一个新的靶点在多囊肾病

实验性药物在动物模型中的大小和数量的减少

2010年9月13日
波士顿，大众。•在工作中提出了一种新的治疗方法多囊性肾脏病（PKD），一个领先的原因肾衰竭，研究人员波士顿儿童医院在小鼠模型中，能够阻断液体填充囊肿的形成，这是疾病的标志。他们的研究结果，使用的化合物抑制c-Met受体，将发表在临床调查杂志9月13日在线版。

PKD是最常见的致命的遗传疾病影响的美国白种人目前，有没有批准的治疗，阻止囊肿的生长，导致肾功能丧失的渐进而无情。患者必须经常进行慢性透析或等待一个肾移植。

“这项研究使我们在PKD治疗的新靶点，说：”乔丹kreidberg，博士，在儿童肾脏科, the study's senior investigator。 "If we can get more supportive data in mice, it may provide the basis for a clinical trial in humans。"

Hopes were raised when animal models showed promise in drugs inhibiting mTOR, a protein that coordinates cell growth 和 proliferation 和 has been shown to be hyper-activated in the disease。 However, the reasons for this hyper-activation aren't well understood, 和 much-anticipated clinical trials of mTOR inhibitors, published August 26 in the New Engl和 Journal of Medicine, showed little or no effect on cyst growth, in part because toxicity limited their dosing。

The new study, led by Kreidberg 和 first author Shan Qin, MD, PhD, took a closer look at the molecular pathways, 和 showed that mTOR hyper-activation results from unwanted activity of c-Met, the receptor for hepatocyte growth factor。

Kreidberg 和 Qin used a mouse model for PKD created by collaborators at Brigham 和 Women's Hospital, in which the PKD1 gene (mutated in 85 percent of PKD patients) is deleted。 When they blocked c-Met activity in mouse embryonic kidneys, using a small molecule called 448101 Met Kinase Inhibitor, also known as SU11274 (Calbiochem, La Jolla, Calif。), cyst formation was reduced to the level seen in normal kidneys。

They then gave the compound to pregnant mice carrying embryos that lacked PKD1。 The kidneys of those embryos had a markedly reduced size 和 number of cysts as compared with untreated embryos。

“最近在囊肿形成的生物学研究提供了可能的治疗方法，可以防止或延缓多囊肾囊肿患者进展的希望，但第一次临床试验，没有工作，说：”哈蒙威廉，医学博士, director of Pediatric Nephrology at Children's。 "Dr。 Kreidberg's discoveries are very promising in suggesting exciting new approaches to treating a very serious disease。"

Kreidberg hopes these discoveries, if replicated in adult mice, will lead to clinical testing of c-Met inhibitors in patients with PKD。 He suggests that these drugs could potentially be combined with mTOR inhibitors, as well as drugs targeting other PKD pathways under study。

"PKD is quite complex, with several regulatory pathways involved, 和 multiple places to target with therapy," he says。 "It will likely benefit from sub-toxic doses of multiple agents, similar to 癌症 chemotherapy。"

c-Met inhibitors are more specific 和 limited in their action than mTOR inhibitors, so may be less toxic, Kreidberg adds。 "There are many ongoing 癌症 trials with c-Met inhibitors, so there's going be increasing information on their safety 和 pharmacology that might help us translate this to a treatment for PKD。"

除了它的作用癌症, c-Met is essential for embryonic development 和 wound healing。 Normally, after it's been activated, it is tagged for degradation。 But Kreidberg 和 colleagues show that in PKD, c-Met is never tagged, because the molecule that does the tagging get trapped inside a structure in the cell known as the Golgi apparatus。

The findings are consistent with the observation of excess amounts of c-Met in the cells lining the kidney cysts of PKD patients。 "c-Met is probably part of a development pathway that's turned on again, sometime in early or mid-adulthood," says Kreidberg。

Polycystic kidney disease, the fourth leading cause of 肾衰竭, affects more than 700,000 people in the U。S。, far surpassing other genetic disorders such as囊性纤维化和镰刀形细胞病。

The study was funded by the National Institute of Diabetes 和 Digestive 和 Kidney Diseases (NIDDK) of the National Institutes of Health。

接触：
艾琳的长跑冠军
617-919-3110
erin。mccolgan@childrens。harvard。edu

波士顿儿童医院 is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children 和 adults since 1869。 More than 1,100 scientists, including nine members of the National Academy of Sciences, 12 members of the Institute of Medicine 和 13 members of the Howard Hughes Medical Institute comprise Children's research community。 Founded as a 20-bed hospital for children, 波士顿儿童医院 today is a 396-bed comprehensive center for pediatric 和 adolescent health care grounded in the values of excellence in patient care 和 sensitivity to the complex needs 和 diversity of children 和 families。 Children's also is the primary pediatric teaching affiliate of Harvard Medical School。 For more information about the hospital 和 its research visit:www。childrenshospital。org/newsroom。

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