TFEB

引言溶酶体贮积症（LSD）具有共同的表型，包括溶酶体增大和溶酶体贮积缺陷，是由溶酶体相关基因突变引起的。尽管已经探索了基因疗法和酶替代疗法，但目前还没有针对LSD的有效常规疗法。在溶酶体重组过程中，当功能性溶酶体库减少时，溶酶体脂质和蛋白质被回收以恢复溶酶体功能。2024年3月22日，浙江大学冯新华团队在Nature Communications 发表题为“SNX8 enables lysosome reformation and reverses lysosomal storage disorder”的研究论文，该研究报道了分选连接蛋白SNX8促进溶酶体管化，这是溶酶体重组所需的过程，并且SNX8的缺失导致人类细胞中LSD的表型特征。SNX8过表达挽救了细胞中LSD的特征，而基于AAV的SNX8向大脑的递送挽救了小鼠的LSD表型。重要的是，通过筛选天然化合物库，研究鉴定了三种小分子，它们增强了SNX8-溶酶体结合并逆转了人类细胞和小鼠中的LSD表型。总之，该研究为LSD的治疗提供了潜在的解决方案。溶酶体贮积症（LSD）是由编码水解酶、转运蛋白、离子通道和运输蛋白的溶酶体相关基因突变引起的毁灭性代谢疾病。目前已鉴定出60多种不同类型的LSD，LSD的特点是将物质储存在溶酶体中，导致LSD之间共有的继发性溶酶体相关功能障碍。然而，它们基本上共享其他溶酶体表型，例如溶酶体增大、消化减少、膜运输/定位缺陷和溶酶体重组受损LSD的严重程度取决于致病突变的性质，但即使是轻度LSD亚型也可能导致青少年死亡，而严重亚型可导致婴儿期发病和儿童期死亡。作为遗传性疾病，LSD不能完全治愈，除非病因基因得到纠正，这在临床上尚不可用。目前，酶替代疗法（ERT）、基因疗法和底物减少疗法仍然是少数已建立或正在临床试验中的方法，但每种方法都有严重的局限性或缺点。上述所有疗法的一个共同缺点是它们对LSD的特定亚型具有特异性。 由于每种类型的LSD的发生率都非常低，因此需要对大多数LSD进行广谱治疗。最近的研究表明，考虑到大多数LSD表型是由继发性溶酶体功能障碍而不是原发性基因缺陷引起的，在全球范围内增强溶酶体功能可能是广谱LSD治疗的一种有前途的方法。溶酶体功能上调存在两种重要途径。一种是通过TFEB激活溶酶体基因的转录，另一种是在功能性溶酶体数量减少的情况下激活溶酶体重组。TFEB激活是增强溶酶体功能的有效方法。一些报告表明，通过过表达TFEB 或分子TFEB 激活剂来激活 TFEB 介导的转录可减少 LSD 或神经退行性疾病（ND）表型。然而，由于 TFEB 激活导致大多数溶酶体基因的表达上调，其作用是非特异性的，并可能导致细胞应激。另一方面，溶酶体重整是在消耗的溶酶体上发生的按需过程。因此，靶向溶酶体重整可能是LSD治疗的更具体的策略。由于LSD细胞通常表现出溶酶体功能降低和溶酶体重组受损，促进溶酶体重整应恢复功能性溶酶体并减少细胞损伤。在过去十年中，溶酶体重整途径的许多成分被鉴定出来，包括mTOR和PIP5K1B作为启动，驱动蛋白-1，动力蛋白和dynactin作为驱动力，网格蛋白和PIP5K1A等作为膜出芽和原溶酶体的生成。由于管状结构是溶酶体重整的平台，因此小管的形成对整个重整过程至关重要。然而，负责肾小管形成和维持的因素仍未确定。模式图（Credit: Nature Communications）分选连接蛋白（SNX）是一类膜结合蛋白，具有磷酸肌醇结合PX结构域。SNX家族的 12个成员携带BAR域能够诱导膜曲率，因此被赋予了肾小管形成能力。事实上，发现多种 SNX-BAR 蛋白介导内体小管形成并参与内体逆行运输。该研究报告了溶酶体小管的形成需要SNX8的功能，并且在较小程度上需要SNX2的功能，SNX8是SNX-BAR家族的两个成员。在LSD模型细胞系和小鼠模型中，SNX8或SNX2/SNX8缺失均可诱导LSD表型，而SNX8过表达可挽救LSD表型。此外，还发现了一些可以通过上调SNX8来降低LSD表型的小分子。综上所述，研究结果可能会为LSD患者带来潜在的广谱疗法。原文链接https://doi.org/10.1038/s41467-024-46705-x责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述

本研究表明发现APAP过量会损害小鼠肝脏TFEB和TFEB介导的溶酶体生物生成。小鼠肝脏中TFEB的基因操作表明TFEB对AILI具有保护作用。 在治疗剂量下，对乙酰氨基酚(APAP)是一种安全有效的药物，但在动物和人类中，过量使用会导致严重的肝损伤，导致急性肝衰竭。在美国和许多西方国家，APAP过量是导致急性肝衰竭的最常见原因。该小鼠模型在临床上与apap诱导的肝损伤(AILI)高度相关，因此了解小鼠AILI的病理生理对确定新的治疗靶点和干预策略具有直接的临床影响。 图片来源: https://doi.org/10.1016/j.apsb.2023.10.017 近日，来自美国堪萨斯大学的研究者们在Acta Pharm Sin B.杂志上发表了题为“High-throughput screening of novel TFEB agonists in protecting against acetaminophen-induced liver injury in mice”的文章，该研究表明基因和药理激活TFEB可能是预防AILI的一种很有前途的方法。 巨噬(Macroautophagy)是细胞内溶酶体降解的一种主要途径，它负责降解错误折叠/受损的蛋白质和细胞器。先前的研究表明，自噬通过选择性去除受损的线粒体和APAP蛋白加合物来保护细胞免受对乙酰氨基酚(APAP)诱导的损伤(AILI)。溶酶体是在自噬末期通过与自噬体融合进行自噬降解的关键细胞器。 在本研究中研究者发现 TFEB是溶酶体生物发生的主要转录因子，它被APAP破坏，导致小鼠肝脏溶酶体生物发生减少。肝脏TFEB功能的遗传丧失和获得分别加重或保护了AILI。从机制上讲，TFEB的过表达增加了APAP蛋白加合物的清除和线粒体的生物发生，以及SQSTM1/p62依赖的NRF2的激活，从而预防AILI。研究者还对TFEB进行了无偏倚的基于细胞成像的高通量化学筛选，并确定了一组TFEB激动剂。在这些激动剂中，盐霉素，一种抗球虫和抗菌药物，激活TFEB并保护小鼠免受AILI。 盐碱霉素对APAP过量致小鼠肝损伤的保护作用 图片来源: https://doi.org/10.1016/j.apsb.2023.10.017 总之，本研究表明发现APAP过量会损害小鼠肝脏TFEB和TFEB介导的溶酶体生物生成。小鼠肝脏中TFEB的基因操作表明TFEB对AILI具有保护作用。更重要的是，盐霉素(一种从高通量筛选中发现的TFEB激动剂)对TFEB的药理激活可以保护小鼠免受AILI的影响。这些发现支持通过靶向肝脏TFEB来预防AILI的潜在有益方法。（生物谷 Bioon.com） 参考文献 Xiaojuan Chao et al. High-throughput screening of novel TFEB agonists in protecting against acetaminophen-induced liver injury in mice. Acta Pharm Sin B.  2024 Jan;14(1):190-206. doi: 10.1016/j.apsb.2023.10.017.

NEW YORK, March 19, 2024 /PRNewswire/ -- Seelos Therapeutics, Inc. (Nasdaq: SEEL) ("Seelos"), a clinical-stage biopharmaceutical company focused on the development of therapies for central nervous system disorders and rare diseases, today provided an update on top-line data of the Phase 2/3 HEALEY ALS Platform trial. This study was performed in collaboration with The Sean M. Healey and AMG Center, which is viewed as an influential force in ALS research and in caring for the ALS community. Their unique and innovative approach continues to be a benefit to the ALS community and its contributions have helped bring the last two FDA approved therapies for ALS to market. We plan to request a meeting with the FDA to discuss potential next steps for the program The study was designed to evaluate SLS-005 (IV trehalose), a low molecular weight disaccharide that stabilizes misfolded proteins and activates autophagy, in decreasing the slope of the ALS Functional Rating Scale (ALSFRS-R) and separation from placebo in Function and Mortality in an all-comers population of Persons with ALS (PALS). While the study did not meet statistical significance in the primary and secondary endpoint in the Full Analysis Set (FAS)2, by showing a 13% improvement in Function and Mortality with an 88% success probability (versus the pre-specified 98%), it showed a potential signal of efficacy in a pre-specified subgroup (ERF)1. In the pre-specified subgroup of PALS treated with SLS-005, without RELYVRIO®, the top-line data favored SLS-005 versus placebo in efficacy measures in the Efficacy RELYVRIO® Free (ERF)1 data set (n=130), including: a 22% improvement in slope of change in ALSFRS-R assessment adjusted for mortality, with an 89% success probability, at 24 weeks the rate of decline in ALSFRS-R slope (points per month) also favored the SLS-005 treatment group versus placebo over 6 months (-0.80 and -1.07 points per month, respectively) a 25% slowing of Slow Vital Capacity (SVC) decline versus placebo (-11.5% for SLS-005 and -15.4% for placebo) at 24 weeks Additional analysis and information from these data accessible here. "The HEALEY platform is designed to detect signals of efficacy and we believe the observed signal and success probability is competitive to other recently FDA-approved therapies for ALS which also failed to achieve statistical significance when measured for function and mortality on similar primary and efficacy endpoints," said Raj Mehra Ph.D., Chairman and Chief Executive Officer of Seelos. "We plan to request a meeting with the FDA to discuss potential next steps for the program and will continue our potential partner discussions." Seelos has not yet received the full dataset and upon receiving it in the near future, Seelos plans to run additional analyses, including biomarkers of neurodegeneration, neurofilament light chain (NfL), exploratory efficacy results, subgroups and post-hoc analyses. SLS-005 was generally well-tolerated and comparable to placebo in safety. There was an imbalance of deaths/death equivalents observed in the study, with more events seen in the SLS-005 group compared to placebo, all were considered unrelated to the study drug. Populations – ERF1, FAS2 and ERO3: Seelos received top-line results for Regimen E (RGE). This included a Full Analysis Set (FAS), an Efficacy Regimen Only (ERO) population and an Efficacy RELYVRIO® Free (ERF) population. FAS includes shared placebo from all regimens, including RGE (n=204) and the RGE SLS-005 participants (n=120). The Efficacy Regimen Only (ERO) population includes 120 RGE SLS-005 and 41 RGE placebo participants. 31 participants in the ERO population received RELYVRIO® during the SLS-005 RGE study, thus confounding results from this population. The ERF analyses exclude participants who initiated RELYVRIO® during the study. ERF represents the participants who followed the protocol as envisioned (n=130, i.e., the ERF population comprises 81% of ERO/RGE participants). About SLS-005 (trehalose injection, 90.5 mg/mL for intravenous infusion) SLS-005 is a low molecular weight disaccharide (0.342 kDa) that crosses the blood brain barrier and is thought to stabilize proteins and activate autophagy through the activation of Transcription Factor EB (TFEB), a key factor in lysosomal and autophagy gene expression. The activation of TFEB is an emerging therapeutic target for a number of diseases with pathologic accumulation of storage material. In animal models of several diseases associated with abnormal cellular protein aggregation or storage of pathologic material, SLS-005 has been shown to reduce aggregation of misfolded proteins and reduce accumulation of pathologic material. SLS-005 has previously received Orphan Drug Designation for the treatment of ALS from the U.S. Food and Drug Administration and from the European Medicines Agency in the EU. SLS-005 is an investigational treatment and is not currently approved by any health authority for medicinal use. About Amyotrophic Lateral Sclerosis (ALS) According to the National Institute of Neurological Disorders and Stroke, amyotrophic lateral sclerosis (ALS) is a group of rare neurological diseases that mainly involve the nerve cells (neurons) responsible for controlling voluntary muscle movement. In ALS, both the upper motor neurons and the lower motor neurons degenerate or die and stop sending messages to the muscles. Unable to function, the muscles gradually weaken, start to twitch (called fasciculations), and waste away (called atrophy). Eventually, the brain loses its ability to initiate and control voluntary movements. The disease is progressive, meaning the symptoms get worse over time. The majority of ALS cases (90 percent or more) are considered sporadic. This means the disease seems to occur at random with no clearly associated risk factors and no family history of the disease. Although family members of people with sporadic ALS are at an increased risk for the disease, the overall risk is very low, and most will not develop ALS. Most people with ALS eventually die from respiratory failure, usually within 3 to 5 years from when the symptoms first appear. However, about 10 percent of people with ALS survive for 10 or more years. Currently, there is no cure for ALS and no effective treatment to halt or reverse the progression of the disease. A 1-point change in the ALSFRS-R score can indicate a meaningful difference in a person's ability to function independently with activities of daily living (ADL's), including eating, bathing, dressing or walking.4 4. FDA Center for Drug Evaluation and Research, Application Number 209176Orig1s000, Office Director Memo, Ellis F. Unger, MD, May 4, 2017. Paganoni S, et al. New Eng J Med. 2020. About Seelos Therapeutics Seelos Therapeutics, Inc. is a clinical-stage biopharmaceutical company focused on the development and advancement of novel therapeutics to address unmet medical needs for the benefit of patients with central nervous system (CNS) disorders and other rare diseases. The Company's robust portfolio includes several late-stage clinical assets targeting indications including Acute Suicidal Ideation and Behavior (ASIB) in Major Depressive Disorder (MDD), amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia (SCA), as well as early-stage programs in Huntington's disease, Alzheimer's disease, and Parkinson's disease. For more information, please visit our website: , the content of which is not incorporated herein by reference. Forward Looking Statements Statements made in this press release, which are not historical in nature, constitute forward-looking statements for purposes of the safe harbor provided by the Private Securities Litigation Reform Act of 1995. These statements include, among others, those regarding the Phase 2/3 study of SLS-005, statements regarding the competitiveness of the results to recently approved FDA therapies for ALS, statements regarding any planned meetings and discussions with the FDA, statements regarding The Sean M. Healey and AMG Center's contributions to the ALS community, statements regarding the timing of Seelos's receipt of the full dataset for the trial, statements regarding additional analyses to be run by Seelos and statements regarding SLS-005's prospects and any future analyses that may be conducted. These statements are based on Seelos' current expectations and beliefs and are subject to a number of risks and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. Risks associated with Seelos' business and plans described herein include, but are not limited to, the risk of not successfully executing its preclinical and clinical studies, not being able to move forward with the development of SLS-005, and not gaining marketing approvals for SLS-005 and/or its other product candidates; the risk that prior clinical results may not be replicated in future studies and trials (including the risk that the results from the prior studies of SLS-005 may not be replicated or may be materially different from the results of the top-line data from the SLS-005 study); the risks that clinical study results may not meet any or all endpoints of a clinical study and that any data generated from such studies may not support a regulatory submission or approval; the risks associated with the implementation of Seelos' business strategy; the risks related to raising capital to fund its development plans and ongoing operations; the risks related to Seelos' current stock price; as well as other factors expressed in Seelos' periodic filings with the U.S. Securities and Exchange Commission, including its most recent Annual Report on Form 10-K and Quarterly Reports on Form 10-Q. Although we believe that the expectations reflected in our forward-looking statements are reasonable, we do not know whether our expectations will prove correct. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, even if subsequently made available by us on our website or otherwise. We do not undertake any obligation to update, amend or clarify these forward-looking statements, whether as a result of new information, future events or otherwise, except as may be required under applicable securities laws. Contact Information: Anthony Marciano Chief Communications Officer Seelos Therapeutics, Inc. (Nasdaq: SEEL) 300 Park Avenue, 2nd Floor New York, NY 10022 (646) 293-2136 anthony.marciano@seelostx.com Mike Moyer Managing Director LifeSci Advisors, LLC 250 West 55th St., Suite 3401 New York, NY 10019 (617) 308-4306 mmoyer@lifesciadvisors.com Company Codes: NASDAQ-NMS:SEEL