Adeno-Associated Virus Serotype 8 Gene Transfer Rescues a Neonatal Lethal Murine Model of Propionic Acidemia

Chandler, Randy J.; Chandrasekaran, Suma; Carrillo-Carrasco, Nuria; Senac, Julien S.; Hofherr, Sean E.; Barry, Michael A.; Venditti, Charles P.

doi:10.1089/hum.2010.164

Cited by 39 publications

(53 citation statements)

References 21 publications

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“…However, these studies demonstrated efficacy only at early time points. 22,29,30 This work supports the ability of single AAV treatment to mitigate some PA phenotypes over the lifespan of mice.…”

Section: Discussionsupporting

confidence: 67%

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Long-Term Sex-Biased Correction of Circulating Propionic Acidemia Disease Markers by Adeno-Associated Virus Vectors

et al. 2015

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Propionic academia (PA) occurs because of mutations in the PCCA or PCCB genes encoding the two subunits of propionyl-CoA carboxylase, a pivotal enzyme in the breakdown of certain amino acids and odd-chain fatty acids. There is no cure for PA, but dietary protein restriction and liver transplantation can attenuate its symptoms. We show here that a single intravenous injection of adeno-associated virus 2/8 (AAV8) or AAVrh10 expressing PCCA into PA hypomorphic mice decreased systemic propionylcarnitine and methyl citrate for up to 1.5 years. However, long-term phenotypic correction was always better in male mice. AAV-mediated PCCA expression was similar in most tissues in males and females at early time points and differed only in the liver. Over 1.5 years, luciferase and PCCA expression remained elevated in cardiac tissue for both sexes. In contrast, transgene expression in the liver and skeletal muscles of female, but not male, mice waned—suggesting that these tissues were major sinks for systemic phenotypic correction. These data indicate that single systemic intravenous therapy by AAV vectors can mediate long-term phenotype correction for PA. However, tissue-specific loss of expression in females reduces efficacy when compared with males. Whether similar sex-biased AAV effects occur in human gene therapy remains to be determined.

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Section: Discussionsupporting

confidence: 67%

“…22,29,30 To determine if single intravenous AAV treatment could mediate long-lasting metabolite correction, propionylcarnitine and MeCit levels were monitored in male and female mice over 1.5 years after injection (Fig. 4).…”

Section: Long-term Biochemical Effects Of Single Aav8-pccaco Therapymentioning

confidence: 99%

Long-Term Sex-Biased Correction of Circulating Propionic Acidemia Disease Markers by Adeno-Associated Virus Vectors

et al. 2015

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“…Nonintegrating vectors based on adenovirus or adenoassociated virus (AAV) have shown high transduction efficiency in neonatal gene transfer; however, both vector systems suffer significant loss of transgene expression because of dilution of vector genome during rapid cell proliferation, especially in liver (Wang et al, 2005;Cunningham et al, 2008;Hu et al, 2011). Despite the reduction of transgene expression levels and vector genome copies, therapeutic effects or long-term rescue of neonatal lethality have been demonstrated in several animal models (Daly et al, 2001;CarrilloCarrasco et al, 2010;Chandler and Venditti, 2010;Yiu et al, 2010;Chandler et al, 2011;Cotugno et al, 2011;Hu et al, 2011). In these cases, expression of the normal gene in a small percentage of stably transduced cells accounts for the clinical effects.…”

Section: Introductionmentioning

confidence: 99%

Hepatic Gene Transfer in Neonatal Mice by Adeno-Associated Virus Serotype 8 Vector

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et al. 2012

Human Gene Therapy

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For genetic diseases that manifest at a young age with irreversible consequences, early treatment is critical and essential. Neonatal gene therapy has the advantages of achieving therapeutic effects before disease manifestation, a low vector requirement and high vector-to-cell ratio, and a relatively immature immune system. Therapeutic effects or long-term rescue of neonatal lethality have been demonstrated in several animal models. However, vigorous cell proliferation in the newborn stage is a significant challenge for nonintegrating vectors, such as adeno-associated viral (AAV) vector. Slightly delaying the injection age, and readministration at a later time, are two of the alternative strategies to solve this problem. In this study, we demonstrated robust and efficient hepatic gene transfer by self-complementary AAV8 vector in neonatal mice. However, transduction quickly decreased over a few weeks because of vector dilution caused by fast proliferation. Delaying the injection age improved sustained expression, although it also increased neutralizing antibody (NAb) responses to AAV capsid. This approach can be used to treat genetic diseases with slow progression. For genetic diseases with early onset and severe consequences, early treatment is essential. A second injection of vector of a different serotype at a later time may overcome preexisting NAb and achieve sustained therapeutic effects.

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“…Our previous work and the work of others showed that treatment of PA mice with liver-biased AAV8 and Ad5 vectors is able to significantly reduce systemic PA metabolites (Chandler et al, 2011;Guenzel et al, 2013). However, liver-biased vectors are not absolutely liver specific, and so they may also deliver the PCCA protein to additional nonhepatic cells (Fig.…”

Section: Discussionmentioning

confidence: 94%

Effects of Adeno-Associated Virus Serotype and Tissue-Specific Expression on Circulating Biomarkers of Propionic Acidemia

et al. 2014

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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

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Adeno-Associated Virus Serotype 8 Gene Transfer Rescues a Neonatal Lethal Murine Model of Propionic Acidemia

Cited by 39 publications

References 21 publications

Long-Term Sex-Biased Correction of Circulating Propionic Acidemia Disease Markers by Adeno-Associated Virus Vectors

Long-Term Sex-Biased Correction of Circulating Propionic Acidemia Disease Markers by Adeno-Associated Virus Vectors

Hepatic Gene Transfer in Neonatal Mice by Adeno-Associated Virus Serotype 8 Vector

Effects of Adeno-Associated Virus Serotype and Tissue-Specific Expression on Circulating Biomarkers of Propionic Acidemia

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