Kato Naoki, Nakanishi Kuniaki, Nemoto Koichi
Dept. Orthopaedic Surgery, Saitama Medical University, Japan.
Cent Nerv Syst Agents Med Chem. 2009 Dec;9(4):300-6. doi: 10.2174/187152409789630406.
Hepatocyte growth factor (HGF) was originally identified as a molecule that could stimulate DNA synthesis in rat and human hepatocytes by autophosphorylation of the proto-oncogene c-met, which is a high-affinity receptor for HGF. Although it was at first considered that HGF could exert biological effects only on specific target cells, it has since been demonstrated that HGF mediates inflammatory responses to tissue injury and also regulates cell growth, cell motility, and morphogenesis in a wide variety of cell types, including cells within the nervous system. In the nervous system, HGF plays a role as a potent neurotrophic and angiogenetic factor. This factor promotes both the survival of neurons and the regeneration of injured nerves, and may also function as target-derived axonal chemoattractants, guiding axons to their target. These observations raised hopes that HGF protein might be useful for the clinical treatment of nervous system disorders. However, administration of HGF as a recombinant protein is still beset by a number of problems, such as a short serum half-life and poor access to the central nervous system by the systemic route because of the presence of the blood-brain barrier. These problems can be major obstacles to the clinical use of this factor in a recombinant protein form, and has highlighted the need to develop innovative therapeutic strategies for more efficient delivery into the nervous system. Gene transfer into the nervous system has enormous therapeutic potential for a wide variety of disorders. It appears to have advantages over the administration of single or multiple bolus doses of a recombinant protein because gene transfer can achieve an optimally high, local concentration within the nervous system. In this article, we demonstrate the efficacy of HGF gene transfer and provide an overview of ideal treatment regimes for various nervous injuries and disorders.
肝细胞生长因子（HGF）最初被鉴定为一种可通过原癌基因c-met的自磷酸化刺激大鼠和人类肝细胞中DNA合成的分子，c-met是HGF的高亲和力受体。尽管最初认为HGF仅能对特定靶细胞发挥生物学作用，但后来已证明HGF介导对组织损伤的炎症反应，并且还调节多种细胞类型（包括神经系统内的细胞）的细胞生长、细胞运动和形态发生。在神经系统中，HGF作为一种强大的神经营养和血管生成因子发挥作用。该因子促进神经元的存活和受损神经的再生，还可能作为靶源性轴突化学引诱剂，引导轴突到达其靶标。这些观察结果引发了人们的希望，即HGF蛋白可能对神经系统疾病的临床治疗有用。然而，将HGF作为重组蛋白给药仍然受到一些问题的困扰，例如血清半衰期短以及由于血脑屏障的存在，全身途径难以进入中枢神经系统。这些问题可能是该因子以重组蛋白形式临床应用的主要障碍，并凸显了开发创新治疗策略以更有效地递送至神经系统的必要性。基因转移到神经系统对多种疾病具有巨大的治疗潜力。它似乎比单次或多次推注重组蛋白给药具有优势，因为基因转移可以在神经系统内实现最佳的高局部浓度。在本文中，我们展示了HGF基因转移的疗效，并概述了针对各种神经损伤和疾病的理想治疗方案。
