COL4A3

ELX-02 Granted Orphan Drug Designation (ODD) from U.S. Food and Drug Administration (FDA) for Treatment of Alport Syndrome Pre-Investigational New Drug (IND) Meeting Requested with U.S. FDA for ELX-02 to Discuss Planned next Study In Nonsense Mutation Alport Syndrome Signed Global Licensing Partnership for ZKN-013 with Almirall Pharmaceuticals with $3M upfront and up to $470M in milestones and Tiered Royalties on Global Sales New Paper Published on Autosomal Dominant Polycystic Kidney Disease (ADPKD) shows that ELX-02 treatment prevents cyst formation in diseased PKD organoids with nonsense mutations and a single healthy gene copy WATERTOWN, Mass., April 16, 2024 (GLOBE NEWSWIRE) --Eloxx Pharmaceuticals, Inc. (OTC: ELOX), a leader in ribosomal RNA-targeted genetic therapies for rare diseases, today provided program updates for ELX-02 and ZKN-013, including Orphan Drug Designation (ODD) for ELX-02. Eloxx has significantly advanced the development of ELX-02 for the treatment of Alport syndrome with Nonsense Mutations (NMAS). Additionally, with the global licensing partnership with Almirall announced in March, the company has begun the development of ZKN-013 for the treatment of Recessive Dystrophic Epidermolysis Bullosa (RDDEB) and Familial Adenomatous Polyposis (FAP) patients with nonsense mutations. The publication of a recent paper on Autosomal Dominant Polycystic Kidney Disease (ADPKD), confirms the potential of ELX-02 for the treatment of all rare genetic kidney diseases with nonsense mutations in the disease causing genes. “The recent ELX-02 program updates, including Orphan Drug Designation for ELX-02 for the treatment of Alport Syndrome highlights the significant unmet medical needs of Alport Syndrome patients with Nonsense Mutations,” said Sumit Aggarwal, President and Chief Executive Officer of Eloxx. “The designation further strengthens our belief that ELX-02 has the potential to be transformational in supporting the ultra-rare subset of Alport Syndrome patient population with nonsense mutations. We look forward to engaging the FDA on initiating the larger clinical trial to support the potential for regulatory marketing approval of ELX-02 in this patient population.” ELX-02: Regulatory and Clinical Updates for Alport Syndrome Nonsense Mutation Program ELX-02 Granted ODD from U.S. FDA: In April, the FDA Office of Orphan Products Development (OOPD) granted ODD for ELX-02 for the treatment of Alport Syndrome. The designation was based on a review of the prevalence of NMAS and the data from the Proof-of-concept Phase 2 Study that Eloxx announced top-line results for in 2023. FDA ODD is granted to investigational therapies addressing rare medical diseases or conditions that affect fewer than 200,000 people in the United States with a reasonable clinical or preclinical hypothesis for efficacy in the target population. Requested a Pre-Investigational New Drug (IND) meeting with U.S. FDA: The request for a pre-IND meeting formally initiates communications with the FDA regarding development of ELX-02 for the treatment of NMAS. The purpose of the pre-IND meeting will be to request feedback on the Eloxx’s planned clinical trial in nonsense mutation Alport syndrome patients. Presented Clinical Data Updates at Alport Workshop Meeting in March: Prof. Daniel Gale presented updated results from the Proof-of Concept Study in 3 NMAS patients treated with ELX-02 Meaningful reduction in Podocyte Foot Process Effacement after treatment measured as an average 60% increase in Filtration Slit Density in post treatment kidney biopsies in all 3 patients. Results confirm the expression of functional collagen 4 protein in-line with the mechanism of protein induction of ELX-02. Changes in UPCR noted to be consistent with biopsy results with reduction or stabilization of proteinuria during or up to 2 months post completion of dosing. ZKN-013: Update on Global Licensing Partnership with Almirall In March 2024, Eloxx announced an exclusive license agreement with Almirall to develop and commercialize ZKN-013 in orphan indications including RDEB and FAP with nonsense mutations. Received $3 million in upfront payment Additional payments of ELX-02 of up to $470 million and tiered royalties on global sales: Eloxx shall be eligible for additional payments throughout the potential development phases, including regulatory and sales milestones of up to $470 million as well as tiered royalties on any potential global sales Initiated Phase 1 Single Ascending Dose (SAD) study: Initiated Phase 1 SAD study in Australia with initial results expected in 2nd half of 2024 Recently Published Paper on Autosomal Dominant Polycystic Kidney Disease (ADPKD) may Have Other Rare Kidney Disease Applications A paper was published in April 2024, on ADPKD titled Genetics of cystogenesis in base-edited human organoids reveal therapeutic strategies for polycystic kidney disease, authored by Courtney E. Vishy, Chardai Thomas, Thomas Vincent, Daniel K. Crawford, Matthew M. Goddeeris, and Benjamin S. Freedman. Freedman and colleagues engineered base-edited human iPS cells to resolve the functional genetics of human PKD. They discovered that cyst formation in diseased organoids could be prevented with a single healthy gene copy. This insight enables the demonstration of both genetic and pharmacological therapeutic approaches for clinically relevant nonsense mutations and may have the potential to support other rare kidney diseases. About Nonsense Mutation Alport Syndrome Nonsense Mutation Alport syndrome (NMAS) is an ultra-rare Type IV Collagenopathy characterized by nonsense mutations in the genes (COL4A3, COL4A4, and COL4A5) that result in a less than full length (truncated) Type 4 Collagen. This disorder mostly affects children with a median age at diagnosis of 9 to 20 years. It is characterized by rapid and progressive damage to the kidneys, ear, and eyes, starting with worsening of kidney morphology to proteinuria and finally kidney failure, hearing loss and eye abnormalities. 90% NMAS patients progress to kidney failure and hearing loss before the age of 30. There are no approved therapies. It is estimated that there are approximately 11,000 NMAS patients in the US and >20,000 patients in US, Europe, Japan and China. About Eloxx Pharmaceuticals Eloxx Pharmaceuticals, Inc. is engaged in the science of ribosome modulation, leveraging its innovative TURBO-ZM™ chemistry technology platform in an effort to develop novel Ribosome Modulating Agents (RMAs) and its library of Eukaryotic Ribosome Selective Glycosides (ERSGs). Eloxx’s lead investigational product candidate, ELX-02, is a small molecule drug candidate designed to restore production of full-length functional proteins. ELX-02 is in Phase 2 clinical development for the treatment of Alport syndrome in patients with nonsense mutations. For more information, please visit . Forward-looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements other than statements of historical facts contained in this press release, including without limitation, statements regarding the potential future payments and future benefits under the license agreement, achievement of key milestones under the license agreement and the expected timeline for clinical development and efficacy of ZKN-013 are forward-looking statements. Forward-looking statements can be identified by the words “aim,” “may,” “will,” “would,” “should,” “expect,” “explore,” “plan,” “anticipate,” “could,” “intend,” “target,” “project,” “contemplate,” “believe,” “estimate,” “predict,” “potential,” “seeks,” or “continue” or the negative of these terms similar expressions, although not all forward-looking statements contain these words. Forward-looking statements are based on management's current plans, estimates, assumptions and projections based on information currently available to us. Forward-looking statements are subject to known and unknown risks, uncertainties and assumptions, and actual results or outcomes may differ materially from those expressed or implied in the forward-looking statements due to various important factors, including, but not limited to: our ability, or our licensees’ ability, to progress any product candidates in preclinical or clinical trials; the uncertainty of clinical trial results and the fact that positive results from preclinical studies are not always indicative of positive clinical results; the scope, rate and progress of our, and our licensees’ preclinical studies and clinical trials and other research and development activities; the competition for patient enrollment from drug candidates in development;; our ability to obtain the capital necessary to fund our operations; the cost of filing, prosecuting, defending and enforcing any patent claims and other intellectual property rights; our ability to obtain financing in the future through product licensing, public or private equity or debt financing or otherwise; our ability to meet the continued listing requirements of the Nasdaq Capital Market; general business conditions, regulatory environment, competition and market for our products; and business ability and judgment of personnel, and the availability of qualified personnel and other important factors discussed under the caption “Risk Factors” in our Quarterly Report on Form 10-Q for the quarterly period ended September 30, 2023, as any such factors may be updated from time to time in our other filings with the SEC, accessible on the SEC’s website at and the “Financials & Filings” page of our website at All forward-looking statements speak only as of the date of this press release and, except as required by applicable law, we have no obligation to update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. Contact Investors John Woolford john.woolford@westwicke.com 443.213.0506 Media Laureen Cassidy laureen@outcomescg.com Source: Eloxx Pharmaceuticals

本文中，小编整理了科学家们发表的多篇类器官研究领域的新成果，分享给大家！【1】Cell：新研究首次构建出首个多心室心脏类器官，有望用于揭示人类心脏发育和疾病之谜doi：10.1016/j.cell.2023.10.030每年有1800万人死于心脏病，但新疗法的开发却面临瓶颈：迄今为止，还没有整个人类心脏的生理模型。近日，一篇发表在国际杂志Cell上题为“Multi-chamber cardioids unravel human heart development and cardiac defects”的研究报告中，来自奥地利科学院分子生物技术研究所等机构的科学家们通过研究开发出一种能够反映心脏复杂结构的新型多心室心脏类器官（multi-chamber heart organoids），这使得科学家们能够推进药物开发、毒理学研究和了解心脏发育的筛选平台。图片来源：Cell, 2023, doi:10.1016/j.cell.2023.10.030。心血管疾病是导致全球死亡的主要原因，但目前只有少数新疗法即将问世。同样地，每 50名新生儿中就有一人患有先天性心脏缺陷，但是由于人们对先天性心脏缺陷的原因知之甚少，因此相关的疗法也少之又少。在了解心脏病和心脏畸形方面，人们缺少的是一种包含人类心脏主要区域的模型。如今，Mendjan团队推出了首个生理类器官模型，它包括所有主要的发育中心脏的结构，从而让人们能够研究心脏疾病和发育。2021年，Mendjan实验室展示了首个由人类诱导性多能干细胞形成的心室样心脏类器官模型。这些自组织心脏类器官（heart organoids， 也称为cardioids）再现了胚胎发育早期心脏左心室腔的发育过程。Mendjan说，“这些心脏类器官是一个原理证明，也是向前迈出的重要一步。大多数成年疾病影响的是将含氧血液泵入整个身体的左心室，而先天性心脏缺陷影响的主要是对建立和维持血液循环至关重要的其他心脏区域。”在这项新的研究中，Mendjan团队扩展了他们之前的研究工作。他们首先为每个发育中的心脏结构分别制作了心脏类器官模型。Mendjan解释说，“然后我们问：如果我们让所有这些类器官共同发育，我们是否能得到一种像早期人类心脏一样协调跳动的心脏模型？”【2】Cell Rep：利用在培养皿中培育的类器官或能识别出驱动肿瘤生长的特殊基因doi：10.1016/j.celrep.2023.113355体细胞拷贝数增加在多种癌症类型中普遍存在，然而其在致癌发生过程中所发挥的作用目前研究人员尚未充分评估过，这部分是由于复制增益会跨越较大的染色体区域，从而就会模糊因果位点。近日，一篇发表在国际杂志Cell Reports上题为“Functional screening of amplification outlier oncogenes in organoid models of early tumorigenesis”的研究报告中，来自斯坦福大学医学院等机构的科学家们通过研究发现了一种新方法来筛选引起多种不同类型癌症生长的基因，并识别出了在口腔癌和食管鳞状癌中非常有希望的潜在靶点。文章中，研究人员利用称之为类器官的三维器官组织模型，从癌症基因组图谱中识别并测试潜在的基因靶点。研究者Ameen Salahudeen博士解释道，癌症基因组图谱中有大量的数据，这一领域目前已经开发出了能延长患者寿命的精准药物，但这些数据中仅有一小部分能告诉我们癌症是如何生长的以及是否其能作为新型药物靶点；我们需要一种可扩展的功能性方法来从驱动癌症生长的原因以及是否其能被靶向作用方面对数据进一步深入分析。为了能阐明引起肿瘤生长的基因，研究人员决定重点关注能展示两种情况的基因组区域，即具有相同基因异常高拷贝的基因组区域，这在许多癌症类型中都非常常见；以及具有较高RNA表达水平的基因组区域，这或许表明这些基因参与到了肿瘤的生长过程中，为此研究人员利用了其所开发的新型算法来进一步研究。随后研究人员在基因组中确定了6种不同癌症类型的潜在区域，包括食管癌、口腔癌、结肠癌、胃癌、胰腺癌和肺癌；下一步他们为这6个器官构建了特定的肿瘤类器官，并在类器官中测试了其候选基因来观察哪些基因与生长中的肿瘤有关。【3】Nature子刊：利用人诱导性多能干细胞成功构建出模拟阿尔波特综合征的肾脏类器官doi：10.1038/s42003-023-05203-4近日，一篇发表在国际杂志Communications Biology上题为“iPSC-derived type IV collagen α5-expressing kidney organoids model Alport syndrome”的研究报告中，来自日本京都大学和神户大学的研究人员构建出诱导性多能干细胞（induced pluripotent stem cell， iPSC）衍生的肾脏类器官来模拟由COL4A5基因突变引起的阿尔波特综合征（Alport syndrome， AS），并证实一种化学伴侣（chemical chaperone）在挽救由这种基因突变引起的蛋白错误折叠和胶原蛋白错误组装方面的实用性。据估计，在美国和欧洲，AS的患病率分别为五千分之一到五万分之一，而在日本，估计约有1200人患有这种疾病。它是第二种最常见的遗传性肾小球肾炎（glomerulonephritis），由多个基因（COL4A3、COL4A4 或 COL4A5）突变引起。这些基因所编码的蛋白在肾小球基底膜（glomerular basement membrane， GBM）中形成一种特殊类型的胶原蛋白（即α3α4α5[IV]胶原蛋白）。这种疾病在生命早期表现为终末期肾病（end-stage renal disease， ESRD）。遗憾的是，由于缺乏体外模型来推断和校正AS患者胶原蛋白组装的缺陷，目前尚无根治性治疗方法，它的致病机制也不完全清楚。在这项新的研究中，这些作者制造出源自两名X连锁AS患者的iPSC，用于制造肾脏类器官。具体来说，他们从一名因 COL4A5 基因 G545D 错义突变而导致轻度 AS 的患者和另一名因 T552Sfs*6移码突变（产生截短的胶原蛋白 α5(IV)）而导致重度 AS 的患者身上采集了血液样本，用于产生 iPSC 进行研究。这些作者还利用CRISPR/Cas9基因组编辑系统逆转了这名轻度AS患者的COL4A5 G545D错义突变，生成了AS突变得到校正的iPSC细胞系。根据之前报道的分化方案并加以一些改进，他们通过患者特异性和健康对照iPSC衍生的肾元祖细胞（nephron progenitor cell）构建出肾脏类器官。值得注意的是，这些作者观察到，在机械搅拌下自由浮动培养肾脏类器官有助于促进它们的成熟，这是这项新研究的一个关键特征，因为在肾脏发育过程中，肾小球基底膜的胶原蛋白成分会从α1α1α2（IV）转变为α3α4α5（IV）异源三聚体。【4】Nat Microbiol：实验室培育的人类皮肤类器官有助揭示猴痘病毒感染之谜doi：10.1038/s41564-023-01489-6皮肤类器官（skin organoids）为正在进行的抗击猴痘病毒（mpox virus）的药物研发提供了一个强大的平台。一种在实验室中研究猴痘病毒感染的新模型系统为了解这种病毒攻击皮肤细胞的机制提供了有价值的见解，为发现创新性药物来对抗这种新出现的病原体提供了潜在的催化剂。近日，一篇发表在国际杂志Nature Microbiology上题为“Mpox virus infection and drug treatment modelled in human skin organoids”的研究报告中，来自荷兰伊拉斯姆斯大学医学中心、莱顿大学医学中心和沙特阿拉伯阿卜杜拉国王科技大学的研究人员证实实验室培养的人类皮肤---干细胞衍生的称为皮肤类器官的三维结构---能够有效促进猴痘病毒的积极复制。研究者Intikhab Alam表示，科学家们如今可以利用这种模型来研究猴痘病毒如何致病，并测试新的治疗方法。感染了猴痘病毒的人通常会出现皮疹和皮肤损伤，通常会导致疤痕和毁容。如今这些实验室培育的皮肤类器官有助于说明其中的原因。图片来源：Nature Microbiology, 2023, doi:10.1038/s41564-023-01489-6。这些作者报告了猴痘病毒在角质细胞---皮肤外层的主要细胞类型--中的驻留情况。在那里，这种病毒进行了四个步骤的组装，他们能够在高倍显微镜下观察到这一过程。他们进行的基因表达分析表明，许多病毒基因在感染后几天内被激活。这种激活反过来又似乎诱导宿主细胞发生变化，导致与免疫和细胞死亡有关的多个人类基因的活性发生改变。这些基因的改变很可能会损害皮肤的保护屏障，从而导致感染者身上出现特征性病变。【5】Cell：成功构建出可以研究人类小胶质细胞的发育和功能的类器官模型doi：10.1016/j.cell.2023.04.022小胶质细胞位于人类免疫系统和大脑的交汇处，是一种专门的大脑免疫细胞，在发育和疾病中发挥着至关重要的作用。尽管小胶质细胞的重要性是无可争议的，但对它们进行建模和研究仍然是一项艰巨的任务。与一些可以在体外或非人类模型中研究的人类细胞不同，当将人类小胶质细胞从人脑环境中移除时，很难对它们进行研究。近日，一篇发表在国际杂志Cell上题为“An in vivo neuroimmune organoid model to study human microglia phenotypes”的研究报告中，来自美国索尔克生物科学研究所的研究人员在一项新的研究中开发出一种类器官（organoid）模型，即一种模拟人体组织特征的三维细胞集合。该模型使得他们能够首次在人类来源的活组织中研究人类小胶质细胞的发育和功能。此外，他们研究了患有巨头畸形自闭症谱系障碍（macrocephalic autism spectrum disorder， 在这种疾病中，患儿头围大于大于97%的其他婴儿）的儿童的患者源性小胶质细胞，以确定大脑环境是否会影响更具反应性的小胶质细胞的发育。这些研究结果强调了免疫细胞和大脑相互作用的重要性，并提高了对神经退行性和发育性疾病的理解，如自闭症谱系障碍和阿尔茨海默病。研究者Fred H. Gage教授说道，在大脑环境之外，小胶质细胞几乎失去了所有的功能和意义。我们知道，如果我们找到了一种在类器官中复制人类大脑环境的方法来研究人类小胶质细胞，那么我们最终将有一种工具来研究健康和患病的大脑如何影响小胶质细胞以及健康和患病小胶质细胞如何影响大脑。”类器官出现于大约10年前，已成为一种弥合细胞和人类研究之间差距的流行工具。类器官比其他实验室系统更能模拟人类发育和器官产生，使得科学家们能够在更现实的环境中研究药物或疾病如何影响人类细胞。大脑类器官通常是在培养皿中培养的，但由于缺乏血管、存活时间短以及无法维持不同的细胞类型（如小胶质细胞），大脑类器官在结构和功能上受到限制。为了构建一种包含成熟小胶质细胞的大脑类器官模型以便我们能够对小胶质细胞进行研究，我们使用了一种新的移植技术来创建一种类似人类大脑的环境。因此，我们终于可以制造出一种人类大脑类器官，它具有协调人类小胶质细胞生长、行为和功能所需的所有特征。”【6】Mol Psychiatry：白介素-6或能刺激类器官并增加其放射状胶质细胞的水平doi：10.1038/s41380-023-01997-1孕期关键窗口期的母源性免疫激活（MIA，Maternal immune activation）与后代机体长期的神经发育缺陷相关，包括人类自闭症谱系障碍（ASD）风险的增加等，来自妊娠期母亲机体的白介素6（IL-6）是MIA改变胎儿发育中大脑的主要分子介导子。近日，一篇发表在国际杂志Molecular Psychiatry上题为“Human brain organoid model of maternal immune activation identifies radial glia cells as selectively vulnerable”的研究报告中，来自图宾根大学等机构的科学家们通过研究通过研究发现，将处于特定生长阶段的类器官暴露于白介素-6中就会增加放射状胶质细胞（radial glia cells）的水平，从而就为经历过感染的孕妇为何更有可能生出患有自闭症的后代提供了一定的线索和提示。这篇文章中，研究人员利用类器官作为模型进行研究，分析了母源性感染对于生长中胎儿大脑的影响。为了进一步理解孕妇在抵御感染的过程中对发育中胎儿的大脑所产生的可能性影响，研究人员利用干细胞培育出了大脑类器官，旨在模拟发育中胎儿的大脑，下一步，为了检测孕妇抵御感染所产生的影响，他们先将类器官暴露于高水平的白介素-6中，白介素-6是机体在抵御感染时白细胞所产生的一种特殊分子。此前研究结果表明，这种暴露会导致胎儿小鼠机体炎症并影响大脑的发育，持续5-10天的暴露能模拟感染期，而且在类器官生长到45天地时候就能模拟妊娠早期的大脑皮层的发育。暴露后来自类器官的组织能表现出放射状胶质细胞水平的增加，研究人员还发现了与胶质细胞相关的基因表达的改变，而且发现在治疗35天后，类器官中上皮层神经元的发育出现了异常的改变，此外他们还惊讶地观察到类器官中基因表达的差异，而这些差异并未在以相同方式治疗的小鼠模型机体中观察到，这就表明，怀孕小鼠机体的免疫反应所产生的影响或许与人类并不相同。【7】Nat Biotechnol：构建出研究脂肪肝的类器官模型doi：10.1038/s41587-023-01680-4近日，一篇发表在国际杂志Nature Biotechnology上题为“Engineered human hepatocyte organoids enable CRISPR-based target discovery and drug screening for steatosis”的研究报告中，来自荷兰乌得勒支大学和马克西玛王后儿童肿瘤中心等研究机构的研究人员构建出新型的人类脂肪肝类器官模型。他们利用这些模型来阐明药物反应，并建立了一个CRISPR筛选平台来识别新型疾病介质和潜在的治疗靶标。这些模型将有助于测试和开发治疗脂肪肝的新型药物，并有助于促进对疾病生物学的更好理解。针对人胎儿肝细胞类器官的精确基因编辑评估脂肪肝的遗传易感性。图片来源：Nature Biotechnology, 2023, doi:10.1038/s41587-023-01680-4。脂肪在肝脏中的堆积是一种在世界范围内越来越常见的疾病，全世界有超过四分之一的人口受到影响。患有脂肪肝会导致炎症，损害肝功能，并最终导致瘢痕组织的形成。不同的原因会导致脂肪肝的发展，其中饮食和生活方式是最常见的促成因素。此外，遗传学也可以发挥重要作用。例如，遗传性脂质代谢紊乱使患者更有可能患上脂肪肝，而一些突变则提高了患此病的风险。令人担忧的是，目前没有任何治疗脂肪肝的方法可以阻止或逆转这种疾病。随着这种疾病的发展，出现不可逆转的肝脏损伤和需要进行肝脏移植的风险大大增加。此外，患有脂肪肝的人患肝癌的风险也在增加。由于模型系统的稀缺性，确定治疗这种疾病的方法具有挑战性。小鼠的代谢差别很大，因此不能作为人类疾病的代表性模型系统。此外，目前基于人类的体外模型有几个缺点。对这些模型进行基因改造是很困难的，而且目前不可能快速产生大量的细胞。【8】Nat Biotechnol：重磅！科学家开发出全球首个具有免疫系统的类器官！doi：10.1038/s41587-022-01558-x在很多方面，我们的肠道都会充当机体以及我们周围世界的前门，其能帮助消化食物并吸收药物，当有害细菌、病毒和过敏原入侵机体时，肠道就会发出警报。当肠道功能失调或者无法在发育过程中正常形成时就会发生多种多样的胃肠道疾病，比如炎性肠病、嗜酸性食管炎和乳糜泻等，从温和到致命性的很多感染性疾病也都会从肠道中开始。近日，一篇发表在国际杂志Nature Biotechnology上题为“In vivo development of immune tissue in human intestinal organoids transplanted into humanized mice”的研究报告中，来自辛辛那提儿童医院等机构的科学家们通过研究构建了一种较好的模型来帮助研究人类胃肠道疾病，文章中，研究人员成功开发出了一种新一代复杂的肠道类器官，其包括功能性免疫系统的关键元件，这是迄今为止科学家们开发出的首个包含功能性免疫系统的任何类型（心脏、肝脏、胃等）的体内类器官。医学博士Michael Helmrath说道，这种类器官不仅能支持迁移的免疫组织（而不是排斥它），而且这些免疫细胞和结构也能继续改善肠道自身的发育，尤其是具有识别外来抗原的能力。这项研究基于此前2011年研究人员开展的研究，此前他们开发出了肠道类器官，而该研究团队也是世界上首个利用诱导多能干细胞（iPSCs）产生功能性肠道类器官的团队。研究者表示，当在培养皿中生长28天后，这种微小的类器官球体就会达到几毫米大小，随后就来到了下一个关键步骤，研究者将类器官移植到免疫抑制的小鼠体内来避免人体组织的排斥反应。【9】Sci Transl Med：科学家在实验室培育出一种用于研究人类胃食管癌的新型类器官模型doi：10.1126/scitranslmed.abq6146肿瘤抑制基因肿瘤蛋白p53（TP53）和细胞周期蛋白依赖性激酶抑制剂2A（CDKN2A）的失活通常会在胃食管连接部位（GEJ，gastroesophageal junction）肿瘤发生的早期发生，然而，由于目前研究人员缺乏GEJ的特异性疾病模型，而且在GEJ部位TP53和CDKN2A失活的促癌结果尚未被阐明。近日，一篇发表在国际杂志Science Translational Medicine上题为“Generation and multiomic profiling of a TP53/CDKN2A double-knockout gastroesophageal junction organoid model”的研究报告中，来自南加利福尼亚大学等机构的科学家们通过研究利用人类组织开发了一种在实验室生长的三维类器官模型，其或能用来帮助深入理解GEJ处癌症发生的早期阶段及其过程，GEJ，即消化系统的食物管与胃的连接处。图片来源：https://www.science.org/doi/10.1126/scitranslmed.abq6146这项研究中，研究人员提出了一种利用药物来治疗GEJ癌症的可能性生物性靶点，而且他们已经证明了这种药物能减缓或阻断小鼠机体中肿瘤的生长。据美国癌症协会数据显示，胃食管癌每年在全球会引发100多万人死亡，在过去10年里其发病率增加了两倍多，即从每年的50万例增加到了100万例，反酸、吸烟、幽门螺旋杆菌感染都是诱发食管癌和胃癌已经确定的风险因素。但研究人员认为，一直以来他们都很难阐明癌症到底是如何从胃部和食管的交界处开始出现的，部分原因是缺少用于研究的生物相关GEJ特异性早期疾病模型。医学博士Stephen Meltzer说道，由于我们没有一种能区分GEJ肿瘤的特异性模型，因此胃食管癌经常被归类为食管癌或胃癌，而并不是GEJ癌，这项研究中，我们所开发的模型不仅能帮助识别出GEJ位点处肿瘤生长期间所发生的关键变化，还能建立一种策略帮助进一步研究更好地理解其它器官中肿瘤是如何发生的。【10】Cancer Discov：科学家成功制造出人类骨髓“类器官”来改善抗癌疗法doi：10.1158/2159-8290.CD-22-0199由于缺乏能再现人类骨髓复杂性的模型，这或许就会阻碍科学家们对正常和恶性造血机制的研究以及对新型疗法的验证；近日，一篇发表在国际杂志Cancer Discovery上题为“Human bone marrow organoids for disease modelling， discovery and validation of therapeutic targets in hematological malignancies”的研究报告中，来自牛津大学等机构的科学家们通过研究首次制造出了能捕捉人类骨髓关键特征的骨髓“类器官”（organoids），这项新技术或能帮助同时筛选多种抗癌药物，并检测单一癌症患者个体化疗法治疗的效果。文章中，研究人员描述了这种新方法，其能产生一种特殊的类器官，并能忠实地模拟造血骨髓（产生血细胞）的细胞、分子和架构特征。研究者指出，这种特殊的类器官能提供一种微环境来接受并支持来自于血液恶性肿瘤患者机体细胞的生存，包括多发性骨髓瘤细胞等，这些细胞在人体外是很难维持生长和生存的。研究者Abdullah Khan说道，值得注意的是，我们发现，这种新型骨髓类器官中的细胞不仅在活性和功能方面与真正的骨髓细胞相似，而且在架构关系方面也很相似，其细胞类型能在类器官中自我组织并进行排列，就好像其在人体的骨髓中一样。这种栩栩如生的结构或许就能帮助研究人员研究骨髓中的细胞如何相互作用来支持正常的血细胞产生，以及这一点是如何在骨髓纤维化（bone marrow fibrosis）中被扰乱，骨髓疤痕会在骨髓中堆积，并引起骨髓功能衰竭，骨髓纤维化会在特定类型的血液癌症患者中发生，且仍然无法治愈。为了正确理解血液癌症发生的机制和原因，研究人员还需要利用实验系统来密切模仿真正的人类骨髓的工作机制，而此前研究人员还未拥有这样的系统。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！

Kidney morphology improved in all three patients with protein re-expression consistent with disease regression in its Phase 2 open-label clinical trial of ELX-02 for the treatment of Alport Syndrome ELX-02 improved podocyte foot process effacement in all three treated patients by an average of 60% based on blinded biopsy analysis by NIPOKA GmbH Clinical data from Phase 2 study of ELX-02 for Alport Syndrome included in presentations at the American Society of Nephrology (ASN) Kidney Week 2023 Significant progress toward completion of a strategic partnership for ZKN-013 WATERTOWN, Mass., Nov. 13, 2023 (GLOBE NEWSWIRE) -- Eloxx Pharmaceuticals, Inc. (OTC: ELOX), a leader in ribosomal RNA-targeted genetic therapies for rare diseases, today reported its financial results for the three months ended September 30, 2023, and provided a business update. Completed Phase 2 open label trial of ELX-02 for the treatment of Alport Syndrome patients with nonsense mutations. Analysis of biopsy samples provided unequivocal clinical evidence of both morphology and ELX-02’s disease modifying potential.Collagen Alpha 5 protein expression observed in the glomerular basement membrane post treatment in all patients. Data from the Phase 2 study of ELX-02 for Alport Syndrome was included in two presentations at the American Society of Nephrology (ASN) Kidney Week 2023.Significant progress towards completing a strategic partnership for ZKN-013Raised additional cash in ongoing efforts to strengthen balance sheet. “We are excited about the recent progress across our pipeline and remain committed to advancing our programs for the benefit of our patients and stakeholders,” said Sumit Aggarwal, President and Chief Executive Officer of Eloxx. Third Quarter 2023 and Subsequent Highlights ELX-02 in Nonsense Mutation Alport Syndrome Confirmed that all three patients showed an improvement in morphology and proteinuria in its proof-of-concept Phase 2 open-label clinical trial (NCT05448755) of ELX-02 for the treatment of Alport Syndrome after eight weeks of treatment. All patients had Autosomal Recessive Alport Syndrome with a nonsense mutation on one allele. No collagen 4 alpha 5 was expressed in the glomerular basement membrane (GBM) at baseline.Collagen 4 Alpha 5 expression in the GBM post-treatment was reported post-treatment based on immunofluorescence staining of patient biopsiesELX-02 increased the filtration slit density (FSD) by an average of 60% as compared to baseline levels, consistent with reduction of podocyte foot process effacement. Biopsies were analyzed on a blinded basis by NIPOKA GmbH. FSD was estimated for 15 to 20 glomeruli per sample.Data supporting FSD as a precise histopathological estimator of podocyte health and its inverse correlation with proteinuria was presented at the ASN meeting on November 2, 2023. Visual assessment of improvement in foot process effacement in Transmission Electron Micrography (TEM) images was independently confirmed by highly regarded renal pathologist and TEM expert.All three treated patients had reduced proteinuria variability and two patients had a reduction in proteinuria compared to baseline during or in 2 months post treatment consistent with improvement in kidney morphology.ELX-02 was well-tolerated in the study with no discontinuations. Data from the Phase 2 study of ELX-02 for Alport Syndrome was included in two presentations at the ASN Kidney Week 2023. ZKN-013 in nonsense mutation Recessive Dystrophic Epidermolysis Bullosa (RDEB), Junctional Epidermolysis Bullosa (JEB) and Familial Adenomatous Polyposis Eloxx made significant progress in completing a strategic transaction for ZKN-013. Following FDA clearance to begin a single ascending dose trial in healthy volunteers for ZKN-013 for the treatment of recessive RDEB and JEB, Eloxx received significant strategic interest in ZKN-013.Should these discussions lead to a transaction, it will allow Eloxx to remain focused on fully maximizing the potential of ELX-02 in rare kidney diseases and continue funded discovery efforts on our TURBO-ZM platform. Third Quarter 2023 Financial Results For the three months ended September 30, 2023, we incurred a net loss of $3.6 million, or $1.31 per share, which included $0.4 million in stock-based compensation. For the same period in the prior year, we incurred a net loss of $7.5 million, or $3.47 per share, which included $0.7 million in stock-based compensation. R&D expenses were $1.3 million for the three months ended September 30, 2023, which included $0.1 million in stock-based compensation. For the same period in the prior year, R&D expenses were $4.9 million, which included $0.3 million of stock-based compensation. The decrease was primarily related to a decrease in expenses related to subcontractors, advisors, and laboratory supplies in connection with preclinical research and development activities related to inhaled delivery of ELX-02 in CF, a decrease in CFF funded activities, a decrease in salaries and other personnel costs, a decrease related to stock-based compensation, and a decrease in facility and overhead expenses. General and administrative (G&A) expenses were $2.4 million for the three months ended September 30, 2023, which included $0.4 million in stock-based compensation. For the same period in the prior year, G&A expenses were $2.3 million, which included $0.4 million of stock-based compensation. The increase was primarily related to a $0.2 million increase in expenses attributable to professional and consulting fees, offset by a decrease of $0.1 million related to facility and overhead expenses. As of September 30, 2023, we had unrestricted cash and cash equivalents of $4.8 million. During the quarter, we raised gross proceeds of $2.0 million from the sale of shares of common stock, pre-funded warrants and warrants. Additionally, we sold shares of common stock through our ATM program during the quarter for gross proceeds of $1.8 million. Eloxx remains focused on its liquidity position and raising additional capital in the near term in order to fund its operating plan through the end of 2023 and beyond. Assuming that we initiate Phase 3 clinical trial activities when sufficient funding allows, and that we maintain compliance with our debt covenants, we believe that our current cash position will be sufficient to fund our operations through the end of the fourth quarter of 2023. As previously reported, we received a delisting determination from the Listing Qualifications Department of the Nasdaq Stock Market LLC as the company did not regain compliance with the Nasdaq Listing Rule 5550(b)(2), which requires a listed company to have at least $35 million in market value of listed securities. Effective October 16, 2023, trading of our common stock was suspended on the Nasdaq Capital Market and began trading on the OTC Pink Marketplace under the symbol “ELOX.” On October 26, 2023, we requested a review of the Nasdaq delisting determination by the Nasdaq Listing Council. Trading of or common stock on the Nasdaq Capital Market will remain suspended pending a decision by the Nasdaq Listing Council. About Nonsense Mutation Alport Syndrome Nonsense Mutation Alport syndrome is a rare Type IV Collagenopathy characterized by mutations in the genes (COL4A3, COL4A4, and COL4A5) that result in a less than full length (truncated) Type 4 Collagen. This disorder mostly affects children with a median age at diagnosis of 9 to 20 years. It is characterized by rapid and progressive damage to the kidneys, ear and eyes, starting with worsening of kidney morphology to proteinuria and finally kidney failure, hearing loss and eye abnormalities. It is estimated that there are approximately 7,500 patients in the US and 20,000 patients in US, Europe, Japan and China with Nonsense Mutation Alport Syndrome. These patients have no approved treatment options. About Eloxx Pharmaceuticals Eloxx Pharmaceuticals, Inc. is engaged in the science of ribosome modulation, leveraging its innovative TURBO-ZM™ chemistry technology platform in an effort to develop novel Ribosome Modulating Agents (RMAs) and its library of Eukaryotic Ribosome Selective Glycosides (ERSGs). Eloxx’s lead investigational product candidate, ELX-02, is a small molecule drug candidate designed to restore production of full-length functional proteins. ELX-02 is in Phase 2 clinical development for the treatment of Alport syndrome in patients with nonsense mutations. For more information, please visit www.eloxxpharma.com. Forward-looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements other than statements of present and historical facts contained in this press release, including without limitation, statements regarding our cash runway to fund our operating plan, our plans to raise additional capital, our ability to comply with the covenants in our debt agreement, the expected timing of and results from trials of our product candidates, the potential of our product candidate to treat nonsense mutations, the outcome of the Nasdaq Listing Council’s review of the delisting determination; the strategic partnership for the clinical development of ZKN-013 are forward-looking statements. Forward-looking statements can be identified by the words “aim,” “may,” “will,” “would,” “should,” “expect,” “explore,” “plan,” “anticipate,” “could,” “intend,” “target,” “project,” “contemplate,” “believe,” “estimate,” “predict,” “potential,” “seeks,” or “continue” or the negative of these terms similar expressions, although not all forward-looking statements contain these words. Forward-looking statements are based on management's current plans, estimates, assumptions and projections based on information currently available to us. Forward-looking statements are subject to known and unknown risks, uncertainties and assumptions, and actual results or outcomes may differ materially from those expressed or implied in the forward-looking statements due to various important factors, including, but not limited to: our ability to obtain the capital necessary to fund our operations; our ability to regain and maintain compliance with the continued listing requirements of the Nasdaq Capital Market; our ability to progress any product candidates in preclinical or clinical trials; the uncertainty of clinical trial results and the fact that positive results from preclinical studies are not always indicative of positive clinical results; the scope, rate and progress of our preclinical studies and clinical trials and other research and development activities; the competition for patient enrollment from drug candidates in development; the impact of the global COVID-19 pandemic on our clinical trials, operations, vendors, suppliers, and employees;; the cost of filing, prosecuting, defending and enforcing any patent claims and other intellectual property rights; our ability to obtain financial in the future through product licensing, public or private equity or debt financing or otherwise;; general business conditions, regulatory environment, competition and market for our products; and business ability and judgment of personnel, and the availability of qualified personnel and other important factors discussed under the caption “Risk Factors” in our Quarterly Report on Form 10-Q for the quarterly period ended September 30, 2023, as any such factors may be updated from time to time in our other filings with the SEC, accessible on the SEC’s website at www.sec.gov and the “Financials & Filings” page of our website at https://investors.eloxxpharma.com/financials-filings. All forward-looking statements speak only as of the date of this press release and, except as required by applicable law, we have no obligation to update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. Contact InvestorsJohn Woolfordjohn.woolford@westwicke.com443.213.0506 MediaLaureen Cassidylaureen@outcomescg.com Source: Eloxx Pharmaceuticals ELOXX PHARMACEUTICALS, INC. AND SUBSIDIARIESUNAUDITED CONDENSED CONSOLIDATED BALANCE SHEETS(Amounts in thousands, except share and per share data) September 30, 2023 December 31, 2022ASSETS Current assets: Cash and cash equivalents $4,775 $19,207 Restricted cash 219 261 Prepaid expenses and other current assets 635 661 Total current assets 5,629 20,129 Property and equipment, net 107 169 Operating lease right-of-use asset 306 825 Total assets $ 6,042 $ 21,123 LIABILITIES AND STOCKHOLDERS’ DEFICIT Current liabilities: Accounts payable $3,134 $3,020 Accrued expenses 2,442 2,799 Current portion of long-term debt 2,819 3,980 Advances from collaboration partners 12,966 12,535 Warrant liabilities 1,695 — Current portion of operating lease liability 315 712 Derivative liabilities 95 45 Total current liabilities 23,466 23,091 Long-term debt, net of current portion 2,621 8,557 Operating lease liability 3 135 Total liabilities 26,090 31,783 Total stockholders’ deficit: (20,048) (10,660)Total liabilities and stockholders’ deficit $ 6,042 $ 21,123 ELOXX PHARMACEUTICALS, INC. AND SUBSIDIARIESUNAUDITED CONSOLIDATED STATEMENTS OF OPERATIONS(Amounts in thousands, except share and per share data) Three Months Ended September 30, Nine Months Ended September 30, 2023 2022 2023 2022 Operating expenses: Research and development $1,250 $4,880 $7,076 $20,430 General and administrative 2,387 2,262 6,184 7,961 Total operating expenses 3,637 7,142 13,260 28,391 Loss from operations (3,637) (7,142) (13,260) (28,391)Other (income) expense, net (45) 366 903 1,355 Net loss $ (3,592) $ (7,508) $ (14,163) $ (29,746) Net loss per share, basic and diluted $ (1.31) $ (3.47) $ (5.96) $ (13.73)Weighted average number of shares of common stock used in computing net loss per share, basic and diluted 2,747,687 2,166,404 2,377,599 2,166,344