Leriglitazone can improve energy production in patient-derived cells
Oral therapy found to boost function of mitochondria in preclinical models
Leriglitazone, an oral treatment candidate for neurological diseases, can improve the function of mitochondria — known as the powerhouse of the cell — in lab studies with cells from Rett syndrome patients and in a mouse model of the disease.
Specifically, leriglitazone therapy restored energy production and reduced oxidative stress associated with Rett. Oxidative stress is caused by an imbalance between the body’s production of harmful reactive oxygen species and its antioxidant defenses.
“Given these results and the knowledge on leriglitazone safety on both healthy subjects and pediatric patients, this work constitutes the preclinical evidence for a clinical trial with leriglitazone in Rett syndrome and other diseases with mitochondrial involvement,” researchers wrote in the study “Mitochondrial modulation with leriglitazone as a potential treatment for Rett syndrome,” which was published in the Journal of Translational Medicine.
Affecting girls almost exclusively, Rett syndrome is chiefly caused by mutations in the MECP2 gene, which codes for a protein of the same name. The MeCP2 protein regulates how genes important for brain development and function are read.
Mitochondria dysfunction found in cells from Rett patients in previous studies
Previous studies have shown that cells of the central nervous system (brain and spinal cord) in Rett patients have impairments in mitochondria. While targeting dysfunctions in the mitochondria has been proposed as a therapeutic target in Rett, few attempts have been made to improve mitochondrial function.
Researchers in Spain, along with collaborators from leriglitazone’s developer, Minoryx Therapeutics, investigated the effects of this potential therapy in Rett. Leriglitazone is a PPAR-gamma agonist, or activator, able to cross the blood-brain barrier and penetrate the brain, and has shown promise for neurological diseases such as Friedreich’s ataxia. The blood-brain barrier controls the movement of substances and cells between the blood and the brain.
PPAR-gamma has a wide range of functions inside the cell, including protection against oxidative stress and inflammation.
Using fibroblasts, a type of connective tissue cell, from eight Rett patients with different MECP2 mutations and disease severity, the researchers found that mitochndoria from Rett patients were less interconnected and ramified compared to fibroblasts from healthy people, who served as controls. Also, mitochondria in Rett fibroblasts had impaired energy production and higher oxidative stress.
The same mitochondrial dysfunctions were seen in a female mouse model of Rett. Specifically, even before symptoms were evident, the mice had alterations in energy production and oxidative damage to lipids (fat-like molecules) in the brain.
Mice at the full symptomatic stage (7 months old) showed more significant decreases in energy production in brain areas called the hippocampus and cerebellum compared with controls. In contrast, energy, as assessed by levels of a molecule called ATP, was increased in the brain’s outer layer (cortex) “suggesting that alterations are dynamic both between brain areas and through neurodevelopment,” the scientists wrote. Oxidative damage to lipids, called lipid peroxidation, followed a similar pattern.
… this work constitutes the preclinical evidence for a clinical trial with leriglitazone in Rett syndrome and other diseases with mitochondrial involvement.
Leriglitazone treatment led to increased energy production
The researchers then tested whether these dysfunctions could be corrected with leriglitazone. In Rett fibroblasts, treatment for 48 hours significantly increased energy production by 50%, reduced levels of superoxide, a type of reactive oxygen species, by 20%, and also decreased oxidative damage.
No effects were seen in mitochondrial network shape or dynamics.
Adding a PPAR-gamma inhibitor, called GW9662, blocked leriglitazone’s effects. “These results confirmed the beneficial effect of [PPAR-gamma] pathway activation in the recovery of the bioenergetic deficits in Rett syndrome fibroblasts,” the scientists wrote.
Next, they assessed whether the benefits seen in lab studies would be maintained in Rett mice. Leriglitazone was administered orally at a dose of 75 mg/kg/day from weaning until 7 months of age. Treatment normalized both energy production and lipid peroxidation in the hippocampus and cerebellum. No changes were seen in the cortex.
“The results regarding lipid peroxidation were opposite to the expected, as we initially predicted an increase in lipid peroxidation and subsequent correction through treatment with leriglitazone. However, lipid metabolism has been described to be altered in several Rett syndrome samples,” the researchers noted, “thus alterations in lipids profiles could be contributing to the counterintuitive interpretation of the results.”
Treatment improved overall health assessment
Oxidative damage in the cerebellum was also reduced by leriglitazone. In parallel, treatment improved overall health, as assessed by the General Health Score. This parameter evaluates mobility, breathing abnormalities, tremor, and physical deterioration.
Leriglitazone-treated mice developed a milder from of Rett which was especially apparent in the fully symptomatic phase of the disease. The animals’ natural explorative behaviour was enhanced and signs of brain inflammation were resolved following treatment.
In addition, the researchers assessed the benefits of leriglitazone in fibroblasts from a patient with a rare mitochondrial disorder. Similar to what was seen in Rett, treatment with leriglitazone boosted energy production and lessened oxidative stress.
Overall, “this work provides preclinical evidence foundational for a clinical trial with leriglitazone for the treatment of Rett syndrome,” the researchers wrote, adding that the therapy could also extend to other “primary mitochondrial diseases in which bioenergetic functions are altered.”