hINHBE小鼠模型在加速靶向人源INHBE基因RNAi疗法进入临床中的应用
2024-07-23 来源:本站 点击次数:766
很多有减肥需求的朋友，对司美格鲁肽一定不会陌生，这种药物不但可以用于治疗Ⅱ型糖尿病，对于肥胖人群减重也非常有效。早在2021年该药物就在美国获批了用于非糖尿病成年人减肥的适应症。2024年的6月25日，以改善成年人肥胖/超重的“减肥版”司美格鲁肽，也获得了中国国家药监局的批准。
然而，“神药”也不完美，据相关研究报道，司美格鲁肽约40%的减重来自骨骼和肌肉的减少，且大部分患者在停药后体重会迅速反弹。
基于此，全球众多药物研发机构正在积极寻找新的靶点，以期开发出一款更安全更有效的药物。在这样的浪潮下，INHBE应运而生。
Fig.2 Protein-truncating variants in INHBE associated with favorable fat distribution[2]
南模生物长期致力于药物靶点人源化模型研究领域，自主研发了hINHBE小鼠模型（目录号：NM-HU-233512），该模型利用同源重组，将小鼠INHBE基因进行人源化修饰。这将有助于加速靶向人源INHBE基因的RNAi疗法进入临床阶段，相关验证数据如下：
Fig.2 Detection of human INHBE expression in liver in hINHBE knockin mice by WB.
Abbr. M, marker; WT, wild type; HO, homozygous; PC, positive control, Hep G2 cells.
Note. The anti-human INHBE Antibody cross-reacted with mouse INHBE and humanized INHBE. Arrow indicates expected molecular weight and asterisk indicates a nonspecific band.
Fig.3 Detection of hINHBE expression in serum by ELISA (n=3).
Note. The human INHBE Elisa kit cross-reacted with mouse INHBE and humanized INHBE.
参考文献：
[1]Deaton AM, Dubey A, Ward LD, et al. Rare loss of function variants in the hepatokine gene INHBE protect from abdominal obesity. Nat Commun. 2022;13(1):4319. Published 2022 Jul 27. doi:10.1038/s41467-022-31757-8
[2]Akbari P, Sosina OA, Bovijn J, et al. Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes. Nat Commun. 2022;13(1):4844. Published 2022 Aug 23. doi:10.1038/s41467-022-32398-7
[3] Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989-1002. doi:10.1056/NEJMoa2032183
[4] Lundgren JR, Janus C, Jensen SBK, et al. Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined. N Engl J Med. 2021;384(18):1719-1730. doi:10.1056/NEJMoa2028198
[5] Aronne LJ, Sattar N, Horn DB, et al. Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial. JAMA. 2024;331(1):38-48. doi:10.1001/jama.2023.24945
然而，“神药”也不完美，据相关研究报道，司美格鲁肽约40%的减重来自骨骼和肌肉的减少，且大部分患者在停药后体重会迅速反弹。
基于此，全球众多药物研发机构正在积极寻找新的靶点，以期开发出一款更安全更有效的药物。在这样的浪潮下，INHBE应运而生。
INHBE概述
INHBE基因编码的是抑制素亚基βE（Inhibin Subunit Beta E），是TGF-β（转化生长因子-β）蛋白质超家族的成员，主要在肝脏中表达。其肝脏表达水平与人类的胰岛素抵抗和体重指数正相关。INHBE蛋白的罕见预测功能缺失（pLOF）突变患者腹部脂肪明显减少，代谢状况良好，且罹患心血管疾病和Ⅱ型糖尿病的风险显著降低。
Fig.1 Gene-level associations with waist-to-hip ratio adjusted for BMI[1]
Fig.2 Protein-truncating variants in INHBE associated with favorable fat distribution[2]
靶向INHBE药物研发现状
INHBE的出现吸引了多家RNAi领先企业布局，如Arrowhead、Wave Life Sciences等。药渡检索结果显示，目前INHBE靶点在研药物共3个，均处于临床前研究阶段。其中，Arrowhead计划在年底前提交ARO-INHBE临床试验申请，Wave Life将在今年确定INHBE GalNAc-siRNA的临床候选药物，并计划在明年提交临床试验申请。与GLP-1R这一热门靶点相比，INHBE靶点的竞争程度相对温和，有着巨大的市场潜力。
（来源于药渡）
南模生物长期致力于药物靶点人源化模型研究领域，自主研发了hINHBE小鼠模型（目录号：NM-HU-233512），该模型利用同源重组，将小鼠INHBE基因进行人源化修饰。这将有助于加速靶向人源INHBE基因的RNAi疗法进入临床阶段，相关验证数据如下：
Fig.1 Detection of INHBE expression in liver by RT-PCR.
Wild type: only one band at 192 bp with primers F1/R1 (mInhbe);
Homozygous: only one band at 217 bp with primers F2/R2 (hINHBE).
Abbr. M, DNA marker; HO, homozygous; WT, wild type.
Abbr. M, marker; WT, wild type; HO, homozygous; PC, positive control, Hep G2 cells.
Note. The anti-human INHBE Antibody cross-reacted with mouse INHBE and humanized INHBE. Arrow indicates expected molecular weight and asterisk indicates a nonspecific band.
Note. The human INHBE Elisa kit cross-reacted with mouse INHBE and humanized INHBE.
参考文献：
[1]Deaton AM, Dubey A, Ward LD, et al. Rare loss of function variants in the hepatokine gene INHBE protect from abdominal obesity. Nat Commun. 2022;13(1):4319. Published 2022 Jul 27. doi:10.1038/s41467-022-31757-8
[2]Akbari P, Sosina OA, Bovijn J, et al. Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes. Nat Commun. 2022;13(1):4844. Published 2022 Aug 23. doi:10.1038/s41467-022-32398-7
[3] Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989-1002. doi:10.1056/NEJMoa2032183
[4] Lundgren JR, Janus C, Jensen SBK, et al. Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined. N Engl J Med. 2021;384(18):1719-1730. doi:10.1056/NEJMoa2028198
[5] Aronne LJ, Sattar N, Horn DB, et al. Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial. JAMA. 2024;331(1):38-48. doi:10.1001/jama.2023.24945
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