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

2021 ◽  
Vol 7 (2) ◽  
pp. eabb1703
Author(s):  
Pike-See Cheah ◽  
Shilpa Prabhakar ◽  
David Yellen ◽  
Roberta L. Beauchamp ◽  
Xuan Zhang ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Suppressor Gene ◽  
Brain Pathology ◽  
Adeno Associated Virus ◽  
Condensed Form ◽  
Life Threatening ◽  
Cell Growth And Proliferation

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.

scholarly journals Therapeutic Trial of Metformin and Bortezomib in a Mouse Model of Tuberous Sclerosis Complex (TSC)

PLoS ONE ◽  
2012 ◽  
Vol 7 (2) ◽  
pp. e31900 ◽  
Author(s):  
Neil Auricchio ◽  
Izabela Malinowska ◽  
Reuben Shaw ◽  
Brendan D. Manning ◽  
David J. Kwiatkowski
Keyword(s):  
Mouse Model ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Therapeutic Trial

scholarly journals Metabolomic studies identify changes in transmethylation and polyamine metabolism in a brain-specific mouse model of tuberous sclerosis complex

2018 ◽  
Vol 27 (12) ◽  
pp. 2113-2124 ◽  
Author(s):  
James McKenna ◽  
David Kapfhamer ◽  
Jason M Kinchen ◽  
Brandi Wasek ◽  
Matthew Dunworth ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Polyamine Metabolism

scholarly journals Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model

2019 ◽  
Vol 116 (10) ◽  
pp. 4496-4501 ◽  
Author(s):  
Omar Akil ◽  
Frank Dyka ◽  
Charlotte Calvet ◽  
Alice Emptoz ◽  
Ghizlene Lahlou ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Autosomal Recessive ◽  
Therapeutic Option ◽  
The Other ◽  
Therapeutic Window ◽  
Congenital Deafness ◽  
Adeno Associated Virus ◽  
Coding Sequence ◽  
Packaging Capacity

Autosomal recessive genetic forms (DFNB) account for most cases of profound congenital deafness. Adeno-associated virus (AAV)-based gene therapy is a promising therapeutic option, but is limited by a potentially short therapeutic window and the constrained packaging capacity of the vector. We focus here on the otoferlin gene underlying DFNB9, one of the most frequent genetic forms of congenital deafness. We adopted a dual AAV approach using two different recombinant vectors, one containing the 5′ and the other the 3′ portions of otoferlin cDNA, which exceed the packaging capacity of the AAV when combined. A single delivery of the vector pair into the mature cochlea ofOtof−/−mutant mice reconstituted the otoferlin cDNA coding sequence through recombination of the 5′ and 3′ cDNAs, leading to the durable restoration of otoferlin expression in transduced cells and a reversal of the deafness phenotype, raising hopes for future gene therapy trials in DFNB9 patients.

scholarly journals The differential effects of prenatal and/or postnatal rapamycin on neurodevelopmental defects and cognition in a neuroglial mouse model of tuberous sclerosis complex

2012 ◽  
Vol 21 (14) ◽  
pp. 3226-3236 ◽  
Author(s):  
Sharon W. Way ◽  
Natalia S. Rozas ◽  
Henry C. Wu ◽  
James McKenna ◽  
R. Michelle Reith ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Differential Effects
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