Gal A activity.
Main Results:
- Administration of AAV2/8-hGLA significantly increased plasma and tissue α-Gal A activity in FD mice.
- Gb3 and Lyso-Gb3 levels were substantially normalized.
- Stable α-Gal A expression was observed for at least 38 weeks post-administration.
Conclusions:
- AAV2/8-hGLA gene therapy is effective in treating Fabry disease in a mouse model.
- The therapy leads to sustained liver expression and secretion of functional α-Gal A.
- These findings support the clinical development of AAV2/8-hGLA for Fabry disease.
More Related Videos
09:20Isolation of Next-Generation Gene Therapy Vectors through Engineering, Barcoding, and Screening of Adeno-Associated Virus AAV Capsid Variants
Published on: October 18, 2022
04:43Author Spotlight: Optimizing Digital Droplet PCR Method for Accurate Adeno-Associated Viral Genome Quantification
Published on: October 11, 2024
