Friedreich's ataxia (FRDA) is an inherited neurodegenerative disease caused by a deficiency in the nuclear-encoded mitochondrial protein frataxin. At present there is no effective cure or treatment for FRDA. The DMA abnormality found in 98% of FRDA patients is the unstable hyper-expansion of a GAA triplet in the first intron of the frataxin gene, which adopts a triplex DMA structure that interferes with gene transcription. In prior studies, we have successfully developed synthetic pyrrole-imidizole polyamides to target GAA repeat DMA. These molecules bind duplex GAA DNA with high affinity and relieve repression of the frataxin gene in lymphoid cells derived from FRDA patients. We now wish to explore whether these molecules will activate the frataxin gene in neuronal cells, and in a mouse knock-in model for FRDA, and to determine the pharmacological properties of these molecules. We will explore the relationship between polyamide composition and function with a new series of molecules. Deconvolution microscopy will be used to monitor the subcellular localization and kinetics of uptake of fluorescent dye-polyamide conjugates in cultured cell lines and in lymphoid cells from FRDA patients. Real-time PCR will be used to determine the effects of polyamides on frataxin mRNA expression in human FRDA cell lines, lymphoid cells isolated from FRDA donor blood, and in neuronal cell lines established from expanded frataxin knock-in mice. The effects of polyamides on cellular frataxin protein will be determined by western blotting, and the genome-wide effects of polyamide treatment will be assessed by DNA microarray analysis. Animal studies will be performed in normal mice to determine the bioavailability, tissue distribution, pharmacokinetics, half-lives of the compounds in serum, toxicity, and maximum tolerated dosage. Expanded GAA allele knock-in mice will be used to determine whether the GAA-specific compounds activate frataxin gene expression in vivo. If polyamides fail to cross the blood-brain barrier, alternative chemistries and delivery systems will be investigated. ? ? This proposal is aimed at the development of new drugs to treat the inherited neurological disease Friedreich's ataxia (FRDA). FRDA is a genetic disease, in which a region of the affected gene, called frataxin, is expanded in size by the addition of repeats of the simple sequence GAA. These repeats inactivate the gene, and we have developed small molecules that reverse this inactivation by targeting the GAA repeats. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS055158-01
Application #
7080111
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (95))
Program Officer
Gwinn, Katrina
Project Start
2006-04-01
Project End
2011-01-31
Budget Start
2006-04-01
Budget End
2007-01-31
Support Year
1
Fiscal Year
2006
Total Cost
$418,275
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Gottesfeld, Joel M; Rusche, James R; Pandolfo, Massimo (2013) Increasing frataxin gene expression with histone deacetylase inhibitors as a therapeutic approach for Friedreich's ataxia. J Neurochem 126 Suppl 1:147-54
Jia, Haiqun; Pallos, Judit; Jacques, Vincent et al. (2012) Histone deacetylase (HDAC) inhibitors targeting HDAC3 and HDAC1 ameliorate polyglutamine-elicited phenotypes in model systems of Huntington's disease. Neurobiol Dis 46:351-61
Ku, Sherman; Soragni, Elisabetta; Campau, Erica et al. (2010) Friedreich's ataxia induced pluripotent stem cells model intergenerational GAA?TTC triplet repeat instability. Cell Stem Cell 7:631-7
Xu, Chunping; Soragni, Elisabetta; Chou, C James et al. (2009) Chemical probes identify a role for histone deacetylase 3 in Friedreich's ataxia gene silencing. Chem Biol 16:980-9
Hu, Fang; Chou, C James; Gottesfeld, Joel M (2009) Design and synthesis of novel hybrid benzamide-peptide histone deacetylase inhibitors. Bioorg Med Chem Lett 19:3928-31
Gottesfeld, Joel M; Pandolfo, Massimo (2009) Development of histone deacetylase inhibitors as therapeutics for neurological disease. Future Neurol 4:775-784
Thomas, Elizabeth A; Coppola, Giovanni; Desplats, Paula A et al. (2008) The HDAC inhibitor 4b ameliorates the disease phenotype and transcriptional abnormalities in Huntington's disease transgenic mice. Proc Natl Acad Sci U S A 105:15564-9
Gottesfeld, Joel M (2007) Small molecules affecting transcription in Friedreich ataxia. Pharmacol Ther 116:236-48