研究者在4月的《肠》(Gut 2007;56:524-533.)杂志上报告,结合核因子κB (NFkB)的一种寡核苷酸的直接传送可改善小鼠炎性肠病(IBD),并恢复组织内环境稳定。
美国Intermune公司的Rolf O. Ehrhardt博士及其同事指出,NFkB是IBD的一种主要转录调节物。研究组合成了一种专门结合NFkB并阻断相关炎症递质的寡核苷酸。由于这种寡核苷酸的稳定性和化学作用,不需要使用病毒被膜辅助传送。
在结肠炎小鼠模型中,这种寡核苷酸的肠内使用可导致疾病严重性呈剂量依赖性减轻和正常体重的较快速恢复。这种治疗还引起结肠病理学减轻和几种促炎症标志物组织水平降低,包括TNF-α、白介素6和白介素1b。研究组还发现,粘膜上皮和平滑肌细胞层细胞增生快速恢复至正常。
根据这些发现,Ehrhardt博士总结说,这种药物不但能够成功地抑制炎症,而且还支持粘膜修复机制,后者对于粘膜内环境稳定的维持十分重要。
原始出处:
Gut 2007;56:524-533
INFLAMMATORY BOWEL DISEASE
Non-viral delivery of nuclear factor-B decoy ameliorates murine inflammatory bowel disease and restores tissue homeostasis
Christopher G De Vry, Srinivasa Prasad, Laszlo Komuves, Carlos Lorenzana, Christi Parham, Tina Le, Sarvesh Adda, Jennifer Hoffman, Nicole Kahoud, Radhika Garlapati, Radha Shyamsundar, Kim Mai, Jie Zhang, Tony Muchamuel, Maya Dajee, Brian Schryver, Leslie M McEvoy and Rolf O Ehrhardt
Department of Research, Corgentech, Inc, South San Francisco, California, USA
Correspondence to:
Dr R O Ehrhardt
Clinical Science, Intermune, Inc, 3280 Bayshore Blvd, Brisbane, CA 94005, USA; rehrhardt@intermune.com
Background: Nuclear factor-B (NF-B) is a key transcriptional regulator of inflammatory bowel disease (IBD).
Aim: To investigate the therapeutic potential of a locally administered "non-viral" nuclear factor-B decoy (NFBD) in multiple experimental models of IBD.
Methods: A fully phosphorothioated decoy oligonucleotide with improved stability that specifically binds NF-B and blocks inflammatory mediators regulated by this transcription factor without the help of viral envelope-assisted delivery was developed. The therapeutic effects of NFBD were studied in the trinitrobenzene sulphonic acid, oxazolone and dextran sodium sulphate induced colitis models.
Results: Intracolonic administration of NFBD results in the delivery of NFBD to inflammatory cells and a reduction of NF-B heterodimers. In the T helper cell 1-driven trinitrobenzene sulphonic acid-induced colitis model, mice receiving NFBD treatment exhibit a dose-dependent reduction in disease severity and a more rapid recovery to normal body weight, similar to a clinically relevant dose of budesonide. Clinical efficacy was corroborated by considerable reductions in colitis pathology and tissue levels of several pro-inflammatory markers, including tumour necrosis factor , interleukin 6, interleukin 1ß and monocyte chemotactic protein 1. NFBD also mitigates disease activity in the T helper cell 2-like oxazolone colitis and epithelial injury-related acute dextran sodium sulphate colitis models. Interestingly, restoration of tissue homeostasis is observed in NFBD-treated animals with the rapid re-emergence of functional goblet cells and a return to normal patterns of cell proliferation in the mucosal epithelium and smooth muscle cell layers.
Conclusions: These data support the potential use of "naked" NFBD as a cross-functional therapeutic in IBD, and show for the first time that it can facilitate the restoration of colon homeostasis and function.