Edited by: Institute of Neurobiology and Molecular Medicine - INMM and
Institute of Molecular Biology and Pathology - IBPM
The design and realization of artificial regulatory genes represents an important and promising tool for the development of new therapeutic strategies for the cure of genetic diseases and cancer. In particular, the use of "synthetic regulator genes" may allow the up-regulation, down-regulation or suppression of "target genes" involved in different pathologies.
We realized a novel synthetic regulator gene named "Jazz", designed to control the expression of the utrophin gene which has great potentiality in the therapy of Duchenne muscle dystrophy (DMD). The research was conducted in the laboratories of Dr. Passananti (CNR-IBPM) and Dr. Mattei (CNR-INMM) in collaboration with Dr. Fanciulli (Regina Elena Cancer Institute of Rome) and Prof. Kay E. Davies (Medical Research Council, University of Oxford, UK).
The synthetic gene "Jazz" (which is a good candidate for gene therapy due to its very small size), once integrated in the genomic DNA of mice, demonstrated the ability to specifically up-regulate the expression levels of the target utrophin gene in skeletal muscle.
It has been shown previously that utrophin partially replaces dystrophin, ameliorating the conditions of mdx mice (the murine model of DMD). Therefore over-expression of the utrophin gene represents one of the main therapeutic strategies proposed in the last years for the cure of DMD. We demonstrated that "Jazz" is able to specifically recognize the target gene utrophin in mouse muscular tissues and to up-regulate significantly its expression. Mice expressing the "Jazz" gene are the first transgenic model producing a synthetic gene/protein able to regulate gene expression.
We plan to crossbreed "Jazz" mice with dystrophic mdx mice. This double mutant mouse will supply both an important tool for gene therapy projects and a model system for wide pharmacological tests to identify new molecules able to up-regulate utrophin levels to be used in the cure of Duchenne muscular dystrophy.
References
Mattei E, Corbi N, Di Certo MG, Strimpakos G, Severini C, Onori A, Desantis A, Libri V, Buontempo S, Floridi A, Fanciulli M, Baban D, Davies KE, Passananti C. Utrophin up-regulation by an artificial transcription factor in transgenic mice. PLoS ONE. Aug 22;2:e774, 2007.
Onori A, Desantis A, Buontempo S, Di Certo MG, Fanciulli M, Salvatori L, Passananti C, and Corbi N. The artificial 4-zinc-finger protein Bagly binds human utrophin promoter A at the endogenous chromosomal site and activates transcription.Biochem. Cell Biol. 2007 June;85: 358-365.
Corbi N, Libri V, Onori A, Passananti C. Synthetic zinc finger peptides:old and novel applications. Biochem. Cell Biol. 2004 July;82:1-9.
Focus