PIP5K1B

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

Garden City, NY, May 03, 2023 (GLOBE NEWSWIRE) -- ProPhase Labs, Inc. (Formerly Known as Quigley Corporation) (NASDAQ: PRPH) (“ProPhase”), a next-generation biotech, genomics and diagnostics company, today provided an update regarding its progress and development strategy for Linebacker-1 (LB-1). Linebacker is a small molecule, multi-kinase inhibitor that is being developed by the Company’s wholly owned subsidiary, ProPhase BioPharma, Inc. (“PBIO”), as a potential mono-therapy and co-therapy option for hard-to-treat cancers. Originally viewed as a co-therapy, the pre-clinical data generated has given PBIO reason to believe that LB-1 will also be very effective as a mono-therapy. In Q1 of 2023, ProPhase collaborated with Eurofins, a globally recognized leading drug discovery company, to execute an in-depth analysis (KINOMEscan™ Profiling Service) of Linebacker-1 to determine how many cancer-relevant kinases were affected by Linebacker-1 out of a possible 468 enzymes. ProPhase was excited to learn that numerous critically important kinase targets were inhibited more than 99%. Some of the most inhibited pathways are those well known to promote tumorigenesis, such as the phosphoinositide 3-kinase family (e.g., PIKfyive, PIP5k1 and 2) and the mitogen-activated protein kinase family (e.g., MEK3, 4, and 5). Importantly, the Eurofins analysis revealed several unique targets affected by Linebacker-1 that cancer research organizations highlight as critically important, for which no other pharmaceutical company has developed drugs to treat. We believe the unique interplay of Linebacker with multiple cancer-dependent pathways will be a true differentiator within current treatment paradigms. Kinase families have been explored since the very beginning of targeted cancer therapies, as they are often upregulated and/or dysregulated in a number of cancer situations. There are 538 kinases encoded into the human genome and many of them have already been targeted as key areas for intervention in this multi-billion-dollar space. The largest targeted drugs starting with Novartis’s Gleevec and extending to Nexavar, Xalkori, Tasigna, and many others have led the way toward treating many types of cancers as chronic conditions. Billions of development dollars have gone into this area, but there are still many untargeted areas in the kinase space, providing a unique opportunity for Linebacker-1 to become a breakthrough drug in the fight against cancer. In line with these impressive results, Linebacker-1 has demonstrated strong preclinical potential in a number of difficult diseases, including tough-to-treat lung and gastric cancers. As development continues, we intend to position Linebacker-1 as a potential new option for cancer patients suffering from a current lack of quality treatment options. At ProPhase we believe in following biological foundations. Often times, scientific data is under appreciated in the pharmacological space. The decision to further mine existing results for valuable and directed data is therefore a priority for us. Analyzing the current Linebacker results against over 200 cancer models and 500 protein-protein interactions, ProPhase will now embark into a cutting-edge, machine learning stage in which all Linebacker-driven interactions and outcomes will be cross-referenced in a manner that further elucidates specific pathways particularly impacted by this one-of-a-kind molecule. This will allow for a more accurate and more likely-to-succeed path towards the clinic, ultimately saving time, money, and most importantly, patients’ lives. We intend to focus a majority of 2023 on developing a more in-depth understanding of the unique pathways we believe Linebacker may impact, as well as taking the necessary steps to meet the requirements for an IND submission to the FDA including: Cross-over analysis and machine learning to elucidate most affected signaling pathways Maximum Tolerated Dose (MTD) studies and safety confirmations Opportunities for synergies with existing, but underwhelming, commercial medicines Optimization of treatable neoplastic conditions within unsaturated areas “The two-year bear market for microcap companies has led to some phenomenal opportunities in the biotech and life sciences space and specifically for our company,” said Ted Karkus, CEO of ProPhase Labs. “The financial success of our diagnostic business over the past two years enabled us to acquire some fantastic under-valued assets, while strengthening our company’s core infrastructure. We are confident that we will be able to leverage this infrastructure and platform to develop our new, exciting initiatives with multi-billion-dollar potential, including our development of the Linebacker portfolio. These continuing positive preliminary results from the Linebacker-1 pre-clinical studies continue to bolster our confidence and support the new directions that we are taking with our company with the goal of continuing to significantly grow the underlying value. We look forward to providing updates in the coming weeks on additional Linebacker pre-clinical studies that are being conducted in parallel. We also look forward to providing updates on other strategic initiatives that have so much potential.” About Linebacker Linebacker is a modified polyphenol. Polyphenols are substances found in many nuts, vegetables and berries. Linebacker compounds are modified Myricetin, which is a common plant-derived flavonoid. Myricetin exhibits a wide range of activities that include strong antioxidant, anti-cancer, antidiabetic and anti-inflammatory activities. It displays activities that are related to the central nervous system. LB-1 is Mono-chlorinated Myricetin with a Chlorine atom substituted for the Hydroxy group at 5’ (position 5 on the B-ring). LB-2 is Di-chlorinated Myricetin with Chlorine atoms substituted for the Hydroxy groups at 5’ and 7 (position 5 on the B-ring and position 7 on the A-ring). About Eurofins Eurofins Discovery has supported Drug Discovery research for over 40 years. They are recognized as the industry leader for providing drug discovery researchers with the largest and most diverse portfolio of standard and custom in vitro safety & pharmacology assays and panels for drug screening and profiling. In addition to their in vitro safety pharmacology strengths, they also offer a broad portfolio of over 3500 drug discovery services and 1800 products. These include medicinal and synthetic chemistry, in vitro pharmacology, safety pharmacology & efficacy, ADME-Tox, cell-based phenotypic assays, and custom proteins and assay development capabilities. Eurofins supports a variety of drug discovery targets such as GPCRs, Kinases, Ion Channels, Nuclear Hormone Receptors and other proteins & enzymes. Their broad global service capabilities and decades of experience in providing drug discovery services result in the delivery of high quality, reproducible study performance with few repeats and high client satisfaction. Eurofins Discovery's capabilities, expertise, knowledge and skill sets enable them to provide their clients with the benefit of being able to work with a single outsourcing provider (CRO) for their drug discovery programs. About ProPhase Labs ProPhase Labs, Inc. (Nasdaq: PRPH) (“ProPhase”) is a next-generation biotech, genomics and diagnostics company. Our goal is to create a healthier world with bold action and the power of insight. We’re revolutionizing healthcare with industry-leading Whole Genome Sequencing solutions, while developing potential game changer diagnostics and therapeutics in the fight against cancer. This includes a potentially life-saving cancer test focused on early detection of esophageal cancer and potential breakthrough cancer therapeutics with novel mechanisms of action. Our world-class CLIA labs and cutting-edge diagnostic technology provide wellness solutions for healthcare providers and consumers. We develop, manufacture, and commercialize health and wellness solutions to enable people to live their best lives. We are committed to executional excellence, smart diversification, and a synergistic, omni-channel approach. ProPhase Labs’ valuable subsidiaries, their synergies, and significant growth underscores our multi-billion dollar potential. Forward Looking Statements Except for the historical information contained herein, this document contains forward looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including statements regarding our strategy, plans, objectives and initiatives and our beliefs regarding the potential of Linebacker-1 to treat various hard-to-treat cancers. Management believes that these forward-looking statements are reasonable as and when made. However, such forward-looking statements involve known and unknown risks, uncertainties, and other factors that may cause actual results to differ materially from those projected in the forward-looking statements. These risks and uncertainties include but are not limited to our ability to obtain and maintain necessary regulatory approvals, general economic conditions, consumer demand for our products and services, challenges relating to entering into and growing new business lines, the competitive environment, and the risk factors listed from time to time in our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q and any other SEC filings. The Company undertakes no obligation to update forward-looking statements except as required by applicable securities laws. Readers are cautioned that forward-looking statements are not guarantees of future performance and are cautioned not to place undue reliance on any forward-looking statements. For more information, visit . Media Relations and Institutional Investor Contact: ProPhase Labs, Inc. 267-880-1111 investorrelations@prophaselabs.com Retail Investor Relations Contact: Renmark Financial Communications John Boidman 514-939-3989 Jboidman@renmarkfinancial.com Source: ProPhase Labs, Inc. ###