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Expression of a large coding sequence: Gene therapy vectors for Ataxia Telangiectasia
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Expression of a large coding sequence: Gene therapy vectors for Ataxia Telangiectasia
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Journal Article
Expression of a large coding sequence: Gene therapy vectors for Ataxia Telangiectasia
2023
Overview
Ataxia telangiectasia is a monogenetic disorder caused by mutations in the
ATM
gene. Its encoded protein kinase ATM plays a fundamental role in DNA repair of double strand breaks (DSBs). Impaired function of this kinase leads to a multisystemic disorder including immunodeficiency, progressive cerebellar degeneration, radiation sensitivity, dilated blood vessels, premature aging and a predisposition to cancer. Since allogenic hematopoietic stem cell (HSC) transplantation improved disease outcome, gene therapy based on autologous HSCs is an alternative promising concept. However, due to the large cDNA of ATM (9.2 kb), efficient packaging of retroviral particles and sufficient transduction of HSCs remains challenging.
We generated lentiviral, gammaretroviral and foamy viral vectors with a GFP.F2A
.
Atm fusion or a GFP transgene and systematically compared transduction efficiencies. Vector titers dropped with increasing transgene size, but despite their described limited packaging capacity, we were able to produce lentiviral and gammaretroviral particles. The reduction in titers could not be explained by impaired packaging of the viral genomes, but the main differences occurred after transduction. Finally, after transduction of
Atm
-deficient (ATM-KO) murine fibroblasts with the lentiviral vector expressing Atm, we could show the expression of ATM protein which phosphorylated its downstream substrates (pKap1 and p-p53).
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
