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Updated: Apr 26, 2026
Production and Titering of Recombinant Adeno-associated Viral Vectors
Published on: November 27, 2011
Effects of adeno-associated virus serotype and tissue-specific expression on circulating biomarkers of propionic
Adam J Guenzel1, Matthew L Hillestad, Dietrich Matern
11 Virology and Gene Therapy Graduate Program, Mayo Clinic , Rochester, MN 55905.
Insights
Gene therapy using adeno-associated virus (AAV) vectors shows promise for treating propionic acidemia (PA). Targeting both liver and muscle tissues is crucial for effectively correcting this metabolic disorder.
Area of Science:
- Biochemistry
- Genetics
- Metabolic Disorders
Background:
- Propionic acidemia (PA) is a severe autosomal recessive metabolic disorder resulting from propionyl-CoA carboxylase (PCC) deficiency.
- Current treatments for PA, including dietary protein restriction and liver transplantation, have limitations.
- A hypomorphic mouse model (Pcca(-/-)(A138T)) with 2% wild-type PCC activity was previously established to study PA.
Purpose of the Study:
- To investigate the efficacy of liver- or muscle-directed adeno-associated virus (AAV) gene therapy in treating systemic PA.
- To compare the therapeutic effects of different AAV serotypes and tissue-specific promoters in a mouse model of PA.
Main Methods:
- Utilized AAV vectors (AAV1, AAV8, AAVrh10) with varying tissue tropisms for gene delivery.
- Employed tissue-specific promoters (MCK6 for muscle, TTR for liver) to direct gene expression.
- Administered systemic gene therapy to Pcca(-/-)(A138T) mice and monitored biochemical markers of PA.
Main Results:
- All tested AAV vectors, including AAV1, AAV8, and AAVrh10, significantly corrected circulating propionylcarnitine (C3) and methyl citrate levels.
- Targeted gene therapy with AAV1 (muscle-specific) and AAV8 (liver-specific) demonstrated long-term correction of PA metabolites.
- Liver-specific AAV8-TTR-PCCA therapy showed superior metabolic correction compared to muscle-specific AAV1-MCK-PCCA therapy.
Conclusions:
- Targeted AAV gene therapy, particularly when involving both liver and muscle, offers a potential alternative to liver transplantation for PA.
- Correction of multiple tissue types, not solely the liver, is essential for fully addressing the systemic pathology of PA.
- This study highlights the potential of tissue-specific and broad gene therapy approaches for cell-autonomous systemic genetic diseases like PA.
Abstract:
Propionic acidemia (PA) is an autosomal recessive inborn error of metabolism caused by deficiency of propionyl-CoA carboxylase (PCC). This enzyme is composed of six PCCA and six PCCB subunits and mediates a critical step in catabolism of odd chain fatty acids and certain amino acids. Current treatment options for PA are limited to stringent dietary restriction of protein consumption and some patients undergo elective liver transplantation. We previously generated a hypomorphic model of PA, designated Pcca(-/-)(A138T), with 2% of wild-type enzyme activity that mimics many aspects of the human disease. In this study, we used the differing tissue tropisms of adeno-associated virus (AAV) to probe the ability of liver or muscle-directed gene therapy to treat systemic aspects of this disease that affects many cell types. Systemic therapy with muscle-biased AAV1, liver-biased AAV8, and broadly tropic AAVrh10 mediated significant biochemical corrections in circulating propionylcarnitine (C3) and methyl citrate by all vectors. The innate tissue bias of AAV1 and AAV8 gene expression was made more specific by the use of muscle-specific muscle creatine kinase (specifically MCK6) and hepatocyte-specific transthyretin (TTR) promoters, respectively. Under these targeted conditions, both vectors mediated significant long-term correction of circulating metabolites, demonstrating that correction of muscle and likely other tissue types in addition to liver is necessary to fully correct pathology caused by PA. Liver-specific AAV8-TTR-PCCA mediated better correction than AAV1-MCK-PCCA. These data suggest that targeted gene therapy may be a viable alternative to liver transplantation for PA. They also demonstrate the effects of tissue-specific and broad gene therapy on a cell autonomous systemic genetic disease.
