干細胞治療法令引發(fā)科學家的恐慌

     無論在任何國家，那些提供尚未證實的干細胞治療的診所，常和衛(wèi)生監(jiān)管部門玩起貓捉老鼠的游戲。然而意大利則頒布了干細胞治療官方處理方式，其衛(wèi)生部長Renato Balduzzi頒布命令，對于32個身患絕癥的病人干細胞治療可以繼續(xù)進行，其中大部分是兒童，盡管所涉及干細胞還未根據(jù)意大利法律安全標準制造。
    3月21日，這種讓人始料不及的決定嚇壞了科學家，他們認為這種治療很危險，因為它從未經(jīng)過嚴格的測試。在米蘭大學干細胞研究者Elena Cattaneo看來，這就是點石成金式的煉金術(shù)。
    該決定頒布是在接連數(shù)周的媒體壓力要求出于同情給予治療的情形下出臺的，這一療法是由Brescia-based Stamina基金會開發(fā)的，且在過去六年中歷經(jīng)數(shù)次禁止?，F(xiàn)在，病人在呼吁將這個治療普及到所有身患無法治愈疾病的病人上。數(shù)百人于3月23日在羅馬舉行抗議，包括一名身涂“pro-Stamina”支持標語的裸體婦女（下圖）。
 

    Stamina基金會總裁烏迪內(nèi)大學的心理學家Davide Vannoni表示，干細胞治療的宣傳為其贏得9000名新患者。他希望能進一步修改法律，讓他可以擴大治療。一個月前，The Hyena電視節(jié)目的調(diào)查報告稱，身患絕癥如脊髓性肌萎縮癥的兒童的治療被拒，意大利商界名人呼吁放寬干細胞治療政策。
    在帕維亞大學從事科學與法律的教授Amedeo Santosuosso表示，在意大利，未經(jīng)證實的治療可在將死之人無其他選擇的緊急情況下酌情使用，且國家衛(wèi)生服務(wù)是免費提供這種治療。法律規(guī)定，衛(wèi)生行政部門批準這種治療的質(zhì)量，但某些條款不是很明確。Stamina存有潛在問題，在Stamina基因會治療的案例中，沒有明確表明治療是有效的，所以在他看來酌情使用是不合法的。
    Vannoni表示，他是于2004年在俄羅斯成功完成病毒引發(fā)的面癱治療后開發(fā)了這種療法。他邀請了俄羅斯和烏克蘭科學家至都靈開發(fā)這種方法。此外，Vannoni稱Stamina已經(jīng)治療80個左右的病人，包括，帕金森病人、阿爾茨海默氏癥以及肌肉萎縮的病人。他并未公開利用骨髓間質(zhì)干干細胞進行治療的結(jié)果等詳細資料。在他的計劃中，從患者身上提取的細胞，經(jīng)實驗室培養(yǎng)操作，最后注入患者。
    Vannoni承認，他雖沒有公布，但這種方法絕不是煉金術(shù)。每次治療都會使用多種類型細胞來更換受損組織或分泌能減少炎癥、抗感染的分子或促進血管生長。不管是什么病，某種類型的細胞將發(fā)揮正確的效果。
    2007年歐盟的一項法規(guī)曾要求，干細胞治療必須遵循藥品安全性和有效性法規(guī)。Vannoni將他的實驗室搬至圣馬力諾共和國，在那里干細胞治療法規(guī)不是那么嚴格。但他得的研究受到都靈檢察官Raffaele Guariniello的關(guān)注，根據(jù)他調(diào)查得出結(jié)論：“Vannoni的實驗對公眾是有害的”。Vannoni表示Guariniello借國際壓力以阻止他在圣馬力諾的工作，于是，他又搬至雅斯特，但是在這里Guariniello再次阻止了他的工作。
    從那以后，Vannoni 遷移至布雷西亞的公立醫(yī)院。去年5月，一個來自意大利的藥品局(AIFA)、國際空間站( ISS)以及國家衛(wèi)生部研究所組成的代表團參觀了布雷西亞實驗室，并報道了實驗室混亂狀況，道德委員會做出如此評論主要基于信息不足、沒有詳細的操作規(guī)程、沒有患者隨訪等。
    患者和家屬開始求助于法律制度，以繼續(xù)酌情使用這種治療。許多法院得出的結(jié)論是，接受治療服務(wù)是病人的權(quán)利，醫(yī)療衛(wèi)生必須提供這種服務(wù)，且在某些情況下，布雷西亞實驗室再次提供了細胞治療。
一些被迫治療的結(jié)果僅公布出了至今唯一的臨床結(jié)果。雅斯特Burlo Garafalo兒童醫(yī)院的臨床醫(yī)生治療了5個帶有I型脊肌萎縮癥的嬰兒，并于去年10月公布了結(jié)果。他們發(fā)現(xiàn)治療并未改變疾病發(fā)展過程。Vannoni認為治療失敗是因為醫(yī)生沒有嚴格執(zhí)行他所謂的雞尾酒細胞療法。
    3月7日，當衛(wèi)生部長Balduzzi授權(quán)為帶有異染性腦白質(zhì)營養(yǎng)不良致命疾病的三歲兒童繼續(xù)治療時，這也表明干細胞是一個良好的實驗設(shè)施(GMP)。與自己的監(jiān)管機構(gòu)對立的Balduzzi這一做法激怒了科學家們。包括Cattaneo 和Santosuosso在內(nèi)的 13個學者給Balduzzi發(fā)表了一封公開信，并警告他這一做法的危險性。
    羅馬大學干細胞科學家Paolo Bianco參與簽署了這封公開信。他表示這種授權(quán)糟糕透頂：“現(xiàn)在部長正在允許非GMP標準，一個未經(jīng)授權(quán)、未公開、未知的實踐稱為’治療’。”
    Balduzzi這項法令有可能是他即將離任意大利政府頒布的最后一項立法?？茖W家希望他的繼任者能尊重AIFA及其他科學機構(gòu)。AIFA 總裁Luca Pani拒絕對該政治決定發(fā)表評論，但表示他的機構(gòu)堅持關(guān)于布雷西亞干細胞制劑的安全性和有效性的聲明，并表示我們依舊堅守這一禁令。

【原文檢索】
http://www.nature.com/news/stem-cell-ruling-riles-researchers-1.12678

Stem-cell ruling riles researchers
---Italian health minister’s support for a controversial treatment appals the country’s scientists.
Clinics that offer unproven stem-cell treatments often end up playing cat and mouse with health regulators, no matter which country they operate in. In Italy, however, one such treatment now has official sanction. The country’s health minister, Renato Balduzzi, has decreed that a controversial stem-cell treatment can continue in 32 terminally ill patients, mostly children — even though the stem cells involved are not manufactured according to Italy’s legal safety standards.

The unexpected decision on 21 March has horrified scientists, who consider the treatment to be dangerous because it has never been rigorously tested. In the opinion of stem-cell researcher Elena Cattaneo of the University of Milan: “It is alchemy”.
The decision followed weeks of media pressure to authorize compassionate use of the therapy, which was developed by the Brescia-based Stamina Foundation and has been repeatedly banned in the past six years. Now, patient groups are pushing for the treatment to be available to anyone with an incurable illness. Hundreds protested in Rome on 23 March, including a naked woman with pro-Stamina slogans painted on her skin.
Stamina Foundation president Davide Vannoni, a psychologist at the University of Udine, says that the publicity around the treatment has won him 9,000 new patients. He hopes that further modifications to the law will allow him to expand the therapy.

A month ago, an investigatory television programme, The Hyena, reported that children with incurable diseases such as spinal muscular atrophy were being denied supposedly important treatment, and Italian show-business personalities joined the call to relax rules on stem-cell treatment.

In Italy, the compassionate use of as-yet-unapproved therapies is allowed on an emergency basis for dying individuals who have no other options, and the national health service must provide them for free. The law requires that health authorities approve the quality of such therapies, but some of its terms are ambiguous, says Amedeo Santosuosso, a Milanese judge and a professor at the University of Pavia who specializes in science and law. “That has been the underlying problem in the Stamina debacle,” he says. “In the case of the Stamina Foundation therapy, there is no suggestion that it might be efficacious, so in my opinion compassionate use is not legitimate.”

Vannoni says that he developed the therapy after having successful stem-cell treatment for a virus-induced facial paralysis in 2004 in Russia. He invited a Russian and a Ukrainian scientist to Turin to develop the method and says that Stamina has since treated 80 or so patients — including people with Parkinson’s disease, Alzheimer’s and muscle-wasting disorders. He has not published the outcomes or precise details of his therapy, which uses the mesenchymal stem cells from bone marrow that differentiate into bone, fat and connective tissue. In his protocol, the cells are extracted from patients, manipulated in the laboratory and then re-infused.

Vannoni acknowledges that he has not published outcomes but says that the method is far from alchemy. Each treatment uses five types of cell, he explains, with their claimed characteristics tuned to replace damaged tissue or to secrete molecules that could reduce inflammation, fight infection or promote blood-vessel growth. ”Whatever the disease, one of the types of cell is going to have the right effect,” he says.

When a 2007 European Union regulation required that stem-cell therapies follow the same safety and efficacy rules as pharmaceuticals, Vannoni moved his lab to the republic of San Marino. “There, rules were not so strict,” he says.

But his work had drawn the attention of a Turin prosecutor, Raffaele Guariniello, whose investigations concluded that Vannoni’s operation could be “dangerous to public health”. Vannoni says that Guariniello marshalled international pressure to stop him working in San Marino, so he moved to Trieste, where he says Guariniello again stopped his work.

From there, Vannoni moved to a public hospital in Brescia. Last May, a delegation including representatives of the Italian Medicines Agency (AIFA) and the ISS, the health ministry’s national institute, visited the Brescia lab and reported chaotic conditions: ethics-committee approvals had been based on inadequate information, and there were no detailed protocols or patient follow-up, for example. The AIFA closed the lab, stating that the facilities could not be trusted to produce contamination-free preparations.

Patients and families turned to the legal system to allow treatments to continue as compassionate use; many of the courts concluded that it was a patient’s right to receive treatment and that health services must offer it, and in some cases the Brescia lab once again supplied cells.

Some of the compelled treatments led to the only publication of clinical results so far. Clinicians at the Burlo Garafalo Children’s Hospital in Trieste treated five babies with type I spinal muscular atrophy and published the results last October (M. Carrozzi et al. Neuromuscul. Disord. 22, 1032–1034; 2012). They found that “the treatment did not change the course of the disease”, says co-author Marco Carrozzi. Vannoni argues that the therapy failed because the clinicians did not use his exact cocktail of cells.

Setting himself against his own regulatory agencies, Balduzzi had earlier angered scientists when, on 7 March, he authorized continued therapy for a three-year-old child with the deadly disease metachromatic leuko¬dystrophy — provided that the stem cells were created in a good manufacturing practice (GMP) facility. Thirteen academics, including Cattaneo and Santosuosso, published an open letter to Balduzzi warning him of the dangers (see go.nature.com/pb1wdl; in Italian).

That authorization was bad enough, says Paolo Bianco, a stem-cell scientist at the University of Rome who co-signed the letter. “Now the minister is allowing the non-GMP version and saying that an unauthorized, unpublished, unknown practice is a ‘treatment’.”

Balduzzi’s decree is likely to be his last legislative act in Italy’s outgoing government, and scientists hope that his successor will respect the role of the AIFA and other science-based agencies. AIFA president Luca Pani declined to comment on the political decision but says that his agency is sticking to its statements on the safety and efficacy of the stem-cell preparations from Brescia. “Our ban holds,” he says.

Nature
495, 418–419 (28 March 2013) doi:10.1038/495418a