Compound found in broccoli may be ‘strong’ drug candidate for FA

Sulforaphane, a compound found in broccoli and other vegetables, was shown in a laboratory study to improve nerve cell survival in Friedreich’s ataxia (FA) and to act on several biological processes implicated in the rare progressive disease.

The scientists say the compound may be “a strong … drug candidate” for treating FA. Indeed, in sensory nerve cells  — a type of specialized neurons — from three patients with distinct disease-causing mutations, sulforaphane generally had broader effects than Skyclarys (omaveloxolone), the only approved treatment for FA, and a medication for another neurodegenerative condition.

In their study, the researchers had tested suloraphane versus both Skyclarys and dimethyl fumarate, an approved multiple sclerosis drug sold under the brand name Tecfidera. The data showed the broccoli compound “was more effective than [either of the others] in improving cell viability,” the team wrote.

“Sulforaphane already has an established safety record in children and adults, and its pure and bioactive form is commercially available,” Faith Kwa, PhD, the study’s lead author and an associate professor at Swinburne University of Technology in Australia, said in a university press release. “This means if clinical trials prove successful, its rollout could accelerate the path to patient impact.”

According to Kwa, “this discovery brings us closer to a future where children with Friedreich ataxia experience a better quality of life, greater independence, and an improved chance of long-term survival.”

The study, “Unlocking Sulforaphane’s Potential in Friedreich Ataxia: Further Evidence from Preclinical Investigations Using Induced Pluripotent Stem Cell-Derived Sensory Neurons,” was published in the journal Antioxidants & Redox Signaling.

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FA is caused in most cases by excessive repeats of three DNA building blocks — together known as GAA — in the FXN gene. Generally, a greater number of repeats is associated with an earlier disease onset and more severe symptoms.

This genetic mutation interferes with the production of frataxin, a protein important for mitochondria, which serve as the powerhouses of the body’s cells. Low frataxin levels are associated with mitochondrial dysfunction, oxidative stress — when the body’s antioxidant defenses no longer provide efficient protection against toxic oxidant molecules — inflammation, and ultimately cell death.

Sensory neurons in the dorsal root ganglia, clusters of nerve cells that transmit sensory signals to the brain and spinal cord, are among the cells affected earliest in FA.

Sulforaphane shown to increase levels of frataxin, low in FA

Sulforaphane — which also has shown potential for cancer prevention — activates Nrf2, a protein that helps regulate cells’ defenses against oxidative stress. Preclinical work suggested it also can increase frataxin levels, low in FA, and influence other pathways that are abnormal in patients.

The researchers previously found that sulforaphane activated antioxidant defenses and eased inflammatory signals in cells with excessive GAA repeats. The compound also increased the proportion of living sensory neurons compared with dimethyl fumarate and Skyclarys — which also works by activating Nrf2.

Now, the team used induced pluripotent stem cells (iPSCs) generated from three patients with GAA repeat lengths of 450, 550, and 867. iPSCs, which can develop into many cell types, were converted into sensory neurons.

The neurons were exposed for 24 hours to varying concentrations of sulforaphane, dimethyl fumarate, or Skyclarys. In cells with 867 GAA repeats — the largest repeat expansion tested — sulforaphane was the only candidate to significantly improve cell survival. At two concentrations, the proportion of viable cells increased by as much as 8.5% when compared with untreated cells.

In neurons with 450 repeats, all three treatments significantly increased cell survival. Sulforaphane increased it by 10.2%, dimethyl fumarate by 13.9%, and Skyclarys by 14.3%, the data showed. When results from all three cell lines were pooled, several concentrations of sulforaphane were found to increase viability by about 7%-10%.

[Sulforaphane appears to’ target the underlying cause of the disease. … We are hoping to gain funding to conduct clinical trials and further prove the positive impact the broccoli compound could have on those suffering from [Friedreich’s] ataxia.

The researchers also examined whether the treatments could increase frataxin levels. In the pooled analysis, the lowest sulforaphane dose tested increased FXN gene activity by 1.22 times, while no significant effects were observed with dimethyl fumarate or Skyclarys. In the 450-repeat cell line, higher sulforaphane doses increased frataxin protein by as much as 1.37 times. No treatment increased frataxin protein in the 867-repeat cell line.

Beyond frataxin, sulforaphane showed broad activity against several processes involved in FA, including antioxidant activity and inflammation. There also was activity against epigenetics, which are chemical markers that regulate gene activity without changing the genetic code.

Altogether, the researchers concluded that “this study has provided robust preclinical evidence that [sulforaphane] appears to be the most versatile option for targeting multiple pathways in sensory neurons derived from [FA] patient iPSCs.”

Kwa said the broccoli compound appears to “target the underlying cause of the disease,” but noted that studies specific to FA are needed.

“We are hoping to gain funding to conduct clinical trials and further prove the positive impact the broccoli compound could have on those suffering from Friedreich ataxia,” Kwa said.