A Monoclonal Antibody TrkB Receptor Agonist as a Potential Therapeutic for Huntington’s Disease

Huntington’s disease (HD) is a devastating, genetic neurodegenerative disease caused by a tri-nucleotide expansion in exon 1 of the huntingtin gene. HD is clinically characterized by chorea, emotional and psychiatric disturbances and cognitive deficits with later symptoms including rigidity and dementia. Pathologically, the cortico-striatal pathway is severely dysfunctional as reflected by striatal and cortical atrophy in late-stage disease. Brain-derived neurotrophic factor (BDNF) is a neuroprotective, secreted protein that binds with high affinity to the extracellular domain of the tropomyosin-receptor kinase B (TrkB) receptor promoting neuronal cell survival by activating the receptor and down-stream signaling proteins. Reduced cortical BDNF production and transport to the striatum have been implicated in HD pathogenesis; the ability to enhance TrkB signaling using a BDNF mimetic might be beneficial in disease progression, so we explored this as a therapeutic strategy for HD. Using recombinant and native assay formats, we report here the evaluation of TrkB antibodies and a panel of reported small molecule TrkB agonists, and identify the best candidate, from those tested, for in vivo proof of concept studies in transgenic HD models.亨廷顿舞蹈症（Huntington’s disease, HD）是一种毁灭性的遗传性神经退行性疾病，由亨廷顿基因第1外显子的三核苷酸重复扩增引发。该病的临床表型为舞蹈症、情绪与精神障碍及认知功能缺损，晚期还会出现肌强直和痴呆。病理层面，皮层-纹状体通路存在严重功能障碍，疾病晚期可通过纹状体与皮层萎缩得到印证。脑源性神经营养因子（Brain-derived neurotrophic factor, BDNF）是一种具备神经保护作用的分泌型蛋白，可高亲和力结合原肌球蛋白受体激酶B（tropomyosin-receptor kinase B, TrkB）的胞外结构域，通过激活该受体及其下游信号蛋白促进神经元存活。现有研究表明，皮层BDNF生成减少以及向纹状体的运输缺陷参与了HD的发病过程；使用BDNF模拟物增强TrkB信号通路的策略或可延缓疾病进展，因此本研究将该方向作为HD的治疗方案展开探索。本研究采用重组及天然检测体系，对TrkB抗体以及一组已报道的小分子TrkB激动剂进行了评估，并从受试化合物中筛选出最优候选物，用于转基因HD模型的体内概念验证研究。