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Updated: Jun 8, 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
Adeno-associated virus serotype 8 gene transfer rescues a neonatal lethal murine model of propionic acidemia
Randy J Chandler1, Suma Chandrasekaran, Nuria Carrillo-Carrasco
1Organic Acid Research Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Insights
Adeno-associated viral (AAV) gene transfer rescued over 64% of propionic acidemia (PA) mice from early death. This gene therapy approach shows promise for treating this metabolic disorder.
Area of Science:
- Biochemistry
- Genetics
- Metabolic Disorders
Background:
- Propionic acidemia (PA) is a severe autosomal recessive metabolic disorder.
- Deficiency in propionyl-coenzyme A carboxylase (PCC) leads to metabolic instability and multisystemic complications.
- Current therapies offer limited success, highlighting the need for novel treatments.
Purpose of the Study:
- To evaluate the efficacy of adeno-associated viral (AAV) gene transfer for treating propionic acidemia (PA).
- To determine if AAV-mediated delivery of the PCCA gene can rescue a murine model of PA.
Main Methods:
- A murine model of PA (Pcca(-/-)) with early-onset lethality was utilized.
- An AAV serotype 8 (AAV8) vector expressing human PCCA cDNA was administered via intrahepatic injection to newborn mice.
- Metabolic markers and PCC enzyme levels were assessed in treated and untreated mice.
Main Results:
- AAV8-mediated gene transfer rescued over 64% of Pcca(-/-) mice, enabling survival beyond 16 days.
- PCC enzyme levels were restored to above wild-type levels in the liver of treated mice.
- Treated mice showed significantly reduced plasma 2-methylcitrate levels, indicating restored enzymatic activity.
Conclusions:
- AAV gene delivery of PCCA is an effective strategy to rescue Pcca(-/-) mice from neonatal lethality.
- This gene transfer approach substantially ameliorates key metabolic markers of propionic acidemia.
- AAV8-mediated gene therapy represents a potential therapeutic option for PA, a disorder with limited treatment alternatives.
Abstract:
Propionic acidemia (PA) is an autosomal recessive disorder of metabolism caused by a deficiency of propionyl-coenzyme A carboxylase (PCC). Despite optimal dietary and cofactor therapy, PA patients still suffer from lethal metabolic instability and experience multisystemic complications. A murine model of PA (Pcca(-/-)) of animals that uniformly die within the first 48 hr of life was used to determine the efficacy of adeno-associated viral (AAV) gene transfer as a potential therapy for PA. An AAV serotype 8 (AAV8) vector was engineered to express the human PCCA cDNA and delivered to newborn mice via an intrahepatic injection. Greater than 64% of the Pcca(-/-) mice were rescued after AAV8-mediated gene transfer and survived until day of life 16 or beyond. Western analysis of liver extracts showed that PCC was completely absent from Pcca(-/-) mice but was restored to greater than wild-type levels after AAV gene therapy. The treated Pcca(-/-) mice also exhibited markedly reduced plasma levels of 2-methylcitrate compared with the untreated Pcca(-/-) mice, which indicates significant PCC enzymatic activity was provided by gene transfer. At the time of this report, the oldest treated Pcca(-/-) mice are over 6 months of age. In summary, AAV gene delivery of PCCA effectively rescues Pcca(-/-) mice from neonatal lethality and substantially ameliorates metabolic markers of the disease. These experiments demonstrate a gene transfer approach using AAV8 that might be used as a treatment for PA, a devastating and often lethal disorder desperately in need of new therapeutic options.
