Developing therapeutically more efficient Neurturin variants for treatment of Parkinson's disease
Developing therapeutically more efficient Neurturin variants for treatment of Parkinson's disease
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DOI：
10.1016/j.nbd.2016.07.008
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发表时间：
2016-12-01
影响因子：
6.1
通讯作者：
Saarma, Mart
中科院分区：
文献类型：
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作者：
Runeberg-Roos, Pia;Piccinini, Elisa;Saarma, Mart
在帕金森病中脑多巴胺能神经元退化和死亡。口服药物和深部脑刺激可以缓解最初的症状，但疾病会继续发展。生长因子可能支持存活，增强活性，甚至再生退化的多巴胺神经元，已经在患者中尝试了混合结果。由于生长因子不能通过血脑屏障，因此必须经颅内输送。因此，它们在脑组织中的有效扩散至关重要。为了改善生长因子neurturin（NRTN）的扩散，我们修改了其附着于细胞外基质中硫酸乙酰肝素的能力。我们提出了四种新的，生物学上完全活性的变体，减少肝素结合。其中两种变体在体外比WT NRTN更稳定，并且在大鼠脑中扩散更好。我们还表明，NRTN的变体之一扩散比其密切的同源GDNF在猴脑中。具有最高稳定性和最宽扩散的变体再生多巴胺纤维，并改善帕金森病6-羟基多巴胺模型中大鼠的状况，比GDNF更有效，GDNF先前在临床试验中显示出适度的疗效。新的NRTN变体可能有助于解决NRTN在人脑组织中分布不足的主要问题。(C)2016 Elsevier Inc. All rights reserved.
In Parkinson's disease midbrain dopaminergic neurons degenerate and die. Oral medications and deep brain stimulation can relieve the initial symptoms, but the disease continues to progress. Growth factors that might support the survival, enhance the activity, or even regenerate degenerating dopamine neurons have been tried with mixed results in patients. As growth factors do not pass the blood-brain barrier, they have to be delivered intracranially. Therefore their efficient diffusion in brain tissue is of crucial importance. To improve the diffusion of the growth factor neurturin (NRTN), we modified its capacity to attach to heparan sulfates in the extracellular matrix. We present four new, biologically fully active variants with reduced heparin binding. Two of these variants are more stable than WT NRTN in vitro and diffuse better in rat brains. We also show that one of the NRTN variants diffuses better than its close homolog GDNF in monkey brains. The variant with the highest stability and widest diffusion regenerates dopamine fibers and improves the conditions of rats in a 6-hydroxydopamine model of Parkinson's disease more potently than GDNF, which previously showed modest efficacy in clinical trials. The new NRTN variants may help solve the major problem of inadequate distribution of NRTN in human brain tissue. (C) 2016 Elsevier Inc. All rights reserved.