Felici Roberta, Buonvicino Daniela, Muzzi Mirko, Cavone Leonardo, Guasti Daniele, Lapucci Andrea, Pratesi Sara, De Cesaris Francesco, Luceri Francesca, Chiarugi Alberto
Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale G. Pieraccini 6, 50139, Florence, Italy.
Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale G. Pieraccini 6, 50139, Florence, Italy.
Neuropharmacology. 2017 May 1;117:74-84. doi: 10.1016/j.neuropharm.2017.01.039. Epub 2017 Feb 1.
Mitochondrial encephalopathies are fatal, infantile neurodegenerative disorders caused by a deficit of mitochondrial functioning, for which there is urgent need to identify efficacious pharmacological treatments. Recent evidence shows that rapamycin administered both intraperitoneally or in the diet delays disease onset and enhances survival in the Ndufs4 null mouse model of mitochondrial encephalopathy. To delineate the clinical translatability of rapamycin in treatment of mitochondrial encephalopathy, we evaluated the drug's effects on disease evolution and mitochondrial parameters adopting treatment paradigms with fixed daily, oral doses starting at symptom onset in Ndufs4 knockout mice. Molecular mechanisms responsible for the pharmacodynamic effects of rapamycin were also evaluated. We found that rapamycin did not affect disease development at clinically-relevant doses (0.5 mg kg). Conversely, an oral dose previously adopted for intraperitoneal administration (8 mg kg) delayed development of neurological symptoms and increased median survival by 25%. Neurological improvement and lifespan were not further increased when the dose raised to 20 mg kg. Notably, rapamycin at 8 mg kg did not affect the reduced expression of respiratory complex subunits, as well as mitochondrial number and mtDNA content. This treatment regimen however significantly ameliorated architecture of mitochondria cristae in motor cortex and cerebellum. However, reduction of mTOR activity by rapamycin was not consistently found within the brain of knockout mice. Overall, data show the ability of rapamycin to improve ultrastructure of dysfunctional mitochondria and corroborate its therapeutic potential in mitochondrial disorders. The non-clinical standard doses required, however, raise concerns about its rapid and safe clinical transferability.
线粒体脑肌病是由线粒体功能缺陷引起的致命性婴儿神经退行性疾病，迫切需要确定有效的药物治疗方法。最近的证据表明，腹腔注射或饮食中添加雷帕霉素可延缓线粒体脑肌病Ndufs4基因敲除小鼠模型的疾病发作并提高生存率。为了阐明雷帕霉素治疗线粒体脑肌病的临床可转化性，我们在Ndufs4基因敲除小鼠出现症状时开始采用固定每日口服剂量的治疗方案，评估了该药物对疾病进展和线粒体参数的影响。还评估了雷帕霉素药效学作用的分子机制。我们发现，在临床相关剂量（0.5mg/kg）下，雷帕霉素不影响疾病发展。相反，先前用于腹腔注射的口服剂量（8mg/kg）可延缓神经症状的发展，并使中位生存期延长25%。当剂量提高到20mg/kg时，神经功能改善和寿命并未进一步增加。值得注意的是，8mg/kg的雷帕霉素不影响呼吸复合体亚基的表达降低以及线粒体数量和线粒体DNA含量。然而，这种治疗方案显著改善了运动皮层和小脑中线粒体嵴的结构。然而，在基因敲除小鼠的大脑中并未始终发现雷帕霉素降低mTOR活性。总体而言，数据表明雷帕霉素能够改善功能失调线粒体的超微结构，并证实其在线粒体疾病中的治疗潜力。然而，所需的非临床标准剂量引发了对其快速和安全临床可转化性的担忧。
