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.