强迫染色体进入循环，可以切断镰刀细胞病

24个月前重返列表：中介

2014年8月14日，科学家们已经改变了红细胞中的关键生物事件，导致细胞产生一种血红蛋白通常在新生儿期后消失。因为这种血红蛋白不受导致镰刀形细胞病的遗传基因突变的影响，因此，细胞培养的研究结果可能会引起一种新的治疗使人衰弱的血液疾病的治疗方法。

该方法利用蛋白质工程技术力量的染色质纤维，染色体的物质，为环状结构，与DNA上特定的地点优先激活的基因调节血红蛋白。“我们已经证明了重组基因的表达在造血细胞的新方法，”该研究的领导者GERD A。 Blobel，MD，PhD，谁掌握了弗兰克E。魏泽III赋予在费城儿童医院小儿血液的椅子。“如果我们能将这种方法转化为临床，这可能成为治疗镰刀型细胞病的新疗法。”

Blobel博士和他的同事，包括乌兰邓博士，以前在Blobel实验室成员目前实验室成员，和杰瑞米·W·rupon，医学博士，博士，他们的研究结果发表在今天的在线细胞。

Key to the researcher’s strategy is a developmental transition that normally occurs in the blood of newborns。 A biological switch regulates a changeover from fetal hemoglobin to adult hemoglobin as it begins to silence the genes that produce fetal hemoglobin。 This has major consequences for patients with the mutation that causes sickle cell disease (SCD)。

Fetal hemoglobin is not affected by this mutation。 But as adult hemoglobin starts to predominate, patients with the SCD mutation begin to experience painful, sometimes life-threatening disease symptoms as misshapen red blood cells disrupt normal circulation, clog blood vessels and damage organs。

Hematologists have long known that sickle cell patients with elevated levels of fetal hemoglobin compared to adult hemoglobin have a milder form of the disease。 “This observation has been a major driver in the field to understand the molecular basis of the mechanisms that control the biological switch, with the ultimate goal to reverse it,” said Blobel。

In previous research, Blobel’s team used bioengineering techniques to adapt zinc-finger proteins to latch onto specific DNA sites far apart on a chromosome。 The chromatin loop that results transmits regulatory signals for specific genes。

In their current work, the scientists custom-designed zinc fingers to flip the biological switch in blood-forming cells, reactivating the genes expressing fetal hemoglobin at the expense of the genes expressing adult hemoglobin。 The researchers achieved these results in cultured blood cells from adult mice and adult humans。

The next step, said Blobel, is to apply this proof-of-concept technique to preclinical models, by testing the approach in animals genetically engineered to have manifestations of SCD similar to that found in human patients。 If this strategy corrects the disease in animals, it may set the stage to move to human trials。

In principle, added Blobel, the forced chromatin looping approach could also be applied to other hemoglobin-related disorders, such as certain forms of thalassemia in which elevated fetal hemoglobin levels might be beneficial。

Financial support for this study came from the National Institutes of Health (grants 5R37DK058044, RO1HL119479, DK015508, and HL102449), the Associazione Veneta per la Lotta alla Talassemia, the European Community and a fellowship award from the American Heart Association。 Other co-authors were from Weill Cornell Medical College, the National Institutes of Health, the Howard Hughes Medical Institute, and Sangamo BioSciences, which designed the zinc finger proteins。 In addition to his position at Children’s Hospital, Blobel is also at the Perelman School of Medicine at the University of Pennsylvania。

Rupon and Blobel presented portions of this research in December 2013 at the annual meeting of the American Society of Hematology。