Animal Studies Targeting Mitochondria Help Prolong Survival, Review Shows
Studies in animal models investigating mitochondrial abnormalities in amyotrophic lateral sclerosis (ALS) found that therapies targeting mitochondria — the powerhouses of cells — are consistently effective in prolonging survival, a review concluded.
The review study, “Targeting mitochondrial dysfunction in amyotrophic lateral sclerosis: a systematic review and meta-analysis,” was published in the journal Brain Communications.
A common feature of many neurodegenerative diseases such as ALS is the abnormal function of the mitochondria, which are small structures within the cell that produce energy.
Multiple research efforts to find therapies to treat these mitochondrial defects have focused on a variety of pathway targets, including mitochondrial metabolism, inflammation, programmed cell death (apoptosis), and oxidative stress. Preclinical research using animal models is the critical first step in evaluating the potential of new therapies before they are tested in humans.
Now, a team of researchers at the University of Edinburgh in the United Kingdom decided to conduct a review and analysis of the current preclinical literature to examine the overall potential of targeting the mitochondria to treat ALS.
The team searched three major medical databases — PubMed, Medline, and Embase — using terms such as “motor neuron disease,” “amyotrophic lateral sclerosis,” and “mitochondria.” Terminology used for animal models, including mice, rats, fruit flies (Drosophila), zebrafish, C. elegans (roundworm), and yeast also were searched across the databases.
More than 2,100 articles were identified. From those, a total of 76 studies were selected for analysis, after the team eliminated duplicate studies and others that did not have results that could be properly compared.
A statistical analysis of these 76 studies found that, overall, animals receiving therapies targeting the mitochondria lived significantly longer than those in the control groups, which usually receive no treatment or a sham treatment.
The researchers also conducted a secondary analysis examining how the timing of intervention affects survival. This assessment was done by grouping studies based on whether the therapy was given before symptoms, at their onset, or after the appearance of the symptoms.
When therapies were given prior to symptoms, the studies demonstrated a statistically significant improvement in survival compared with controls. While there was no difference found when treatments were given after the onset of symptoms, the researchers cautioned that this likely could be due to insufficient data. There were too few available studies focusing on treatments given after symptom onset, they said.
Further analysis was conducted to compare eight different pathway targets, including metabolism, inflammation, apoptosis, and oxidative stress.
Out of all the therapies tested, oxidative stress was the most frequently targeted pathway. However, there was no statistically significant difference in efficacy between therapies that targeted these different pathways.
A final assessment of publication bias was conducted to identify studies included in the analysis that may differ systematically and thus improperly influence the overall results. One study was found and removed, and the analysis was recalculated. While the size of the effect was reduced, treating mitochondria defects remained significantly more effective in comparison with no or sham treatments.
“The extant preclinical literature indicates that targeting mitochondrial dysfunction may prolong survival in amyotrophic lateral sclerosis, particularly if the intervention is administered early,” the researchers said.
The team pointed out that the focus of the current literature is treating animals before symptoms appear. This makes the results difficult to translate to the clinic, due to the challenges in ALS of early detection in the absence of biomarkers.
“We therefore recommend that preclinical studies focus on interventions at or after symptom onset to improve the translational potential of these studies,” they said.