Genotoxicity in gene therapy: an account of vector integration and designer nucleases.
Genotoxicity is a collective term that includes any process which affects the integrity of genomic DNA. With regard to gene therapy, the insertion of genetic elements and the expression of DNA-modifying proteins are the main mediators of genotoxic side effects. The practicability of gene-addition-type gene therapy protocols has been demonstrated in several successful clinical trials, but the risk of insertional mutagenesis remains a major obstacle. Targeted strategies aimed at correcting a mutation directly in the genome can preserve temporal and tissue-specific expression of the afflicted gene. However, sufficient gene targeting frequency can only be achieved upon expression of tailor-made nucleases. Partly because of insufficient specificity, such designer nucleases can challenge genome integrity. Here, the origin and the consequences of genotoxicity are reviewed, with a focus on assays that have been developed to assess genotoxicity. In addition, approaches to reduce toxicity associated with the major gene therapy strategies are discussed.
Hannover Medical School, Department of Virology, OE 5230, Carl-Neuberg-Str 1, D-30625 Hannover, Germany. bohne.jens@mh-hannover.de
Jens
J
Bohne
Toni
T
Cathomen
D004720:Endonucleases / Q000235:genetics* / Q000378:metabolism*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000009:adverse effects*; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D009152:Mutagenicity Tests; D014780:Viruses / Q000235:genetics
D004720:Endonucleases