蛋白質工程能不能設計出特異針對朊病毒的抗體？

求分析

@曹鵬 的答案很好了。

關於如何透過血腦屏障，現在有不少新進展。

比如去年，我記得美國有個課題組用超聲的方法打開血腦屏障。前一段時間也看到了血腦屏障的配體門控通道的報道。實在不行，你可以car-t一下，CD19CAR好像是可以治療中樞白血病的，那麼理論上也可以進中樞。

我想，總歸是有辦法的。

Antibodies against PrP could be one potential treatment for prion diseases. Potential treatments for any disease usually start in a test tube, then move on to a mouse, and then finally move on to humans.

針對朊病毒的抗體可以用來治療，一般從細胞到鼠再到上臨床人體。

Antibodies are no exception. When prion-infected cells in a dish were treated with antibodies against PrP, the infection was completely cleared [Enari 2001, Peretz 2001]. Shortly thereafter, antibodies were shown to be effective in treating prion-infected mice under certain conditions [White 2003]. As of earlier this year, the MRC Prion Unit in London has started discussing the possibility of launching a clinical trial of an anti-PrP antibody named PRN100 to treat sporadic Creutzfeldt-Jakob disease. As of this writing, no trial has officially been announced and the MRC Prion Unit has not provided any estimates of when a trial might begin.

抗體也不例外也要走細胞模型-鼠-臨床人體的流程，朊病毒感染的細胞能夠被抗體完全清除。在小鼠模型上，也取得了部分成功。早年英國某研究所啟動了抗朊病毒的臨床實驗治療散發的克雅氏病。但目前沒有任何官方聲明的推動臨床實驗進程，也沒有什麼動向說何時開始。

The major challenge for such a clinical trial will be that antibodies are huge – around a thousand times larger than most small molecule drugs. One difficulty in developing drugs for prion diseases – or any other brain disease – is that in order to be effective, any treatment will need to get past the blood-brain barrier. The cells surrounding blood vessels in the brain are so tightly packed that even many small molecule drugs can』t get from the blood into the brain – only a special subset can do so. Antibodies are so large that only a vanishingly small amount of them can cross the blood brain barrier.

抗體臨床運用最主要的問題就是抗體體積巨大，比小分子葯大上千倍，而穿不過血腦屏障，達不到治療效果。就算是小分子葯也只有一部分藥物能夠穿過血管進入大腦。抗體巨大的體積能夠穿過的微乎其微。

In the original mouse study that showed how antibodies could be effective, some groups of mice were infected with prions peripherally, meaning outside of the brain [White 2003]. When these mice were treated early on with antibodies, the antibodies were able to cure the infection before it ever reached the brain, and the mice never got sick. That』s an amazing result, and to this day, antibodies are the only treatment shown to completely cure peripheral prion infections in mice. However, when mice were infected directly in their brain or when they weren』t treated until after the infection had reached the brain, the antibodies had no detectable effect: the mice died at the same time as mice that weren』t treated with any antibodies.

原初在小鼠身上的實驗證明抗體是有效的，但有些實驗組是在外周感染的病毒，在大腦外部。因此當這些老鼠早期在病毒侵染大腦之前，可以得到有效的治療。非常神奇的結果，甚至直到今天這些抗體依然是直接完全治癒外周感染朊病毒小鼠的唯一方法。但是一旦小鼠被感染朊病毒直接大腦或者直到他們感染不被治療侵入大腦，這些抗體則完全失效，這些治療組小鼠與非治療組同樣會同批死亡。所以抗體如何穿過大腦的血腦屏障是一個重要又棘手的問題。

相關文獻

2002年自然科學雜誌，單克隆抗體抑制朊病毒複製和疾病進程。
Monoclonal antibodies inhibit prion replication and delay the development of prion disease
http://www.nature.com/nature/journal/v422/n6927/full/nature01457.html

2012年 美國生物化學雜誌，人抗朊病毒抗體阻止朊肽細纖維形成和神經毒性
J Biol Chem. 2012 Apr 13;287(16):12858-66. doi: 10.1074/jbc.M111.255836. Epub 2012 Feb 23.
Human anti-prion antibodies block prion peptide fibril formation and neurotoxicity.