title: Mouse studies to shape clinical trials for mitochondrial diseases: high fat diet in Harlequin mice.
abstract: BACKGROUND
  Therapeutic options in human mitochondrial oxidative phosphorylation (OXPHOS) diseases have been poorly evaluated mostly because of the scarcity of cohorts and the inter-individual variability of disease progression. Thus, while a high fat diet (HFD) is often recommended, data regarding efficacy are limited. Our objectives were 1) to determine our ability to evaluate therapeutic options in the Harlequin OXPHOS complex I (CI)-deficient mice, in the context of a mitochondrial disease with human hallmarks and 2) to assess the effects of a HFD.
  
  
  RESULTS
  Before launching long and expensive animal studies, we showed that palmitate afforded long-term death-protection in 3 CI-mutant human fibroblasts cell lines. We next demonstrated that using the Harlequin mouse, it was possible to draw solid conclusions on the efficacy of a 5-month-HFD on neurodegenerative symptoms. Moreover, we could identify a group of highly responsive animals, echoing the high variability of the disease progression in Harlequin mice.
  
  
  CONCLUSIONS
  These results suggest that a reduced number of patients with identical genetic disease should be sufficient to reach firm conclusions as far as the potential existence of responders and non responders is recognized. They also positively prefigure HFD-trials in OXPHOS-deficient patients.
authors.affiliation: INSERM, U676, Paris, France.
authors.forename: Manuel
authors.initials: M
authors.lastname: Schiff
authors.forename: Paule
authors.initials: P
authors.lastname: Bénit
authors.forename: Riyad
authors.initials: R
authors.lastname: El-Khoury
authors.forename: Dimitri
authors.initials: D
authors.lastname: Schlemmer
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Benoist
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
mesh_terms: D000818:Animals; D001284:Atrophy; D002331:Carnitine / Q000494:pharmacology; D002417:Cattle; D016923:Cell Death / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects / Q000473:pathology; D002986:Clinical Trials as Topic; D019610:Cytoprotection / Q000187:drug effects; D059305:Diet, High-Fat; D018450:Disease Progression; D004579:Electron Transport / Q000187:drug effects; D042967:Electron Transport Complex I / Q000172:deficiency; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D028361:Mitochondrial Diseases / Q000150:complications / Q000473:pathology / Q000628:therapy*; D009410:Nerve Degeneration / Q000150:complications / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D010168:Palmitates / Q000008:administration & dosage / Q000494:pharmacology; D010641:Phenotype; D045442:Rotarod Performance Test; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D019802:Succinic Acid / Q000494:pharmacology
chemical_list: D010168:Palmitates; D012710:Serum Albumin, Bovine; D019802:Succinic Acid; D042967:Electron Transport Complex I; D002331:Carnitine