Genomic discovery of potent chromatin insulators for human gene therapy.
Nat Biotechnol
; 33(2): 198-203, 2015 Feb.
Article
em En
| MEDLINE
| ID: mdl-25580597
ABSTRACT
Insertional mutagenesis and genotoxicity, which usually manifest as hematopoietic malignancy, represent major barriers to realizing the promise of gene therapy. Although insulator sequences that block transcriptional enhancers could mitigate or eliminate these risks, so far no human insulators with high functional potency have been identified. Here we describe a genomic approach for the identification of compact sequence elements that function as insulators. These elements are highly occupied by the insulator protein CTCF, are DNase I hypersensitive and represent only a small minority of the CTCF recognition sequences in the human genome. We show that the elements identified acted as potent enhancer blockers and substantially decreased the risk of tumor formation in a cancer-prone animal model. The elements are small, can be efficiently accommodated by viral vectors and have no detrimental effects on viral titers. The insulators we describe here are expected to increase the safety of gene therapy for genetic diseases.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Repressoras
/
Cromatina
/
Terapia Genética
/
Elementos Isolantes
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article