在过去的几十年中,成人中枢神经系统自我修复/再生的能力得到了反复证明,但仍在争论中。减少的神经源性生态位活动与严重的神经元损失并行,代表了神经退行性疾病病程的基本标志。我们和其他人已经证明内源性TGFβ系统代表疾病进展的潜在致病参与者,特别是肌萎缩侧索硬化症(ALS),通过产生和促进神经退行性和神经再生过程的不平衡。新型人/灵长类动物特异性LNAGapmer反义寡核苷酸“NVP-13”,靶向TGFBR2,有效降低其表达并降低TGFβ信号转导,同时增强了人神经元祖细胞和非人灵长类动物中枢神经系统的神经源性生态位活性。这里,我们研究了NVP-13的体内药理学,安全,在GLP毒理学研究方法中,在非人灵长类食蟹猴中重复鞘内注射13周后的耐受性。在最初13周的第1、15、29、43、57、71和85天,在3个月内鞘内给予NVP-131、2或4mgNVP-13/动物。我们能够证明良好的局部和全身耐受性,在生理上没有不良事件,血液学,临床化学,以及雌性和雄性食蟹猴的微观发现。在本研究的条件下,未观察到的不良反应水平(NOAEL)至少为4mg/动物NVP-13。
The capability of the adult central nervous system to self-repair/regenerate was demonstrated repeatedly throughout the last decades but remains in debate. Reduced neurogenic niche activity paralleled by a profound neuronal loss represents fundamental hallmarks in the disease course of neurodegenerative disorders. We and others have demonstrated the endogenous TGFβ system to represent a potential pathogenic participant in disease progression, of amyotrophic lateral sclerosis (ALS) in particular, by generating and promoting a disequilibrium of neurodegenerative and neuroregenerative processes. The novel human/primate specific LNA Gapmer Antisense Oligonucleotide \"NVP-13\", targeting TGFBR2, effectively reduced its expression and lowered TGFβ signal transduction in vitro and in vivo, paralleled by boosting neurogenic niche activity in human neuronal progenitor cells and nonhuman primate central nervous system. Here, we investigated NVP-13 in vivo pharmacology, safety, and tolerability following repeated intrathecal injections in nonhuman primate cynomolgus monkeys for 13 weeks in a GLP-toxicology study approach. NVP-13 was administered intrathecally with 1, 2, or 4 mg NVP-13/animal within 3 months on days 1, 15, 29, 43, 57, 71, and 85 in the initial 13 weeks. We were able to demonstrate an excellent local and systemic tolerability, and no adverse events in physiological, hematological, clinical chemistry, and microscopic findings in female and male Cynomolgus Monkeys. Under the conditions of this study, the no observed adverse effect level (NOAEL) is at least 4 mg/animal NVP-13.