Potential therapy ATH434 may target toxic iron buildup in cells

Compound, in clinical tests in other disease, could be an effective iron chelator

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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An experimental compound called ATH434, currently being evaluated in clinical trials for a neurological disorder called multiple system atrophy, also may have the potential to treat Friedreich’s ataxia (FA).

Data specifically indicate that ATH434 could help to reduce the toxic buildup of iron in cells that is characteristic of FA.

The research was conducted by scientists at Alterity Therapeutics, the company developing ATH434, in collaboration with those at Wayne State University in Detroit. The team presented the findings at the World Orphan Drug Congress USA 2024, held in Boston, in the poster, “Biophysical Characteristics of ATH434, a Unique Iron-Targeting Drug for Treating Friedreich’s Ataxia.”

“By acting as an iron chaperone, ATH434 has potential to reduce labile iron levels and thus slow disease progression. Given these new data, we are excited to evaluate FA as a potential new indication for ATH434,” David Stamler, MD, CEO of Alterity, said in a company press release.

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In lab tests, ATH434 worked to lower excess ferrous iron levels

FA is caused by mutations in the gene that provides instructions for making the frataxin protein. Frataxin is important for the function of mitochondria, a cell’s so-called powerhouse. One of the protein’s essential jobs is to help mitochondria utilize iron, a nutrient that’s needed for many crucial biological processes.

A lack of functional frataxin protein means mitochondria cannot use iron efficiently, and iron can accumulate to toxic levels in cells as a consequence. This toxic buildup is thought to be one of the key biochemical mechanisms that drives FA progression.

“The genetic defect in Friedreich’s Ataxia leads to reduced function of frataxin, a protein necessary for utilizing labile iron, thus leading to iron accumulation in disease,” Stamler said.

Theoretically, iron chelators — molecules that “sponge up” excess iron to remove it from cells — might be used to treat FA by reducing the toxic buildup of iron. But traditional iron chelators have proven ineffective, and in some cases led to disease worsening.

These paradoxical findings may be due to some details of iron chemistry. Specifically, different types of iron have different electric charges. In FA, the main type of iron that builds to toxic levels is ferrous iron, which carries an electrical charge of 2+.

Traditional chelators usually aren’t very good at removing ferrous, or labile, iron. Instead, they tend to sponge up iron salts with a charge of 3+, known as ferric iron. The fact that traditional chelators have little effect on the type of iron that’s toxic in FA, but have high affinity for a type of iron needed for cellular activities may explain why they’ve proven ineffective or even detrimental in Friedreich’s ataxia.

In their poster, the scientists presented findings from a battery of chemical tests showing that ATH434, a novel iron chelator, is very good at soaking up the ferrous iron that builds to toxic levels in FA. At the same time, ATH434 has very low affinity for ferric iron.

Tests indicate that ATH434 ‘behaves like a chaperone to redistribute iron’

As such, the researchers said the novel compound could allow for selectively targeting toxic ferrous iron in the disease.

“The unique iron binding properties of ATH434 suggests this drug could be suited to assist in intracellular iron targeting and delivery,” the team wrote.

“This investigation provides important insights into the mechanism of action of ATH434, namely that it selectively targets the labile iron implicated in the pathology of important neurodegenerative diseases. In this way, ATH434 behaves like a chaperone to redistribute iron within the body,” Stamler said.

“There has historically been great interest in targeting iron in general to treat these diseases, and we now have clear evidence that ATH434 is very different from traditional iron chelators,” Stamler added.