《自然》研究前沿:首次体内碱基编辑(基因编辑)拯救小鼠的早老综合征(附儿童照),老鼠寿命从7个月延长到17个月

来源: 2021-01-06 10:57:55 [] [博客] [旧帖] [给我悄悄话] 本文已被阅读: 次 (526610 bytes)
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摘要:Hutchinson–Gilford早衰综合征(HGPS或早衰)通常是由 LMNA基因的显性负性C•G到T•A突变(c.1824 C> T; p.G608G) 编码核纤层蛋白A。这种突变导致RNA错剪,产生 progerin,一种有毒的蛋白质,会引起快速衰老并缩短儿童的寿命到14岁 。腺嘌呤基础编辑器(ABE)转换 将目标A•T碱基对定位为G•C碱基对,副产物最少,并且没有 需要双链DNA断裂或供体DNA模板5,6 。这里我们描述 使用ABE直接纠正培养的成纤维细胞中的致病性HGPS突变 源自早衰症儿童和HGPS小鼠模型。慢病毒递送 对患有HGPS的儿童的成纤维细胞进行ABE的检测可纠正87-91%的 致病性等位基因,减轻RNA错剪接,降低progerin和 纠正核异常。无偏目标DNA和RNA编辑 分析未检测到治疗的患者来源成纤维细胞的靶标编辑。在 对人类LMNA c.1824 C> T等位基因纯合的转基因小鼠 眶后注射编码ABE的腺伴随病毒9(AAV9) 对病原体突变进行实质性,持久的纠正(整个过程中约20–60% 注射后六个月的各个器官),恢复正常的RNA剪接和 降低progerin蛋白水平。体内碱基编辑拯救了血管 小鼠的病理学,保留血管平滑肌细胞计数并预防 外膜纤维化。出生后第14天单次注射表达ABE的AAV9 改善活力,并将小鼠的平均寿命从215延长至510 天。这些发现证明了体内碱基编辑的可能性 通过直接纠正其根源来治疗HGPS和其他遗传病。

原文:

In vivo base editing rescues Hutchinson– Gilford progeria syndrome in mice

Luke W. Koblan1,2,3,13, Michael R. Erdos4,13, Christopher Wilson1,2,3, Wayne A. Cabral4 , Jonathan M. Levy1,2,3, Zheng-Mei Xiong4 , Urraca L. Tavarez4 , Lindsay M. Davison5 , Yantenew G. Gete6 , Xiaojing Mao6 , Gregory A. Newby1,2,3, Sean P. Doherty5 , Narisu Narisu4 , Quanhu Sheng7 , Chad Krilow4 , Charles Y. Lin8,9,12, Leslie B. Gordon10,11, Kan Cao6 , Francis S. Collins4 , Jonathan D. Brown5 & David R. Liu1,2,3

Hutchinson–Gilford progeria syndrome (HGPS or progeria) is typically caused by a dominant-negative C•G-to-T•A mutation (c.1824 C>T; p.G608G) in LMNA, the gene that encodes nuclear lamin A. This mutation causes RNA mis-splicing that produces progerin, a toxic protein that induces rapid ageing and shortens the lifespan of children with progeria to approximately 14 years1–4 . Adenine base editors (ABEs) convert targeted A•T base pairs to G•C base pairs with minimal by-products and without requiring double-strand DNA breaks or donor DNA templates5,6 . Here we describe the use of an ABE to directly correct the pathogenic HGPS mutation in cultured fbroblasts derived from children with progeria and in a mouse model of HGPS. Lentiviral delivery of the ABE to fbroblasts from children with HGPS resulted in 87–91% correction of the pathogenic allele, mitigation of RNA mis-splicing, reduced levels of progerin and correction of nuclear abnormalities. Unbiased of-target DNA and RNA editing analysis did not detect of-target editing in treated patient-derived fbroblasts. In transgenic mice that are homozygous for the human LMNA c.1824 C>T allele, a single retro-orbital injection of adeno-associated virus 9 (AAV9) encoding the ABE resulted in substantial, durable correction of the pathogenic mutation (around 20–60% across various organs six months after injection), restoration of normal RNA splicing and reduction of progerin protein levels. In vivo base editing rescued the vascular pathology of the mice, preserving vascular smooth muscle cell counts and preventing adventitial fbrosis. A single injection of ABE-expressing AAV9 at postnatal day 14 improved vitality and greatly extended the median lifespan of the mice from 215 to 510 days. These fndings demonstrate the potential of in vivo base editing as a possible treatment for HGPS and other genetic diseases by directly correcting their root cause.

In vivo base editing rescues Hutchinson–Gilford progeria syndrome in mice | Nature

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这个早老综合征的平均寿命只有13岁,75%死于心脏病, -杨别青- 给 杨别青 发送悄悄话 杨别青 的博客首页 杨别青 的个人群组 (166062 bytes) () 01/06/2021 postreply 11:20:19

张锋(CRISPR基因编辑)和刘大卫(碱基编辑)是全世界基因编辑顶尖科学家,是华人的骄傲, -杨别青- 给 杨别青 发送悄悄话 杨别青 的博客首页 杨别青 的个人群组 (0 bytes) () 01/06/2021 postreply 11:23:11

公司股价两日连涨35% -杨别青- 给 杨别青 发送悄悄话 杨别青 的博客首页 杨别青 的个人群组 (0 bytes) () 01/08/2021 postreply 08:17:45

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