Mifepristone boosts survival, muscle size in SMA mouse model
Study: Combining medication with gene therapy improved treatment responses
- Mifepristone improved survival and muscle size in SMA mouse models.
- It reduced Klf15 activity, addressing SMA's metabolic issues.
- Combining mifepristone with gene therapy enhanced treatment responses.
Mifepristone, a glucocorticoid blocker, increased survival and muscle size in a mouse model of spinal muscular atrophy (SMA), according to a recent study.
Combining mifepristone with a gene therapy construct similar to the one used in Zolgensma and Itvisma, which is intended to increase levels of the SMN protein, improved tissue- and sex-specific responses to treatment. Most SMA cases result in an inadequate amount of SMN, a key protein for the survival of motor neurons that control movement.
Mifepristone treatment also improved motor function in an SMA model using the worm Caenorhabditis elegans (C. elegans). At the molecular level, mifepristone reduced the activity of the Klf15 gene, which encodes a protein that regulates metabolic processes.
“Overall, our study supports the relevance of using [glucocorticoid]-antagonist drugs as secondary therapies alongside SMN-dependent treatments for targeting both neuromuscular and metabolic pathologies [disease-related changes] in SMA,” researchers wrote.
The study, “Mifepristone alone and in combination with scAAV9-SMN1 gene therapy improves disease phenotypes in Smn2B/- spinal muscular atrophy mice,” was published in Scientific Reports.
Treatment significantly increased mobility in worm
Approved SMA therapies have improved motor function and extended survival by working to increase SMN protein levels. In an effort to achieve further benefits, researchers are exploring treatment strategies that work in various ways and have effects on other bodily systems.
Metabolic perturbations in SMA are well-documented in both animal models and patients, including changes in fatty acids, amino acids (the building blocks of proteins), and glucose. In fact, dietary supplements have extended the survival of SMA mice, further supporting the importance of metabolic problems in SMA.
Mifepristone is a glucocorticoid receptor blocker approved to end an early pregnancy. In previous work, the team conducting the present study found that the modulation of the glucocorticoid (GC)-Klf15 pathway improved weight and survival in SMA mice.
In this study, the scientists assessed mifepristone’s ability to reduce GC-induced Klf15 activity in cell lines from distinct metabolic tissues, including muscle, liver, and brown adipose (fat) tissue. The effects were dependent on cell type and their developmental stage. For instance, mifepristone treatment in differentiated (specialized) myotubes, precursors of skeletal muscle fibers, reduced Klf15 activity levels significantly at all three doses tested compared to untreated cells.
Next, the scientists investigated the therapeutic potential of mifepristone in C. elegans, a model of severe SMA. This model shows slowed growth, impaired mobility, and pharyngeal pumping, a key feeding behavior in C. elegans that involves the muscle contraction and relaxation of the pharynx to move food through the digestive tract.
Treatment with mifepristone significantly increased mobility and pharyngeal pumping in C. elegans, compared to untreated animals. However, the worms continued to be smaller in size than controls, “suggesting that mifepristone does not rescue the growth defects present in SMA worms,” the researchers wrote.
No benefits were observed in terms of survival or distance traveled.
Mifepristone increased survival of SMA mice by 2 to 3 days
The researchers then moved on to a mouse model of SMA. These mice exhibited a significant increase in Klf15 activity in an arm muscle compared to control animals, which began early after symptoms became noticeable. Similar results were seen in precursors of muscle cells derived from SMA patients.
Mifepristone increased the animals’ survival by a median of 2 to 3 days at two different doses. The higher dose also reduced the time mice took to right themselves during disease progression.
At the molecular level, the treatment reduced Klf15 activity in brown adipose tissue, though not in liver or muscle tissue. These results suggest “increased activity of [mifepristone] in adipose tissue, likely due to the increased metabolic rate,” the researchers wrote.
Additionally, mifepristone significantly increased the size of muscle fibers, which are responsible for muscle contraction.
Mifepristone did not improve the survival of severe Taiwanese SMA mice or the SMA C. elegans, suggesting that peripheral pathologies may have a greater impact … in milder forms of [SMA].
Further analysis demonstrated that mifepristone impacted the activity of metabolic genes HKII, Glut4, and PGC1alpha, which were previously reported as being impacted in SMA mice in a dose-dependent manner.
However, in a more severe mouse model of SMA, mifepristone treatment did not improve survival, weight, or righting reflex compared to untreated animals.
“Mifepristone did not improve the survival of severe Taiwanese SMA mice or the SMA C. elegans, suggesting that peripheral pathologies may have a greater impact … in milder forms of [SMA],” the researchers wrote.
Notably, the combination of mifepristone with gene therapy resulted in tissue-, sex-, and disease state-specific improvements compared to gene therapy alone.
About the Author
