15-PGDH

A drug that boosts strength in injured or aging mice restores connections between nerves and muscle and suggests ways to combat weakness in humans due to aging, injury or disease. A small molecule previously shown to enhance strength in injured or old laboratory mice does so by restoring lost connections between nerves and muscle fibers, Stanford Medicine researchers have found. The molecule blocks the activity of an aging-associated enzyme, or gerozyme, called 15-PGDH that naturally increases in muscles as they age. The study showed that levels of the gerozyme increase in muscles after nerve damage and that it is prevalent in muscle fibers of people with neuromuscular diseases. The research is the first to show that damaged motor neurons -- nerves connecting the spinal cord to muscles -- can be induced to regenerate in response to a drug treatment and that lost strength and muscle mass can be at least partially regained. It suggests that, if similar results are seen in humans, the drug may one day be used to prevent muscle loss of muscle strength due to aging or disease or to hasten recovery from injury. It's estimated that sarcopenia, or debilitating muscle frailty, affects about 30% of people over 80 and costs the United States around $380 billion each year. "There is an urgent, unmet need for drug treatments that can increase muscle strength due to aging, injury or disease," said Helen Blau, PhD, professor of microbiology and immunology. "This is the first time a drug treatment has been shown to affect both muscle fibers and the motor neurons that stimulate them to contract in order to speed healing and restore strength and muscle mass. It's unique." Blau, the Donald E. and Delia B. Baxter Foundation Professor and director of the Baxter Laboratory for Stem Cell Biology, is the senior author of the study, which was published online Oct. 11 in Science Translational Medicine. Postdoctoral scholar Mohsen Bakooshli, PhD, and former postdoctoral scholar Yu Xin Wang, PhD, are the lead authors of the study. Wang is now an assistant professor at the Sanford Burnham Prebys Medical Discovery Institute in San Diego. Addressing loss of strength The finding is the latest from the Blau laboratory focused on understanding how muscles weaken from aging or disease, and whether it's possible to combat this decline. In 2021, the group showed that blocking the activity of 15-PGDH in 24-month-old laboratory mice significantly enhances the animals' leg strength and endurance when running on a treadmill. (Laboratory mice typically live about 26 to 30 months.) But it wasn't clear exactly how. The new research shows that the effect is due to the restoration of lost connections between the nerves and the muscle. These connections, called neuromuscular junctions, are how the brain signals muscles to contract, allowing us to pick up a water glass, jog to the mailbox or hoist a toddler into a car seat. As we age, some of these connections are lost, causing muscle contractions to become less powerful and muscles to atrophy. People typically lose muscle mass and strength -- as much as 10% per decade -- after the age of 50. Conditions other than aging can also destabilize these connections, including the disuse of muscles due to bedrest after illness or injury, or muscle-wasting diseases like spinal muscular atrophy or amyotrophic lateral sclerosis (also known as ALS). Blau's previous research showed that a molecule called PGE2 is critical to the function of stem cells in muscle fibers that repair damage -- including the microtears from exercise that lead to an increase in muscle mass and strength. They subsequently showed that levels of 15-PGDH, which breaks down PGE2, increase in the muscles with age and that the loss of strength with aging could be overcome by inhibiting the activity of this PGE2-degrading enzyme. "PGE2 is part of the body's natural healing mechanism, and its levels increase in muscle after injury," Blau said. "We wanted to learn how age triggers an increase in 15-PGDH, and therefore the degradation and loss of PGE2." A lack of nerves The researchers knew that muscles become less innervated, or infiltrated with nerves, as people and animals age. They wondered if that loss could be what triggers the rising levels of 15-PGDH. "We found that when you cut the nerve that innervates the leg muscles of mice, the amount of 15-PGDH in the muscle increases rapidly and dramatically," Blau said. "This was an exciting new insight. But what surprised us most was that when these mice are treated with a drug that inhibits 15-PGDH activity, the nerve grows back and makes contact with the muscle more quickly than in control animals, and that this leads to a faster recovery of strength and function." Additional experiments showed that treatment with the drug restored neuromuscular junctions lost during aging and increased muscle strength and function in old laboratory mice. The researchers also identified discrete clumps of 15-PGDH in the muscle fibers of people with several types of neuromuscular disorders suggesting that the gerozyme may have a role in causing these human disorders. Blau and her colleagues plan to investigate at a molecular level how neural growth is stimulated by blocking 15-PGDH activity. Blau has also co-founded a company, Epirium Bio, to develop similar drugs for use in humans. Although her lab is still conducting animal studies, the company hopes to launch a clinical trial within the next year or so. "Our next steps will be to examine whether blocking 15-PGDH function in people with spinal muscular atrophy can increase lost muscle strength in combination with gene therapy or other treatments," Blau said. "We are also looking at ALS to see if something like this might help these patients. It's really exciting that we are able to affect both muscle function and motor neuron growth." The research was supported by the National Institutes of Health (grants K99NS120278, R00NS120278, R01-AG020961, R01-AG069858 and R01-RHG009674), the Canadian Institutes of Health, a Stanford Translational Research and Applied Medicine pilot grant, the Donald E. and Delia B. Baxter Foundation, the Li Ka Shing Foundation, the Milky Way Research Foundation and the California Institute for Regenerative Medicine. Blau is an inventor on several patents related to the research and a co-founder, consultant and equity holder of Epirium Bio, which has licensed patents regarding 15-PGDH inhibition to improve muscle strength.

对于多细胞生物，代谢和免疫是生命活动的基本需求，二者之间协同又对立的作用通过多种机制维持平衡。在代谢-免疫调节回路中，调节性T细胞（Treg）是感知并响应局部及全身代谢线索的传感器，沟通能量代谢与免疫功能，通过建立免疫耐受来维持生理稳态。代谢→Treg→免疫全身线索激素是信息传递信使，通过血液循环靶向目标细胞或者器官进行代谢调控，同样在代谢-免疫回路中也是Treg的上游指令分子。胰岛素，在葡萄糖水平升高时被分泌，高胰岛素水平能够阻碍Treg细胞抑制炎症反应的能力。胰高血糖素，有助于维持外周Treg细胞数量，并能够抑制Tconv细胞增殖，以进行葡萄糖稳态和炎症调节。瘦素，由脂肪组织（AT）分泌，高瘦素水平与Treg细胞数量成反比。mTOR通路中有瘦素受体，能够驱动CD4+T细胞合成、刺激Tconv细胞激活和发挥促炎功能，并同时降低Treg的反应性和存活。生长素释放肽，由胃和小肠在热量限制（CR）的条件下产生，能够降低代谢率，降低运动和其他形式的能量消耗。生长素释放肽表达升高能够抑制Tconv细胞增殖和产生细胞因子的能力，并诱导Treg发挥抗炎作用。糖皮质激素，在禁食和压力条件下释放，其强大的免疫调节作用源于对Tconv和INFγ的信号传导的抑制，并且还包括促进Treg细胞存活、成熟、分化以及FoxP3的表达。局部组织线索除感知全身代谢线索外，组织驻留Treg对局部代谢信号的响应是建立各处免疫耐受的关键。消化道、脂肪、肌肉是能量摄取和消耗的主要组织，其中巨大的能量波动能够通过Treg参与免疫反应。胃肠道消化道中有大量共生菌和饮食抗原，Treg对于这两类抗原的免疫耐受至关重要。除上述胰岛素与胰高血糖素外，微生物群的局部代谢产物如丁酸、丙酸有助于促进结肠中Treg细胞的生成和效应功能。Immunity. 2022 Nov 8;55(11):1981-1992. 脂肪组织（AT）AT通过储存能量来发挥内分泌调控作用，是维持代谢稳态的关键组织。长链脂肪酸会促进炎症发生，在三酰甘油合成的过程中，二酰甘油转移酶（DGAT1/2）能够减弱长链脂肪酸对驻留Treg的毒性作用，并通过游离二酰基阻碍蛋白激酶C的激活来维持FoxP3的表达，同时FoxP3通过维持脂肪酸氧化（FAO）对脂肪酸的利用，促进其细胞内代谢以抑制长链脂肪酸诱导的细胞死亡。PGE2是一类不饱和脂肪酸有机物，AT驻留Treg特异性高表达羟前列腺素脱氢酶（HPGD）来氧化PGE2，以对PGE2水平进行微调。AT中PPARγ-PPRE信号参与脂质代谢，细胞增殖、分化、凋亡，以及免疫反应，PPAR-γ活性增强能够诱导Treg增殖，并减少Tconv数量、IFNγ产生水平来减弱全身炎症反应。此外，AT中的驻留Treg还能够感知脂肪细胞衍生物（瘦素、抵抗素、脂联素）、促炎细胞因子（TNF-α、IL-6）、以及肥胖因素来调节免疫反应。Immunity. 2022 Nov 8;55(11):1981-1992. 肌肉骨骼肌通过从血液中摄取大量葡萄糖，对控制血糖稳定有重要作用。肌肉损伤后Treg会迅速聚集，通过调控常驻巨噬细胞和肌卫星细胞促进组织修复，间接参与糖代谢调节。Immunity. 2022 Nov 8;55(11):1981-1992. 相关药物以代谢作为切入点，进而调控Treg是多种疾病的治疗思路，相应的各类药物均以此作为治疗靶点糖皮质激素类药物，种类繁多，能够通过Treg细胞发挥抗炎作用。雷帕霉素，作为新型免疫抑制剂，能够Tconv增殖和效应功能，并逆转Treg的无能状态同时促进其扩增。二甲双胍，诱导Treg持续扩张。吡格列酮（PPAR-γ激动剂），增加Treg上FoxP3表达水平，促进Treg细胞增殖和功能，同时减弱Tconv细胞增殖能力。热量限制模拟物（CRM），通过诱导自噬（Treg还是线粒体）维持其抑制功能，通过自噬进行线粒体质量控制甲氨蝶呤，激活AMPK以抑制mTOR通路，促进Treg细胞的免疫抑制功能。小结我们通过饮食摄入营养，产生的能量波动部分被Treg检测，对能量和免疫防御进行微调，Treg在其中的作用关键，是治疗自身炎症以及代谢紊乱相关疾病的重要靶点。参考资料de Candia P et al. Regulatory T cells as metabolic sensors. Immunity. 2022 Nov 8;55(11):1981-1992. Judge A et al. Metabolism. Essays Biochem. 2020 Oct 8;64(4):607-647. 更多精彩视频，尽在佰傲谷视频号，欢迎关注~本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处﹀ 点亮在看，传递信息♥

ONCR-719 is uniquely engineered to use the Epidermal Growth Factor Receptor (EGFR/EGFRvIII) for viral entry, which is highly expressed in glioblastoma multiforme (GBM); data show that the canonical entry receptor for HSV-1, NECTIN-1, is only minimally expressed in human GBM tumors. ONCR-719 expresses four immunomodulatory payloads, including IL-12, an anti-PD-1 nanobody, 15-hydroxyprostaglandin dehydrogenase (HPGD), and a novel macrophage-modulating Fc-enhanced antibody to reverse GBM’s immunosuppressed tumor microenvironment.ONCR-719 is derived from a potent HSV-1 strain that is engineered with fusogenic mutations to enhance viral spread and oncolysis and with Oncorus’ clinically validated microRNA attenuation strategy for safety. ANDOVER, Mass., Nov. 18, 2022 (GLOBE NEWSWIRE) -- Oncorus, Inc. (Nasdaq: ONCR), a viral immunotherapy company focused on driving innovation to transform outcomes for cancer patients, today announced the presentation of preclinical data for ONCR-719 in a poster at the 2022 Society for Neuro-Oncology (SNO) Annual Meeting, taking place November 17-20, 2022 in Tampa, Florida. ONCR-719 is a novel, armed oncolytic HSV-1 vector engineered with targeted entry via EGFR/EGFRvIII and expresses four immunomodulatory payloads designed to reverse GBM’s immunosuppressive tumor microenvironment. In addition, ONCR-719 is derived from a potent HSV-1 isolate to drive oncolysis, is engineered with fusogenic mutations to enhance viral spread, and uses Oncorus’ clinically validated microRNA attenuation strategy to inhibit viral replication in healthy cells. Highlights from the preclinical poster describing ONCR-719, previously known as ONCR-GBM, include: Minimal expression of HSV-1 virus entry receptor, NECTIN-1, on human GBM samples suggests targeted oncolytic viruses are required to effectively treat human GBM tumors.ONCR-719 has been engineered to enter tumor cells using either EGFR/EGFRvIII or NECTIN-1 as an entry receptor, thereby increasing virus tropism for GBM tumors.EGFR-targeting and engineered fusogenic mutations in ONCR-719 enhance virus spread and tumor immunogenicity by driving syncytia formation in human GBM tumor cell lines.ONCR-719 is engineered to include IL-12, an anti-PD-1 nanobody, 15-hydroxyprostaglandin dehydrogenase (HPGD), and a novel macrophage modulating-Fc enhanced antibody. These payloads confer enhanced T cell recruitment and activation and target the immune suppressive macrophages and myeloid cells in the tumor microenvironment. Multiple payloads or transgenes were screened using in vivo orthotopic GBM models to identify immune-modulatory payloads to target the GBM microenvironment.Together, EGFR/EGFRvIII targeting, oncolytic potency, and incorporation of rationally designed payloads within ONCR-719 leads to enhanced anti-tumor efficacy and complete responses in preclinical orthotopic GBM models.ONCR-719 is engineered for safety in the central nervous system using multiple CNS-specific microRNA targets, Oncorus’ clinically proven strategy to limit viral replication in healthy cells. When injected intracranially in an HSV-1 sensitive mouse, ONCR-719 demonstrates a greater than 50,000-fold tolerability window compared to the unattenuated strain. “Oncolytic viruses are well-positioned to treat this aggressive form of brain cancer. We are excited to share ONCR-719 as a cutting-edge preclinical candidate that is engineered to improve outcomes and can stimulate a productive and durable anti-tumor immune response across multiple mouse models following a single intratumoral injection,” said Theodore (Ted) Ashburn, M.D., Ph.D., President and Chief Executive Officer of Oncorus. “Most notably, we’ve enabled the virus to use EGFR for entry, which is expressed at high levels in GBM. Underscoring the importance of this advance is our data showing that the canonical entry receptor for HSV, NECTIN-1, is only minimally expressed in GBM cells, which arguably makes using EGFR for entry an essential capability for such an agent. By utilizing our clinically proven microRNA attenuation strategy, ONCR-719 is engineered to protect healthy brain tissue while replicating at its full potential in tumor cells.” “GBM is the most common type of primary brain tumor in adults; it’s a devastating disease that has a great unmet need with a 5-year overall survival of approximately 7 percent,” said Tooba Cheema, Ph.D., Senior Director, Translational Medicine and ONCR-719 Program Leader at Oncorus. “We engineered ONCR-719 to overcome the common impediment that this treatment class faces, limited spread of virus in the highly immunosuppressive GBM tumor microenvironment. We are pleased with the results demonstrated in preclinical models and look forward to seeing how our innovations translate into improved outcomes for GBM patients.” ONCR-719 is the company’s second candidate from its HSV Platform and is developed from a clinical isolate of HSV-1 selected for oncolytic potency across cancer cell lines. Further development of ONCR-719 is dependent on a strategic partnership or additional financing. About Oncorus At Oncorus, we are focused on driving innovation to deliver next-generation viral immunotherapies to stimulate the immune system and transform outcomes for cancer patients. We are advancing a portfolio of intratumorally (iTu) and intravenously (IV) administered viral immunotherapies for multiple indications with significant unmet need based on our Herpes Simplex Virus (HSV) and self-amplifying viral RNA/LNP Platforms. Designed as a next-generation viral immunotherapy, our HSV Platform improves upon key characteristics of this therapeutic class to enhance systemic activity with immune stimulating payloads. Our lead HSV program, ONCR-177, currently in the clinic, is designed to be directly administered into a tumor, resulting in high local concentrations of therapeutic agent and its five encoded transgenes, as well as low systemic exposure to the therapy, which could limit systemic toxicities. Our pioneering self-amplifying vRNA/LNP Platform, highlighted by our product candidates ONCR-021 and ONCR-788, involves a highly innovative, novel combination of RNA and LNP-based modalities designed to realize the potential of RNA medicines for cancer. Please visit www.oncorus.com to learn more. Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements regarding the utility and potential of Oncorus’ HSV Platform and the engineering of ONCR-719, including its ability to reverse GBM’s immunosuppressed tumor microenvironment, enhance viral spread and oncolysis, inhibit viral replication in certain healthy cells and increase virus tropism for GBM tumors; the ability of oncolytic viruses to treat aggressive brain cancer; ONCR-719’s ability to improve patient safety and efficacy outcomes; and Oncorus’ ability to progress ONCR-719 into the clinic. The words “may,” “might,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “expect,” “estimate,” “seek,” “predict,” “future,” “project,” “potential,” “continue,” “target” and similar words or expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, risks associated with: Oncorus’ ability to successfully demonstrate the safety, tolerability and efficacy of its product candidates and obtain regulatory approval thereof; the adequacy of Oncorus’ existing capital resources and availability of financing on commercially reasonable terms; Oncorus’ ability to obtain the requisite components for its product candidates manufactured in accordance with regulatory requirements; the expansion of Oncorus’ in-house manufacturing capabilities; the impact of COVID-19 on Oncorus’ operations and the timing and anticipated results of its ongoing and planned clinical trials; the accuracy of the Oncorus’ estimates regarding expenses, future revenue, capital requirements and needs for additional financing; and Oncorus’ ability to obtain, maintain and protect its intellectual property. These and other risks and uncertainties are described in greater detail in the section entitled “Risk Factors” in Oncorus’ Annual Report on Form 10-K for the year ended December 31, 2021, filed with the Securities and Exchange Commission (“SEC”) on March 9, 2022, and Oncorus’ Quarterly Reports on Form 10-Q for the quarters ended March 31, 2022, June 30, 2022 and September 30, 2022, filed with the SEC on May 4, 2022, August 4, 2022 and November 2, 2022, respectively, as well as discussions of potential risks, uncertainties, and other important factors in the other filings that Oncorus makes with the SEC from time to time. These documents are available under the “SEC filings” page of the Investors section of Oncorus’ website at http://investors.oncorus.com. Any forward-looking statements represent Oncorus’ views only as of the date of this press release and should not be relied upon as representing its views as of any subsequent date. Oncorus explicitly disclaims any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements. Oncorus Investor Contact:Stern Investor Relations Julie SeidelJulie.seidel@sternir.com