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马西替尼治疗肌萎缩侧索硬化症（ALS）：临床前概述Masitinib for the treatment of amyotrophic lateral sclerosis (ALS): preclinical overview |
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| 课程网址: | http://videolectures.net/encals2017_barbeito_masitinib_preclinica... |
| 主讲教师: | Luis Barbeito |
| 开课单位: | 蒙得维的亚巴斯德学院 |
| 开课时间: | 2017-07-21 |
| 课程语种: | 英语 |
| 中文简介: |  |
| 课程简介: | Masitinib is a selective oral tyrosine kinase inhibitor targeting CSF1R and c-Kit. Clinical data from the phase 3 study (AB10015) of masitinib in amyotrophic lateral sclerosis (ALS) demonstrated a clinically meaningful retardation of disease progression on its primary endpoint (change from baseline to week 48 in ALSFRS-R). Findings showed that masitinib administered at 4.5 mg/kg/day as an add-on to riluzole generated a therapeutic benefit with acceptable toxicity in ALS patients experiencing ALSFRS-R progression of <1.1 points/month at baseline. Significant slowing of disease was evident in terms of: • ∆ALSFRS-R and ALSFRS-R slope, indicating a slowed loss of function; • Time elapsed between treatment initiation and ∆ALSFRS-R of nine points (PFS), indicating delayed disease progression; • ALSAQ-40 score, indicating reduced decline in quality-of-life; and • FVC, which is considered a surrogate measure of overall survival. The positive benefit–risk balance of study AB10015 signals that masitinib could provide an important new therapeutic option in this difficult to treat population. These positive clinical findings are supported by equally compelling preclinical data, showing masitinib to generate a neuroprotective effect through targeting aberrant microglial cells and regulating neuroinflammation. It is well-established in the literature that proliferation and accumulation of microglial cells (microgliosis), in particular the emergence of aberrant glial cells, is a major neuropathological feature for ALS animal models. This disease mechanism is regulated by the CSF1/CSF1R signaling pathway, making microglia a viable target for masitinib. We have previously reported that masitinib treatment of SOD1G93A rats, initiated 7 days after paralysis onset (therapeutic setting), generated a robust protective effect as evidenced by a significantly prolonged post-paralysis survival with respect to control (40% improvement, p<0.001). Immunohistochemistry data additionally showed that masitinib treatment: prevented microglia proliferation, migration and transformation into aberrant glial cells; reduced the number of aberrant glial cells in the degenerating spinal cord; improved microgliosis and motor neuron pathology; inhibited emergence of microglia proinflammatory phenotype; and inhibited microgliosis along the degenerating spinal cord. Emergent data show masitinib is also capable of producing protective effects in the peripheral nervous system of SOD1G93A rats after paralysis onset. Strong upregulation of CSF1 and IL-34 in the degenerating sciatic nerve was observed, as well as a high infiltration of macrophages and mast cells. Masitinib treatment resulted in reduced pathological changes in the sciatic nerve, with a sharp decrease of inflammatory infiltrates of CSF1R-expressing macrophages and c-Kit expressing mast cells. Moreover, masitinib was seen to ameliorate neuromuscular pathology during paralysis progression in the ALS rat model, preventing mast cell accumulation around degenerative motor nerve endings, delaying endplate denervation as well as the pathological remodeling of neuromuscular junctions, perisynaptic Schwann cells and mu1scular capillary networks. Considering the persistent failure of candidate ALS drugs over the past 20 years, the abovementioned clinical and preclinical data for masitinib mechanisms of action in both the central and peripheral nervous system, signal a genuine breakthrough. |
| 关 键 词: | 马西替尼; 肌萎缩侧索硬化症; 调节神经炎症 |
| 课程来源: | 视频讲座网 |
| 数据采集: | 2021-12-11：zkj |
| 最后编审: | 2021-12-11：zkj |
| 阅读次数: | 220 |