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Systemic Gene Therapy for Tuberous Sclerosis

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Technical Report,01 Jul 2016,30 Jun 2017

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Massachusetts General Hospital Boston United States

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Tuberous sclerosis complex TSC patients suffer from hamartomas in various organs, including subependymal nodules in the brain, angiomyolipomas in the kidney and liver, and lymphaganioleiomyomatosis LAM of the lungs leading to a range of symptoms, some of which are life-threatening. Current drug treatment has some limitations and there is a pressing need to develop new therapies, especially for children and LAM patients. Our group is focused on developing gene therapy for TSC which has the potential for single application and low-to-no toxicity with genetic replacement of the deficient protein in multiple tissues. We have generated mouse models of TSC1 hamartin deficiency and TSC2 tuberin deficiency by adeno-associated virus AAV delivery of Cre recombinase into Tsc1floxed mice into the brain and kidney, and by xenograft transplantation of human TSC2 LAM cells into immune compromised mice, respectively. In the Tsc1 model we have shown that intravascular IV delivery of an AAV vector encoding hamartin can lead to prolonged survival and normalization of neuronal cell size in the brain. We have also created a condensed version of tuberin, such that the cDNA encoding it fits into an AAV vector. Initial experiments show that injection of this AAV-cTuberin vector into subcutaneous LAM tumors in immune compromised mice curtails tumor growth. AAV has proven to be safe and beneficial in Phase 1 clinical trials for neurologic diseases in adults and children, and AAV9 can deliver genes not only to peripheral tissues, but also to the brain in mice and non-human primates following IV delivery, with transgene expression extending for years.

Subject Categories:

  • Medicine and Medical Research
  • Genetic Engineering and Molecular Biology

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