Pirozzi Marinella, Quattrini Angelo, Andolfi Gennaro, Dina Giorgia, Malaguti Maria Chiara, Auricchio Alberto, Rugarli Elena I
Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
J Clin Invest. 2006 Jan;116(1):202-8. doi: 10.1172/JCI26210. Epub 2005 Dec 15.
Degeneration of peripheral motor axons is a common feature of several debilitating diseases including complicated forms of hereditary spastic paraplegia. One such form is caused by loss of the mitochondrial energy-dependent protease paraplegin. Paraplegin-deficient mice display a progressive degeneration in several axonal tracts, characterized by the accumulation of morphological abnormal mitochondria. We show that adenoassociated virus-mediated (AAV-mediated) intramuscular delivery of paraplegin halted the progression of neuropathological changes and rescued mitochondrial morphology in the peripheral nerves of paraplegin-deficient mice. One single injection before onset of symptoms improved the motor performance of paraplegin-deficient mice for up to 10 months, indicating that the peripheral neuropathy contributes to the clinical phenotype. This study provides a proof of principle that gene transfer may be an effective therapeutic option for patients with paraplegin deficiency and demonstrates that AAV vectors can be successfully employed for retrograde delivery of an intracellular protein to spinal motor neurons, opening new perspectives for several hereditary axonal neuropathies of the peripheral nerves.
外周运动轴突的退化是包括复杂形式的遗传性痉挛性截瘫在内的几种衰弱性疾病的共同特征。其中一种形式是由线粒体能量依赖性蛋白酶 paraplegin 的缺失引起的。Paraplegin 缺陷小鼠在几条轴突束中表现出进行性退化，其特征是形态异常的线粒体积累。我们表明，腺相关病毒介导的（AAV 介导的）paraplegin 肌肉内递送阻止了神经病理变化的进展，并挽救了 paraplegin 缺陷小鼠外周神经中的线粒体形态。在症状出现前单次注射可改善 paraplegin 缺陷小鼠的运动性能长达 10 个月，表明外周神经病变导致了临床表型。这项研究提供了一个原理证明，即基因转移可能是 paraplegin 缺陷患者的一种有效治疗选择，并证明 AAV 载体可成功用于将细胞内蛋白逆行递送至脊髓运动神经元，为几种外周神经遗传性轴索性神经病开辟了新的前景。
