hINHBE小鼠模型在加速靶向人源INHBE基因RNAi療法進入臨床中的應用
很多有減肥需求的朋友，對司美格魯肽一定不會陌生，這種藥物不但可以用于治療Ⅱ型糖尿病，對于肥胖人群減重也非常有效。早在2021年該藥物就在美國獲批了用于非糖尿病成年人減肥的適應癥。2024年的6月25日，以改善成年人肥胖/超重的“減肥版”司美格魯肽，也獲得了中國國家藥監局的批準。
然而，“神藥”也不完美，據相關研究報道，司美格魯肽約40%的減重來自骨骼和肌肉的減少，且大部分患者在停藥后體重會迅速反彈。
基于此，全球眾多藥物研發機構正在積極尋找新的靶點，以期開發出一款更安全更有效的藥物。在這樣的浪潮下，INHBE應運而生。
Fig.2 Protein-truncating variants in INHBE associated with favorable fat distribution[2]
南模生物長期致力于藥物靶點人源化模型研究領域，自主研發了hINHBE小鼠模型（目錄號：NM-HU-233512），該模型利用同源重組，將小鼠INHBE基因進行人源化修飾。這將有助于加速靶向人源INHBE基因的RNAi療法進入臨床階段，相關驗證數據如下：
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.
參考文獻：
[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，“神藥”也不完美，據相關研究報道，司美格魯肽約40%的減重來自骨骼和肌肉的減少，且大部分患者在停藥后體重會迅速反彈。
基于此，全球眾多藥物研發機構正在積極尋找新的靶點，以期開發出一款更安全更有效的藥物。在這樣的浪潮下，INHBE應運而生。
INHBE概述
INHBE基因編碼的是抑制素亞基βE（Inhibin Subunit Beta E），是TGF-β（轉化生長因子-β）蛋白質超家族的成員，主要在肝臟中表達。其肝臟表達水平與人類的胰島素抵抗和體重指數正相關。INHBE蛋白的罕見預測功能缺失（pLOF）突變患者腹部脂肪明顯減少，代謝狀況良好，且罹患心血管疾病和Ⅱ型糖尿病的風險顯著降低。
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藥物研發現狀
INHBE的出現吸引了多家RNAi領先企業布局，如Arrowhead、Wave Life Sciences等。藥渡檢索結果顯示，目前INHBE靶點在研藥物共3個，均處于臨床前研究階段。其中，Arrowhead計劃在年底前提交ARO-INHBE臨床試驗申請，Wave Life將在今年確定INHBE GalNAc-siRNA的臨床候選藥物，并計劃在明年提交臨床試驗申請。與GLP-1R這一熱門靶點相比，INHBE靶點的競爭程度相對溫和，有著巨大的市場潛力。
（來源于藥渡）
南模生物長期致力于藥物靶點人源化模型研究領域，自主研發了hINHBE小鼠模型（目錄號：NM-HU-233512），該模型利用同源重組，將小鼠INHBE基因進行人源化修飾。這將有助于加速靶向人源INHBE基因的RNAi療法進入臨床階段，相關驗證數據如下：
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.
參考文獻：
[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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