干细胞治疗法令引发科学家的恐慌

     无论在任何国家，那些提供尚未证实的干细胞治疗的诊所，常和卫生监管部门玩起猫捉老鼠的游戏。然而意大利则颁布了干细胞治疗官方处理方式，其卫生部长Renato Balduzzi颁布命令，对于32个身患绝症的病人干细胞治疗可以继续进行，其中大部分是儿童，尽管所涉及干细胞还未根据意大利法律安全标准制造。
    3月21日，这种让人始料不及的决定吓坏了科学家，他们认为这种治疗很危险，因为它从未经过严格的测试。在米兰大学干细胞研究者Elena Cattaneo看来，这就是点石成金式的炼金术。
    该决定颁布是在接连数周的媒体压力要求出于同情给予治疗的情形下出台的，这一疗法是由Brescia-based Stamina基金会开发的，且在过去六年中历经数次禁止。现在，病人在呼吁将这个治疗普及到所有身患无法治愈疾病的病人上。数百人于3月23日在罗马举行抗议，包括一名身涂“pro-Stamina”支持标语的裸体妇女（下图）。
 

    Stamina基金会总裁乌迪内大学的心理学家Davide Vannoni表示，干细胞治疗的宣传为其赢得9000名新患者。他希望能进一步修改法律，让他可以扩大治疗。一个月前，The Hyena电视节目的调查报告称，身患绝症如脊髓性肌萎缩症的儿童的治疗被拒，意大利商界名人呼吁放宽干细胞治疗政策。
    在帕维亚大学从事科学与法律的教授Amedeo Santosuosso表示，在意大利，未经证实的治疗可在将死之人无其他选择的紧急情况下酌情使用，且国家卫生服务是免费提供这种治疗。法律规定，卫生行政部门批准这种治疗的质量，但某些条款不是很明确。Stamina存有潜在问题，在Stamina基因会治疗的案例中，没有明确表明治疗是有效的，所以在他看来酌情使用是不合法的。
    Vannoni表示，他是于2004年在俄罗斯成功完成病毒引发的面瘫治疗后开发了这种疗法。他邀请了俄罗斯和乌克兰科学家至都灵开发这种方法。此外，Vannoni称Stamina已经治疗80个左右的病人，包括，帕金森病人、阿尔茨海默氏症以及肌肉萎缩的病人。他并未公开利用骨髓间质干干细胞进行治疗的结果等详细资料。在他的计划中，从患者身上提取的细胞，经实验室培养操作，最后注入患者。
    Vannoni承认，他虽没有公布，但这种方法绝不是炼金术。每次治疗都会使用多种类型细胞来更换受损组织或分泌能减少炎症、抗感染的分子或促进血管生长。不管是什么病，某种类型的细胞将发挥正确的效果。
    2007年欧盟的一项法规曾要求，干细胞治疗必须遵循药品安全性和有效性法规。Vannoni将他的实验室搬至圣马力诺共和国，在那里干细胞治疗法规不是那么严格。但他得的研究受到都灵检察官Raffaele Guariniello的关注，根据他调查得出结论：“Vannoni的实验对公众是有害的”。Vannoni表示Guariniello借国际压力以阻止他在圣马力诺的工作，于是，他又搬至雅斯特，但是在这里Guariniello再次阻止了他的工作。
    从那以后，Vannoni 迁移至布雷西亚的公立医院。去年5月，一个来自意大利的药品局(AIFA)、国际空间站( ISS)以及国家卫生部研究所组成的代表团参观了布雷西亚实验室，并报道了实验室混乱状况，道德委员会做出如此评论主要基于信息不足、没有详细的操作规程、没有患者随访等。
    患者和家属开始求助于法律制度，以继续酌情使用这种治疗。许多法院得出的结论是，接受治疗服务是病人的权利，医疗卫生必须提供这种服务，且在某些情况下，布雷西亚实验室再次提供了细胞治疗。
一些被迫治疗的结果仅公布出了至今唯一的临床结果。雅斯特Burlo Garafalo儿童医院的临床医生治疗了5个带有I型脊肌萎缩症的婴儿，并于去年10月公布了结果。他们发现治疗并未改变疾病发展过程。Vannoni认为治疗失败是因为医生没有严格执行他所谓的鸡尾酒细胞疗法。
    3月7日，当卫生部长Balduzzi授权为带有异染性脑白质营养不良致命疾病的三岁儿童继续治疗时，这也表明干细胞是一个良好的实验设施(GMP)。与自己的监管机构对立的Balduzzi这一做法激怒了科学家们。包括Cattaneo 和Santosuosso在内的 13个学者给Balduzzi发表了一封公开信，并警告他这一做法的危险性。
    罗马大学干细胞科学家Paolo Bianco参与签署了这封公开信。他表示这种授权糟糕透顶：“现在部长正在允许非GMP标准，一个未经授权、未公开、未知的实践称为’治疗’。”
    Balduzzi这项法令有可能是他即将离任意大利政府颁布的最后一项立法。科学家希望他的继任者能尊重AIFA及其他科学机构。AIFA 总裁Luca Pani拒绝对该政治决定发表评论，但表示他的机构坚持关于布雷西亚干细胞制剂的安全性和有效性的声明，并表示我们依旧坚守这一禁令。

【原文检索】
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