Gene therapy for tuberous sclerosis complex type 2 in a mouse model by delivery of AAV9 encoding a condensed form of tuberin.

Autor:	Cheah PS; Molecular Neurogenetics Unit, Department of Neurology and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, MA, USA.; Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia., Prabhakar S; Molecular Neurogenetics Unit, Department of Neurology and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, MA, USA., Yellen D; Molecular Neurogenetics Unit, Department of Neurology and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, MA, USA., Beauchamp RL; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA., Zhang X; Molecular Neurogenetics Unit, Department of Neurology and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, MA, USA., Kasamatsu S; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.; Shriners Hospitals for Children, Boston, MA, USA., Bronson RT; Rodent Histopathology Core Facility, Harvard Medical School, Boston, MA, USA., Thiele EA; Herscot Center for Tuberous Sclerosis Complex, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; The Pediatric Epilepsy Program, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA., Kwiatkowski DJ; Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Stemmer-Rachamimov A; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA., György B; Department of Neurobiology and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA.; Institute of Molecular and Clinical Ophthalmology, Basel, Switzerland.; Department of Ophthalmology, University of Basel, Basel, Switzerland., Ling KH; Department of Genetics, Harvard Medical School, Boston, MA, USA.; Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia., Kaneki M; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.; Shriners Hospitals for Children, Boston, MA, USA., Tannous BA; Molecular Neurogenetics Unit, Department of Neurology and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, MA, USA., Ramesh V; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA., Maguire CA; Molecular Neurogenetics Unit, Department of Neurology and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, MA, USA., Breakefield XO; Molecular Neurogenetics Unit, Department of Neurology and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, MA, USA. breakefield@hms.harvard.edu.
Jazyk:	angličtina
Zdroj:	Science advances [Sci Adv] 2021 Jan 08; Vol. 7 (2). Date of Electronic Publication: 2021 Jan 08 (Print Publication: 2021).
DOI:	10.1126/sciadv.abb1703
Abstrakt:	Tuberous sclerosis complex (TSC) results from loss of a tumor suppressor gene - TSC 1 or TSC 2, encoding hamartin and tuberin, respectively. These proteins formed a complex to inhibit mTORC1-mediated cell growth and proliferation. Loss of either protein leads to overgrowth lesions in many vital organs. Gene therapy was evaluated in a mouse model of TSC2 using an adeno-associated virus (AAV) vector carrying the complementary for a "condensed" form of human tuberin (cTuberin). Functionality of cTuberin was verified in culture. A mouse model of TSC2 was generated by AAV-Cre recombinase disruption of Tsc2 -floxed alleles at birth, leading to a shortened lifespan (mean 58 days) and brain pathology consistent with TSC. When these mice were injected intravenously on day 21 with AAV9-cTuberin, the mean survival was extended to 462 days with reduction in brain pathology. This demonstrates the potential of treating life-threatening TSC2 lesions with a single intravenous injection of AAV9-cTuberin. (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)
Databáze:	MEDLINE
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