ArticleThe journal of gene medicine2008
Co-expression of MGMT(P140K) and alpha-L-iduronidase in primary hepatocytes from mucopolysaccharidosis type I mice enables efficient selection with metabolic correction.
Article in The journal of gene medicine, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 7 citations in OpenAlex.
- New function of a well-known promoter: Enhancer activity of minimal CMV promoter enables efficient dual-cassette transgene expression.The journal of gene medicine · 2021Article
- In vivo enrichment of genetically manipulated platelets for murine hemophilia B gene therapy.Journal of cellular physiology · 2021Article
- miR-143 Regulates Lysosomal Enzyme Transport across the Blood-Brain Barrier and Transforms CNS Treatment for Mucopolysaccharidosis Type I.Molecular therapy : the journal of the American Society of Gene Therapy · 2020Article
- Loss of BRUCE reduces cellular energy level and induces autophagy by driving activation of the AMPK-ULK1 autophagic initiating axis.PloS one · 2019Article
- Normalization and improvement of CNS deficits in mice with Hurler syndrome after long-term peripheral delivery of BBB-targeted iduronidase.Molecular therapy : the journal of the American Society of Gene Therapy · 2014Article
- Engineering a lysosomal enzyme with a derivative of receptor-binding domain of apoE enables delivery across the blood-brain barrier.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- Cell- and gene-based therapeutic approaches for neurological deficits in mucopolysaccharidoses.Current pharmaceutical biotechnology · 2011Review
- Multifaceted roles of alkyltransferase and related proteins in DNA repair, DNA damage, resistance to chemotherapy, and research tools.Chemical research in toxicology · 2011Review
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3 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundSystemic in vivo gene therapy has resulted in widespread correction in animal models when treated at birth. However, limited improvement was observed in postnatally treated animals with mainly targeting to the liver and bone marrow. It has been shown that an O(6)-methylguanine-DNA-methyltransferase variant (MGMT(P140K)) mediated in vivo selection of transduced hematopoietic stem cells (HSC) in animals.
methodsWe investigated the feasibility of MGMT(P140K)-mediated selection in primary hepatocytes from a mouse model of mucopolysaccharidosis type I (MPS I) in vitro using lentiviral vectors.
resultsWe found that multiple cycles of O(6)-benzylguanine (BG)/1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) treatment at a dosage effective for ex vivo HSC selection led to a two-fold increase of MGMT-expressing primary hepatocytes under culture conditions with minimum cell expansion. This enrichment level was comparable to that obtained after selection at a hepatic maximal tolerated dose of BCNU. Similar levels of increase were observed regardless of initial transduction frequency, or the position of MGMT (upstream or downstream of internal ribosome entry site) in the vector constructs. In addition, we found that elongation factor 1alpha promoter was superior to the long-terminal repeat promoter from spleen focus-forming virus with regard to transgene expression in primary hepatocytes. Moreover, the levels of therapeutic transgene expression in transduced, enzyme-deficient hepatocytes directly correlated with the doses of BCNU, leading to metabolic correction in transduced hepatocytes and metabolic cross-correction in neighbouring non-transduced MPS I cells.
conclusionsThese results demonstrate that MGMT(P140K) expression confers successful protection/selection in primary hepatocytes, and provide 'proof of concept' to the prospect of MGMT(P140K)-mediated co-selection for hepatocytes and HSC using BG/BCNU treatment.
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