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Gene supplementation of CYP27A1 in the liver restores bile acid metabolism in a mouse model of cerebrotendinous xanthomatosis

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Title: Gene supplementation of CYP27A1 in the liver restores bile acid metabolism in a mouse model of cerebrotendinous xanthomatosis
Authors: Sara Lumbreras, Ana Ricobaraza, Lucia Baila-Rueda, Manuela Gonzalez-Aparicio, Lucia Mora-Jimenez, Iker Uriarte, Maria Bunuales, Matias A. Avila, Maria J. Monte, Jose J.G. Marin, Ana Cenarro, Gloria Gonzalez-Aseguinolaza, Ruben Hernandez-Alcoceba
Source: Molecular Therapy: Methods & Clinical Development, Vol 22, Iss , Pp 210-221 (2021)
Publisher Information: Elsevier, 2021.
Publication Year: 2021
Collection: LCC:Genetics
LCC:Cytology
Subject Terms: cerebrotendinous xanthomatosis, CTX, adeno-associated virus, gene therapy, chenodeoxycholic acid, cholestanol, Genetics, QH426-470, Cytology, QH573-671
More Details: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disease caused by mutations in the CYP27A1 gene, encoding the sterol 27-hydroxylase. Disruption of the bile acid biosynthesis pathway and accumulation of toxic precursors such as cholestanol cause chronic diarrhea, bilateral juvenile cataracts, tissue deposition of cholestanol and cholesterol (xanthomas), and progressive motor/neuropsychiatric alterations. We have evaluated the therapeutic potential of adeno-associated virus (AAV) vectors expressing CYP27A1 in a CTX mouse model. We found that a vector equipped with a strong liver-specific promoter (albumin enhancer fused with the α1 anti-trypsin promoter) is well tolerated and shows therapeutic effect at relatively low doses (1.5 × 1012 viral genomes [vg]/kg), when less than 20% of hepatocytes overexpress the transgene. This vector restored bile acid metabolism and normalized the concentration of most bile acids in plasma. By contrast, standard treatment (oral chenodeoxycholic acid [CDCA]), while reducing cholestanol, did not normalize bile acid composition in plasma and resulted in supra-physiological levels of CDCA and its derivatives. At the transcriptional level, only the vector was able to avoid the induction of xenobiotic-induced pathways in mouse liver. In conclusion, the overexpression of CYP27A1 in a fraction of hepatocytes using AAV vectors is well tolerated and provides full metabolic restoration in Cyp27a1−/− mice. These features make gene therapy a feasible option for the etiological treatment of CTX patients.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 2329-0501
Relation: http://www.sciencedirect.com/science/article/pii/S2329050121001194; https://doaj.org/toc/2329-0501
DOI: 10.1016/j.omtm.2021.07.002
Access URL: https://doaj.org/article/dbca431b41004c1fa3d3a6751b4526b2
Accession Number: edsdoj.bca431b41004c1fa3d3a6751b4526b2
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  Data: Gene supplementation of CYP27A1 in the liver restores bile acid metabolism in a mouse model of cerebrotendinous xanthomatosis
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  Data: <searchLink fieldCode="AR" term="%22Sara+Lumbreras%22">Sara Lumbreras</searchLink><br /><searchLink fieldCode="AR" term="%22Ana+Ricobaraza%22">Ana Ricobaraza</searchLink><br /><searchLink fieldCode="AR" term="%22Lucia+Baila-Rueda%22">Lucia Baila-Rueda</searchLink><br /><searchLink fieldCode="AR" term="%22Manuela+Gonzalez-Aparicio%22">Manuela Gonzalez-Aparicio</searchLink><br /><searchLink fieldCode="AR" term="%22Lucia+Mora-Jimenez%22">Lucia Mora-Jimenez</searchLink><br /><searchLink fieldCode="AR" term="%22Iker+Uriarte%22">Iker Uriarte</searchLink><br /><searchLink fieldCode="AR" term="%22Maria+Bunuales%22">Maria Bunuales</searchLink><br /><searchLink fieldCode="AR" term="%22Matias+A%2E+Avila%22">Matias A. Avila</searchLink><br /><searchLink fieldCode="AR" term="%22Maria+J%2E+Monte%22">Maria J. Monte</searchLink><br /><searchLink fieldCode="AR" term="%22Jose+J%2EG%2E+Marin%22">Jose J.G. Marin</searchLink><br /><searchLink fieldCode="AR" term="%22Ana+Cenarro%22">Ana Cenarro</searchLink><br /><searchLink fieldCode="AR" term="%22Gloria+Gonzalez-Aseguinolaza%22">Gloria Gonzalez-Aseguinolaza</searchLink><br /><searchLink fieldCode="AR" term="%22Ruben+Hernandez-Alcoceba%22">Ruben Hernandez-Alcoceba</searchLink>
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  Data: Molecular Therapy: Methods & Clinical Development, Vol 22, Iss , Pp 210-221 (2021)
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  Data: Elsevier, 2021.
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  Data: 2021
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  Data: <searchLink fieldCode="DE" term="%22cerebrotendinous+xanthomatosis%22">cerebrotendinous xanthomatosis</searchLink><br /><searchLink fieldCode="DE" term="%22CTX%22">CTX</searchLink><br /><searchLink fieldCode="DE" term="%22adeno-associated+virus%22">adeno-associated virus</searchLink><br /><searchLink fieldCode="DE" term="%22gene+therapy%22">gene therapy</searchLink><br /><searchLink fieldCode="DE" term="%22chenodeoxycholic+acid%22">chenodeoxycholic acid</searchLink><br /><searchLink fieldCode="DE" term="%22cholestanol%22">cholestanol</searchLink><br /><searchLink fieldCode="DE" term="%22Genetics%22">Genetics</searchLink><br /><searchLink fieldCode="DE" term="%22QH426-470%22">QH426-470</searchLink><br /><searchLink fieldCode="DE" term="%22Cytology%22">Cytology</searchLink><br /><searchLink fieldCode="DE" term="%22QH573-671%22">QH573-671</searchLink>
– Name: Abstract
  Label: Description
  Group: Ab
  Data: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disease caused by mutations in the CYP27A1 gene, encoding the sterol 27-hydroxylase. Disruption of the bile acid biosynthesis pathway and accumulation of toxic precursors such as cholestanol cause chronic diarrhea, bilateral juvenile cataracts, tissue deposition of cholestanol and cholesterol (xanthomas), and progressive motor/neuropsychiatric alterations. We have evaluated the therapeutic potential of adeno-associated virus (AAV) vectors expressing CYP27A1 in a CTX mouse model. We found that a vector equipped with a strong liver-specific promoter (albumin enhancer fused with the α1 anti-trypsin promoter) is well tolerated and shows therapeutic effect at relatively low doses (1.5 × 1012 viral genomes [vg]/kg), when less than 20% of hepatocytes overexpress the transgene. This vector restored bile acid metabolism and normalized the concentration of most bile acids in plasma. By contrast, standard treatment (oral chenodeoxycholic acid [CDCA]), while reducing cholestanol, did not normalize bile acid composition in plasma and resulted in supra-physiological levels of CDCA and its derivatives. At the transcriptional level, only the vector was able to avoid the induction of xenobiotic-induced pathways in mouse liver. In conclusion, the overexpression of CYP27A1 in a fraction of hepatocytes using AAV vectors is well tolerated and provides full metabolic restoration in Cyp27a1−/− mice. These features make gene therapy a feasible option for the etiological treatment of CTX patients.
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