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

Cheah PS 1 , Prabhakar S 1 , Yellen D 1 , Beauchamp RL 2 , Zhang X 1 , Kasamatsu S 3 Show all authors , Bronson RT 4 , Thiele EA 5 , Kwiatkowski DJ 6 , Stemmer-Rachamimov A 7 , György B 8 , Ling KH 9 , Kaneki M 3 , Tannous BA 1 , Ramesh V 2 , Maguire CA 1 , Breakefield XO 10

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 Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
  • 3 Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
  • 4 Rodent Histopathology Core Facility, Harvard Medical School, Boston, MA, USA
  • 5 Herscot Center for Tuberous Sclerosis Complex, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
  • 6 Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
  • 7 Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
  • 8 Department of Neurobiology and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA
  • 9 Department of Genetics, Harvard Medical School, Boston, MA, USA
  • 10 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
Sci Adv, 2021 Jan;7(2).
PMID: 33523984 DOI: 10.1126/sciadv.abb1703

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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