编者按：本文由来自上海的一名肌病患者翻译，他在给本站的来信中说，“美国在3月29日已经开始了用基因疗法对杜氏进行性肌营养不良患者进行治疗的
临床试验，这不但对我们肌病患者来说，是一件大事，其实对整个基因治疗界也是一个大事，但在到今天，我还没有在重要的网站上看到这一报道，我已经翻译好了两篇，传给你，不知是否可以刊登，如能刊登将对我们肌病患者这一特弱的群体是一种支持和鼓励。”本站感谢他在第一时间提供的重要信息，他对生活、对科学的热爱值得我们钦佩和学习。我们愿意及时刊登这一消息，表示对他和所有患者朋友的支持，并与所有关心生物技术发展的人们共勉，愿科技的发展更早、更多的惠及那些需要帮助的人们！
美国首次用基因疗法治疗杜氏进行性肌营养不良的针对患者的临床实验正式开始
美国首次用基因疗法治疗杜氏进行性肌营养不良的针对患者的临床实验正式开始。经过美国北卡罗莱纳大学Chapel Hill's医学院和美国匹斯堡大学科学家历经20年的努力研究，旨在论证基因疗法对杜氏进行性肌营养不良患者进行治疗的安全性和有效性的针对患者的临床试验，已于2006年3月28日在美国附属于俄亥俄州立大学的哥伦比亚儿童医院正式拉开序幕。
研究者招募了六位杜氏进行性肌营养不良患者，将通过基因载体将外源的抗肌萎缩蛋白基因注射入这些杜氏进行性肌营养不良的肌肉组织（注：由于抗肌萎缩蛋白基因是人染色体上最大的基因，无法完全装入用于基因递送的腺相关病毒，所以这次被送入的抗肌萎缩蛋白基因，是经由美国匹斯堡大学华裔科学家XIAO XIAO领导的研究小组，研制的截短的，但仍然能维持最基本功能的抗肌萎缩蛋白。这一小型化的抗肌萎缩蛋白基因，在对DMD实验鼠的实验中，显示了良好的效果。）
每个接受临床试验的的杜氏进行性肌营养不良患者一条手臂的肱二头肌将被注射入外源的截短的抗肌萎缩蛋白基因，而另一条手臂的肱二头肌将被注射入用于进行对照的安慰剂，无论是研究者还是受试者都不知道患者的哪条手臂被注射了外源的抗肌萎缩蛋白基因，注射后的几个星期，将在显微镜下对被注射外源的抗肌萎缩蛋白的肌肉组织进行分析，同时还将进行一系列的身体和患者肌肉力量的测试，以便观察这一基因疗法对杜氏进行性肌营养不良患者是否是安全的和外源的微型抗肌萎缩蛋白是否能在杜氏进行性肌营养不良患者的肌肉细胞中持续地表达抗肌萎缩蛋白。
杜氏进行性肌营养不良是由于患者的抗肌萎缩蛋白基因发生突变引起的，表现的症状是患者的肌肉组织呈进行性的萎缩退化，随着时间的推移患者的肌肉力量不断减弱，在显微镜下能清楚的观察到杜氏进行性肌营养不良患者肌肉组织的改变。杜氏进行性肌营养不良起病于幼年期，大多数患者会30岁以前因心力衰竭或呼吸肌麻痹而死亡。杜氏进行性肌营养不良患者的基因缺陷发生在X染色体上，是一种伴性隐性
遗传，所以绝大多数的患者都是男性。
目前的药物治疗最多只能使杜氏进行性肌营养不良患者肌肉组织退化的速度略微减缓。抗肌萎缩蛋白基因是人体最大的基因，使抗肌萎缩蛋白基因小型化，并且使其拥有相当部分的功能，是目前基因治疗领域的最大的挑战。
这次开展的最新的抗肌萎缩蛋白基因疗法结合了两项最先进的技术，包括使外源的抗肌萎缩蛋白基因小型化和用纳米生物材料进行纳米级的基因递送，后者是腺相关病毒载体的进一步发展，这些特制的生物纳米材料是被设计用来专门递送微型的抗肌萎缩蛋白基因的。
这次基因治疗杜氏进行性肌营养不良的患者临床试验得以实施，是与美国北卡罗莱纳大学药理学教授和北卡大学基因治疗研究中心主任Samulski和他的学生，原北卡罗莱纳大学的博士后，目前美国美国匹斯堡大学人类基因治疗中心和
整形外科副教授，华裔科学家XIAO XIAO对此的贡献分不开的。
Samulski是研究进行基因递送的病毒载体的权威，他在上世纪80年代毕业于美国佛罗里达大学，当时他写的毕业
论文就是用腺相关病毒作为基因载体来进行基因治疗。Samulski分离出的腺相关病毒2，目前已经被用于襄性纤维化和其他疾病的基因治疗临床试验
1986年Samulski来到匹斯堡大学，成为生物学系的副教授并且拥有了自己的实验室，他带的第一个研究生就是来自中国湖北的XIAO XIAO，XIAO XIAO毕业后与Samulski 经常进行合作研究。
1993年Samulski来到美国北卡罗莱纳大学，成为该大学新的基因治疗研究中心的主任。XIAO XIAO毕业后，先是进入了企业界，然后来到北卡罗莱纳大学Samulski的基因治疗研究中心从事博士后研究。1996年Samulski的研究小组，报告了他们首次用腺相关病毒递送抗肌萎缩蛋白基因进行杜氏进行性肌营养不良实验鼠肌肉细胞中的成功实验。1998年XIAO XIAO又回到了匹斯堡大学，在那里他继续进行肌肉生物学的研究，但是重点已经放在怎样将过大的抗肌萎缩蛋白基因装入腺相关病毒，而他昔日的导师还在继续对腺相关病毒载体进行更加深入的研究。
XIAO XIAO 在匹斯堡大学开发了微型版的抗肌萎缩蛋白，并渴望用基因载体对这一微型的抗肌萎缩蛋白基因进行试验，于是他又于昔日的恩师进行了联系。Samulski说：“抗肌萎缩蛋白就像一个带有桩子的篱笆，他是人体最大的基因，大约占X染色体的1%，XIAO XIAO拔了钉，拆了桩，使得篱笆变得越来越小，同时还要使其保持一定的功能。XIAO XIAO研制了微型版的抗肌萎缩蛋白，并开始寻找进行基因递送的方法。而当时我们已使得我们研制的基因载体，在治疗一种因酶缺陷引起的疾病—Canavan's基因治疗中达到了临床级的水平，当时美国食品和药品
管理局已经批准了我们用腺相关病毒基因载体将基因物质送入Canavan's病患者的脑组织中，可以我们的研究已经走上了轨道。XIAO XIAO想知道我们北卡大学基因载体的研究已达到了怎样的水平，我告诉他，我们的基因载体已被应用于Canavan's病的基因治疗临床前实验，并在不断改进，我们正在研究一些适合于进行肌肉组织基因治疗的腺相关病毒载体。”
于是这对师生又开始了紧密的合作，并于2003年合作建立了一家名为Asklepios的生物制药公司，该公司拥有Samulski的腺相关病毒和Xiao的微型版抗肌萎缩蛋白基因的专利。2004年7月美国神经肌肉疾病协会出资160万美元资助该公司所从事的基因治疗杜氏进行性肌营养不良的研究。然后美国俄亥俄大学医学院神经学、小儿科学和病理学教授，美国神经肌肉疾病协会哥伦比亚儿童医院诊所的负责人，哥伦比亚儿童医院神经肌肉疾病研究中心主任Mendell也加入了他们的团队，这次基因治疗将在哥伦比亚儿童医院美国神经肌肉疾病协会诊所进行，Mendell将负责这次临床试验的具体实施Mendell（Mendell是一位出色的临床医生）。
在按照美国食品和药品管理局的要求进行了毒性试验后，证明这种微型抗肌萎缩蛋白的基因治疗是无害的，同时最终能够使杜氏进行性肌营养不良患者获益。美国食品药品管理局于2006年3月3日批准了这项临床实验，这是美国第一次对杜氏进行性肌营养不良患者进行基因治疗的临床试验。
主要的研究者Samulski说：“经过了多年的艰苦的临床前的研究，今天我感到很兴奋，我们终于将这一项能够使杜氏进行性肌营养不良患者受益的研究带入了临床试验，我对这次临床试验充满了信心。”
原文：
First clinical trial of gene therapy for muscular dystrophy now under way
The first gene therapy human trial in the United States for a form of muscular dystrophy is under way.
The clinical trial for Duchenne muscular dystrophy (DMD) tests the safety and effectiveness of a therapy that was developed over two decades by scientists at the University of North Carolina at Chapel Hill's School of Medicine and the University of Pittsburgh.
The trial was launched March 28, at Columbus Children's Hospital in Ohio, an affiliate of Ohio State University's School of Medicine. In the trial, six boys with DMD will receive replacement genes for an essential muscle protein.
Each of the boys will receive replacement genes via injection into a bicep of one arm and a placebo in the other arm. Neither the investigators nor the participants will know which muscle got the genes. After several weeks, an analysis of the injected muscle tissue's microscopic appearance, as well as extensive testing of the health and strength of the trial participants, will reveal whether gene therapy for DMD is likely to be safe and whether it's likely to result in persistent production of the essential protein in muscle cells.
Muscular dystrophies are genetic disorders characterized by progressive muscle wasting and weakness that begin with microscopic changes in the muscle. As muscles degenerate over time, the person's muscle strength declines.
Duchenne muscular dystrophy is a genetic disease that begins in early childhood, causes progressive loss of muscle strength and bulk, and usually leads to death in the 20s from respiratory or cardiac muscle failure. DMD occurs when a gene on the X chromosome fails to make the essential muscle protein dystrophin. One of nine types of muscular dystrophy, DMD primarily affects boys.
Currently, the best medical therapy can only slow the progressive muscle weakness of DMD.
The gene for dystrophin is one of the largest genes in the human body, and miniaturizing it, while retaining the crucial elements of its set of DNA instructions, has been among the greatest challenges to the gene therapy field.
The new Biostrophin therapy uses a novel combination of advanced technologies, including a miniaturized replacement dystrophin gene and nano delivery technology called biological nanoparticles. Developed from a virus known as adeno-associated virus (AAV), the nanoparticles are engineered specifically to target and carry the "minidystrophin" gene to muscle cells.
The therapy was made possible by the pioneering research in AAV by Dr. Richard Jude Samulski, professor of pharmacology and director of the Gene Therapy Center at UNC, and Dr. Xiao Xiao, a former UNC postdoctoral researcher in Samulski's laboratory now with the University of Pittsburgh Human Gene Therapy Center and associate professor of orthopedic surgery.
Samulski has long pioneered methodologies for making viruses deliver genes. As a graduate student at the University of Florida in the early 1980s, his thesis project was developing the AAV as a vector for therapeutic genes. This work eventually led to isolation of type-2 AAV, which has been used for gene therapy trials in cystic fibrosis and in several other settings, Samulski said.
"It's what we would call the parent virus that everybody started with."
Samulski moved to the University of Pittsburgh in 1986, joining the biology department as an assistant professor with his own laboratory. His first graduate student was Xiao, who had just come from China. Xiao focused on the lab's AAV vector project. "We've continued to have productive collaborations ever since he graduated from my lab," Samulski said.
In 1993, Samulski moved to the University of North Carolina at Chapel Hill, becoming director of UNC's new Gene Therapy Center. Xiao moved first into industry, then to UNC as a postdoctoral researcher in Samulski's gene therapy center. In 1996, the team published a report of the first muscle gene delivery involving an AAV vector.
Xiao then returned to Pittsburgh in 1998, where he worked on muscle biology with an eye toward gene transfer, while Samulski remained focused on the vector aspects of AAV, the delivery system.
At Pittsburgh, Xiao had developed a miniaturized version of the gene for dystrophin, the muscle protein needed by people with DMD. Eager to test it in a vector, he contacted his former mentor.
"The dystrophy gene is like a long picket fence. It's the largest gene in the human body, occupying 1 percent of the X chromosome," Samulski said. "Xiao Xiao began removing pegs, or pickets, from the fence, making it smaller and smaller but kept testing to see if it would still perform its function," Samulski said.
Xiao then began looking for a way he might move his minidystrophin gene forward clinically.
"We had just finished demonstrating that we could make clinical-grade virus for another genetic disorder called Canavan's disease, an enzyme deficiency disorder," Samulski said. "We were the first academic institution to ever make FDA-certified AAV vectors to go into the brains of children with Canavan's disease. So we had cut our teeth and had a bit of a track record by 2002, and that's when Xiao approached me."
Xiao told Samulski he wanted to put his new minidystrophin gene into an AAV vector and test it.
"He wanted to know if UNC could make the virus, and that's when I told him that we were using this virus for Canavan's disease and for other efforts. We had started improving the vectors, and we had developed some new ones that we thought were better for muscle."
Xiao and Samulski put their projects together and formed Asklepios BioPharmaceutical Inc. (AskBio) in 2003. Along with the rights granted by UNC to Samulski's vector technology, AskBio acquired the intellectual property rights to Xiao's uniquely miniaturized dystrophin gene.
In July 2004, the Muscular Dystrophy Association (MDA) awarded $1.6 million to AskBio to develop gene therapy strategies for DMD.
Rounding out the AskBio team clinically is neurologist Dr. Jerry R. Mendell, co-director of the MDA clinic at Columbus Children's Hospital; professor of pediatrics, neurology and pathology at Ohio State University's School of Medicine; and head of the neuromuscular research program and Center for Gene Therapy at Columbus Children's Research Institute. In the clinical trial at the Columbus Children's Hospital's MDA clinic, Mendell will administer the injections.
Following extensive laboratory toxicity experiments required by the U.S. Food and Drug Administration demonstrating that minidystrophin gene transfer was unlikely to harm and could ultimately benefit muscles affected by DMD, approval was granted March 3, 2006, to proceed with the human trial.
"After years of encouraging pre-clinical results, I'm excited that AskBio will help bring this promising new therapy into the clinic, and look forward with a great deal of optimism to offering this initial step toward hope for the DMD community," Samulski said.
Key to gene therapy vector research at UNC is the Human Applications Laboratory, or HAL. Located in the General Clinical Research Center at UNC Hospitals, this 1,400-square-foot facility was designed specifically for production of various biological reagents, including viral vectors, that may be required for phase 1 (safety and efficacy) clinical trials. The facility is in compliance will FDA requirements for germ-free processing. At the HAL, viral vectors and their components are generated at very high purity and concentration.
Further information on the UNC Gene Therapy Center can be found at:
http://www.med.unc.edu/wrkunits/3ctrpgm/genether/
School of Medicine contacts: Stephanie Crayton, (919) 966-2860 or scrayton@unch.unc.edu; or Tom Hughes, (919) 966-6047 or tahughes@unch.unc.edu
Muscular Dystrophy Association contact: Bob Mackle, (520) 529-5317 or bobmackle@mdausa.org
8岁男童成为美国首位接受基因治疗的杜氏进行性肌营养不良患者
对杜氏进行性肌营养不良患者进行的基因治疗临床试验3月29日在美国俄亥俄州立大学所属的哥伦比亚儿童医院正式进行
从某种意义上说：前沿医学发展的命运，紧紧地掌握在一个八男孩的手中。星期一，一位名叫安德鲁·克巴格的八岁的美国男孩，在两位摄影记者的陪同下，
挂号进入美国俄亥俄州立大学所属的哥伦比亚儿童医院。其中一位记者不断地告诫安德鲁要镇静，不要害怕，真诚地希望他能微笑地面对这一次历史性的基因注射。但是八岁的安德鲁做不到，他头低垂着，下巴有些僵硬，眉头紧锁，反复地挤压手掌，发出咆哮声。
昨天经过美国神经肌肉疾病协会一系列采访和录音，安德鲁成为美国第一位接受基因治疗的杜氏进行性肌营养不良患者，这次基因治疗的目的是为了恢复杜氏进行性肌营养不良患者的肌肉组织，杜氏进行性肌营养不良是一种致命性的进行性肌营养不良，目前没有有效的治疗方法。
俄亥俄大学附属的哥伦比亚儿童医院神经病专家吉瑞·蒙代尔将一种由基因载体和截短的抗肌萎缩蛋白基因混合的，被称为Biostrophin的
制剂，分三次注射到安德鲁的一条手臂，又在安德鲁另一条手臂上注射了三次用作对照的安慰剂。杜氏进行性肌营养不良患者的肌肉细胞中缺失了一种叫做抗肌萎缩蛋白蛋白质，使他们的肌肉组织易受到损害，且不易恢复，最终导致患者肌肉组织持续性的退化，坏死，大多数的患者在12岁以前，就会终身与轮椅相伴，30岁以前会因心力衰竭或呼吸肌麻痹而离开人间。基因治疗的目的是用外源的抗肌萎缩蛋白基因，将杜氏进行性肌营养不良患者X染色体上的有缺陷的抗肌萎缩蛋白基因替换掉，这一基因治疗的方法在实验小鼠、大鼠和狗的动物试验中，取得了令人满意的积极效果。这次治疗的目的是改善杜氏进行性肌营养不良患者被注射的肱二头肌的功能，但是不可能完全逆转安德鲁和其他患者肌营养不良的症状（因为使用的不是全长的外源的抗肌萎缩蛋白基因，而是被截短的抗肌萎缩蛋白基因）
星期一中午，在俄亥俄州立大学哥伦比亚儿童医院的餐桌上，Jude Samulski and Jade Samulski 正在描述他们20年来，在实验室中的努力和导致这一基因治疗临床试验的情况，在他们的餐桌上摆放着用于研究的手提式电脑。
Jude Samulski 是Jade Samulski的叔父，他是美国北卡罗莱纳大学的一位病毒学家，二十年前就开始研究用于将外源的基因导入细胞中的基因载体。这种载体是一种经过基因工程改造的病毒，它对人体无害，而且能有效地进入细胞。而他的研究伙伴，也是他昔日的学生，美国匹斯堡大学的一位来自中国湖北的科学家Xiao Xiao长期以来一直在致力于将过大的抗肌萎缩蛋白基因截短，但是必须保持抗肌萎缩蛋白基因上的关键组件，使其能够被装入Jude Samulski研制的腺相关病毒基因载体，这种基因载体只能装下抗肌萎缩蛋白基因的40%。两位科学家各自研究工作的完美结合，导致了这次具有历史意义的基因治疗得以实施。他们还一起成立了一家名为Asklepios的生物制药公司
Jade Samulski用手提电脑为大家放映了一只老鼠的活动录像，这只老鼠在用这种基因疗法进行治疗前，弯着背，拖着慢吞吞的吃力的步伐，缓慢地走进鼠笼，而当科学家们用基因疗法对其进行治疗后的一个月，它却显得非常有精神，并能灵活地跳到鼠笼的边缘伸展自己的身体。
在Jade Samulski用手提电脑中的另一段录像则显示了一只原先患有类似于杜氏进行性肌营养不良的大鼠，在经过这种基因治疗后，踩单车的速率几乎与正常的大鼠没有什么两样。Jade Samulski说：“当我看到如此美妙的情景后，感到非常兴奋。我们的团队在过去两年多时间里，每周工作七天，每天工作12—15个小时，就是为了看到我们研制的Biostrophin被用于临床对杜氏进行性肌营养不良患者试验的这一天。”
安德鲁是第一位，在未来九个月里将被蒙代尔教授注射Biostrophin的六位8—12岁的杜氏进行性肌营养不良患者。哥伦比亚儿童医院是唯一的被美国食品和药品管理局批准的开展此次临床试验的单位。
接受这次基因治疗的六位杜氏进行性肌营养不良患者，将被严密地观察其身体是否有任何不正常的表现，包括注射点是否有红肿。每位患者在接受治疗后的六个星期，将进行肌肉活组织检查，研究者希望看到被注射入杜氏进行性肌营养不良患者体内的基因在患者血液系统中有较高的含量，特别是在患者的腿部肌肉。
美国俄亥俄州立大学哥伦比亚儿童医院基因治疗研究中心的负责人，这次基因治疗的具体执行者蒙代尔说：“我们希望这一新型的基因治疗的方法，能够改善杜氏进行性肌营养不良患者的生活质量。最终，这一基因治疗的方法，将采用血管注射将治疗的基因送入杜氏进行性肌营养不良患者全身的肌肉组织，包括心肌。”
这一基因治疗的研究由美国神经肌肉疾病协会出资160万美元开展。自从安德鲁的父母麦克和朱丽叶知道自己的儿子患上了不治之症——杜氏进行性肌营养不良后，已经为美国神经肌肉疾病协会筹集了8万美元。如果这次基因治疗的临床试验获得成功，不仅能引来更多的研究资金，而且为杜氏进行性肌营养不良患者治疗提供了美好的前景。安德鲁的母亲说：“我们的首次旅行虽然没有到达月球，但是必须有人走出第一步。”
原文：
Boy, 8, is pioneer for gene therapy
Trial may help treat muscular dystrophy
Wednesday, March 29, 2006
Misti Crane
THE COLUMBUS DISPATCH
Sometimes the next frontier in medical science depends on an 8-year-old boy with a stuffed leopard clenched in his hand.
So it went Monday when Andrew Kilbarger checked into Children’s Hospital, followed by two cameramen, including one who coaxed him into walking into the hospital twice in sincere hope that Andrew would smile for the second take.
He didn’t.
He kept his head down, his chin firm and his leopard close, repeatedly squeezing its paw to make it roar.
Yesterday, after a series of interviews and taping for the Muscular Dystrophy Association, he became the first person to receive experimental gene therapy that aims to restore the muscles of boys suffering with a debilitating and incurable disease.
Dr. Jerry Mendell, a neurologist, injected three shots of the agent, called Biostrophin, into one of Andrew’s arms and three placebo shots into the other.
Inside Andrew’s muscles, a honeycomb-like system of tissue that supports the muscle cells is missing. Without dystrophin, the gene missing in boys with Duchenne muscular dystrophy, the muscle becomes Jell-O-like. Most are in wheelchairs by 12 and die by 20.
The therapy is designed to replace integral parts of the missing gene. In mice, hamsters and dogs, the results have been remarkable.
This study does not have the potential to reverse Andrew’s muscular dystrophy, although it could improve muscle function in the bicep that receives the Biostrophin.
Huddled over their laptops at their lunch table at Children’s Monday, Jude and Jade Samulski described the two decades of work leading up to Andrew’s injections.
Jude is Jade’s uncle and a virologist at the University of North Carolina at Chapel Hill. For 20 years, he’s been working on a mechanism to carry the missing gene into the body. The vessel — he calls it a shuttle — is a re-engineered virus, harmless and efficient at finding its way into tissue.
His partner in the effort, Xiao Xiao, a researcher at the University of Pittsburgh, figured out how to shrink the dystrophin gene to its essential elements so it would fit into the virus, which is big enough to carry about 40 percent of the gene.
Once combined, the miniaturized gene travels inside the shuttle to the muscle, ideally replacing what is missing.
Jade Samulski, who serves as director of program management, helped the duo come up with a name for their company: Asklepios Biophar maceutical, after the Greek god of healing.
On their computer screens, the Samulskis showed video of rodents, before and after. A mouse, hunched and slow, shuffled around its cage. A month after treatment, it moved briskly and reached up the side of the cage, stretching its body.
In another video, a previously diseased hamster is shown post-injection running on a treadmill and keeping pace with a healthy hamster.
"This is like the pinnacle of all this research. It’s pretty exciting," Jude Samulski said Monday. The team has been working 12- to 15-hour days seven days a week for more than two years hoping to see Biostrophin tested in humans.
Andrew is one of six boys 8 to 12 years old who Mendell will inject in the next nine months.
Children’s is the only hospital working on the study, which is designed to prove to the Food and Drug Administration that the experimental gene therapy is safe.
The boys will be monitored to see whether there are any reactions, including redness and swelling. Six weeks after each boy is injected, Mendell will take samples of his muscles.
Researchers are hopeful it will lead to tests in which doctors inject the gene therapy into the bloodstream at higher doses, perhaps in the legs.
"Then, we could really improve the quality of life," said Mendell, who leads the neuromuscular research program and gene therapy center at the Columbus Children’s Research Institute.
Eventually, bloodstream injections would theoretically deliver the gene to all the muscles, including the heart, he said.
The research is supported by $1.6 million from the Muscular Dystrophy Association.
Since Andrew’s parents, Mike and Julie, learned he had the disease in 2001, they’ve raised $80,000 for the MDA.
For the Kilbargers, who live in Lancaster, the experiment is a chance to contribute more than money to further research that might improve the outlook for boys with the disease.
They understand it’s just the start of studies that could go on for years before a treatment could be approved.
"We don’t hit the moon our first trip. Somebody has to step up. Somebody has to be the first one," Mrs. Kilbarger said.
"Andrew’s only stipulation was that Mommy stay with him the whole time. That and a few Matchbox cars."
mcrane@dispatch.com
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