Biochemical Correction of Short-Chain Acyl-Coenzyme A Dehydrogenase Deficiency After Portal Vein Injection of rAAV8-SCAD

Beattie, Stuart G.; Goetzman, Eric S.; Conlon, Thomas J.; Germain, Sean; Walter, Glenn A.; Campbell-Thompson, Martha; Matern, Dietrich; Vockley, Jerry; Flotte, Terence R.

doi:10.1089/hum.2007.168

Cited by 11 publications

(7 citation statements)

References 40 publications

(45 reference statements)

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“…Additionally, we have previously noted that C 16 -CoA ACAD activity in BAT is about 10 times higher than liver activity, which is in keeping with the known high metabolic rate of BAT [11]. In contrast, the C 4 -CoA BAT activity measured in this study is several times lower than C 4 -CoA activity that we previously recorded in liver [17]. SCAD may constitute a metabolic bottleneck in BAT that is not present in other tissues.…”

Section: Discussionsupporting

confidence: 86%

Brown adipose tissue function in short-chain acyl-CoA dehydrogenase deficient mice

Skilling

Coen

Fairfull

et al. 2010

Biochemical and Biophysical Research Communications

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Brown adipose tissue is a highly specialized organ that uses mitochondrial fatty acid oxidation to fuel nonshivering thermogenesis. In mice, mutations in the acyl-CoA dehydrogenase family of fatty acid oxidation genes are associated with sensitivity to cold. Brown adipose tissue function has not previously been characterized in these knockout strains. Short-chain acyl-CoA dehydrogenase (SCAD) deficient mice were found to have increased brown adipose tissue mass as well as modest cardiac hypertrophy. Uncoupling protein-1 was reduced by 70% in brown adipose tissue and this was not due to a change in mitochondrial number, nor was it due to decreased signal transduction through protein kinase A which is known to be a major regulator of uncoupling protein-1 expression. PKA activity and in vitro lipolysis were normal in brown adipose tissue, although in white adipose tissue a modest increase in basal lipolysis was seen in SCAD−/ − mice. Finally, an in vivo norepinephrine challenge of brown adipose tissue thermogenesis revealed normal heat production in SCAD−/− mice. These results suggest that reduced brown adipose tissue function is not the major factor causing cold sensitivity in acyl-CoA dehydrogenase knockout strains. We speculate that other mechanisms such as shivering capacity, cardiac function, and reduced hepatic glycogen stores are involved.

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Section: Discussionsupporting

confidence: 86%

Brown adipose tissue function in short-chain acyl-CoA dehydrogenase deficient mice

Skilling

Coen

Fairfull

et al. 2010

Biochemical and Biophysical Research Communications

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“…9,10,11 New AAV serotypes, such as AAV9, have improved expression and wider transduction profiles. 12,13 Merritt and colleagues 14 showed limited biochemical correction of VLCAD deficiency using systemic injections with AAV8.…”

Section: Introductionmentioning

confidence: 99%

Long-term Correction of Very Long-chain Acyl-CoA Dehydrogenase Deficiency in Mice Using AAV9 Gene Therapy

et al. 2012

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Very long-chain acyl-coA dehydrogenase (VLCAD) is the rate-limiting step in mitochondrial fatty acid oxidation. VLCAD-deficient mice and patients clinical symptoms stem from not only an energy deficiency but also long-chain metabolite accumulations. VLCAD-deficient mice were treated systemically with 1 × 1012 vector genomes of recombinant adeno-associated virus 9 (rAAV9)-VLCAD. Biochemical correction was observed in vector-treated mice beginning 2 weeks postinjection, as characterized by a significant drop in long-chain fatty acyl accumulates in whole blood after an overnight fast. Changes persisted through the termination point around 20 weeks postinjection. Magnetic resonance spectroscopy (MRS) and tandem mass spectrometry (MS/MS) revealed normalization of intramuscular lipids in treated animals. Correction was not observed in liver tissue extracts, but cardiac muscle extracts showed significant reduction of long-chain metabolites. Disease-specific phenotypes were characterized, including thermoregulation and maintenance of euglycemia after a fasting cold challenge. Internal body temperatures of untreated VLCAD−/− mice dropped below 20 °C and the mice became lethargic, requiring euthanasia. In contrast, all rAAV9-treated VLCAD−/− mice and the wild-type controls maintained body temperatures. rAAV9-treated VLCAD−/− mice maintained euglycemia, whereas untreated VLCAD−/− mice suffered hypoglycemia following a fasting cold challenge. These promising results suggest rAAV9 gene therapy as a potential treatment for VLCAD deficiency in humans.

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“…Magnetic resonance spectroscopy (MRS) demonstrated a reduction of the lipid peak in injected TA muscle. Biochemical correction of SCAD-deficiency after rAAV8-mediated delivery of mSCAD to the livers of SCAD-deficient mice has also been recently demonstrated [7]. A significant reduction of circulating butyrylcarnitine was found in AAV8-mSCAD injected SCAD −/− mice 6 weeks after treatment.…”

Section: Introductionmentioning

confidence: 92%

Recombinant adeno‐associated virus‐mediated gene delivery of long chain acyl coenzyme A dehydrogenase (LCAD) into LCAD‐deficient mice

Beattie

Goetzman

Tang

et al. 2008

The Journal of Gene Medicine

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Background Very long chain acyl coenzyme A (CoA) dehydrogenase (VLCAD) deficiency is a relatively common mitochondrial β-oxidation disorder. The most severe form of VLCAD deficiency presents with neonatal cardiomyopathy and hepatic failure and is generally fatal within the first year of life. Mice deficient for long chain acyl CoA dehydrogenase (LCAD) closely resemble the clinical syndrome observed in VLCAD-deficient humans. Recombinant adeno-associated viral (rAAV) vectors with pseudotype capsids were investigated for their potential towards correcting the phenotype observed in mice heterozygous (+/−) for LCAD (i.e. liver and muscle steatosis). Methods rAAV containing the mouse LCAD cDNA (mLCAD) under the transcriptional control of the CMV/chicken β-actin hybrid promoter were injected intramuscularly into the tibialis anterior (TA) muscle of LCAD+/− mice or injected into the portal vein to transduce hepatocytes. Results Ten weeks post-injection of rAAV1-mLCAD into the TA muscle, significantly increased levels of mLCAD within mitochondria were demonstrated by immunostaining of TA sections, immunoblotting of mitochondrial isolates and by the electron transfer flavoprotein (ETF) fluorescence reduction enzyme activity assay. Magnetic resonance spectroscopy of vector-injected TA muscle demonstrated a reduction in the lipid content compared to phosphate-buffered saline-injected mice, whereas a systemic effect was observed as a reduction in liver macrosteatosis. Eight weeks after portal vein injection of rAAV8-mLCAD into LCAD+/− mice, increased levels of mLCAD within hepatocyte mitochondria were demonstrated by immunostaining and also by the ETF assay. Scoring of the hepatosteatosis observed in partially deficient LCAD mice indicated a reduction in the lipid content within livers of vector-treated mice. Conclusions These studies show that rAAV-mediated delivery of mLCAD was efficient and led to an amelioration of local and systemic pathologies observed in partially deficient LCAD mice.

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Biochemical Correction of Short-Chain Acyl-Coenzyme A Dehydrogenase Deficiency After Portal Vein Injection of rAAV8-SCAD

Cited by 11 publications

References 40 publications

Brown adipose tissue function in short-chain acyl-CoA dehydrogenase deficient mice

Brown adipose tissue function in short-chain acyl-CoA dehydrogenase deficient mice

Long-term Correction of Very Long-chain Acyl-CoA Dehydrogenase Deficiency in Mice Using AAV9 Gene Therapy

Recombinant adeno‐associated virus‐mediated gene delivery of long chain acyl coenzyme A dehydrogenase (LCAD) into LCAD‐deficient mice

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