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

Pike-See Cheah; Shilpa Prabhakar; David Yellen; Roberta L Beauchamp; Xuan Zhang; Shingo Kasamatsu; Roderick T Bronson; Elizabeth A Thiele; David J Kwiatkowski; Anat Stemmer-Rachamimov; Bence György; King-Hwa Ling; Masao Kaneki; Bakhos A Tannous; Vijaya Ramesh; Casey A Maguire; Xandra O Breakefield

doi:10.1126/sciadv.abb1703

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

Sci Adv. 2021 Jan 8;7(2):eabb1703. doi: 10.1126/sciadv.abb1703. Print 2021 Jan.

Authors

Pike-See Cheah^{1

2}, Shilpa Prabhakar¹, David Yellen¹, Roberta L Beauchamp³, Xuan Zhang¹, Shingo Kasamatsu^{4

5}, Roderick T Bronson⁶, Elizabeth A Thiele^{7

8}, David J Kwiatkowski⁹, Anat Stemmer-Rachamimov¹⁰, Bence György^{11

12

13}, King-Hwa Ling^{14

15}, Masao Kaneki^{4

5}, Bakhos A Tannous¹, Vijaya Ramesh³, Casey A Maguire¹, Xandra O Breakefield¹⁶

Affiliations

¹ 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.
² Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia.
³ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁴ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
⁵ Shriners Hospitals for Children, Boston, MA, USA.
⁶ Rodent Histopathology Core Facility, Harvard Medical School, Boston, MA, USA.
⁷ Herscot Center for Tuberous Sclerosis Complex, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁸ The Pediatric Epilepsy Program, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
⁹ Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁰ Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
¹¹ Department of Neurobiology and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA.
¹² Institute of Molecular and Clinical Ophthalmology, Basel, Switzerland.
¹³ Department of Ophthalmology, University of Basel, Basel, Switzerland.
¹⁴ Department of Genetics, Harvard Medical School, Boston, MA, USA.
¹⁵ Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia.
¹⁶ 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.

Abstract

Tuberous sclerosis complex (TSC) results from loss of a tumor suppressor gene - TSC1 or TSC2, 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).

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

Abstract

Publication types

Grants and funding