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  • In a more than five year

    2018-11-14

    In a more than five-year-long study, we used a non-isogenic respiratory chain (RC) deficient mouse strain, namely the Harlequin (Hq) mouse, to test a set of drugs. We previously attributed the Hq mouse phenotype to a partial defect of RC complex I (CI) activity (Vahsen et al., 2004), due to a retroviral insertion in the X-linked AIF (apoptosis inducing factor) gene, leading to the formation of a hypomorphic allele (Klein et al., 2002). Noticeably, the complete inactivation of AIF in genetically-engineered mice (Pospisilik et al., 2007) or deleterious mutations in humans (Ghezzi et al., 2010) have a wider impact on the RC, affecting also complexes III and/or IV. The knockout, knockdown or hypomorphic mutation of the AIF causes a defect in CHCHD4-dependent RC biosynthesis in human cell lines in vitro, as well as in mice in vivo (Hangen et al., 2015). Similarly, mutations that occur in the human gene encoding for AIFM1 and that affect the binding of AIF to CHCHD4 cause mitochondriopathies that manifest as a severe X-linked mt encephalomyelopathy in infants (Meyer et al., 2015). A spectacular inter-individual variability in time of onset and severity characterizes the Hq disease in the CW/BL genetic background (Bénit et al., 2008). We previously reported these variable features associated with the partial loss of CI activity in the Hq mouse and showed the positive effect of a high-fat diet on the disease course (Schiff et al., 2011). In a further attempt to identify disease-attenuating drugs in Hq mice, we selected three drugs postulated to have different mechanisms of action, being either PPAR-α (bezafibrate; BZ) or PPAR-γ (pioglitazone; PIO) agonist or having an antioxidant effect (melatonin; ML), this latter a priori not linked to the activation of the melatonin-specific receptor. These three drugs have been previously reported as having a potential action against mitochondriopathies, ML (Reiter et al., 2007), BZ (Wenz et al., 2008) and PIO (Pinto et al., 2016). Here, we report that PIO may improve the Hq phenotype, presumably through the inhibition of excessive glycolysis.
    Materials and Methods
    Results
    Discussion While prenatal diagnosis can now be offered to ever more Silvestrol presenting at risk for a genetic mt disease, no effective cure exists for these conditions (Viscomi et al., 2015). The development of rational therapeutic strategies (apart from gene therapy) is hampered by our limited understanding of the pathogenic mechanisms underlying most of these diseases. Indeed they may or may not be associated with ATP shortage, poor oxygen handling, metabolic imbalance, abnormal programmed cell death or conversely proliferation, this depending on each mutation in specific gene, possibly varying in different organs or cell types. In this context, we decided to investigate a set of three drugs, each potentially acting on mt functions, on a preclinical model of RC defective mice, the Hq strain. Based on a first 6-month-long trial using 163 Hq mice, we left aside melatonin and bezafibrate, showing no positive effect in our assay conditions, to focus on PIO, which improved several traits of the Hq phenotype. This observation was possible despite the choice to study a limited number of genetically distinct individuals harboring the Hq mutation (about 15 individuals per condition). Nonetheless, we observed that most individuals were poorly performing upon PIO treatment. Only a few PIO-treated Hq mice improved their neuromuscular performances reaching WT values. This inter-individual variability in the PIO response was observed in the F1 mice bred from founders having a mixed genetic background (B6CBACaAw-J/A-Pdc8/J) housed under identical conditions. Such a heterogeneous response to treatment is not an unusual observation in mt diseases. It has been reported for idebenone treatment of Leber Hereditary Optic Neuropathy (which results from CI-deficiency) (Klopstock et al., 2013) and Friedreich ataxia (which results from reduced CI, CII and CIII functions secondary to a generalized deficiency of the iron-sulfur proteins) (Schiff and Rustin, 2016). In keeping with this, Bayesian analyses of patient\'s scores measuring performance on different clinical scales (ICARS, FARS or SARA) failed to disclose statistically significant effect of PIO on Friedreich ataxia patients (Andriss et al., 2015). However, similarly to our pre-clinical study on PIO-treated Hq mice, when individual scores of treated vs untreated FRDA patients were considered, a sub-group of patients (about 20%) manifested a consistent improvement (2year trial) irrespective to the evaluation scale. Because of this wide inter individual response to therapy observed in mt diseases, we thus recommend that trials should stratify the results according to the possible existence of responders vs. non-responders categories. Our results corroborate the idea that pharmacological trials against mt disease can be fully valid even if carried out on a limited number of patients, provided that the need for personalized stratification is taken into account. They predict that lack of careful and personalized data analysis of clinically heterogeneous patient groups (even though the diagnosis of their RC defect makes them appear molecularly homogeneous) will lead to further failures in clinical trials. Thus, we need to identify biomarkers that allow recognizing the minority of patients that may profit from pharmacological treatments.