Friedreich’s ataxia therapy may protect cells against stress in SMA
Researchers suggest omaveloxolone could complement existing treatments
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- SMA involves insufficient SMN protein, leading to motor neuron issues, metabolic problems, and oxidative stress.
- Omaveloxolone, an existing drug, increased anti-stress proteins and SMN levels in lab-grown SMA cells.
- This suggests omaveloxolone could complement current SMA therapies by mitigating cellular stress.
Omaveloxolone, a therapy designed to promote anti-stress responses in cells, may help correct stress-related dysfunction in certain cells from people with spinal muscular atrophy (SMA), according to a lab-based study.
The treatment works by boosting levels of proteins that help fight stress, including several in a signaling pathway called NRF2. It also boosted levels of the survival motor neuron (SMN) protein, which is deficient in SMA. This suggests the medication may have secondary effects on certain processes underlying SMA, researchers suggested.
“These results support further investigation of NRF2 activation, including [omaveloxolone], as a potential adjunctive [add-on] strategy in SMA,” they wrote.
The study, “Pharmacological Activation of NRF2 by Omaveloxolone Upregulates NRF2-Target Proteins in SMA Type I Human Fibroblasts,” was published in The FASEB Journal.
The systemic impact of SMA
In SMA, mutations in the SMN1 gene result in insufficient SMN protein production. Because SMN plays an important role in maintaining the specialized nerve cells that support movement, called motor neurons, this leads to neuromuscular symptoms. A backup gene called SMN2 can produce functional SMN, but at a much lower level than SMN1.
In addition to motor neurons, SMA affects other cells throughout the body. Recent research has found that cells of people with SMA show problems with metabolism and the cellular structures that produce energy, known as mitochondria.
The disease can also affect redox homeostasis, which is the delicate balance of oxidation and reduction reactions within cells. When the balance becomes disrupted, oxidative stress, a process that can harm cells, may occur.
“SMA is increasingly recognized as a multisystem disorder involving peripheral tissues, where metabolic and redox abnormalities may contribute to disease complexity beyond the neuromuscular compartment,” the researchers wrote.
Proteins in the NRF2 pathway can help counteract and adapt to oxidative stress. The research team hypothesized that boosting these proteins could have positive effects for cells from people with SMA.
To do this, they used omaveloxolone, which is approved as Skyclarys for Friedreich’s ataxia. “From a translational perspective, [omaveloxolone] is notable because it is clinically approved for Friedreich’s ataxia, a neurodegenerative and multisystem disorder involving impaired mitochondrial homeostasis and oxidative stress,” the team wrote.
In a laboratory setting, the researchers exposed cells from healthy individuals and individuals with SMA type 1 to omaveloxolone. They used fibroblasts, a type of cell found in connective tissues that play important roles in healing.
Omaveloxolone increased the survival of both control and SMA cells. As soon as 48 hours after the first omaveloxolone treatment, exposed SMA cells had significantly higher viability than unexposed SMA cells.
Based on this timeline, the researchers established a dosing protocol for the cells. Every 24 hours for two days, they exposed cells to omaveloxolone or a control substance. They examined changes in levels of relevant proteins before and after this treatment.
Before omaveloxolone exposure, levels of two NRF2 signaling proteins, NQO1 and xCT, were significantly lower in SMA cells than in control cells. A related metabolic protein called PGC1-alpha was also significantly lower in the SMA fibroblasts, as was SMN.
As expected, omaveloxolone significantly increased levels of NRF2 signaling proteins for both types of cells. While the levels of SMN and PGC1-alpha were unchanged in control cells, SMA fibroblasts had significant increases in all of the measured proteins.
“These results identify reduced NRF2 pathway output as a feature of SMN-deficient fibroblasts and support further investigation of the mechanistic relationship between NRF2-dependent stress-response signaling and SMN regulation,” the team wrote.
The reason for the increase in SMN levels was unclear. The team hypothesized that increasing NRF2 signaling could make the cellular environment more conducive to SMN stability, which might help the protein function more effectively.
Signaling in the NRF2 pathway could also have indirect effects on SMN production, they proposed. For instance, this process could increase the amount of protein created using the backup gene SMN2.
“In combination with approved therapies … [omaveloxolone] may complement SMN-targeted approaches by mitigating cellular stress and redox imbalance, thereby addressing pathogenic [disease-related] mechanisms that are not directly corrected by SMN restoration alone,” the team concluded.
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