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Published on: October 31, 2012
Short-term rescue of neonatal lethality in a mouse model of propionic acidemia by gene therapy
Sean E Hofherr1, Julien S Senac, Christopher Y Chen
1Division of Infectious Diseases, Department of Internal Medicine, and Translational Immunovirology Program, Mayo Clinic, Rochester, MN 55905, USA
Insights
Gene therapy offers a potential treatment for propionic acidemia (PA), a serious metabolic disorder. Adenovirus vectors expressing PCCA showed promise in extending lifespan in a mouse model, demonstrating a proof of principle for PA gene therapy.
Area of Science:
- Biochemistry
- Genetics
- Molecular Biology
Background:
- Propionic acidemia (PA) is an autosomal recessive metabolic disorder caused by PCCA or PCCB gene mutations.
- Current treatments involving dietary restriction are insufficient, leading to progressive neurological damage from hyperammonemia.
- PA can be fatal if left untreated, necessitating novel therapeutic strategies.
Purpose of the Study:
- To evaluate gene therapy approaches for propionic acidemia (PA) using a stringent mouse model.
- To assess the efficacy of adenovirus serotype 5 (Ad5) vectors in treating PCCA deficiency.
- To investigate the role of polyethylene glycol (PEG) modification in altering viral tropism for enhanced liver transduction.
Main Methods:
- Developed a stringent mouse model of PCCA deficiency with early mortality.
- Administered first-generation and helper-dependent Ad5 vectors expressing human PCCA cDNA via intraperitoneal injection.
- Utilized luciferase imaging and dsRed expression to assess viral transduction efficiency.
- Employed PEG modification of Ad5 vectors to detarget peritoneum and retarget liver transduction.
- Evaluated adeno-associated virus serotype 8 (AAV8) for gene therapy efficacy.
Main Results:
- Both unmodified and PEG-modified Ad5 vectors expressing PCCA demonstrated a significant, albeit transient, increase in lifespan in the PA mouse model.
- PEG modification successfully detargeted Ad5 from the peritoneum and retargeted it for liver transduction.
- AAV8-mediated transduction also resulted in only transient rescue of lifespan.
- Gene therapy with Ad5 vectors provided the first proof of principle for treating PA.
Conclusions:
- Gene therapy using Ad5 vectors shows potential for treating propionic acidemia (PA).
- PEG modification of Ad5 vectors can effectively alter viral tropism, enhancing liver transduction for gene therapy applications.
- While transient, the observed lifespan extension highlights the therapeutic potential of gene therapy for PA, warranting further investigation.
Abstract:
Propionic acidemia (PA) is a metabolic disorder that causes mental retardation and that can be fatal if untreated. PA is inherited in an autosomal recessive fashion involving mutations in PCCA or PCCB encoding the alpha and beta subunits of propionyl-CoA carboxylase (PCC). Current treatment is based on dietary restriction of substrate amino acids, which attenuates symptoms. However, patients still experience episodes of hyperammonemia that can cause progressive neurologic damage. In this paper, we have tested gene therapy approaches to PA in a stringent mouse model of PCCA deficiency, in which homozygous knockout mice are born but die within 36 hr. In this work, we have delivered first-generation and helper-dependent adenovirus serotype 5 (Ad5) vectors expressing the human PCCA cDNA by intraperitoneal injection into newborn mice. Unmodified Ad5 vectors mediated extensive transduction of the peritoneum with weak liver transduction as determined by luciferase imaging and dsRed expression. In contrast, modification of Ad5 with polyethylene glycol detargeted the virus from the peritoneum and retargeted it for transduction in the liver. When vectors expressing PCCA were injected, significant increases in life span were observed for both the unmodified and polyethylene glycol (PEG)-modified Ad5 vectors. However, this rescue was transient. Similarly, adeno-associated virus serotype 8-mediated transduction also produced only transient rescue. These data show first proof of principle for gene therapy of PA and demonstrate the potential utility of PEG to modify viral tropism in an actual gene therapy application.
