Shortening trinucleotide repeats using highly specific endonucleases: a possible approach to gene therapy?
Trinucleotide repeat expansions are involved in more than two dozen neurological and developmental disorders. Conventional therapeutic approaches aimed at regulating the expression level of affected genes, which rely on drugs, oligonucleotides, and/or transgenes, have met with only limited success so far. An alternative approach is to shorten repeats to non-pathological lengths using highly specific nucleases. Here, I review early experiments using meganucleases, zinc-finger nucleases (ZFN), and transcription-activator like effector nucleases (TALENs) to contract trinucleotide repeats, and discuss the possibility of using CRISPR-Cas nucleases to the same end. Although this is a nascent field, I explore the possibility of designing nucleases and effectively delivering them in the context of gene therapy.
Institut Pasteur, Department Genomes and Genetics, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 3525, 25 Rue du Dr Roux, 75015 Paris, France.
Guy-Franck
GF
Richard
D000818:Animals; D004720:Endonucleases / Q000145:classification / Q000378:metabolism* / Q000627:therapeutic use; D015316:Genetic Therapy; D042822:Genomic Instability; D006801:Humans; D015202:Protein Engineering; D013379:Substrate Specificity; D019680:Trinucleotide Repeat Expansion; D018911:Trinucleotide Repeats
D004720:Endonucleases
CRISPR-Cas; TALEN; ZFN; double-strand break; meganuclease; tandem repeats