One episode of low intensity aerobic exercise prior to systemic AAV9 administration augments transgene delivery to the heart and skeletal muscle
Abstract Introduction The promising potential of adeno-associated virus (AAV) gene delivery strategies to treat genetic disorders continues to grow with an additional three AAV-based therapies recently approved by the Food and Drug Administration and dozens of others currently under evaluation in cl...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-10-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-023-04626-1 |
| _version_ | 1797556892999876608 |
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| author | Christina A. Pacak Silveli Suzuki-Hatano Fatemeh Khadir Audrey L. Daugherty Mughil Sriramvenugopal Bennett J. Gosiker Peter B. Kang William Todd Cade |
| author_facet | Christina A. Pacak Silveli Suzuki-Hatano Fatemeh Khadir Audrey L. Daugherty Mughil Sriramvenugopal Bennett J. Gosiker Peter B. Kang William Todd Cade |
| author_sort | Christina A. Pacak |
| collection | DOAJ |
| description | Abstract Introduction The promising potential of adeno-associated virus (AAV) gene delivery strategies to treat genetic disorders continues to grow with an additional three AAV-based therapies recently approved by the Food and Drug Administration and dozens of others currently under evaluation in clinical trials. With these developments, it has become increasingly apparent that the high doses currently needed for efficacy carry risks of toxicity and entail enormous manufacturing costs, especially for clinical grade products. Strategies to increase the therapeutic efficacy of AAV-mediated gene delivery and reduce the minimal effective dose would have a substantial impact on this field. We hypothesized that an exercise-induced redistribution of tissue perfusion in the body to favor specific target organs via acute aerobic exercise prior to systemic intravenous (IV) AAV administration could increase efficacy. Background Aerobic exercise triggers an array of downstream physiological effects including increased perfusion of heart and skeletal muscle, which we expected could enhance AAV transduction. Prior preclinical studies have shown promising results for a gene therapy approach to treat Barth syndrome (BTHS), a rare monogenic cardioskeletal myopathy, and clinical studies have shown the benefit of low intensity exercise in these patients, making this a suitable disease in which to test the ability of aerobic exercise to enhance AAV transduction. Methods Wild-type (WT) and BTHS mice were either systemically administered AAV9 or completed one episode of low intensity treadmill exercise immediately prior to systemic administration of AAV9. Results We demonstrate that a single episode of acute low intensity aerobic exercise immediately prior to IV AAV9 administration improves marker transgene delivery in WT mice as compared to mice injected without the exercise pre-treatment. In BTHS mice, prior exercise improved transgene delivery and additionally increased improvement in mitochondrial gene transcription levels and mitochondrial function in the heart and gastrocnemius muscles as compared to mice treated without exercise. Conclusions Our findings suggest that one episode of acute low intensity aerobic exercise improves AAV9 transduction of heart and skeletal muscle. This low-risk, cost effective intervention could be implemented in clinical trials of individuals with inherited cardioskeletal disease as a potential means of improving patient safety for human gene therapy. |
| first_indexed | 2024-03-10T17:09:30Z |
| format | Article |
| id | doaj.art-f69833ae695641cf9607659cc8cf2067 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-03-10T17:09:30Z |
| publishDate | 2023-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-f69833ae695641cf9607659cc8cf20672023-11-20T10:43:59ZengBMCJournal of Translational Medicine1479-58762023-10-0121111310.1186/s12967-023-04626-1One episode of low intensity aerobic exercise prior to systemic AAV9 administration augments transgene delivery to the heart and skeletal muscleChristina A. Pacak0Silveli Suzuki-Hatano1Fatemeh Khadir2Audrey L. Daugherty3Mughil Sriramvenugopal4Bennett J. Gosiker5Peter B. Kang6William Todd Cade7Paul and Sheila Wellstone Muscular Dystrophy Center and Department of Neurology, University of Minnesota Medical SchoolCollege of Medicine, Department of Pediatrics, University of FloridaPaul and Sheila Wellstone Muscular Dystrophy Center and Department of Neurology, University of Minnesota Medical SchoolPaul and Sheila Wellstone Muscular Dystrophy Center and Department of Neurology, University of Minnesota Medical SchoolCollege of Medicine, Department of Pediatrics, University of FloridaCollege of Medicine, Department of Pediatrics, University of FloridaPaul and Sheila Wellstone Muscular Dystrophy Center and Department of Neurology, University of Minnesota Medical SchoolPhysical Therapy Division, Department of Orthopaedic Surgery, Duke University School of MedicineAbstract Introduction The promising potential of adeno-associated virus (AAV) gene delivery strategies to treat genetic disorders continues to grow with an additional three AAV-based therapies recently approved by the Food and Drug Administration and dozens of others currently under evaluation in clinical trials. With these developments, it has become increasingly apparent that the high doses currently needed for efficacy carry risks of toxicity and entail enormous manufacturing costs, especially for clinical grade products. Strategies to increase the therapeutic efficacy of AAV-mediated gene delivery and reduce the minimal effective dose would have a substantial impact on this field. We hypothesized that an exercise-induced redistribution of tissue perfusion in the body to favor specific target organs via acute aerobic exercise prior to systemic intravenous (IV) AAV administration could increase efficacy. Background Aerobic exercise triggers an array of downstream physiological effects including increased perfusion of heart and skeletal muscle, which we expected could enhance AAV transduction. Prior preclinical studies have shown promising results for a gene therapy approach to treat Barth syndrome (BTHS), a rare monogenic cardioskeletal myopathy, and clinical studies have shown the benefit of low intensity exercise in these patients, making this a suitable disease in which to test the ability of aerobic exercise to enhance AAV transduction. Methods Wild-type (WT) and BTHS mice were either systemically administered AAV9 or completed one episode of low intensity treadmill exercise immediately prior to systemic administration of AAV9. Results We demonstrate that a single episode of acute low intensity aerobic exercise immediately prior to IV AAV9 administration improves marker transgene delivery in WT mice as compared to mice injected without the exercise pre-treatment. In BTHS mice, prior exercise improved transgene delivery and additionally increased improvement in mitochondrial gene transcription levels and mitochondrial function in the heart and gastrocnemius muscles as compared to mice treated without exercise. Conclusions Our findings suggest that one episode of acute low intensity aerobic exercise improves AAV9 transduction of heart and skeletal muscle. This low-risk, cost effective intervention could be implemented in clinical trials of individuals with inherited cardioskeletal disease as a potential means of improving patient safety for human gene therapy.https://doi.org/10.1186/s12967-023-04626-1Gene therapySystemic gene deliveryAdeno-associated virusAAVAAV9Aerobic exercise |
| spellingShingle | Christina A. Pacak Silveli Suzuki-Hatano Fatemeh Khadir Audrey L. Daugherty Mughil Sriramvenugopal Bennett J. Gosiker Peter B. Kang William Todd Cade One episode of low intensity aerobic exercise prior to systemic AAV9 administration augments transgene delivery to the heart and skeletal muscle Journal of Translational Medicine Gene therapy Systemic gene delivery Adeno-associated virus AAV AAV9 Aerobic exercise |
| title | One episode of low intensity aerobic exercise prior to systemic AAV9 administration augments transgene delivery to the heart and skeletal muscle |
| title_full | One episode of low intensity aerobic exercise prior to systemic AAV9 administration augments transgene delivery to the heart and skeletal muscle |
| title_fullStr | One episode of low intensity aerobic exercise prior to systemic AAV9 administration augments transgene delivery to the heart and skeletal muscle |
| title_full_unstemmed | One episode of low intensity aerobic exercise prior to systemic AAV9 administration augments transgene delivery to the heart and skeletal muscle |
| title_short | One episode of low intensity aerobic exercise prior to systemic AAV9 administration augments transgene delivery to the heart and skeletal muscle |
| title_sort | one episode of low intensity aerobic exercise prior to systemic aav9 administration augments transgene delivery to the heart and skeletal muscle |
| topic | Gene therapy Systemic gene delivery Adeno-associated virus AAV AAV9 Aerobic exercise |
| url | https://doi.org/10.1186/s12967-023-04626-1 |
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