Mamber Stephen W, Long Vit, Rhodes Ryan G, Pond-Tor Sunthorn, Wheeler Lyn R, Fredericks Kellie, Vanscoy Brian, Sauniere Jean-Frederic, Steinschneider Remy, Laurent Jean-Claude, McMichael John
The Institute for Therapeutic Discovery, Delanson, NY.
Nonlinearity Biol Toxicol Med. 2004 Apr;2(2):67-87. doi: 10.1080/15401420490464295.
Diseases and conditions involving the deposition of excessive amounts of collagen include scleroderma, fibrosis, and scar and surgical adhesion formation. Diseases such as scleroderma may result from acute and chronic inflammation, disturbances in the normal parenchymal area, and activation of fibroblasts. ML-05, a modified form of the hemolytic and cytotoxic bacterial toxin, streptolysin O, is being developed for the treatment of such collagen-related disorders. At sublytic concentrations in vitro, ML-05 was shown to activate CD44 expression. This may modulate production of collagen, hyaluronate, and their associated enzymes to allow a restoration of normal extracellular matrices within tissues. More importantly, ML-05 appeared to decrease skin collagen levels in two in vivo models of collagen disorders, the tight skin mouse (Tsk) model of scleroderma, and the bleomycin-induced mouse skin fibrosis model. In the Tsk model, levels of hydroxyproline (a measure of total collagen) decreased by 25% in the Tsk+ML-05 treatment group relative to the Tsk+saline control group over a 3-month period. In the bleomycin-induced skin fibrosis study, hydroxyproline levels decreased from 15-22% over a 6-week period in a bleomycin-induced ML-05 treatment group (relative to levels in a bleomycin-induced, untreated control group). Hydroxyproline levels in samples from this treatment group were only slightly greater than levels in an uninduced control group at 8 weeks. Thus, ML-05 treatment appeared to reduce collagen levels in two separate mouse skin fibrosis models, one genetically based and the other chemically induced.
涉及过量胶原蛋白沉积的疾病和病症包括硬皮病、纤维化以及瘢痕和手术粘连形成。诸如硬皮病之类的疾病可能由急性和慢性炎症、正常实质区域的紊乱以及成纤维细胞的激活引起。ML - 05是溶血和细胞毒性细菌毒素链球菌溶血素O的一种改良形式，目前正在开发用于治疗此类与胶原蛋白相关的病症。在体外亚溶细胞浓度下，ML - 05被证明可激活CD44表达。这可能调节胶原蛋白、透明质酸及其相关酶的产生，以使组织内的细胞外基质恢复正常。更重要的是，在两种胶原蛋白病症的体内模型中，即硬皮病的紧皮小鼠（Tsk）模型和博来霉素诱导的小鼠皮肤纤维化模型中，ML - 05似乎降低了皮肤胶原蛋白水平。在Tsk模型中，在3个月的时间里，相对于Tsk + 生理盐水对照组，Tsk + ML - 05治疗组的羟脯氨酸（总胶原蛋白的一种衡量指标）水平下降了25%。在博来霉素诱导的皮肤纤维化研究中，在博来霉素诱导的ML - 05治疗组中，羟脯氨酸水平在6周内下降了15 - 22%（相对于博来霉素诱导的未治疗对照组的水平）。在8周时，该治疗组样本中的羟脯氨酸水平仅略高于未诱导对照组的水平。因此，ML - 05治疗似乎在两种不同的小鼠皮肤纤维化模型中降低了胶原蛋白水平，一种是基于基因的，另一种是化学诱导的。
