美国肯塔基大学医学院Matthew S. Gentry团队的一项最新研究发现，可利用抗体与酶融合的技术靶向清除拉福拉病（LD）中的致病性拉福拉小体（LB）。相关论文发表在2019年10月刊的《细胞—代谢》杂志上。

研究人员证明了人胰腺α-淀粉酶降解LB。研究人员将这种淀粉酶融合到了一个可穿透细胞的抗体片段上，并且这种抗体与酶的融合体（VAL-0417）能够在体外降解LB，并显著降低了Epm2a-/-小鼠体内的LB负荷。使用代谢组学和多变量分析，研究人员证明了对EPM2a-/-小鼠的VAL-0417治疗可将代谢表型逆转为野生型。VAL-0417是用于LD治疗的有望药物，也是顽固性癫痫的潜在精确治疗手段。

据介绍，LD是由EPM2A或EPM2B基因的隐性突变引起的致命性儿童癫痫病。LD的标志是在大脑和其他组织中不溶性多糖沉积物在细胞内的积累，这些沉积物被称为拉福拉小体（LB）。在LD小鼠模型中，糖原合成的遗传性降低消除了LB的形成并拯救了神经表型。因此，LB已成为改善LD的治疗靶标。

附：英文原文

Title: Targeting Pathogenic Lafora Bodies in Lafora Disease Using an Antibody-Enzyme Fusion

Author: M. Kathryn Brewer, Annette Uittenbogaard, Grant L. Austin, Dyann M. Segvich, Anna DePaoli-Roach, Peter J. Roach, John J. McCarthy, Zoe R. Simmons, Jason A. Brandon, Zhengqiu Zhou, Jill Zeller, Lyndsay E.A. Young, Ramon C. Sun, James R. Pauly, Nadine M. Aziz, Bradley L. Hodges, Tracy R. McKnight, Dustin D. Armstrong, Matthew S. Gentry

Issue&Volume: VOLUME 30, ISSUE 4

Abstract: 

Lafora disease (LD) is a fatal childhood epilepsy caused by recessive mutations in either the EPM2A or EPM2B gene. A hallmark of LD is the intracellular accumulation of insoluble polysaccharide deposits known as Lafora bodies (LBs) in the brain and other tissues. In LD mouse models, genetic reduction of glycogen synthesis eliminates LB formation and rescues the neurological phenotype. Therefore, LBs have become a therapeutic target for ameliorating LD. Herein, we demonstrate that human pancreatic α-amylase degrades LBs. We fused this amylase to a cell-penetrating antibody fragment, and this antibody-enzyme fusion (VAL-0417) degrades LBs in vitro and dramatically reduces LB loads in vivo in Epm2a −/− mice. Using metabolomics and multivariate analysis, we demonstrate that VAL-0417 treatment of Epm2a −/− mice reverses the metabolic phenotype to a wild-type profile. VAL-0417 is a promising drug for the treatment of LD and a putative precision therapy platform for intractable epilepsy.

DOI: 10.1016/j.cmet.2019.07.002

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30375-4