研究者在4月的《腸》（Gut 2007;56:524-533.）雜志上報告，結(jié)合核因子κB (NFkB)的一種寡核苷酸的直接傳送可改善小鼠炎性腸病(IBD),，并恢復組織內(nèi)環(huán)境穩(wěn)定。
美國Intermune公司的Rolf O. Ehrhardt博士及其同事指出,，NFkB是IBD的一種主要轉(zhuǎn)錄調(diào)節(jié)物。研究組合成了一種專門結(jié)合NFkB并阻斷相關(guān)炎癥遞質(zhì)的寡核苷酸,。由于這種寡核苷酸的穩(wěn)定性和化學作用,，不需要使用病毒被膜輔助傳送。
在結(jié)腸炎小鼠模型中,，這種寡核苷酸的腸內(nèi)使用可導致疾病嚴重性呈劑量依賴性減輕和正常體重的較快速恢復,。這種治療還引起結(jié)腸病理學減輕和幾種促炎癥標志物組織水平降低，包括TNF-α,、白介素6和白介素1b,。研究組還發(fā)現(xiàn),，粘膜上皮和平滑肌細胞層細胞增生快速恢復至正常,。
根據(jù)這些發(fā)現(xiàn)，Ehrhardt博士總結(jié)說,，這種藥物不但能夠成功地抑制炎癥,，而且還支持粘膜修復機制，后者對于粘膜內(nèi)環(huán)境穩(wěn)定的維持十分重要,。
原始出處:
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; [email protected]
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.
