MDR3

RTY-694 is a potent, orally active ABCB4/BSEP positive functional modulator (PFM) that improves bile composition and enhances bile flow The differentiated mechanism of a dual-targeted ABCB4/BSEP PFM addresses the underlying pathophysiology of cholestasis and cholangitis associated with multiple hepatobiliary diseases, including primary sclerosing cholangitis RTY-694 improved bile composition and demonstrated reductions in bile duct injury, cholestasis, inflammation and fibrosis Oct. 22, 2024 -- Rectify Pharmaceuticals, Inc., (“Rectify”) a biotechnology company developing positive functional modulators (PFMs), small molecule therapeutics that restore and enhance membrane protein function, today announced that RTY-694 was selected as the lead PFM for its hepatobiliary program and is advancing to first-in-human clinical trials for primary sclerosing cholangitis (PSC). “Rectify was founded to harness the untapped therapeutic potential of restoring or enhancing membrane protein function to address the underlying drivers of disease. The selection of RTY-694 as our lead candidate for the treatment of PSC marks an important milestone for our company and validates our breakthrough proprietary PFM platform for developing therapies that restore and enhance membrane protein function,” said Rajesh Devraj, Ph.D., President and Chief Executive Officer of Rectify. “With this lead candidate nomination and a strong pipeline of earlier stage programs for cardio-renal-metabolic and neurodegenerative diseases, we are poised to establish PFMs as a novel small molecule modality and Rectify as the industry-leading PFM company.” Pol Boudes, M.D., Chief Medical Officer of Rectify, added “We believe our differentiated dual-targeted approach of addressing ABCB4 and BSEP transporter dysfunction to improve bile composition and enhance bile flow has the potential to rectify the core pathophysiology of PSC and multiple hepatobiliary diseases. We look forward to advancing RTY-694 to first-in-human clinical trials as we pursue our mission of helping patients with serious diseases.” PSC is a debilitating orphan bile duct disease characterized by inflammation, fibrosis, and narrowing of the medium and large intra- and extra-hepatic bile ducts that leads to cholangitis, cholestasis and ultimately liver failure. Patients living with PSC experience a high symptom burden that reduces their quality of life and often requires hospitalization. They also face a 400-fold higher rate of developing cholangiocarcinoma, a bile duct cancer, compared to the general population. Many patients will eventually require liver transplant due to disease progression and complications. There are currently no approved medications for the treatment of PSC. RTY-694 is an orally acting dual-targeted PFM that addresses the core pathophysiology of PSC disease progression by increasing the function of the ABCB4 and BSEP transporters, two membrane proteins that play a critical role in maintaining bile composition and bile flow. In translational mouse models, RTY-694 demonstrated improvements in bile duct health, inflammation and fibrosis including: Increases in biliary phospholipids, a key bile component that buffers inflammatory free cholesterol and detergent bile acids Reductions in serum bile acids, ALT and ALP levels Improvements in ductular reaction characterized by a reduction in cholangiocyte proliferation and inflammation Reductions in TGF-β activation and periportal fibrosis Rectify is advancing Positive Functional Modulators (PFMs), a novel class of oral, small molecules that restore and enhance membrane protein function to address the underlying cause of serious diseases. Rectify’s PFMs have potential to modulate the activity of wild-type and mutated membrane bound proteins, a historically difficult challenge with a small molecule approach. The Company’s breakthrough product platform enables efficient and rapid discovery of first- and best-in-class small molecule therapies with the potential to address membrane protein dysfunction for treatment of rare and common diseases, including liver, cardio-renal-metabolic, and neurodegenerative diseases. Rectify was founded and seeded by Atlas Venture who co-led the $100M Series A round with Omega Funds and were joined by Forbion and Longwood Fund. The content above comes from the network. if any infringement, please contact us to modify.

CAMBRIDGE, Mass., Oct. 17, 2024 (GLOBE NEWSWIRE) -- Rectify Pharmaceuticals, Inc., (“Rectify”) a biotechnology company developing positive functional modulators (PFMs), small molecule therapeutics that restore and enhance membrane protein function, today announced that it will present two preclinical posters at the upcoming American Association for the Study of Liver Diseases 75th Annual The Liver Meeting®, taking place in San Diego, CA, November 15 – 19, 2024. The presented data will showcase the potential of the Company’s novel dual-targeting small molecule to restore levels and function of two ABC transporter proteins implicated in hepatobiliary diseases. The Company will introduce characterization of a new translational mouse model of hepatobiliary injury driven by abnormal bile composition and bile flow applicable to human cholangiopathy. Details for the presentations are as follow: Title: Identification and in vitro characterization of a novel BSEP and ABCB4 dual-acting positive functional modulator targeting the treatment of a broad range of hepatobiliary diseasesAbstract Number: 4367Session Date and Time: Monday, November 18, 2024, from 1:00 p.m. to 2:00 p.m. PST Title: Abcb4/Mdr2 haploinsufficiency predisposes mice to biliary injury and secondary cholestasis and defines a translational model of toxic bile induced hepatobiliary injury in human cholangiopathy Abstract Number: 4018Session Date and Time: Monday, November 18, 2024, from 1:00 p.m. to 2:00 p.m. PST The posters will be made available on the Rectify website following the presentations. About Rectify Pharmaceuticals, Inc. (“Rectify”) Rectify is advancing Positive Functional Modulators (PFMs), a novel class of oral, small molecules that restore and enhance membrane protein function to address the underlying cause of serious diseases. Rectify’s PFMs have potential to modulate the activity of wild-type and mutated membrane bound proteins, a historically difficult challenge with a small molecule approach. The Company’s breakthrough product platform enables efficient and rapid discovery of first- and best-in-class small molecule therapies with the potential to address membrane protein dysfunction for treatment of rare and common diseases, including liver, cardio-renal-metabolic, and neurodegenerative diseases. Rectify was founded and seeded by Atlas Venture who co-led the $100M Series A round with Omega Funds and were joined by Forbion and Longwood Fund. For more information, please visit www.rectifypharma.com or follow us on X and LinkedIn. Contact MediaMichael RubensteinLifeSci Communications+1 646-386-1613mrubenstein@lifescicomms.com

“小酌怡情，狂饮伤身”，酒精使用障碍（AUD）影响着全球数百万人。但当前药物治疗策略有限，AUD仍具有较高的发病率和致死率。 一般认为，肝脏是解酒的重要器官，其中的乙醛脱氢酶2（ALDH2）可降解乙醇代谢产物乙醛（AcH），也是AUD治疗的靶点。 事实上，肠道在这一环节也发挥了很大作用。美国国立卫生研究院Bin Gao团队在Nature Communications杂志发表了研究成果，表明肝-肠轴而非单独的肝脏，协同驱动系统性AcH的清除和自愿饮酒行为。 一、研究内容与思路 1、肝脏和肠道ALDH2协同清除血液乙醛（AcH） 作者构建了10种不同器官特异性ALDH2敲除小鼠的小鼠模型来寻找除肝脏外参与酒精代谢与系统AcH清除的器官，并检测急性酒精灌胃后，血清中乙醇（EtOH）与AcH的水平。 结果发现，全身ALDH2基因敲除小鼠血清中的AcH水平增加了18.11倍，而肝细胞中ALDH2基因敲除小鼠和脂肪细胞中ALDH2基因敲除小鼠的血清中AcH水平分别增加了2.88倍和1.83倍。肠上皮细胞特异性ALDH2敲除小鼠的血清中AcH水平有上升的趋势，但没有达到统计学显著性。其他特异性敲除小鼠AcH无变化。 进一步，作者敲除了小鼠肝脏和肠道中的ALDH2，发现无论接受低剂量或高剂量乙醇灌胃后，血清中AcH均显著升高，且明显比单独在肝脏或肠道中ALDH2敲除小鼠更高。 研究思路1：肝脏是酒精代谢的主要器官，但是其他器官是否参与这一环节、又是怎么参与这一环节的，仍有待探讨。对此，作者构建了10种不同器官特异性ALDH2敲除小鼠来进行研究，最终发现肠道和肝脏中的ALDH2协同促进了系统性的AcH清除。 2、AcH通过胆汁排泄从肝脏转移到肠道 作者发现，酒精灌胃或腹腔注射酒精后，胆囊容积增大，胆汁中的AcH水平约为血清中的5倍，而胆汁和血清中的酒精水平相近。进一步检测酒精灌胃后不同肠段局部AcH水平，在胃肠道腔中检测到了高浓度的AcH，且AcH在十二指肠中浓度最高，结肠浓度最低。对此，作者对小鼠进行了胆管结扎（BDL）实验，发现阻断肝脏到十二指肠腔的胆汁分泌可以显著降低十二指肠腔中的AcH水平。 研究思路2：肝细胞不仅通过窦道膜向循环中分泌物质，还通过小管道膜将物质排泄到胆管中，进入胆囊，然后释放到十二指肠中。对此，作者探讨了肝源性AcH是否也通过胆汁外流分泌到肠道中，以及肠道中各个部位的AcH浓度变化。 3、肠道微生物群不参与肠道AcH清除 作者构建了不被肠道微生物自然定植的无菌（GF）小鼠来探讨肠道AcH的清除是否与肠道微生物群相关，结果发现：在酒精给药后，GF和特异性无病原体（SPF）对照小鼠的AcH、EtOH和ALDH2表达均相似，但GF小鼠比对照小鼠产生更多的胆汁，这可能导致乙醇给药后GF小鼠十二指肠管腔AcH水平升高。 对此，作者给予小鼠抗生素混合物以彻底根除肠道微生物群的影响，发现肠道细菌的这种短期消耗不会影响胆汁的产生量，且抗生素混合物处理小鼠与对照小鼠AcH、EtOH和ALDH2表达无差异。 此外，作者还对GF小鼠和对照小鼠禁食12小时，随后进行肠内注射AcH，然后进行腔内内容物和门静脉血液采集以进行AcH测量，发现GF和对照小鼠之间的AcH水平没有差异。 研究思路3：既然涉及到肠道，那么肠道微生物群是否在这一环节扮演重要角色？对此，作者开展实验研究肠道微生物群对AcH的代谢是否存在影响，最终发现肠道微生物不参与这一过程。 4、肠道AcH通过肠道/肝脏ALDH2首过代谢清除 作者构建了肠道ALDH2敲除小鼠来研究ALDH2怎么参与肠腔AcH清除。 首先发现，与正常小鼠对比，ALDH2敲除小鼠给予酒精灌胃后，十二指肠腔、门静脉血液和肝组织的AcH水平增高。给予两组小鼠肠内AcH注射后检测肠道管腔和门静脉AcH水平发现，ALDH2敲除小鼠的门静脉血和十二指肠管腔AcH水平高于正常小鼠，且门静脉血AcH水平比十二指肠管腔内含量低约10倍，提示管腔AcH主要由肠上皮ALDH2代谢，但可通过门静脉血吸收，效率低。 进一步，作者给予肝脏ALDH2敲除小鼠肠内注射AcH，发现ALDH2敲除小鼠的肝脏和胆汁AcH水平高于正常小鼠，表明肠道腔内AcH被重新吸收回肝脏，由肝脏ALDH2进一步代谢。 研究思路4：研究发现，肝脏通过调节ALDH2代谢AcH，那么肠道中的AcH是否也是通过ALDH2来进行代谢的，以及如何代谢，这一过程与肝脏有无关系。 5、胆汁流动动力学调节血液和肝脏AcH清除率 作者采用乙醇灌注离体肝脏灌注，从门静脉收集灌注液，从胆囊收集胆汁，并测量AcH水平来检测有多少肝脏产生的AcH分泌到胆汁和循环中。结果发现，肝细胞分泌的AcH中约有30%和70%分别进入胆汁和循环。 进一步测试了胆汁流动是否影响AcH清除率，发现接受BDL的小鼠血清中的AcH水平大约高出两倍，肝脏AcH水平高出30%。之后，作者使用了多药耐药蛋白2 KO（Mdr2−/−）和胆盐出口泵KO（Bsep−/−）小鼠进行验证，两种小鼠模型的特征是肝内胆汁淤积和胆汁流量减少。实验发现，相比于正常小鼠，Mdr2−/−和Bsep−/−小鼠的胆汁AcH较低。 给予正常小鼠可以促进胆汁合成和分泌的熊去氧胆酸（UDCA）饮食，发现相比于正常饮食小鼠，UDICA喂养的小鼠表现出较低的肝脏和胆汁AcH水平。给予正常小鼠几种靶向特定胆汁酸转运蛋白的抑制剂，发现胆汁流动被抑制或外排且血清AcH水平升高。最后，作者还发现接受这些治疗的小鼠肝脏和血清AcH的改变不是由于肝脏ALDH2活性和表达的改变。 研究思路5：之前的研究发现，AcH通过胆汁排泄从肝脏转移到肠道，那胆汁流动（合成和分泌）对于AcH的清除是否存在影响。 6、干预胆汁排泄可调解饮酒行为 作者利用黑暗中饮酒行为实验（Drinking in the dark, DID）与双瓶选择（2- bottle choice, 2-BC）实验来评估调节胆汁流动后小鼠饮酒行为的变化。给予小鼠UDCA饮食或正常饮食，发现UDCA饮食的小鼠在DID实验中消耗的酒精比正常小鼠更多，并表现出比正常小鼠更强的酒精偏好。 为减少肝内胆汁排泄，作者构建了Mdr2基因敲除小鼠（Mdr2-/-）并进行了DID或2-BC实验。与正常小鼠相比，Mdr2-/-小鼠在DID实验中酒精消耗更少，并且表现出较低的酒精偏好。 研究思路6：胆汁流动会影响AcH代谢。那就从实际意义出发，对胆汁合成和分泌进行一些干预对饮酒有什么影响。 7、肝脏和肠道ALDH2协同调解饮酒行为 接下来，作者检测了酒精灌胃后，肝脏-肠道ALDH2双重敲除（dKO小鼠），ALDH2单器官基因敲除小鼠，以及野生型小鼠（WT小鼠）的门静脉血、胆汁，十二指肠腔中，小脑的AcH水平。 结果发现，相比于ALDH2单器官基因敲除以及WT小鼠，dKO小鼠在各种样本中都检测出最高的AcH水平；dKO小鼠呼吸熵和碳水化合物氧化水平显著抑制，并与ALDH2单器官基因敲除小鼠表现出明显不同的代谢模式；dKO小鼠与其他组小鼠相比，饮酒行为/酒精偏好受到明显抑制，酒精摄入量显著减少 。 研究思路7：上一部分发现干预胆汁排泄可以影响饮酒喜好。那么，对肝脏/肠道的ALDH2进行干预，又会对饮酒喜好产生什么影响？ 二、小结 首先研究者进行了大范围筛查，探讨哪些器官对AcH代谢存在影响。发现了肠道后，将肝脏-肠道联系起来，肠道又涉及肠道菌群，肝脏代谢又常与胆汁流动联系，对此作者进行了延伸研究。最后，明确整个过程后又落到实际，探讨了这些作用环节对于饮酒喜好的影响。 综上所述，该项研究表明，肝-肠轴相较于单独的肝脏作用，能够协调作用促进系统AcH的清除和调控饮酒行为，联合靶向肝脏和肠道ALDH2，以及胆汁流动和分泌的调控，可能是治疗AUD的潜在策略。 参考文献： Fu, Yaojie et al. “Coordinated action of a gut-liver pathway drives alcohol detoxification and consumption.” Nature metabolism, 10.1038/s42255-024-01063-2. 20 Jun. 2024, doi:10.1038/s42255-024-01063-2 撰写 | MIE 编辑 | 小饼干 来源 | 梅斯学术 本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！