本帖最后由 凤凰涅盘 于 2012-12-8 22:45 编辑
http://www.medicalnewstoday.com/releases/253628.php
After years of basic research, scientists at Johannes Gutenberg University Mainz (JGU) are increasingly able to understand the mechanisms underlying the human Usher syndrome and are coming ever closer to finding a successful treatment approach. The scientists in the Usher research group of Professor Dr. Uwe Wolfrum are evaluating two different strategies. These involve either the repair of mutated genes or the deactivation of the genetic defects using agents. Based on results obtained to date, both options seem promising. Usher syndrome is a congenital disorder that causes the loss of both hearing and vision.
Usher syndrome is the most common form of congenital deaf-blindness in humans, occurring in 1 in 6,000 of the population. Those suffering from the disease are drastically handicapped in everyday life as they lose the use of the two most important sensory organs, i.e., their ears and eyes. In the most severe cases, patients are born deaf and begin to suffer from vision impairment in the form of retinal degeneration in puberty that result in complete blindness. While it is possible to compensate for the loss of hearing with hearing aids and cochlear implants, no therapy was previously available for the ophthalmic component of the disorder. Scientists at Mainz University are currently undertaking preclinical translational research in an attempt to find an answer to this problem.
The investigations undertaken by the team of Dr. Kerstin Nagel-Wolfrum focused on the nonsense mutation in the USH1C gene that had been identified as the cause of the most severe form of Usher syndrome in a German family. The nonsense mutation is a stop signal generated by the DNA that causes premature termination of synthesis of the protein harmonin, which is encoded by USH1C.
The research team published its latest findings with regard to gene repair as a possible treatment of Usher syndrome in the opthalmologic journal Investigative Opthalmology & Visual Science*. During her doctoral research, Dr. Nora Overlack managed to repair the USH1C gene with the help of molecular scissors' generated using the so-called zinc-finger nuclease technique. Using zinc-finger nuclease, the scientists first initiated a double sequence DNA cleavage at the site of the disease-generating mutation. This surgical incision on the molecular level was then repaired by means of the cell's own repair mechanism in the form of homologous recombination and the introduction of a non-mutated USH1C DNA sequence. The mutated gene sequence was thus replaced with the non-mutated sequence. The efficacy of the zinc-finger nuclease technique with regard to genetic repair was demonstrated in a cell culture model at both the genome and the protein level.
The research team has also recently published the latest results of its pharmaco-genetic approach to the treatment of Usher syndrome patients with nonsense mutations in the journal EMBO Molecular Medicine. In this case, Dr. Tobias Goldman and the other team members compared various molecules that can induce read-through of the stop signal and thus provide for normal protein synthesis. In addition, they evaluated the retinal biocompatibility of the various molecules. The research focused on PTC124 (Ataluren®) and 'designer' aminoglycosides. These aminoglycosides are derived from clinically tested antibiotics and have been modified by Professor Dr. Timor Bassov of the Technicon in Haifa/Israel to improve their capacity to read-through the mutation and reduce their toxicity. The Mainz researchers had already been successful in using one of the first generation designer aminoglycosides to read-through the nonsense mutations in the USH1C gene.
They were now able to show that PTC124 (Ataluren®) and a second generation aminoglycoside (NB54) in particular would induce read-through of the stop signal in the mutated USH1C gene. This meant that protein synthesis continued, so that the active gene product was synthesized in the cell and organ cultures. Both active substances, PTC124 and NB54, generally enhanced read-through efficacy and exhibited improved tolerability in mouse and human retinal cultures in comparison with clinically employed antibiotics. The team also successfully documented read-through of the mutation in vivo a mouse model.
"Our gene-based treatment strategies, involving gene repair as well as read-through therapy, represent valuable and promising alternatives to viral gene addition and may actually be the only treatment option for the large and isoform-rich USH genes. We hope that these alternatives will make a significant contribution to the therapy of both Usher syndrome patients as well as others with severe genetic retinal pathologies and other genetic disorders," explains Dr. Kerstin Nagel-Wolfrum.
In addition to continuing its preclinical studies into the use of the active substances, the Mainz Usher research team plans to make its new Usher syndrome therapy available to patients as soon as possible.
The translational biomedical research into the treatment of Usher syndrome was carried out with the help of financial support from the EU-FP7 project SYSCILIA, the FAUN foundation, and the Foundation Fighting Blindness (FFB). The two involved doctoral candidates were research assistants and colleagues in the Research Training Group 1044: "Developmental and disease-induced modifications of the nervous system" supported by the German Research Foundation. The work of the Usher syndrome researchers is integrated in the Research Unit Translational Neurosciences (FTN) at Johannes Gutenberg University Mainz.
经过多年的基础研究，科学家们，在约翰内斯·古腾堡大学美因茨（JGU）是越来越能理解人类Usher综合征的机制，并越来越接近找到一个成功的治疗方法。亚瑟教授乌韦·沃尔夫鲁姆博士的研究小组的科学家正在评估两种不同的策略。这些涉及修复或失活的突变基因的遗传缺陷使用的代理。根据获得的结果，这两个选项似乎是有前途的。Usher综合征是一种先天性的疾病，导致损失的听力和视力。 Usher综合征是最常见的一种先天性聋哑失明的人口在6000人，发生在1。那些患有疾病的急剧人士在日常生活中，他们失去了使用的两个最重要的感觉器官，即，他们的耳朵和眼睛。在最严重的情况下，病人是天生又聋又开始受到视力障碍青春期，导致完全失明的视网膜变性的形式。虽然它是可能的，以补偿听力损失，助听器和人工耳蜗植入，没有治疗的眼科组成部分的障碍。在美因茨大学的科学家目前正在进行临床前转译研究，试图找到这个问题的答案 克斯廷的Nagel-沃尔夫鲁姆博士的团队进行的调查主要集中在USH1C基因的无义突变的原因，已被确定为的Usher综合征最严重的形式在一个德国家庭。无义突变是一个停止信号所产生的早产儿终止合成的的蛋白质harmonin，所编码的USH1C的DNA，使 该研究小组公布了其最新的研究结果与基因修复作为一种可能的治疗Usher综合征的opthalmologic杂志调查眼科及视觉科学 *。她的博士的研究期间，博士的娜拉Overlack管理，到修复的USH1C的基因分子剪刀的使用所谓的锌指核酸酶技术生成的帮助。使用锌指核酸酶，科学家们首先发起了一个双乳沟部位的疾病产生突变的DNA序列。这在分子水平上的手术切口，然后修复细胞自身的修复机制在同源重组和非突变的USH1C DNA序列引入的形式的装置。突变的基因序列，从而与非突变序列取代。锌指核酸酶基因修复技术方面的疗效被证明在细胞培养模型的基因组和蛋白质水平的 研究团队最近还公布了最新的治疗结果，其药理遗传学的方法在杂志EMBO分子医学的Usher综合征患者与无义突变。在这种情况下，博士托比亚斯Goldman和其他团队成员相比，可诱导读通过的停止信号，从而提供用于正常的蛋白质合成的各种分子。此外，他们评估的各种分子的视网膜的生物相容性。该研究主要集中在PTC124（Ataluren®）和“设计师”的氨基糖苷类抗生素。这些来自临床测试抗生素氨基糖苷类和修改过的教授，博士的东帝汶Bassov的Technicon在海法/以色列，以提高自己的能力，通过突变和降低其毒性。美因兹的研究人员已经是成功的在使用读通过在USH1C基因的无义突变的第一代设计师氨基糖苷类之一。 他们现在能够显示，PTC124（Ataluren®）和第二代氨基糖苷类（NB54）特别会诱发读通过的停止信号在突变USH1C基因。这意味着，蛋白质合成继续，从而使合成的活性基因产物在细胞和器官培养。这两种活性物质，PTC124和NB54，普遍增强通读疗效，并表现出改善的耐受性在与临床采用抗生素相比，在小鼠和人眼视网膜的文化。该小组还成功地记录读通过的突变的小鼠模型体内。 “我们的基因为基础的治疗策略，涉及基因修复以及读通过治疗，病毒基因外代表有价值，有前途的替代，实际上可能是唯一的治疗方法的选择和亚型丰富的USH基因。我们希望，这些替代品将作出重大贡献的两个Usher综合征患者以及其他严重的遗传性视网膜病症和其他遗传性疾病的治疗，“博士解释说克斯廷的Nagel-沃尔夫鲁姆。 除了继续使用的活性物质，其临床前研究，美因茨迎来的研究小组计划，使其新Usher综合征的治疗尽快提供给患者。 转化生物医学研究的Usher综合征的治疗进行了EU-FP7项目SYSCILIA，FAUN基础，和基金会战斗失明（FFB）的金融支持与帮助。这两个涉及博士生研究助理和他的同事在研究培训集团1044：“神经系统”，由德国研究基金会支持的发育和疾病引起的修改。Usher综合征的研究人员的工作集成在约翰内斯古腾堡美因茨大学的研究单位转译神经科学（FTN）。 |
