Therapeutic efficacy of rscAAVrh74.miniCMV.LIPA gene therapy in a mouse model of lysosomal acid lipase deficiency
Lysosomal acid lipase deficiency (LAL-D) presents as one of two rare autosomal recessive diseases: Wolman disease (WD), a severe disorder presenting in infancy characterized by absent or very low LAL activity, and cholesteryl ester storage disease (CESD), a less severe, later onset disease form. Rec...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-09-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050122001115 |
| _version_ | 1828154025254584320 |
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| author | Patricia Lam Anna Ashbrook Deborah A. Zygmunt Cong Yan Hong Du Paul T. Martin |
| author_facet | Patricia Lam Anna Ashbrook Deborah A. Zygmunt Cong Yan Hong Du Paul T. Martin |
| author_sort | Patricia Lam |
| collection | DOAJ |
| description | Lysosomal acid lipase deficiency (LAL-D) presents as one of two rare autosomal recessive diseases: Wolman disease (WD), a severe disorder presenting in infancy characterized by absent or very low LAL activity, and cholesteryl ester storage disease (CESD), a less severe, later onset disease form. Recent clinical studies have shown efficacy of enzyme replacement therapy for both forms of LAL-D; however, no gene therapy approach has yet been developed for clinical use. Here, we show that rscAAVrh74.miniCMV.LIPA gene therapy can significantly improve disease symptoms in the Lipa−/− mouse model of LAL-D. Treatment dramatically lowered hepatosplenomegaly, liver and spleen triglyceride and cholesterol levels, and serum expression of markers of liver damage. Measures of liver inflammation and fibrosis were also reduced. Treatment of young adult mice was more effective than treatment of neonates, and enzyme activity was elevated in serum, consistent with possible bystander effects. These results demonstrate that adeno associated virus (AAV)-mediated LIPA gene-replacement therapy may be a viable option to treat patients with LAL-D, particularly patients with CESD. |
| first_indexed | 2024-04-11T22:34:09Z |
| format | Article |
| id | doaj.art-cd5ce87369f0442fa45d6b329279a144 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-04-11T22:34:09Z |
| publishDate | 2022-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-cd5ce87369f0442fa45d6b329279a1442022-12-22T03:59:16ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012022-09-0126413426Therapeutic efficacy of rscAAVrh74.miniCMV.LIPA gene therapy in a mouse model of lysosomal acid lipase deficiencyPatricia Lam0Anna Ashbrook1Deborah A. Zygmunt2Cong Yan3Hong Du4Paul T. Martin5Center for Gene Therapy, Abigail Wexner Research Institute, Nationwide Children’s Hospital, 700 Children’s Dr., Columbus, OH 43205, USACenter for Gene Therapy, Abigail Wexner Research Institute, Nationwide Children’s Hospital, 700 Children’s Dr., Columbus, OH 43205, USACenter for Gene Therapy, Abigail Wexner Research Institute, Nationwide Children’s Hospital, 700 Children’s Dr., Columbus, OH 43205, USADepartment of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USACenter for Gene Therapy, Abigail Wexner Research Institute, Nationwide Children’s Hospital, 700 Children’s Dr., Columbus, OH 43205, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43205, USA; Corresponding author Paul T. Martin, Center for Gene Therapy, Abigail Wexner Research Institute, Nationwide Children’s Hospital, 700 Children’s Dr., Columbus, OH 43205, USA.Lysosomal acid lipase deficiency (LAL-D) presents as one of two rare autosomal recessive diseases: Wolman disease (WD), a severe disorder presenting in infancy characterized by absent or very low LAL activity, and cholesteryl ester storage disease (CESD), a less severe, later onset disease form. Recent clinical studies have shown efficacy of enzyme replacement therapy for both forms of LAL-D; however, no gene therapy approach has yet been developed for clinical use. Here, we show that rscAAVrh74.miniCMV.LIPA gene therapy can significantly improve disease symptoms in the Lipa−/− mouse model of LAL-D. Treatment dramatically lowered hepatosplenomegaly, liver and spleen triglyceride and cholesterol levels, and serum expression of markers of liver damage. Measures of liver inflammation and fibrosis were also reduced. Treatment of young adult mice was more effective than treatment of neonates, and enzyme activity was elevated in serum, consistent with possible bystander effects. These results demonstrate that adeno associated virus (AAV)-mediated LIPA gene-replacement therapy may be a viable option to treat patients with LAL-D, particularly patients with CESD.http://www.sciencedirect.com/science/article/pii/S2329050122001115liver diseaselysosomal storage disorderlysosomal acid lipasecholesteroltriglyceridegene therapy |
| spellingShingle | Patricia Lam Anna Ashbrook Deborah A. Zygmunt Cong Yan Hong Du Paul T. Martin Therapeutic efficacy of rscAAVrh74.miniCMV.LIPA gene therapy in a mouse model of lysosomal acid lipase deficiency Molecular Therapy: Methods & Clinical Development liver disease lysosomal storage disorder lysosomal acid lipase cholesterol triglyceride gene therapy |
| title | Therapeutic efficacy of rscAAVrh74.miniCMV.LIPA gene therapy in a mouse model of lysosomal acid lipase deficiency |
| title_full | Therapeutic efficacy of rscAAVrh74.miniCMV.LIPA gene therapy in a mouse model of lysosomal acid lipase deficiency |
| title_fullStr | Therapeutic efficacy of rscAAVrh74.miniCMV.LIPA gene therapy in a mouse model of lysosomal acid lipase deficiency |
| title_full_unstemmed | Therapeutic efficacy of rscAAVrh74.miniCMV.LIPA gene therapy in a mouse model of lysosomal acid lipase deficiency |
| title_short | Therapeutic efficacy of rscAAVrh74.miniCMV.LIPA gene therapy in a mouse model of lysosomal acid lipase deficiency |
| title_sort | therapeutic efficacy of rscaavrh74 minicmv lipa gene therapy in a mouse model of lysosomal acid lipase deficiency |
| topic | liver disease lysosomal storage disorder lysosomal acid lipase cholesterol triglyceride gene therapy |
| url | http://www.sciencedirect.com/science/article/pii/S2329050122001115 |
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