Progetto: Analysis of HDAC inhibitor effects on DNA methylation in a Friedreich ataxia mouse model and isolating neuronal precursor cells for preclinical therapeutic investigations

Principal researcher: Dr. Mark Pook, Biosciences, School of Health Sciences & Social Care, Brunel University, Cleveland Road, Uxbridge, UB8 3PH UK

Lay summary: We have recently generated a human FXN GAA repeat expansion-based transgenic mouse model of Friedreich ataxia. These mice exhibit decreased levels of frataxin mRNA and protein, associated with DNA hypermethylation in a region upstream of the GAA repeat sequence within FXN intron 1. Comparative decreases in histone acetylation have also been detected in the promoter, GAA upstream and GAA downstream regions of the FXN transgene. Therefore, this is an excellent FRDA mouse model in which to investigate the therapeutic epigenetic effects of compounds such as novel histone deacetylase (HDAC) inhibitors. Indeed, with the current funding we are now testing the effects of a novel HDAC inhibitor on histone modifications and frataxin expression levels in tissues from our FRDA mouse model. However, with GoFAR funding now we like to examine the effects of the novel HDAC inhibitor on DNA methylation of the FXN transgene within our FRDA mouse model. We would also like to isolate neuronal precursor cells from our FRDA mouse model, so that similar therapeutic testing can be investigated at a cellular level rather than a tissue level.

Isolating neuronal precursor cells for preclinical therapeutic investigations.

In collaboration with Massimo Pandolfo, we will isolate neuronal precursor cells from the brain tissue of our FRDA mice. This will provide a relevant cell-based resource, complementing the tissue-based mouse model studies, for preclinical therapeutic testing of FRDA.

These studies will provide important basic preclinical information regarding HDAC inhibitor therapy in particular. They will also provide a very useful resource (neuronal precursor cells) for the investigation of other potential FRDA therapies.
*Questi studi forniranno importanti informazioni precliniche di base riguardanti in particolare la terapia con gli inibitori HDAC. Inoltre forniranno una risorsa di grande utilità (Cellule dei precursori neuronali) per la ricerca di altre potenziali terapie per la Atassia di Freidreich.

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