Accession Number : AD1050202


Title :   Systemic Gene Therapy for Tuberous Sclerosis


Descriptive Note : Technical Report,01 Jul 2016,30 Jun 2017


Corporate Author : Massachusetts General Hospital Boston United States


Personal Author(s) : Breakefield,Xandra O ; Prabhakar,Shilpa


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/1050202.pdf


Report Date : 01 Jul 2017


Pagination or Media Count : 11


Abstract : 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.


Descriptors :   gene therapy , sclerosis , brain , neoplasms , disease vectors


Subject Categories : Medicine and Medical Research
      Genetic Engineering and Molecular Biology


Distribution Statement : APPROVED FOR PUBLIC RELEASE