Related Experiment Video
Updated: Jun 16, 2026
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
Rescue of lysosomal acid lipase deficiency in mice by rAAV8 liver gene transfer
Marine Laurent1,2, Rim Harb1,2, Christine Jenny1,2
1Genethon, 91000, Evry, France.
Insights
Gene therapy using rAAV8 vectors successfully treated lysosomal acid lipase deficiency (LAL-D) in mice. This approach corrected lipid accumulation and offered a potential new therapy for LAL-D patients.
Area of Science:
- Genetics and Molecular Biology
- Biochemistry
- Medical Research
Background:
- Lysosomal acid lipase deficiency (LAL-D) is a severe genetic disorder causing fatal lipid accumulation.
- Mutations in the LIPA gene lead to multi-organ failure and early death in untreated patients.
- Current treatment involves supportive enzyme replacement therapy via weekly injections.
Purpose of the Study:
- To characterize a novel mouse model of LAL-D (Lipa-/-).
- To develop and evaluate a curative gene therapy for LAL-D.
- To determine the efficacy of in vivo gene therapy in correcting the LAL-D phenotype.
Main Methods:
- Developed a Lipa-/- mouse model for LAL-D.
- Administered recombinant adeno-associated virus serotype 8 (rAAV8) vector encoding the human LIPA transgene.
- Utilized a hepatocyte-specific promoter for targeted gene expression.
- Assessed disease lethality, lipid levels, and mitochondrial function.
Main Results:
- Defined the minimal rAAV8 dose for rescuing disease lethality.
- Successfully corrected cholesterol and triglyceride accumulation in multiple organs and blood.
- Identified and reversed mitochondrial impairment in LAL-D mice through gene therapy.
Conclusions:
- In vivo gene therapy with rAAV8 vectors provides stable, long-term LAL expression.
- The gene therapy strategy effectively corrects the LAL-D phenotype in the established mouse model.
- This approach represents a promising new therapeutic option for LAL-D patients.
Background:
Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive disorder caused by mutations in the LIPA gene, which results in lipid accumulation leading to multi-organ failure. If left untreated, the severe form of LAL-D results in premature death within the first year of life due to failure to thrive and hepatic insufficiency. Weekly systemic injections of recombinant LAL protein, referred as enzyme replacement therapy, is the only available supportive treatment.
Method:
Here, we characterized a novel Lipa-/- mouse model and developed a curative gene therapy treatment based on the in vivo administration of recombinant (r)AAV8 vector encoding the human LIPA transgene under the control of a hepatocyte-specific promoter.
Results:
Here we define the minimal rAAV8 dose required to rescue disease lethality and to correct cholesterol and triglyceride accumulation in multiple organs and blood. Finally, using liver transcriptomic and biochemical analysis, we show mitochondrial impairment in Lipa-/- mice and its recovery by gene therapy.
Conclusions:
Overall, our in vivo gene therapy strategy achieves a stable long-term LAL expression sufficient to correct the disease phenotype in the Lipa-/- mouse model and offers a new therapeutic option for LAL-D patients.
