Targeting DNA Repair Protein Could Treat Friedreich's Ataxia

Could targeting a protein involved in DNA repair reduce the cause of Friedreich’s ataxia? Data from a study conducted at the University of California, San Diego suggests that could be the case.

Anasheh Halabi, M.D., Ph.D. and a team of researchers have found that targeting the MLH3 protein involved in DNA repair can reduce the GAA repeat expansion that results in the rare neuromuscular disease.

The finding was published in Nucleic Acids Research this week in an article titled “GAA-TTC repeat expansion in human cells is mediated by mismatch repair complex MutLy and depends upon the endonuclease domain in MLH3 isoform one.” It adds to the existing knowledge about the mechanisms involved in Friedrich’s ataxia, and could potentially lead to new development of disease-modifying therapies.

Cells have an array of mechanisms that ensure the genetic code is correct, however, they can fail, promoting the increase of disease-causing mutations. One such system is DNA mismatch repair (MMR), which compromises the MutS complex, responsible for recognizing genetic errors, and the MutL protein, responsible for repairing them. In the study, Dr Halabi and her team evaluated the contribution of MutL complex, which has been implicated in the promotion of the GAA expansions that cause Friedreich’s ataxia.

To get a better understanding of the role of the complex, the team genetically manipulated human cells to silence the genes encoding MutL proteins. The cells carried 176 repetitions of the GAA sequence, much like what is found in patients with Friedreich’s Ataxia.

The MutL complexes combine the MLH1 protein, the core subunit of the complex, with one of 3 potential partners: PMS2, PMS1, or MLH3. It was observed that the lack of MLH1 significantly reduced expansion of GAA repeats versus control cells, and this reduction was also found in cells that lacked MLH3. The discovery strongly suggests that the MLH1-MLH3 complex could be implicated in GAA triplet expansion — meaning it is present in disease progression.

The team also tested the potential of the splice-switching oligonucleotide (SSO) strategy to prevent MLH3 production, which consists of small molecules binding to RNA sequences to promote the skipping of small coding regions. Cells were treated with SSO in an attempt to achieve constant production of smaller MLH3 protein, and after 4 weeks of treatment, the cells displayed slower GAA repeat expansion similar to that seen in the previous experiment.

Lastly, the SSO strategy was tested in cells collected from 3 patients with Friedreich’s ataxia, and after 6 weeks of treatment, the cells exhibited decreased levels of functional MLH3 protein and a slower GAA expansion rate.

Because there is little evidence to support the loss of MLH3 as a contributing factor in cancer development, the researchers suggest that MLH3 has stronger and safer potential as a therapeutic target than does MLH1.

Based on the data, it is suspected that the MutL protein is the active cause of repeat expansion. Together, these results prove that the MLH1-MLH3 complex is a vital intermediary of GAA expansion, and that targeting MLH3 promoters could possibly treat Friedreich’s ataxia.

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