AAV8 gene therapy reverses cardiac pathology and prevents early mortality in a mouse model of Friedreich’s ataxia
Friedreich’s ataxia (FRDA) is an autosomal-recessive disorder primarily attributed to biallelic GAA repeat expansions that reduce expression of the mitochondrial protein frataxin (FXN). FRDA is characterized by progressive neurodegeneration, with many patients developing cardiomyopathy that progress...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-03-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050124000093 |
| _version_ | 1827355871393349632 |
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| author | Joshua C. Chang Molly R. Ryan Marie C. Stark Su Liu Pravinkumar Purushothaman Fria Bolan Caitlin A. Johnson Mark Champe Hui Meng Michael W. Lawlor Sarah Halawani Lucie V. Ngaba David R. Lynch Crystal Davis Elena Gonzalo-Gil Cathleen Lutz Fabrizia Urbinati Bala Medicherla Carlos Fonck |
| author_facet | Joshua C. Chang Molly R. Ryan Marie C. Stark Su Liu Pravinkumar Purushothaman Fria Bolan Caitlin A. Johnson Mark Champe Hui Meng Michael W. Lawlor Sarah Halawani Lucie V. Ngaba David R. Lynch Crystal Davis Elena Gonzalo-Gil Cathleen Lutz Fabrizia Urbinati Bala Medicherla Carlos Fonck |
| author_sort | Joshua C. Chang |
| collection | DOAJ |
| description | Friedreich’s ataxia (FRDA) is an autosomal-recessive disorder primarily attributed to biallelic GAA repeat expansions that reduce expression of the mitochondrial protein frataxin (FXN). FRDA is characterized by progressive neurodegeneration, with many patients developing cardiomyopathy that progresses to heart failure and death. The potential to reverse or prevent progression of the cardiac phenotype of FRDA was investigated in a mouse model of FRDA, using an adeno-associated viral vector (AAV8) containing the coding sequence of the FXN gene. The Fxnflox/null::MCK-Cre conditional knockout mouse (FXN-MCK) has an FXN gene ablation that prevents FXN expression in cardiac and skeletal muscle, leading to cardiac insufficiency, weight loss, and morbidity. FXN-MCK mice received a single intravenous injection of an AAV8 vector containing human (hFXN) or mouse (mFXN) FXN genes under the control of a phosphoglycerate kinase promoter. Compared to vehicle-treated FXN-MCK control mice, AAV-treated FXN-MCK mice displayed increases in body weight, reversal of cardiac deficits, and increases in survival without apparent toxicity in the heart or liver for up to 12 weeks postdose. FXN protein expression in heart tissue was detected in a dose-dependent manner, exhibiting wide distribution throughout the heart similar to wild type, but more speckled. These results support an AAV8-based approach to treat FRDA-associated cardiomyopathy. |
| first_indexed | 2024-03-08T04:50:38Z |
| format | Article |
| id | doaj.art-622f3ceaccb84a80bfa5ed76dfdd8605 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-03-08T04:50:38Z |
| publishDate | 2024-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-622f3ceaccb84a80bfa5ed76dfdd86052024-02-08T05:09:10ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012024-03-01321101193AAV8 gene therapy reverses cardiac pathology and prevents early mortality in a mouse model of Friedreich’s ataxiaJoshua C. Chang0Molly R. Ryan1Marie C. Stark2Su Liu3Pravinkumar Purushothaman4Fria Bolan5Caitlin A. Johnson6Mark Champe7Hui Meng8Michael W. Lawlor9Sarah Halawani10Lucie V. Ngaba11David R. Lynch12Crystal Davis13Elena Gonzalo-Gil14Cathleen Lutz15Fabrizia Urbinati16Bala Medicherla17Carlos Fonck18Astellas Gene Therapies, Inc., South San Francisco, CA 94080, USAAstellas Gene Therapies, Inc., South San Francisco, CA 94080, USAAstellas Gene Therapies, Inc., South San Francisco, CA 94080, USAAstellas Gene Therapies, Inc., South San Francisco, CA 94080, USAFormerly of Astellas Gene Therapies, Inc., South San Francisco, CA 94080, USAAstellas Gene Therapies, Inc., South San Francisco, CA 94080, USAAstellas Gene Therapies, Inc., South San Francisco, CA 94080, USAAstellas Gene Therapies, Inc., South San Francisco, CA 94080, USADiverge Translational Science Laboratory, Milwaukee, WI 53204, USA; Medical College of Wisconsin, Department of Pathology and Laboratory Medicine, Milwaukee, WI 53226, USADiverge Translational Science Laboratory, Milwaukee, WI 53204, USA; Medical College of Wisconsin, Department of Pathology and Laboratory Medicine, Milwaukee, WI 53226, USAChildren’s Hospital of Philadelphia, Philadelphia, PA 19104, USAChildren’s Hospital of Philadelphia, Philadelphia, PA 19104, USAChildren’s Hospital of Philadelphia, Philadelphia, PA 19104, USAThe Jackson Laboratory, Bar Harbor, ME 04609, USAThe Jackson Laboratory, Bar Harbor, ME 04609, USAThe Jackson Laboratory, Bar Harbor, ME 04609, USAFormerly of Astellas Gene Therapies, Inc., South San Francisco, CA 94080, USAAstellas Gene Therapies, Inc., South San Francisco, CA 94080, USAAstellas Gene Therapies, Inc., South San Francisco, CA 94080, USA; Corresponding author: Carlos Fonck, Astellas Gene Therapies, Inc., 225 Gateway Blvd., South San Francisco, CA 94080, USA.Friedreich’s ataxia (FRDA) is an autosomal-recessive disorder primarily attributed to biallelic GAA repeat expansions that reduce expression of the mitochondrial protein frataxin (FXN). FRDA is characterized by progressive neurodegeneration, with many patients developing cardiomyopathy that progresses to heart failure and death. The potential to reverse or prevent progression of the cardiac phenotype of FRDA was investigated in a mouse model of FRDA, using an adeno-associated viral vector (AAV8) containing the coding sequence of the FXN gene. The Fxnflox/null::MCK-Cre conditional knockout mouse (FXN-MCK) has an FXN gene ablation that prevents FXN expression in cardiac and skeletal muscle, leading to cardiac insufficiency, weight loss, and morbidity. FXN-MCK mice received a single intravenous injection of an AAV8 vector containing human (hFXN) or mouse (mFXN) FXN genes under the control of a phosphoglycerate kinase promoter. Compared to vehicle-treated FXN-MCK control mice, AAV-treated FXN-MCK mice displayed increases in body weight, reversal of cardiac deficits, and increases in survival without apparent toxicity in the heart or liver for up to 12 weeks postdose. FXN protein expression in heart tissue was detected in a dose-dependent manner, exhibiting wide distribution throughout the heart similar to wild type, but more speckled. These results support an AAV8-based approach to treat FRDA-associated cardiomyopathy.http://www.sciencedirect.com/science/article/pii/S2329050124000093Friedreich’s ataxiafrataxincardiomyopathyadeno-associated viral vectorAAVgene therapy |
| spellingShingle | Joshua C. Chang Molly R. Ryan Marie C. Stark Su Liu Pravinkumar Purushothaman Fria Bolan Caitlin A. Johnson Mark Champe Hui Meng Michael W. Lawlor Sarah Halawani Lucie V. Ngaba David R. Lynch Crystal Davis Elena Gonzalo-Gil Cathleen Lutz Fabrizia Urbinati Bala Medicherla Carlos Fonck AAV8 gene therapy reverses cardiac pathology and prevents early mortality in a mouse model of Friedreich’s ataxia Molecular Therapy: Methods & Clinical Development Friedreich’s ataxia frataxin cardiomyopathy adeno-associated viral vector AAV gene therapy |
| title | AAV8 gene therapy reverses cardiac pathology and prevents early mortality in a mouse model of Friedreich’s ataxia |
| title_full | AAV8 gene therapy reverses cardiac pathology and prevents early mortality in a mouse model of Friedreich’s ataxia |
| title_fullStr | AAV8 gene therapy reverses cardiac pathology and prevents early mortality in a mouse model of Friedreich’s ataxia |
| title_full_unstemmed | AAV8 gene therapy reverses cardiac pathology and prevents early mortality in a mouse model of Friedreich’s ataxia |
| title_short | AAV8 gene therapy reverses cardiac pathology and prevents early mortality in a mouse model of Friedreich’s ataxia |
| title_sort | aav8 gene therapy reverses cardiac pathology and prevents early mortality in a mouse model of friedreich s ataxia |
| topic | Friedreich’s ataxia frataxin cardiomyopathy adeno-associated viral vector AAV gene therapy |
| url | http://www.sciencedirect.com/science/article/pii/S2329050124000093 |
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