Dataset Information

Long-Term Therapeutic Efficacy of Intravenous AAV-Mediated Hamartin Replacement in Mouse Model of Tuberous Sclerosis Type 1.

ABSTRACT: Tuberous sclerosis complex (TSC) is a tumor suppressor syndrome caused by mutations in TSC1 or TSC2, encoding hamartin and tuberin, respectively. These proteins act as a complex that inhibits mammalian target of rapamycin (mTOR)-mediated cell growth and proliferation. Loss of either protein leads to overgrowth in many organs, including subependymal nodules, subependymal giant cell astrocytomas, and cortical tubers in the human brain. Neurological manifestations in TSC include intellectual disability, autism, hydrocephalus, and epilepsy. In a stochastic mouse model of TSC1 brain lesions, complete loss of Tsc1 is achieved in homozygous Tsc1-floxed mice in a subpopulation of neural cells in the brain by intracerebroventricular (i.c.v.) injection at birth of an adeno-associated virus (AAV) vector encoding Cre recombinase. This results in median survival of 38 days and brain pathology, including subependymal lesions and enlargement of neuronal cells. Remarkably, when these mice were injected intravenously on day 21 with an AAV9 vector encoding hamartin, most survived at least up to 429 days in apparently healthy condition with marked reduction in brain pathology. Thus, a single intravenous administration of an AAV vector encoding hamartin restored protein function in enough cells in the brain to extend lifespan in this TSC1 mouse model.

SUBMITTER: Prabhakar S

PROVIDER: S-EPMC6745533 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Long-Term Therapeutic Efficacy of Intravenous AAV-Mediated Hamartin Replacement in Mouse Model of Tuberous Sclerosis Type 1.

Prabhakar Shilpa S Cheah Pike See PS Zhang Xuan X Zinter Max M Gianatasio Maria M Hudry Eloise E Bronson Roderick T RT Kwiatkowski David J DJ Stemmer-Rachamimov Anat A Maguire Casey A CA Sena-Esteves Miguel M Tannous Bakhos A BA Breakefield Xandra O XO

Molecular therapy. Methods & clinical development 20190816

Tuberous sclerosis complex (TSC) is a tumor suppressor syndrome caused by mutations in <i>TSC1</i> or <i>TSC2,</i> encoding hamartin and tuberin, respectively. These proteins act as a complex that inhibits mammalian target of rapamycin (mTOR)-mediated cell growth and proliferation. Loss of either protein leads to overgrowth in many organs, including subependymal nodules, subependymal giant cell astrocytomas, and cortical tubers in the human brain. Neurological manifestations in TSC include intel ...[more]

PMID: 31534984

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Project description:AIM:To investigate the interdependence between risk factors associated with long-term intellectual development in individuals with tuberous sclerosis complex (TSC). METHOD:The Tuberous Sclerosis 2000 Study is a prospective longitudinal study of individuals with TSC. In phase 1 of the study, baseline measures of intellectual ability, epilepsy, cortical tuber load, and mutation were obtained for 125 children (63 females, 62 males; median age=39mo). In phase 2, at an average of 8 years later, intellectual abilities were estimated for 88 participants with TSC and 35 unaffected siblings. Structural equation modelling was used to determine the risk pathways from genetic mutation through to IQ at phase 2. RESULTS:Intellectual disability was present in 57% of individuals with TSC. Individuals without intellectual disability had significantly lower mean IQ compared to unaffected siblings, supporting specific genetic factors associated with intellectual impairment. Individuals with TSC who had a slower gain in IQ from infancy to middle childhood were younger at seizure onset and had increased infant seizure severity. Structural equation modelling indicated indirect pathways from genetic mutation, to tuber count, to seizure severity in infancy, through to IQ in middle childhood and adolescence. INTERPRETATION:Early-onset and severe epilepsy in the first 2 years of life are associated with increased risk of long-term intellectual disability in individuals with TSC, emphasizing the importance of early and effective treatment or prevention of epilepsy. WHAT THIS PAPER ADDS:Intellectual disability was present in 57% of individuals with tuberous sclerosis complex (TSC). Those with TSC without intellectual disability had significantly lower mean IQ compared to unaffected siblings. Earlier onset and greater severity of seizures in the first 2 years were observed in individuals with a slower gain in intellectual ability. Risk pathways through seizures in the first 2 years predict long-term cognitive outcomes in individuals with TSC.

Dataset Information

Long-Term Therapeutic Efficacy of Intravenous AAV-Mediated Hamartin Replacement in Mouse Model of Tuberous Sclerosis Type 1.

Publications

Long-Term Therapeutic Efficacy of Intravenous AAV-Mediated Hamartin Replacement in Mouse Model of Tuberous Sclerosis Type 1.

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