把动物的研究指出，一个导致亨廷顿病治疗

通过调整的关键信号蛋白的水平，研究人员改进一种亨廷顿病实验动物的运动功能和脑畸形，严重的神经退行性疾病。这一新发现为有这种致命、渐进性疾病的人提供了一种新的治疗方法。

“这项研究显示了一个生物学通路亨廷顿病的发展至关重要的复杂运作，是药物发展高度相关，”该研究的领导者贝弗利L。戴维森博士，在费城儿童医院的细胞与分子治疗中心主任（CHOP）。“我们的研究结果在动物中打开一个潜在的治疗之门，以仔细操纵失调的途径来治疗这种毁灭性的疾病。”

她补充说，恢复适当的平衡这些微妙的生物过程可能在治疗其他神经系统疾病提供了更广泛的好处，如肌萎缩性侧索硬化症（ALS），脆性X智力障碍和自闭症。

该研究小组于12月31日在杂志上发表了其结果神经元。

关于亨廷顿病

Huntington’s disease is an incurable, inherited disease entailing progressive loss of brain cells and motor function, usually beginning in midlife。 A defective gene produces repeated copies of a protein called huntingtin, or HTT。 The mutant HTT protein (mHTT) particularly damages a brain region called the striatum, where it interferes with normal cell growth and other fundamental biological events。 The resulting disease includes involuntary movements and severe cognitive and emotional disturbances。 About 30,000 Americans have Huntington’s disease (HD)。

恢复途径可能有助于逆转疾病

Neuroscientists already knew that a signaling protein called mTORC1 that regulates cell growth and metabolism plays a major role in HD。 Many researchers have proposed that inhibiting or shutting off the mTORC1 pathway, which interacts with the deleterious mHTT proteins, could help treat HD。

The current study contradicts those assumptions。 “We show that the mTORC1 pathway is already impaired in Huntington’s disease, and that improving how the pathway functions actually has a protective effect,” said Davidson。 “However, restoring that pathway must be done very carefully to avoid further harm。 It’s a ‘Goldilocks effect。’ You need to restore the mTORC1 level; either too much or too little is detrimental。”

In mice bred to model features of Huntington’s disease, the study team injected bioengineered viruses as a gene therapy tool to carry DNA that directed the production of regulatory proteins called Rheb and Rhes。 Both proteins act along the mTORC1 pathway。 The treated mice had improvements in brain volume and in their movements。 The mice had improved metabolic functions as well, such as cholesterol levels, dopamine signaling and mitochondrial activity (an indicator of cellular energy production)。 There also were increases in autophagy, an organism’s cleanup process that clears out and recycles mHTT and other proteins。

“It was particularly exciting to see plasticity in the neurons impaired by mHTT,” said Davidson, noting that in the HD mice, brain areas that had begun to atrophy recovered volume and permitted better motor function after the researchers restored mTORC1 activity to more normal levels。 “This shows that brain cells are capable of responding even after disease onset, and hints at the potential for reversing Huntington’s disease。”

The study team performed much of this research in Davidson’s laboratory at the University of Iowa, before she and many of her colleagues moved to CHOP in 2014。 John H。 Lee, the paper’s first author, remains at the University of Iowa, where he is completing his MD/PhD training。

下一步开发潜在的治疗方法

Much work remains to translate these scientific findings into a clinical treatment。 Researchers must identify drug candidates that appropriately activate the mTORC1 pathway。 Although gene therapy vectors delivered to brain were used for this research, Davidson envisions developing a small molecule that can appropriately modulate this pathway。 Such a treatment might be combined with a gene therapy approach, also being pursued by her team and other groups, delivered directly to the brain to curtail mHTT expression。

More broadly, she added, restoring mTORC1 activity to normal levels may benefit patients with other neurological diseases。 Fragile X mental retardation and autism both feature overactive mTORC1 activity, while mTORC1 is reduced in ALS and HD。 “This pathway is poised on a biological teeter-totter,” she concluded, “and our work highlights that it’s essential to control its activity to find the appropriate balance for each disease。”

The National Institutes of Health (grants NS50210 and NS052789-S1) and the Roy J。 Carver Trust supported this study。 In addition to her CHOP position, Davidson is on the faculty of the Perelman School of Medicine at the University of Pennsylvania。

“恢复异常mTORC1活性提高了亨廷顿病小鼠的疾病表型，”神经元, published online Dec。 31, 2014; to appear in print Jan。 21, 2015。

（注：转载时请注明复诊网）