Vascular dementia (VaD) ranks as the second most prevalent form of dementia and poses a considerable global health challenge. Icariin has been recognized for its robust neuroprotective effects in combating VaD. Nonetheless, the underlying mechanisms have not been fully elucidated. An integrated approach involving network pharmacology, molecular docking, and molecular dynamics simulations (MDS) was employed to systematically investigate the potential pharmacological actions of Icariin in counteracting VaD. The AGE/RAGE pathway was identified as a promising anti-inflammatory pathway. A chronic cerebral hypoperfusion mouse model was utilized to establish VaD. Both Icariin and FP S-ZM1 (a RAGE inhibitor) were administered through oral gavage and intraperitoneal injection, respectively. The Morris water maze (MWZ) was used to evaluate cognitive functions. Moreover, immunofluorescence, RT-qP CR, and Western blot analyses were carried out to evaluate the effects of FP S-ZM1 on neuroinflammation. Network analysis identified 14 crucial targets and highlighted the AGE-RAGE signaling cascade in diabetic complications as the foremost KEGG pathway with potential anti-neuroinflammatory property. MDS results suggested a stable binding of the RAGE-Icariin complex. Remarkably, Icariin was found to effectively mitigate cognitive deficits in VaD mice, which was correlated with the upregulation of the P I3K/AKT pathway and downregulation of the JNK/cJUN signaling cascade. Critically, co-administration of FP S-ZM1 enhanced Icariin's ameliorative effects on cognitive deficits, owing to bolstered anti-neuroinflammatory action. This study unveils the potential of Icariin in alleviating cognitive dysfunction and neuroinflammation in VaD, which may be attributed to the modulation of the AGE/RAGE pathway.Communicated by Ramaswamy H. Sarma.

2024-12-01·PHYTOMEDICINE

Geniposide ameliorates diabetic nephropathy in type 2 diabetic mice by targeting AGEs-RAGE-dependent inflammatory pathway

Article

作者: Ni, Ying ; Chen, Chao ; Zhang, Wensheng ; Dong, Zhaoqi ; Zhu, Dina ; Wang, Lei

BACKGROUND:

Diabetic nephropathy (DN) is a prevalent complication of diabetes mellitus and the primary cause of morbidity and mortality in end-stage renal disease. The receptor for advanced glycation end products (RAGE) plays a crucial role in mediating AGE-triggered inflammation, which has been implicated in DN pathogenesis. While geniposide, a natural compound, has demonstrated anti-inflammatory and hypoglycemic properties, its potential to mitigate AGE-induced renal inflammation and consequently impede DN progression remains unexplored.

PURPOSE:

The objective of this study was to ascertain whether geniposide is a novel natural AGEs-RAGE blocker and to investigate its protective effect on renal DN in type 2 diabetic mice.

METHODS:

Binding affinity between geniposide and RAGE was assessed using MicroScale Thermophoresis (MST), molecular docking, and co-immunoprecipitation. RAGE was then subjected to knockdown and overexpression in cellular experiments to evaluate geniposide's effects on AGE-induced inflammatory responses and the RAGE pathway. Finally, db/db mice were employed to validate the renoprotective effects of geniposide in DN.

RESULTS:

Geniposide exhibited higher binding affinity to RAGE's V domain than AGEs, competitively inhibiting AGEs-RAGE interaction through hydrogen bonding. It suppressed RAGE expression and RAGE-dependent inflammatory responses to AGEs, comparable to RAGE siRNA effects. In RAGE-overexpressing cells, geniposide further inhibited AGEs-induced ERK1/2 and NFκB P65 activation, reducing inflammatory marker levels. Long-term oral administration of geniposide to db/db mice improved plasma creatinine, urea, and proteinuria levels, ameliorated pathological changes, and downregulated inflammatory factors such as TNF-α and IL-1β. Moreover, it dose-dependently attenuated enhanced renal expression of RAGE, phosphorylated ERK1/2, IκB-α, and NF-κB P65.

CONCLUSION:

Geniposide effectively attenuates AGEs-induced RAGE activation by directly blocking AGEs-RAGE signal transduction, thereby mitigating inflammatory responses. These findings suggest that geniposide has potential as a high-affinity RAGE antagonist, potentially playing a crucial role in the treatment of DN.

2024-10-01·AGING CELL

Lens capsule advanced glycation end products induce senescence in epithelial cells: Implications for secondary cataracts

Article

作者: Nam, Mi‐Hyun ; Wormstone, Yvette M. ; Cooksley, Grace ; Nahomi, Rooban B. ; Rankenberg, Johanna ; Nagaraj, Ram H. ; Wormstone, I. Michael ; Smith, Andrew J. O.

Abstract:

Posterior capsule opacification (PCO) is a common complication after cataract surgery. Residual lens epithelial cells (LECs) on the anterior lens capsule, after cataract surgery, migrate to the posterior lens capsule and undergo transdifferentiation into myofibroblast‐like cells. Those cells synthesize excessive amounts of extracellular matrix and contribute to fibrosis during PCO. Cellular senescence, a phenomenon that increases with aging, has been implicated in several fibrotic diseases. Here, we have investigated the prevalence of senescent LECs within the lens posterior capsule and the ability of advanced glycation end products (AGEs) in lens capsules to induce senescence, contributing to PCO. Aged lens capsules from pseudophakic human cadaver eyes showed the presence of senescent LECs. In human capsular bags, LECs showed an age‐dependent increase in senescence after 28 days of culture. Human LECs cultured on aged lens capsules for 3 days underwent senescence; this effect was not seen in LECs cultured on young lens capsules. Human LECs cultured on an AGE‐modified extracellular matrix (ECM‐AGEs) showed an AGE‐concentration‐dependent increase in the expression of senescence markers and reactive oxygen species (ROS) levels. Treatment with a RAGE antagonist and ROS inhibitor reduced the expression of senescence and fibrotic markers. Additionally, conditioned media from ECM‐AGEs‐treated cells induced the expression of fibrotic markers in naïve LECs. Together, these suggest that AGEs in the capsule induce senescence of LECs, which triggers the mesenchymal transition of neighboring non‐senescent LECs and contributes to PCO.

项与 VG-301 相关的新闻（医药）

2024-08-08

·GlobeNewswire-Health Care

vTv Therapeutics Announces 2024 Second Quarter Financial Results and Provides Corporate Update

Screened first patient in cadisegliatin pivotal trial for type 1 diabetes (T1D); working to resolve clinical hold Expanded Newsoara Biopharma license agreement for PDE4 inhibitor HPP737 to a global license effective upon payment of the $20 million upfront fee HIGH POINT, N.C., Aug. 08, 2024 (GLOBE NEWSWIRE) -- vTv Therapeutics Inc. (Nasdaq: VTVT), a late-stage biopharmaceutical company with an innovative clinical portfolio of small molecules and lead program in diabetes, today reported financial results for the second quarter ended June 30, 2024, and provided an update on recent corporate developments. “Our small molecule portfolio continues to make significant progress across our partnered and Company driven programs. We were pleased to amend our license with Newsoara Biopharma for PDE4 inhibitor, HPP737, to make it a global license contingent upon receipt of the required upfront fee. Azeliragon, a Cantex-partnered program, recently received Orphan Drug Designation in pancreatic cancer and is advancing in several mid- to late-stage clinical trials with broad indication potential,” said Paul Sekhri, Chairman, President and Chief Executive Officer of vTv Therapeutics. “We were pleased to initiate our pivotal trial in T1D for cadisegliatin, our liver selective glucokinase activator with first-in-class potential in T1D. We are working to resolve our clinical hold and resume the study as quickly as possible. Cadisegliatin has shown a favorable safety profile and has been dosed in over 500 subjects to date, including 300 patients with type 1 and type 2 diabetes. We are encouraged at the potential of cadisegliatin as an oral therapy for improved glycemic control.” Recent Company Highlights Screened First Patient in Cadisegliatin Pivotal Trial for T1D. In June, vTv Therapeutics screened the first patient in the Company’s CATT1 pivotal trial evaluating cadisegliatin as an adjunct treatment of T1D. CATT1 is one of several trials that are planned to form the core of the future regulatory registrational submission for cadisegliatin, a potential first-in-class, oral, liver selective, glucokinase activator for T1D. In July, vTv Therapeutics announced the Food and Drug Administration (FDA) placed a clinical hold on the cadisegliatin clinical program following the discovery of a chromatographic signal in a recent human absorption, distribution, metabolism, and excretion (ADME) study of cadisegliatin that could not be resolved by standard mass spectroscopy. The FDA requires a single in vitro study to characterize this signal before the cadisegliatin program can resume. No patient was dosed in the CATT1 pivotal study at the time of the clinical hold, and past clinical studies did not reveal any clinically concerning safety issues. vTv Therapeutics is actively working with the FDA to resolve the clinical hold as quickly as possible. Cadisegliatin has previously been granted Breakthrough Therapy designation by the FDA for T1D and has shown clinical potential to improve glycemic control and reduce hypoglycemia in patients with diabetes.Expanded to a Global Licensing Agreement for HPP737 with Newsoara Biopharma. In June, vTv Therapeutics amended our license with Newsoara Biopharma for PDE4 inhibitor, HPP737, to make it a global license upon receipt of the required $20 million upfront fee. The terms of the amendment include up to $41 million in development milestones, up to $35 million in sales-related milestones, and royalties in the mid to upper single digits based on sales.Orphan Drug Designation Granted for Azeliragon. In May, Cantex Pharmaceuticals, Inc. announced that the FDA has granted Orphan Drug Designation to azeliragon, a well-tolerated once-a-day oral RAGE antagonist, for the treatment of pancreatic cancer. Azeliragon has also received Orphan Drug Designation for the treatment of glioblastoma. Under our license agreement with Cantex, vTv Therapeutics has the potential to receive 20 – 40% of out licensing income or the fair value of the program in the event of a sale of Cantex, or 20% of Cantex’s net profit from commercial sales. Cantex is evaluating azeliragon in several ongoing Phase 2 trials in cancer indications and one Phase 3 trial for acute kidney injury. Second Quarter 2024 Financial Results Cash Position: The Company’s cash position as of June 30, 2024, was $45.5 million compared to $9.4 million as of December 31, 2023. The increase is attributed to receipt of the proceeds from the private placement financing on February 27, 2024.Research & Development (R&D) Expenses: R&D expenses were $3.4 million and $4.7 million in each of the three months ended June 30, 2024, and 2023, respectively. The decrease of $1.3 million is primarily attributable to lower spending on cadisegliatin, due to decreases in toxicity study costs and drug manufacturing related costs, partially offset by increases in clinical trial start-up costs and an increase in indirect costs and other projects.General & Administrative (G&A) Expenses: G&A expenses were $3.7 million and $3.3 million for each of the three months ended June 30, 2024, and 2023, respectively. The increase of $0.4 million was primarily due to increases in share-based expense, legal expense and higher payroll costs, partially offset by lower other G&A costs.Other Income, Net: Other income for the three months ended June 30, 2024, was $0.2 million and was driven by gains related to the change in the fair value of the outstanding warrants to purchase shares of our own stock. Other income for the three months ended June 30, 2023, was $0.6 million and was driven by an unrealized gain related to our investment in Reneo, as well as gains related to the change in the fair value of the outstanding warrants to purchase shares of our own stock issued to related parties.Net Loss: Net loss attributable to vTv shareholders for the three months ended June 30, 2024, was $5.2 million or $0.81 per basic share. Net loss attributable to vTv shareholders for the comparable period a year ago was $5.6 million or $2.69 per basic share. vTv Therapeutics Inc.Condensed Consolidated Balance Sheets(in thousands) June 30,2024 December 31,2023 (Unaudited) Assets Current assets: Cash and cash equivalents$45,526 $9,446 Accounts receivable 306 102 Prepaid expenses and other current assets 303 1,044 Current deposits 65 65 Total current assets 46,200 10,657 Property and equipment, net 72 117 Operating lease right-of-use assets 186 244 Total assets$46,458 $11,018 Liabilities, Redeemable Noncontrolling Interest and Stockholders’ Equity (Deficit) Current liabilities: Accounts payable and accrued expenses$6,791 $10,242 Current portion of operating lease liabilities 177 169 Current portion of contract liabilities 17 17 Current portion of notes payable — 191 Total current liabilities 6,985 10,619 Contract liabilities, net of current portion 18,669 18,669 Operating lease liabilities, net of current portion 79 169 Warrant liability, related party 158 110 Warrant liability 130 — Total liabilities 26,021 29,567 Commitments and contingencies Redeemable noncontrolling interest — 6,131 Stockholders’ equity (deficit): Class A Common Stock 24 21 Class B Common Stock 6 6 Additional paid-in capital 307,746 256,335 Accumulated deficit (291,301) (281,042)Total stockholders’ equity (deficit) attributable to vTv Therapeutics Inc. 16,475 (24,680)Noncontrolling interest 3,962 — Total stockholders’ equity (deficit) 20,437 (24,680)Total liabilities, redeemable noncontrolling interest and stockholders’ equity (deficit)$46,458 $11,018 vTv Therapeutics Inc.Condensed Consolidated Statements of Operations(in thousands, except per share data) Three Months EndedJune 30, Six Months EndedJune 30, 2024 2023 2024 2023 (Unaudited) (Unaudited)Revenue$— $— $1,000 $— Operating expenses: Research and development 3,439 4,691 6,088 8,633 General and administrative 3,716 3,309 7,694 6,794 Total operating expenses 7,155 8,000 13,782 15,427 Operating loss (7,155) (8,000) (12,782) (15,427)Interest income 553 153 632 253 Other income (expense), net 193 638 (178) 2,191 Loss before income taxes and noncontrolling interest (6,409) (7,211) (12,328) (12,985)Income tax provision — — 100 — Net loss before noncontrolling interest (6,409) (7,211) (12,428) (12,985)Less: net loss attributable to noncontrolling interest (1,229) (1,592) (2,383) (2,867)Net loss attributable to vTv Therapeutics Inc.$(5,180) $(5,619) $(10,045) $(10,118)Net loss attributable to vTv Therapeutics Inc. common shareholders$(5,180) $(5,619) $(10,045) $(10,118)Net loss per share of vTv Therapeutics Inc. Class A common stock, basic and diluted (*)$(0.81) $(2.69) $(1.97) $(4.85)Weighted average number of vTv Therapeutics Inc. Class A common stock, basic and diluted (*) 6,403,444 2,084,973 5,098,877 2,084,973 (*) Adjusted retroactively for reverse stock split About vTv Therapeutics vTv Therapeutics Inc. is a late-stage biopharmaceutical company focused on developing oral, small molecule drug candidates. vTv's clinical pipeline is led by cadisegliatin, a potential adjunctive therapy to insulin for the treatment of type 1 diabetes. vTv and its development partners are investigating additional indications including type 2 diabetes and other chronic conditions. Forward-Looking Statement This release contains forward-looking statements, which involve risks and uncertainties. These forward-looking statements can be identified by the use of forward-looking terminology, including the terms “anticipate,” “believe,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “will,” “would” and, in each case, their negative or other various or comparable terminology. All statements other than statements of historical facts contained in this release, including statements regarding the timing of our clinical trials, our strategy, future operations, future financial position, future revenue, projected costs, prospects, plans, objectives of management and expected market growth are forward-looking statements. These statements involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance, or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. Important factors that could cause our results to vary from expectations include those described under the heading “Risk Factors” in our Annual Report on Form 10-K and our other filings with the SEC. These forward-looking statements reflect our views with respect to future events as of the date of this release and are based on assumptions and subject to risks and uncertainties. Given these uncertainties, you should not place undue reliance on these forward-looking statements. These forward-looking statements represent our estimates and assumptions only as of the date of this release and, except as required by law, we undertake no obligation to update or review publicly any forward-looking statements, whether a result of new information, future events or otherwise after the date of this release. We anticipate that subsequent events and developments will cause our views to change. Our forward-looking statements do not reflect the potential impact of any future acquisitions, merger, dispositions, joint ventures, or investments we may undertake. We qualify all our forward-looking statements by these cautionary statements. ContactAshley RobinsonLifeSci Advisors, LLCarr@lifesciadvisors.com

引进/卖出临床2期突破性疗法孤儿药财报

2023-10-12

·生物制药小编

论溶瘤病毒公司的共性

近几年来，溶瘤病毒可能是除了CAR-T之外设计上最为花哨的存在，例如分泌表达的蛋白从最开始的时候T-VEC用的GM-CSF，到现在大量涌入的各类细胞因子，趋化因子，多肽，抑制免疫检查点的单抗，双抗，花样是层出不穷，方法是日新月异。溶瘤病毒在设计思路不断内卷，追求疗效优异的同时，还有着许多与知名药物，如CAR-T，K药联合使用加强疗效，探索给药窗口，给药恰当时间的各类探索。扩展阅读：溶瘤病毒新产品设计越来越“花哨”本文选取了思路相对较为接近的三家企业，复诺健，滨会生物，亦诺微医药三家的异同进行简析。单纯疱疹病毒的改造由于本文选取的这三家企业都采用的是单纯疱疹病毒作为溶瘤病毒的载体。因此先行了解单纯疱疹病毒的特性相当重要。单纯疱疹病毒(Herps simplex virus，HSV)是一种长约154kb的双链DNA病毒，可在受染宿主细胞核中复制。而采用的HSV载体具有以下优点：①宿主细胞广泛；②病毒滴度高；③外源基因容量大。但是HSV载体的缺点在于它的毒性——其中一些它表达的蛋白可能产生毒性，而HSV本身也是一种神经嗜好的病毒。因此对于HSV的改造许多都是围绕HSV一些毒性蛋白，例如剃除神经毒因子ICP34.5后能够靶向肿瘤，剔除ICP47后能够增强免疫等等。有趣的是，尽管目前常用到的是HSV载体是HSV-1（I型野生型HSV），这三家中只有滨会生物特别去开发了II型HSV。滨会生物开发II型HSV的原因在于克服HSV-1生产周期长、溶瘤活性不足的缺点，开发HSV-II能够减少生产周期、增加溶瘤活性。复诺健：溶瘤病毒+mRNA从管线而言，复诺健的所有管线基本上都是建立在IL-12-IL-15-IL-15Rα表达框的基础上的各类添加，这也是复诺健的核心有效载荷。可以看到目前临床进度最快的VG161就是在这个基础上加了能够表达抑制PD-L1的多肽，也因此VG161也是可以联合BMS的O药，恒瑞的卡瑞利珠单抗，做出基于PD-1抑制剂+PD-L1/IL-12-IL-15-IL-15Rα溶瘤病毒的组合。而在这个基础上还有更深一步的补强，VG161本身采用的是ICP34.5减毒骨架，后续复诺健还开发了一种转录翻译双重调控TTDR非减毒骨架。减毒和非减毒毕竟是双刃剑，减毒了担心疗效，非减毒担心安全。虽然专利未公开但根据该公司官网显示，结合创始人贾为国博士的相关文献可以进行合理的推测。复诺健的做法可能是通过提高选择性，避免对非肿瘤细胞的杀伤。这种TTDR骨架在原本骨架不去减毒的基础上去结合肿瘤抑制性miRNA。例如在2013年的一项研究中，正常细胞中的miRNA-145表达量很高，研究人员就将miRNA-145靶序列的多拷贝整合到必需IE基因如感染细胞蛋白27 (ICP27)或感染细胞蛋白4 (ICP4)的3′-UTR中，而miRNA-145靶序列整合到基因组后，溶瘤病毒就难以在正常细胞中的miRNA复制了。因此可以产生选择性靶向。而在非减毒骨架技术的背景下，复诺健又开发了VG201和VG203。VG201则是能够靶向CEA，VG203能够通过肿瘤特异性的CXCR4来启动，VG301则在VG201技术的基础上更进一步，甚至能分泌双抗达成CEACAM6xCD3 T细胞接合器的组合。而除了目前已知的溶瘤病毒管线之外，该公司还有开发预防猴痘和新冠的mRNA疫苗以及针对HER2激活免疫的mRNA疫苗。未来也许看到该公司mRNA+溶瘤病毒的组合。亦诺微医药：溶瘤病毒+外泌体亦诺微医药可能是这三家中玩得最花的。最开始设计的MVR-T3011倒也还好，后续的T7011不仅能够表达趋化因子和CAR-T靶点，更是找上了CAR-T联合治疗，思路相当有趣。亦诺微MVR-T3011的研究在于oHSV作为载体表达IL-12和PD-1抗体，思路上和复诺健的VG161类似，这也是亦诺微医药此前就已经开发的临床管线MVR-T3011（下图为其结构）。此前MVR-T3011就已经展现了相当不错的疗效。而MVR-T7011则在此基础上进一步进行开发。由于已经有一些将腺病毒或工程化溶瘤痘苗病毒用作溶瘤标记的先例，因此亦诺微医药的研究人员在发现CD19/BCMA双靶点CAR-T无论临床前还是临床后都展现出了对复发和难治性多发性骨髓瘤较好的治疗效果后（所有5名患者对治疗均有反应:1名患者达到sCR，3名达到VGPR，1名达到PR），便决定将CD19和BCMA作为作为靶标。由于oHSV递送至肿瘤的CD19和BCMA对于CAR T细胞治疗这个过程是至关重要的。在CAR T细胞到达靶向肿瘤细胞之前，输注的CAR T细胞需要先从血流到达实体肿瘤区域，渗透到肿瘤基质中，并进一步增加免疫渗透的可用性。而肿瘤细胞中OVs的感染将改变TME中细胞因子或趋化因子的表达谱，从而为肿瘤组织中最佳的CAR T细胞外显率和浸润提供更多的机会。而这里的细胞因子IL-12和趋化因子CCL5正是为此而设。而PD-1/PD-L1则是著名的免疫检查点，将帮助CAR T细胞压倒由PD-1/PD-L1信号通路诱导的抑制，从而减少CAR T细胞的耗竭。因此在MVR-T3011已经具有IL-12，PD-1的情况下，需要在MVR-T3011上插入CD19-BCMA-CCL5.而研究人员通过把截短的CD19和BCMA以及趋化因子CCL5基因插入MVR-T3011的UL37和UL38位点，并借助细菌人工染色体(BAC)技术，T7011被设计成能够选择性感染大范围的实体瘤并驱动CAR靶向肿瘤抗原的肿瘤特异性表达。而上述的三个基因CD19，BCMA，CCL5，串联表达在一个开放阅读框(ORF)中，并采用HSV立即早期(IE)启动子控制下的自剪切多肽T2A。这种构建方式能够在病毒进入肿瘤后快速表达CD19、BCMA以及CCL5。而进入后，截短的非信号CD19和BCMA可以作为CAR靶递送到肿瘤细胞表面，并且CCL5将在溶瘤病毒介导的肿瘤溶解之前释放到TEM中以浸润CAR T细胞。图：T7011的结构另外根据该公司官网展示，该公司还有一款临床前项目T8011，不过T8011目前其设计和思路尚且不明，仅仅知道其针对血液瘤，不过既然编号在7011之后，那和T7011设计思路也可能相关。而在T系列之外，亦诺微还有专门针对胶质母细胞瘤的MVR-C5252（结构如前面图所示，与T3011类似）。胶质母细胞瘤作为脑癌具有特殊的地位，HSV本身是一种神经嗜好的病毒，但是此前用于大脑疗效方面普遍不理想。但C5252的研究却表明与现有的oHSV-1病毒相比，缺失两份拷贝的γ34.5基因和反向内部重复区的oHSV-1，在针对脑肿瘤方面，相对于非脑肿瘤而言，具有出乎意料优越的抗肿瘤活性。当然，亦诺微医药也没有死磕溶瘤病毒，在溶瘤病毒之外还有外泌体技术，目前可查证的是一款工程化外泌体，通过外泌体来包含靶向HER2 mRNA的miRNA进行给药，未来可能可以看到这款外泌体+溶瘤病毒的组合，这和复诺健开发的激活针对HER2免疫的mRNA疗法也有异曲同工之妙。滨会生物：HSV II+细胞治疗如前文所提的那样，滨会生物开发了II型HSV BS001，不过BS001虽然是HSV II型，但设计理念还是借鉴了T-VEC，选择了和T-VEC相似的敲除蛋白ICP47和ICP34.5，并在ICP34.5敲除点位插入了和T-VEC相似的GM-CSF。而另外一款BS006则被设计成能够分泌的PD-L1xCD3的Bite双抗。此外，在去年时滨会生物首创性地提出将SIRPα抗体与溶瘤病毒联用，可能已有相关联合临床进行。从该公司管线来看，该公司尚有VAK细胞治疗管线，适应症为肿瘤胸腹水。VAK技术指的是(Virus activated killer)技术。它是将经病毒oHSV2激活的免疫细胞回输病人体内，从而发挥抗肿瘤作用。一些癌症病人自身免疫细胞功能低下或对癌细胞耐受，病毒可有效激活这些免疫细胞(经VAK技术激活的免疫细胞简称为VAK细胞)，使其发挥强大肿瘤杀伤作用，且VAK细胞在杀伤癌细胞的同时，促进肿瘤相关抗原的释放，有利于诱导特异性抗肿瘤免疫反应。小编总结总的来说，这三家公司对于溶瘤病毒的设计思路虽然各有差别，但总归是越来越复杂，毕竟HSV载体本身能够装载30kb甚至超过30kb的基因组的这个性质给了改装很大的空间。当然技术上的越复杂意味着工艺上的越困难，这对于溶瘤病毒来说也是重要的挑战。另外，这些溶瘤病毒企业都有在溶瘤病毒之外的布局，这也一定程度上反映了溶瘤病毒目前的状况——作为单药使用的效果仍待提高，产品联用是目前的主流。参考来源：Li JM, Kao KC, Li LF, Yang TM, Wu CP, Horng YM, Jia WW, Yang CT. MicroRNA-145 regulates oncolytic herpes simplex virus-1 for selective killing of human non-small cell lung cancer cells. Virol J. 2013 Jul 22;10:241.各公司官网及其专利

细胞疗法信使RNA免疫疗法

2023-10-11

·BioSpace

Galactica Pharmaceuticals Announces the Online Publication of Newest COVID-19 Data at bioRxiv

VILLANOVA, Pa.--(BUSINESS WIRE)-- Galactica Pharmaceuticals, Inc., a biopharmaceutical company focused on developing novel fusion protein molecules, announced today the online publication of its recent COVID-19 in vivo animal data at bioRxiv. Based on three studies in both the mouse and hamster COVID models, Galactica’s investigational RAGE (Receptor for Advanced Glycation End Products) fusion protein is the first and only molecule to have demonstrated both a statistically significant survival benefit and reduction in viral load. The full study, “Anti-Viral and Anti-Inflammatory Therapeutic Effect of RAGE-Ig Protein Against Multiple SARS-CoV-2 Variants of Concern Demonstrated in K18-hACE2 Mouse and Syrian Golden Hamster Models” can be found at . If these very encouraging preclinical data are replicated in human studies, we anticipate that in the treatment of COVID-19 patients, Galactica’s RAGE protein could potentially: Save the lives of many hospitalized COVID-19 patients; Enable COVID-19 patients to be discharged from ICU units and hospitals faster by simultaneously reducing their viral load; Reduce the likelihood that infected patients will spread the virus to others. “Having studied this molecule in eight in vivo animal studies across various disease areas and generated strong data in each one, we remain optimistic that our RAGE protein may prevent the vast majority of COVID-related deaths. We look forward to advancing our RAGE investigational drug into a Phase I/II COVID clinical trial in the coming months. Our investigational drug is expected to initially target hospitalized COVID patients requiring ventilation or expected to do so imminently,” said Lawrence Brown, Galactica’s Chief Executive Officer. “As COVID-19 continues to mutate and prove fatal for certain patient populations, it is imperative that we develop new, effective therapeutics to treat these vulnerable patients,” said Lbachir BenMohamed, Ph.D., Galactica's preclinical COVID investigator. ”Millions of recovered COVID patients are still experiencing long- term COVID symptoms, often for many months post-recovery. Given the unique anti-inflammatory and anti-viral dual benefit of Galactica’s investigational drug, it will be interesting to observe whether this molecule is effective against long COVID symptoms in human populations.” The expected primary endpoint of Galactica’s initial Phase I/II COVID clinical trial is survival. If that endpoint is met, Galactica expects to seek Emergency Use Authorization (EUA) from the United States Food and Drug Administration to quickly make the drug available to hospitalized COVID-19 patients. About RAGE RAGE (Receptor for Advanced Glycation End Products) is the AGEs-specific multi-ligand receptor involved in inflammatory responses to various chronic inflammatory lung diseases. RAGE is known to be highly expressed in the lungs, especially in the alveolar epithelial cells (AECs), in comparison to other organs of the human body. The RAGE pathway has been reported in the pathogenesis of lung diseases such as chronic obstructive pulmonary disease (COPD), interstitial lung diseases, and ARDS. In recent years, the therapeutic intervention of the RAGE pathway has been demonstrated to benefit patients suffering from ARDS, COPD, pulmonary fibrosis, and other pathologies associated with the pulmonary system. RAGE has also been postulated to contribute to diabetic complications by binding a variety of molecules, including AGEs, HMGB1, S100, and integrins. Such interactions lead to inflammatory processes, including the upregulation of adhesion molecules, generation of cytokines and reactive oxygen species, and upregulation of monocyte chemoattractant protein 1, at least in part through the activation of NF-ĸB. The mechanisms by which RAGE inhibitors have been postulated to work include by being a scavenger for soluble AGEs, by acting as a competitive antagonist for membrane-bound RAGEs and for the full-length biologically active RAGEs, and by binding HMGB1 to prevent its interaction with membrane RAGEs. About Galactica Pharmaceuticals, Inc. Galactica is an “IND-ready” biopharmaceutical company focused exclusively on the development of its novel, proprietary RAGE fusion protein. While the initial indication is expected to be the treatment of lung inflammation and Cytokine Storm symptomatic of COVID-19, the molecule is also under development for the treatment of diabetes and diabetic complications and both the dry and wet forms of macular degeneration. Learn more: .

100 项与 VG-301 相关的药物交易

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