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Long-term therapeutic efficacy of intravenous AAV-mediated hamartin replacement in mouse model of tuberous sclerosis type 1

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...

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Main Authors: Prabhakar, Shilpa, Cheah, Pike See, Zhang, Xuan, Zinter, Max, Gianatasio, Maria, Hudry, Eloise, Bronson, Roderick T, Kwiatkowski, David J, Rachamimov, Anat Stemmer, Maguire, Casey A, Sena-Esteves, Miguel, Tannous, Bakhos A, Breakefield, Xandra O
Format: Article
Language:English
Published: Cell Press 2019
Online Access:http://psasir.upm.edu.my/id/eprint/81248/1/Long-term%20therapeutic%20efficacy%20of%20intravenous%20AAV.pdf
http://psasir.upm.edu.my/id/eprint/81248/
https://pubmed.ncbi.nlm.nih.gov/31534984/
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spelling my.upm.eprints.812482021-06-16T02:28:41Z http://psasir.upm.edu.my/id/eprint/81248/ Long-term therapeutic efficacy of intravenous AAV-mediated hamartin replacement in mouse model of tuberous sclerosis type 1 Prabhakar, Shilpa Cheah, Pike See Zhang, Xuan Zinter, Max Gianatasio, Maria Hudry, Eloise Bronson, Roderick T Kwiatkowski, David J Rachamimov, Anat Stemmer Maguire, Casey A Sena-Esteves, Miguel Tannous, Bakhos A Breakefield, Xandra O 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. Cell Press 2019 Article PeerReviewed text en http://psasir.upm.edu.my/id/eprint/81248/1/Long-term%20therapeutic%20efficacy%20of%20intravenous%20AAV.pdf Prabhakar, Shilpa and Cheah, Pike See and Zhang, Xuan and Zinter, Max and Gianatasio, Maria and Hudry, Eloise and Bronson, Roderick T and Kwiatkowski, David J and Rachamimov, Anat Stemmer and Maguire, Casey A and Sena-Esteves, Miguel and Tannous, Bakhos A and Breakefield, Xandra O (2019) Long-term therapeutic efficacy of intravenous AAV-mediated hamartin replacement in mouse model of tuberous sclerosis type 1. Molecular Therapy-Methods & Clinical Development, 15. pp. 18-26. ISSN 2329-0501 https://pubmed.ncbi.nlm.nih.gov/31534984/ 10.1016/j.omtm.2019.08.003
institution Universiti Putra Malaysia
building UPM Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Putra Malaysia
content_source UPM Institutional Repository
url_provider http://psasir.upm.edu.my/
language English
description 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.
format Article
author Prabhakar, Shilpa
Cheah, Pike See
Zhang, Xuan
Zinter, Max
Gianatasio, Maria
Hudry, Eloise
Bronson, Roderick T
Kwiatkowski, David J
Rachamimov, Anat Stemmer
Maguire, Casey A
Sena-Esteves, Miguel
Tannous, Bakhos A
Breakefield, Xandra O
spellingShingle Prabhakar, Shilpa
Cheah, Pike See
Zhang, Xuan
Zinter, Max
Gianatasio, Maria
Hudry, Eloise
Bronson, Roderick T
Kwiatkowski, David J
Rachamimov, Anat Stemmer
Maguire, Casey A
Sena-Esteves, Miguel
Tannous, Bakhos A
Breakefield, Xandra O
Long-term therapeutic efficacy of intravenous AAV-mediated hamartin replacement in mouse model of tuberous sclerosis type 1
author_facet Prabhakar, Shilpa
Cheah, Pike See
Zhang, Xuan
Zinter, Max
Gianatasio, Maria
Hudry, Eloise
Bronson, Roderick T
Kwiatkowski, David J
Rachamimov, Anat Stemmer
Maguire, Casey A
Sena-Esteves, Miguel
Tannous, Bakhos A
Breakefield, Xandra O
author_sort Prabhakar, Shilpa
title Long-term therapeutic efficacy of intravenous AAV-mediated hamartin replacement in mouse model of tuberous sclerosis type 1
title_short Long-term therapeutic efficacy of intravenous AAV-mediated hamartin replacement in mouse model of tuberous sclerosis type 1
title_full Long-term therapeutic efficacy of intravenous AAV-mediated hamartin replacement in mouse model of tuberous sclerosis type 1
title_fullStr Long-term therapeutic efficacy of intravenous AAV-mediated hamartin replacement in mouse model of tuberous sclerosis type 1
title_full_unstemmed Long-term therapeutic efficacy of intravenous AAV-mediated hamartin replacement in mouse model of tuberous sclerosis type 1
title_sort long-term therapeutic efficacy of intravenous aav-mediated hamartin replacement in mouse model of tuberous sclerosis type 1
publisher Cell Press
publishDate 2019
url http://psasir.upm.edu.my/id/eprint/81248/1/Long-term%20therapeutic%20efficacy%20of%20intravenous%20AAV.pdf
http://psasir.upm.edu.my/id/eprint/81248/
https://pubmed.ncbi.nlm.nih.gov/31534984/
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score 13.211869

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