An RNAi therapeutic targeting hepatic DGAT2 in a genetically obese mouse model of nonalcoholic steatohepatitis.
An RNAi therapeutic targeting hepatic DGAT2 in a genetically obese mouse model of nonalcoholic steatohepatitis.
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DOI：
10.1016/j.ymthe.2021.11.007
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发表时间：
2022-03-02
期刊：
影响因子：
--
通讯作者：
Czech MP
中科院分区：
文献类型：
--
作者：
Yenilmez B;Wetoska N;Kelly M;Echeverria D;Min K;Lifshitz L;Alterman JF;Hassler MR;Hildebrand S;DiMarzio C;McHugh N;Vangjeli L;Sousa J;Pan M;Han X;Brehm MA;Khvorova A;Czech MP
非酒精性脂肪性肝炎 (NASH) 是一种严重的肝脏疾病，其特征是甘油三酯蓄积、严重炎症和纤维化。随着最近患病率的增加，NASH 现已成为肝移植的主要原因，但尚无批准的治疗方法。尽管 NASH 进展的确切分子机制尚不清楚，但一个广泛持有的假设是脂肪堆积是该疾病的主要驱动因素。因此，甘油三酯合成的关键酶二酰甘油O-酰基转移酶2（DGAT2）已被探索作为NASH靶点。基于 RNAi 的疗法正在彻底改变肝脏疾病的治疗，最近的化学进展支持通过单次皮下注射实现长期基因沉默。在这里，我们发现了一种功能超强、完全化学稳定的 GalNAc 缀合的小干扰 RNA (siRNA)，其靶向 DGAT2 (Dgat2-1473)，注射后可在野生型和 NSG-PiZ“人源化”小鼠中引发长达 3 个月的 DGAT2 沉默（>80%–90%，p < 0.0001）。使用肥胖驱动的 NASH (ob/ob-GAN) 小鼠模型，Dgat2-1473 给药可预防和逆转甘油三酯积累 (>85%，p < 0.0001)，且不会增加甘油二酯的积累，从而显着改善脂肪肝表型。然而，令人惊讶的是，肝脏脂肪的减少并没有转化为对炎症和纤维化的类似影响。因此，虽然 Dgat2-1473 是一种实用、长效的沉默剂，可潜在地减弱肝脏脂肪变性的治疗效果，但对于 NASH 的治疗效果，可能需要联合靶向第二条途径。肥胖和 2 型糖尿病患者的肝脏脂肪超载可导致严重炎症、纤维化和肝衰竭。一种化学稳定的、GalNAc 缀合的 siRNA 靶向脂质合成酶 DGAT2，经鉴定可在小鼠单次皮下注射后使肝脏脂肪减少 85%；然而，令人惊讶的是，炎症和疤痕却没有受到影响。
Nonalcoholic steatohepatitis (NASH) is a severe liver disorder characterized by triglyceride accumulation, severe inflammation, and fibrosis. With the recent increase in prevalence, NASH is now the leading cause of liver transplant, with no approved therapeutics available. Although the exact molecular mechanism of NASH progression is not well understood, a widely held hypothesis is that fat accumulation is the primary driver of the disease. Therefore, diacylglycerol O-acyltransferase 2 (DGAT2), a key enzyme in triglyceride synthesis, has been explored as a NASH target. RNAi-based therapeutics is revolutionizing the treatment of liver diseases, with recent chemical advances supporting long-term gene silencing with single subcutaneous administration. Here, we identified a hyper-functional, fully chemically stabilized GalNAc-conjugated small interfering RNA (siRNA) targeting DGAT2 (Dgat2-1473) that, upon injection, elicits up to 3 months of DGAT2 silencing (>80%–90%, p < 0.0001) in wild-type and NSG-PiZ “humanized” mice. Using an obesity-driven mouse model of NASH (ob/ob-GAN), Dgat2-1473 administration prevents and reverses triglyceride accumulation (>85%, p < 0.0001) without increased accumulation of diglycerides, resulting in significant improvement of the fatty liver phenotype. However, surprisingly, the reduction in liver fat did not translate into a similar impact on inflammation and fibrosis. Thus, while Dgat2-1473 is a practical, long-lasting silencing agent for potential therapeutic attenuation of liver steatosis, combinatorial targeting of a second pathway may be necessary for therapeutic efficacy against NASH. Liver fat overload in obesity and type 2 diabetes can proceed to severe inflammation, fibrosis, and liver failure. A chemically stabilized, GalNAc-conjugated siRNA targeting lipid synthesis enzyme DGAT2 was identified that decreases liver fat by 85% following single subcutaneous injection in mice; however, inflammation and scarring are surprisingly unaffected.
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DOI：
10.1016/j.ymthe.2017.09.020
发表时间：
2017-11-01
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
Borel F;Tang Q;Gernoux G;Greer C;Wang Z;Barzel A;Kay MA;Shultz LD;Greiner DL;Flotte TR;Brehm MA;Mueller C
通讯作者：
Mueller C
影响因子：
82.9
作者：
Friedman SL;Neuschwander-Tetri BA;Rinella M;Sanyal AJ
通讯作者：
Sanyal AJ
DOI：
10.1002/hep.29477
发表时间：
2018-05
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Friedman SL;Ratziu V;Harrison SA;Abdelmalek MF;Aithal GP;Caballeria J;Francque S;Farrell G;Kowdley KV;Craxi A;Simon K;Fischer L;Melchor-Khan L;Vest J;Wiens BL;Vig P;Seyedkazemi S;Goodman Z;Wong VW;Loomba R;Tacke F;Sanyal A;Lefebvre E
通讯作者：
Lefebvre E
影响因子：
4.8
作者：
Erion, Derek M.;Popov, Violetta;Samuel, Varman T.
通讯作者：
Samuel, Varman T.
影响因子：
13.5
作者：
Gluchowski, Nina L.;Gabriel, Katlyn R.;Walther, Tobias C.
通讯作者：
Walther, Tobias C.