FARA continues to fund a robust research portfolio including drug discovery, cellular and animal model development, biomarker research and clinical studies. Monthly, we will spotlight grants funded through FARA's Scientific Grant Program with a summary of the research work. The following grants were all recently approved for their second year of funding.
The role of iron accumulation and increased lipid synthesis in the pathogenesis of Friedreich's ataxia
Hugo Bellen, Baylor College of Medicine, Houston, Texas
Dr. Bellen identified a fly mutant of frataxin that exhibits an age dependent neurodegenerative phenotype that can be rescued with the human frataxin gene, suggesting that the human and fly frataxin play a conserved role to maintain neuronal function. Kuchuan Chen, a graduate student in the Bellen lab, has shown that fly frataxin mutants exhibit a dramatic increase of iron deposits in multiple tissues. Reducing iron levels in food as well as neuronal activity suppresses the neurodegeneration, suggesting that iron accumulation and an impaired energy state contribute to the neurodegenerative phenotype. Furthermore, a drug that inhibits sphingolipid synthesis called myriocin significantly delayed the demise of neurons. They propose that aberrant iron deposits lead to an abnormal lipid homeostasis that causes toxicity. This project aims to investigate the mechanism of neurodegeneration in the fly frataxin mutant, which may identify new therapeutic strategies. Dr. Bellen has made important progress in his studies of the fly frataxin mutant phenotype in the first year of study. He proposes to expand his research to mice and patient samples (from CCRN Investigator- Dr. Martin Delatycki, Australia) in the second year, an essential step towards establishing the relevance of fly results to mammals.
Small molecule induced exon skipping of MLH3 to slow repeat expansion in an FRDA mouse model
Ed Grabczyk, Louisiana State University Health Sciences Center, New Orleans, Louisiana
Dr. Grabczyk's hypothesis is that the GAA*TTC repeats that cause Friedreich ataxia (FRDA) continue to grow in length over time in the tissues that are affected by the disease. He believes that this is what causes the gradual onset of Friedreich ataxia, and also what causes its progressive nature. The data from his lab indicates that this continued expansion of GAA*TTC repeats requires transcription through the repeat then the sequential actions of several DNA mismatch repair proteins called MutSbeta (MSH2/MSH3 heterodimer) and then MutLgamma (MLH1/MLH3 heterodimer). MutLgamma is the protein complex that cuts the DNA in the repeat to start the expansion. Without the cut, there is no expansion. Human MLH3 has two forms, form 1 cuts DNA, but form 2 does not. Dr. Grabczyk has shown that splice-switching oligonucleotides (SSOs) can be used to preferentially make MLH3 isoform2. When they treat cells with SSOs, the repeat stops expanding. The mouse MLH3 gene is very much like that of humans. There is a mouse model of FRDA called "YG-22" that shows tissue specific GAA*TTC repeat expansion. Dr. Grabczyk will use SSOs to block this expansion in mice as a first step heading to human trials. We look forward to the results of this ongoing work over the next year.
Investigation of the role of mTOR in Friedreich's ataxia and identification of new possible pathways for therapeutic intervention (*Co-Funded with FARA Ireland)
Massimo Pandolfo/ Simona Donatello, Université Libre de Bruxelles, Brussels, Belgium
Drs. Pandolfo and Donatello are investigating the role of a protein called mTOR in FA. The proteins targeted by mTOR are involved in key metabolic processes known to be affected in FA. By modulating the expression of frataxin (FXN) and mTOR, Drs. Pandolfo and Donatello are studying how they interconnect and affect each other, and how the cellular context is important in modulating the disease. It appears that in a cell specific context reduced frataxin is often accompanied by reduced mTOR activation that in turn can activate metabolic pathway, leading to iron preservation. They believe these investigations will shed new light on the still unclear mechanisms that regulate frataxin physiology and may identify new targets for FA treatment and cure.