Thirty male SPF rats aged 28-week-old were divided into blank group (10 rats with anesthesia only). The other 20 rats were with monoiodoacetate (MIA) on the right knee joint to establish pain model of OA, and were randomly divided into control group (injected intraperitoneal injection of normal saline) and treatment group (injected anti-NGF) intraperitoneal after successful modeling, and 10 rats in each group. All rats were received retrograde injection of fluorogold (FG) into the right knee joint. Gait was assessed using catwalk gait analysis system before treatment, 1 and 2 weeks after treatment. Three weeks after treatment, right dorsal root ganglia (DRG) were excised on L4-L6 level, immunostained for calcitonin gene-related peptide (CGRP), and the number of DRGS was counted.

RESULTS:

In terms of gait analysis using cat track system, duty cycle, swing speed and print area ratio in control and treatment group were significantly reduced compared with blank group (P<0.05). Compared with control group, duty cycle and swing speed of treatment group were significantly improved (P<0.05), and there was no significant difference in print area ratio between treatment group and blank group (P>0.05). The number of FG-labeled DRG neurons in control group was significantly higher than that in treatment group and blank group (P<0.05). The expression of CGRP in control group was up-regulated, and differences were statistically significant compared with treatment group (P<0.05).

CONCLUSION:

Intraperitoneal injection of anti-NGF antibody inhibited gait injury and upregulation of CGRP in DRG neurons. The results suggest that anti-nerve growth factor therapy may be of value in treating knee pain. NGF may be an important target for the treatment of knee OA pain.

2024-01-02·Journal of drug targeting

Enhanced neuroprotective activity of ophthalmic delivered nerve growth factor conjugated with cell penetrating peptide against optic nerve injury

Article

作者: Zhang, Jinlong ; Wu, Shipo ; Zhu, Danni ; Li, Yao ; Chen, Wei ; Hou, Lihua ; Song, Xiaohong ; Chen, Yi

Aims: Nerve growth factor is a well characterised neurotrophic factor that play a critical role in the survival, growth and differentiation of neurons both in central and peripheral nervous system. However, it is difficult for the conventional exogenous nerve growth factor administration delivery to the central nervous system due to the biological barrier in human bodies.Results: We validated a series of cell penetrating peptides and found that L-PenetraMax significantly enhanced the efficiency of recombinant human nerve growth factor entry into the rat retina. In the optic nerve crush mice model, eye drop administration of recombinant human nerve growth factor alone promoted retinal ganglion cell survival and axon regeneration at high dose, while the combination of recombinant human nerve growth factor with L-PenetraMax significantly enhanced the neuroprotective efficacy at lower dose, thus potentially enhancing the availability of recombinant human nerve growth factor eye drops in patients with optic neuropathy.Conclusions: This study provides the evidence that the noncovalent coadministration of recombinant human nerve growth factor with L-PenetraMax could be a potent strategy for the non-invasive and sustained ocular delivery of therapeutic proteins for improving the optic nerve injury.

2023-08-14·ACS biomaterials science & engineering

Simultaneous Presentation of Dexamethasone and Nerve Growth Factor via Layered Carbon Nanotubes and Polypyrrole to Interface Neural Cells.

Article

作者: Kim, Dong-Hwan ; Chen, Hailan ; Yang, Dan ; Chen, Chunrong ; Duan, Xiaoge ; Tian, Guangzhao

The implantation of neural electrodes usually induces acute and chronic inflammation, which can result in the formation of glial scars encapsulating the implanted electrodes and the loss of neurons near the active electrode sites. Local presentation of anti-inflammatory drugs or neural protective factors has been evidenced as an effective strategy to modulate inflammatory responses and promote electrode-neuron integration. Here, a novel delivery system for the simultaneous presentation of both anti-inflammatory drugs (dexamethasone, Dex) and nerve-growth-promoting factors (nerve growth factor, NGF) from the electrode sites was developed via layer-structured carbon nanotubes and conductive polymers. The modified electrodes exhibited higher charge storage capacitance and lower electrochemical impedance compared to unmodified electrodes and electrodes coated with polypyrrole/Dex. Dex released from the functional coating under controlled electrochemical stimulation was able to inhibit the lipopolysaccharide-induced secretion or mRNA transcription of inflammatory cytokines, including nitric oxide, TNF-α, and IL-6 in RAW264.7 cells, and control the activation of cultured astrocytes. In addition, the functional coatings did not show a toxic effect on PC12 cells and primary neural cells but exhibited promoted activities on the adhesion, growth, and neurite extension of neural cells.

项与 Nerve growth factor(Amgen, Inc.) 相关的新闻（医药）

2023-05-23

·PRNewswire

DelveInsight Evaluates a Robust Dry Eye Disease Clinical Trial Pipeline as 60+ Influential Pharma Players to Set Foot in the Domain

The prevalence of dry eye disease has been rising over the past few years, which prompts the growing demand for treatment options. The increasing prevalence of dry eye disease and the growing research and development activities to develop novel therapies to treat dry eye disease to drive the market. The companies developing the potential therapies in the last stage of development include Aldeyra Therapeutics, RegeneRx Biopharmaceuticals, Mitotech, and several others. LAS VEGAS, May 23, 2023 /PRNewswire/ -- DelveInsight's ' Dry Eye Disease Pipeline Insight – 2023 ' report provides comprehensive global coverage of pipeline dry eye disease therapies in various stages of clinical development, major pharmaceutical companies working to advance the pipeline space, and the future growth potential of the dry eye disease pipeline domain. Key Takeaways from the Dry Eye Disease Pipeline Report DelveInsight's dry eye disease pipeline report depicts a robust space with 50+ active players working to develop 60+ pipeline therapies for dry eye disease treatment. Key dry eye disease companies such as TearSolutions, Novaliq, HanAll Biopharma, Aldeyra Therapeutics, RegeneRx Biopharmaceuticals, Mitotech, Aerie Pharmaceuticals, Azura Ophthalmics, Stuart Therapeutics, Surface Ophthalmics, Glaukos Corporation, BRIM Biotechnology Inc., Dompé Farmaceutici S.p.A, Okyo Pharma Ltd, AxeroVision, Inc., Palatin Technologies, Seikagaku Corporation, Invirsa, Inc., Allysta Pharmaceutical, Taejoon Pharmaceutical Co., Ltd., Ocular Therapeutix, Inc., Dreamhawk Vision Biotech, Inc., Yuyu Pharma, Inc., Novartis Pharmaceuticals, VivaVision Biotech, Inc, Huons Co., Ltd., and others are evaluating new dry eye disease drugs to improve the treatment landscape. Promising dry eye disease pipeline therapies in various stages of development include Reproxalap, Timbetasin, Visomitin, HL036, CyclASol, Lacripep, AR15512, AZR MD 001, ST-100, SURF-100, SURF-200, GLK-301, BRM421, Oxervate, OK-101, AXR 159, AXR 270, PL9643, SI-614, INV-102, ALY688, TJO-083, OTX-CSI, OTX-DED, SHJ002, YP-P10, ECF843, VVN001, HU007 and others. In March 2023, Selagine, Inc., a spin-out company from the University of Illinois at Chicago (UIC), announced that it has entered into a research, development, and sublicense agreement with Grifols (Nasdaq: GRFS), a global leader in plasma-derived medicines, for the development and commercialization of immunoglobulin eye drops for dry eye disease.Under the agreement, Selagine will receive an upfront payment and annual collaboration fee. In addition, Grifols has committed to fund the development of immunoglobulin eye drops through FDA approval, which will be managed collaboratively by Grifols and Selagine, including the clinical, manufacturing and regulatory activities required for FDA approval for dry eye disease indication. In February 2023, Aldeyra Therapeutics, Inc. announced that the U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for topical ocular reproxalap, a first-in-class investigational new drug candidate, for the treatment of the signs and symptoms of dry eye disease. The FDA assigned a Prescription Drug User Fee Act (PDUFA) date of November 23, 2023. The FDA noted that no potential filing review issues have been identified, and that an advisory committee meeting is not currently planned. In February 2023, Novaliq, announced its plans for filing a Marketing Authorisation Application (MAA) for CyclASol® (ciclosporin ophthalmic solution), a first-of-its-kind anti-inflammatory product for the treatment of dry eye disease (DED) in the European Union. The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) determined that CyclASol® is eligible to be reviewed in a centralized procedure to receive a Union Marketing Authorisation for the European Economic Area (EEA). In January 2023, Bausch + Lomb Corporation and Novaliq GmbH, announced that Ophthalmology, the peer-reviewed journal of the American Academy of Ophthalmology, has published results from the pivotal Phase 3 trial GOBI, which is one of two pivotal Phase 3 trials for NOV03 (perfluorohexyloctane). NOV03 is being investigated to treat the signs and symptoms of dry eye disease (DED) associated with Meibomian gland dysfunction (MGD).In the study, NOV03 was well tolerated with few subjects experiencing ocular adverse events (AEs) (9.6% NOV03 group, 7.5% control group) or treatment-related ocular AEs (6.3% NOV03 group, 3.1% control group). In August 2022, Alcon and Aerie Pharmaceuticals, Inc. announced the companies have entered into a definitive merger agreement through which Alcon acquired Aerie. The transaction affirmed Alcon's commitment to the ophthalmic pharmaceutical space and is expected to add broader pharmaceutical R&D capabilities to Alcon's existing commercial expertise, maximizing the value of its diversified portfolio. Through the transaction, Alcon added the commercial products Rocklatan® (netarsudil and latanoprost ophthalmic solution) 0.02%/0.005% and Rhopressa® (netarsudil ophthalmic solution) 0.02%, as well as AR-15512, a Phase 3 product candidate for dry eye disease, and a pipeline of several clinical and preclinical ophthalmic pharmaceutical product candidates. In May 2022, Yuyu Pharmaceutical presented a poster study for YP-P10, its new dry eye syndrome treatment, during the 2022 ARVO (Association for Research in Vision and Ophthalmology) conference. YP-P10 is a new biopharmaceutical using synthetic peptides, aiming to relieve signs and symptoms of dry eye syndrome caused by inflammation by administering the treatment twice a day. According to preclinical trial results unveiled at the conference, Yuyu confirmed that the candidate had an excellent anti-inflammatory mechanism and corneal epithelial cell healing effect compared to existing drugs. Request a sample and discover the recent advances in dry eye disease drug treatment @ Dry Eye Disease Pipeline Report The dry eye disease pipeline report provides detailed profiles of pipeline assets, a comparative analysis of clinical and non-clinical stage dry eye disease drugs, inactive and dormant assets, a comprehensive assessment of driving and restraining factors, and an assessment of opportunities and risks in the dry eye disease clinical trial landscape. Dry Eye Disease Overview Dry eye disease is characterized as a multifactorial disease of the tears and ocular surface that causes symptoms such as pain, visual disruption, and tear film instability, as well as potential ocular surface damage. It is accompanied by increased tear osmolarity and transient ocular surface irritation. When tear production and drainage are out of balance, dry eyes can result. People with dry eyes either do not produce enough tears or have poor-quality tears. Dry eyes can occur for various reasons, including age, gender, drugs, and medical disorders. Dry eye disease symptoms include redness, stinging, itching, or burning sensations, light sensitivity, watery eyes, stringy mucus near the eye, and blurred vision. A thorough eye examination can detect dry eyes. Dry eye disease treatments seek to restore or maintain the usual number of tears in the eye in order to reduce dryness and associated discomfort and to maintain eye health. The basic approaches used to manage and treat dry eyes include adding tears with over-the-counter artificial tear solutions, conserving tears, boosting tear production, and treating the inflammation of the eyelids or eye surface that contributes to dry eyes. Find out more about drugs for dry eye disease @ New Dry Eye Disease Drugs A snapshot of the Dry Eye Disease Pipeline Drugs mentioned in the report: Learn more about the emerging dry eye disease pipeline therapies @ Dry Eye Disease Clinical Trials Dry Eye Disease Therapeutics Assessment The dry eye disease pipeline report proffers an integral view of dry eye disease emerging novel therapies segmented by stage, product type, molecule type, mechanism of action, and route of administration. Scope of the Dry Eye Disease Pipeline Report Coverage: Global Dry Eye Disease Therapeutic Assessment By Product Type: Mono, Combination, Mono/Combination Dry Eye Disease Therapeutic Assessment By Clinical Stages: Discovery, Pre-clinical, Phase I, Phase II, Phase III Dry Eye Disease Therapeutics Assessment By Route of Administration: Intra-articular, Intraocular, Intrathecal, Intravenous, Ophthalmic, Oral, Parenteral, Subcutaneous, Topical, Transdermal Dry Eye Disease Therapeutics Assessment By Molecule Type: Oligonucleotide, Peptide, Small molecule Dry Eye Disease Therapeutics Assessment By Mechanism of Action: Malondialdehyde inhibitors, Actin modulators, Amyloid inhibitors, Angiogenesis inducing agents, Apoptosis inhibitors, Cell movement activators, Collagen stimulants, Heat-shock protein modulators, MicroRNA modulators, Nerve growth factor stimulants, NF-kappa B inhibitors, Stem cell stimulants, Antioxidants, Electron transport chain complex protein modulators, Lipid modulators, Tumour necrosis factor alpha inhibitors, Eye protein modulators, TRPM8 protein stimulants, Glucocorticoid receptor agonists, Inosine monophosphate dehydrogenase inhibitors, Muscarinic receptor agonists Key Dry Eye Disease Companies: TearSolutions, Novaliq, HanAll Biopharma, Aldeyra Therapeutics, RegeneRx Biopharmaceuticals, Mitotech, Aerie Pharmaceuticals, Azura Ophthalmics, Stuart Therapeutics, Surface Ophthalmics, Glaukos Corporation, BRIM Biotechnology Inc., Dompé Farmaceutici S.p.A, Okyo Pharma Ltd, AxeroVision, Inc., Palatin Technologies, Seikagaku Corporation, Invirsa, Inc., Allysta Pharmaceutical, Taejoon Pharmaceutical Co., Ltd., Ocular Therapeutix, Inc., Dreamhawk Vision Biotech, Inc., Yuyu Pharma, Inc., Novartis Pharmaceuticals, VivaVision Biotech, Inc, Huons Co., Ltd., and others. Key Dry Eye Disease Pipeline Therapies: Reproxalap, Timbetasin, Visomitin, HL036, CyclASol, Lacripep, AR15512, AZR MD 001, ST-100, SURF-100, SURF-200, GLK-301, BRM421, Oxervate, OK-101, AXR 159, AXR 270, PL9643, SI-614, INV-102, ALY688, TJO-083, OTX-CSI, OTX-DED, SHJ002, YP-P10, ECF843, VVN001, HU007, and others. Dive deep into rich insights for new drugs for dry eye disease treatment; visit @ Dry Eye Disease Medications Table of Contents For further information on the dry eye disease pipeline therapeutics, reach out @ Dry Eye Disease Drug Treatment Related Reports Dry Eye Disease Market Dry Eye Disease Market Insights, Epidemiology, and Market Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key dry eye disease companies, including Oyster Point Pharma, Aerie Pharmaceuticals, Azura Ophthalmics, Stuart Therapeutics, Surface Ophthalmics, Glaukos Corporation, among others. Dry Eye Disease Epidemiology Forecast Dry Eye Disease Epidemiology Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, and dry eye disease epidemiology trends. Mild Dry Eye Market Mild Dry Eye Market Insights, Epidemiology, and Market Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key mild dry eye companies, including Allergan Plc., Novartis AG., Otsuka Pharmaceutical Co. Ltd., Santen Pharmaceutical Co. Ltd., among others. Moderate Dry Eye Market Moderate Dry Eye Market Insights, Epidemiology, and Market Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key moderate dry eye companies, including Santen Pharmaceutical Co. Ltd., OASIS Medical, Alcon Inc., Bausch Health Companies Inc., AbbVie Inc., among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +1(919)321-6187 Logo: SOURCE DelveInsight Business Research, LLP

临床3期临床结果并购

2023-04-10

·生物制药小编

文末有抽奖 | 神经生长因子（NGF）概况及其表达纯化研究进展

重组人源神经生长因子介绍神经生长因子（Nerve Growth Factor, NGF）是最早发现和最典型的神经营养因子，同时也是影响神经系统最重要的生物活性分子之一。人神经生长因子（Human Nerve Growth Factor, hNGF）是在人体中发现的一种对正常神经细胞具有营养作用，同时对损伤神经修复机能起调节作用的生物活性因子。NGF不仅可以维持交感神经和感觉神经的生存和功能，促进神经细胞的分化，决定轴突的伸展方向，还能对促进大脑的发育、神经系统的生长，以及损伤神经的再生和功能恢复具有决定性作用（图1）。图1 生长因子作用机制图示完整的hNGF分子由α、β、γ三个亚基组成，其中β亚基（β-NGF）是唯一具有生物学活性的亚基。β亚单位通过非共价链结合而构成活性二聚体，其中，6个半胱氨酸残基之间由二硫键相连，若二硫键结构不正确，NGF将丧失其生物活性。β-NGF对中枢及周围神经元的发育、分化、生长、再生和功能特性的表达，均具有重要的调控作用。目前，NGF 及其受体已成为临床镇痛药物开发的重要靶点，β-NGF已被开发成治疗外周神经损伤的药物，用于治疗神经中毒、周围神经损伤、糖尿病性周围神经病变、老年痴呆病、帕金森氏病、面神经炎，以及神经损伤（包括脊髓损伤、高位截瘫、断指再植、脑损伤等中枢及外围神经系统的损伤）等神经系统疾病。β-NGF也是目前唯一可应用于临床的神经系统蛋白质因子（图2）。图2 神经生长因子（NGF）在调节中枢神经系统疼痛信号中的作用[1]目前商品化的NGF为鼠源性神经生长因子（mNGF），且mNGF与hNGF基因序列相比高度同源（>90％），从下颌下腺分离的mNGF和从胎盘分离的hNGF已成功用于临床，主要用于治疗视神经损伤。除此之外，NGF也对毒性神经病变、外周神经病变和面部神经病变等疾病有疗效。然而，这类动物源性蛋白制品常常具有较高的免疫原性，容易引起人体内的抗原反应，甚至会危及生命。而天然hNGF分布于人体的脑、神经节、虹膜、心脏、脾和胎盘等组织，数量有限，且其中hNGF含量低，分离纯化极其困难，通常无法直接提取获得。因此，利用基因工程技术制备重组人神经生长因子，是解决上述问题的一个主要途径。重组人源神经生长因子的表达利用基因工程技术，以微生物为载体，大批量生产外源蛋白，具有广阔的应用前景。到目前为止，已有多项研究利用哺乳动物细胞、昆虫细胞和大肠杆菌等系统，成功表达出人β-NGF。在上述表达系统中，人们对大肠杆菌的遗传背景和生化特性了解得相对透彻，大肠杆菌本身具备容易操作、生长迅速、营养需求简单等优点。同时，大肠杆菌表达系统具有表达水平高、生产成本低和便于工业化生产等优势，成为制备重组人神经生长因子的首选。但是这一系统本身也存在着若干缺陷：①缺少真核生物的蛋白翻译后修饰和加工过程，如剪切、糖基化和二硫键形成等；②表达的蛋白多以包涵体形式存在，需要经过复杂的复性步骤才能恢复蛋白构象和活性；③较多的背景杂蛋白，纯化工艺复杂；④真核生物和原核生物所偏好的密码子存在差异，部分真核基因在大肠杆菌表达系统中表达量极低，甚至不表达。有研究发现，人β-NGF在大肠杆菌中的表达量不高，而且生物活性极低，主要是由于β-NGF基因及其蛋白的结构特殊，导致其难以在大肠杆菌系统中有效表达。一方面，β-NGF基因中使用了较多的大肠杆菌稀有密码子，导致β-NGF基因在大肠杆菌中表达量不高。另一方面，β-NGF蛋白难以在缺乏翻译后加工修饰系统的大肠杆菌中形成正确的结构，最终导致基于大肠杆菌表达系统的β-NGF蛋白生物活性极低，甚至没有活性。基于上述问题，有研究报道了一种重组人神经生长因子β亚基基因，并提供了利用大肠杆菌表达系统制备重组人神经生长因子的方法。该序列位于人神经生长因子β亚基成熟肽基因序列上游，两序列由肠激酶切割位点连接。分子伴侣可帮助人神经生长因子β亚基（以包涵体形式表达）在体外形成正确的构象，并且能在复性后通过肠激酶的切割作用被去除，从而释放出与天然β-NGF氨基酸序列完全一致，且具有较高生物学活性的成熟肽。中国仓鼠卵巢（CHO）细胞作为使用最为广泛的哺乳动物细胞表达系统之一，常用于重组NGF的表达研究，重组NGF被表达并分泌到细胞外，以游离形式（与天然形态类似）存在于上清液中。相较于大肠杆菌系统，CHO系统不仅具有良好的翻译后修饰能力，还支持大规模生产NGF。在真核细胞中表达，更有利于得到活性较高和更接近自然状态的β-NGF蛋白，具体优点如下：①能够加工表达的蛋白质，如空间构型的折叠、糖基化和磷酸化等；②可识别和除去外源基因中的内含子，进一步剪切加工为成熟的mRNA；③转染目的基因的真核细胞可冻存，复苏后能稳定表达活性目的蛋白。目前，使用真核系统大规模表达、纯化NGF已有成熟工艺，而用原核系统表达的重组人源人神经生长因子（rhNGF）多因不能正确折叠而使生物学活性只有mNGF五十分之一，通常首选真核表达系统来克服蛋白错误折叠等问题。近年来，研究人员通过构建具有前导序列的NGF来帮助其体外复性，虽然复性率有所提高，但产物需经限制酶切后才能获得成熟NGF，后续处理难度相对增加。综合两种表达体系可知，哺乳动物表达系统具有分泌正确装配、折叠与糖基化等特点，更适合表达NGF。韩晓枫团队在COS-7细胞中对NGF进行了瞬时表达，结果表明表达产物具有生物活性，但是无法实现NGF的稳定、长期表达，建议只作为瞬时表达宿主细胞。而CHO细胞具有利于二硫键形成的细胞环境。姜静团队对比了来源于E .coli和CHO表达系统的rhβ‑NGF，发现采用原核系统表达的NGF多以不溶性包含体形式存在（可能是游离蛋白而非跨膜蛋白），这为NGF能否在细胞表面表达存在很大的不确定性本是否。相比之下，通过将NGF的核酸序列与适当的铰链区和跨膜区的核酸序列串联后导入CHO细胞，就可以在重组CHO细胞表面上稳定表达NGF，使NGF存在于细胞表面而非分泌到培养液中，同时确保NGF经过恰当的翻译后加工（包括正确折叠、糖基化等），从而保持天然构象和活性。重组人源神经生长因子的纯化来源于CHO系统的rhNGF中往往含有变异体，如细胞内分泌过程中翻译后修饰、分泌后氨基酸残基侧链发生化学反应，或肽链降解而形成的一系列蛋白。rhNGF在体内以前体形式合成，由于弗林蛋白酶或激素酶原转化酶加工不完全，会产生完全或部分前体。除前体外，由于真核细胞特性，还会产生诸如N端截断（由于翻译后加工导致N端部分氨基酸缺失的序列分子）、氧化、脱酰胺、异构、C末端截断和异常（由于翻译后加工导致结构异常、二硫键异常、异常氧化等变体的统称）等变异体。常规的层析方法能够除去许多工艺相关杂质（如宿主细胞蛋白及核酸等），但是很难除作为产品相关杂质的rhNGF变异体。这些变异体通常与成熟rhNGF一同产生，两者理化性质相近，为大规模纯化增加了难度。目前纯化rhNGF的报道主要包括：1. 史权威团队采用阳离子交换及分子筛两步方法制备了纯度大于98%的rhNGF，但该阳离子交换步骤仅用于清除宿主细胞蛋白等过程杂质；2. 专利CN106478801A采用阳离子交换及疏水层析制备了纯度大于99%的rhNGF，该阳离子交换主要用于捕获产品，目的是清除宿主细胞蛋白等工艺相关杂质；3. 专利CN1268639C利用高效阳离子交换，以线性洗脱方式分离rhNGF氧化、异构、脱酰胺等变体；4. 还有研究通过分析rhNGF及其变异体的理化性质，发现在弱阳离子交换色谱条件下，N端截断及异常变体具有更低的等电点，可采用阶段升高电导率的方法清除变体。想要从包括发酵液、裂解的细菌或哺乳动物细胞中大规模纯化NGF，制备性分离获得具有药物纯度和高产量（基本上不含变体）的rhNGF满足临床需求难度较高，需要一种有效的方法来选择性地从其变体和其它分子、以及pI高的其它多肽中分离出NGF。有研究报道了一种使用疏水作用层析（HIC）来纯化NGF的方法，可以将成分不同或错折叠形成的分子与目标蛋白分开，除去在疏水性上不符合要求的变体，包括经部分加工的前体序列、含有糖基化成熟或前体的形式以及错误折叠和部分折叠的变体。除此以外，另一种制备性阳离子交换层析纯化NGF的方法也被广泛应用，该方法可将电荷变体（如氧化、异天冬氨酸和脱酰胺形式）从成熟的NGF蛋白中分离出来，采用HIC和阳离子交换层析制备的NGF产物基本不含加工和电荷变体。小编总结综上所述，未来有关NGF的研究及应用发展可能主要在如下几个方向：首先，随着基因工程制备rhNGF技术工艺的逐步成熟，最终可实现规模化生产水平。rhNGF因其特性和较高的分子同源性，生产规模不受原料限制，且无动物来源的致病病毒污染，具有更大的发展潜力。我们将重点研究如何优化发酵和纯化条件，获得稳定高效的表达途径，最终高效实现规模化生产。其次，近期文献资料显示，国外相关研究的热点逐渐转向NGF的二肽模拟物，部分学者认为，NGF的二肽模拟物可作为治疗神经损伤的候选药物，具有更加广阔的发展和应用前景。合作意向y目前，甲贝医药针对NGF项目已建立完整的构建、表达、纯化及制剂开发流程，欢迎感兴趣的合作伙伴前来沟通，共同开发。图3 甲贝医药的一站式表达、纯化及制剂开发流程对接人：徐先生，18616852990 微信号：参考来源：[1] https://mosmedpreparaty.ru/news/14000本文不具有任何投资建议和医学意见点击“阅读原文”，填写问卷，前10名有奖~

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2022-12-22

·MedCity News

Current Lack of Innovation in the Pain Space Hurts Society

Current pain medications are addictive (opioids), or potentially damaging to the liver (acetaminophen/Tylenol or kidneys with substantial gastrointestinal toxicity (nonsteroidal anti-inflammatory drugs, NSAIDs). Three notable events in November 2022 underscore the need for innovation in safer pain treatment First, in its updated Clinical Practice Guidelines for Prescribing Opioids, the Centers for Disease Control and Prevention (CDC) encourages physicians to again use opioids in individualized cases for moderate-to-severe acute and chronic pain, responding to a crisis of untreated pain leftover from its prior 2016 guidelines. Second, Regeneron announced that it stopped developing its nerve growth factor (NGF) inhibitor for knee and hip osteoarthritis (OA) pain in a Phase 3 trial. This follows cases of a rapidly progressive form of OA that required joint replacement. Pfizer also discontinued its NGF program for pain in 2021 due to similar safety concerns and unproven pain efficacy over NSAIDs alone. Targeting NGF for pain never made much sense scientifically, as it has a poor pain mechanism of action. Moreover, developing an antibody therapy – rather than a small molecule for the pain space – leaves unanswered how limited U.S. healthcare dollars would absorb the costs for an ailment affecting more than 50 million Americans. And third, Australian regulators are considering restricting the sale of acetaminophen this month after an independent expert report raised concern about overdoses in teenagers, females at the highest risk. The proposals include limiting the amount bought over the counter so that it is not ‘stockpiled’ at home and requires a prescription for those under 18 years of age. Acetaminophen’s liver toxicity risk Acetaminophen has a narrow therapeutic index, and hepatotoxicity is a significant risk with deliberate overuse (e.g., suicide attempt) and unintentional overuse (e.g., consuming acetaminophen without realizing it is present in various prescription and over-the-counter formulations). Furthermore, its use in patients with compromised liver function, particularly in the elderly, poses a significant risk for liver injury. Despite ongoing regulatory and educational efforts over the past several years to improve patient safety, intentional and unintentional acetaminophen overdose remains an essential public health problem. Every year in the U.S, around 30,000 patients are hospitalized due to acetaminophen hepatotoxicity. A safer, non-NSAID alternative to acetaminophen is needed to address acetaminophen hepatotoxicity. Indeed, similar to the discussions currently happening in Australian Regulators, a decade ago the FDA issued a boxed warning highlighting the potential for severe liver injury. In Canada, acetaminophen toxicity persisted despite labeling changes implemented in 2009 and 2016. These labeling standards were made to communicate the dangers of acetaminophen overdose and promote safe use. However, monthly rates of hospital and intensive care unit admissions for accidental acetaminophen overdose were unchanged between April 2004 and March 2020. Kidney, cardiovascular and gastrointestinal (GI) risks with NSAIDs Risks from overuse of NSAIDs include elevated blood pressure, renal toxicity leading to acute kidney injury (AKI) and GI damage. Indeed, most chronic NSAID users have significant small-intestine damage and bleeding. In treating acute pain in the post-operative period, NSAIDs use leads to AKI and complications in patients undergoing surgery. There are several patient populations at risk of NSAID-induced AKI. Patients vulnerable to NSAIDs’ renal toxicity leading to serious adverse outcomes include patients with chronic kidney disease. NSAID exposure was associated with an approximate 1.6-fold rise in the odds of developing AKI in hospitalized pediatric patients and in older people. Prevalence of pain and Opioid Use Disorder (OUD) in the U.S. OUD affects 2.1 million people in the U.S., 16 million people worldwide, and over 120,000 deaths annually attributed to opioids. OUD includes the misuse of prescription pain relievers and the use of heroin. Prescription pain reliever misuse was the second most common form of illicit drug use in the U.S. in 2018, after marijuana use, with 3.6% of the population misusing pain relievers. In the U.S., pain affects more adults than diabetes and cancer, combined with an estimated cost to the healthcare system of $635 billion/year. In September 2022, the CDC released preliminary data that drug overdose deaths exceeded 107,000 in the preceding year, the most significant single-year increase. Drug deaths were disproportionately higher in the younger population than in the older population. Though opioid prescriptions have been declining since 2012, and most overdose deaths are now from fentanyl sold on the street, often laced with other drugs, 14,000+ of these deaths were from prescription painkillers. Additionally, 500,000 emergency visits per year are attributed to misuse of prescription pain killers. Future pain relief innovation Multiple randomized clinical trials have shown that combination non-opioid therapies (large doses of acetaminophen and NSAIDs) are at least as effective as opioids for many common types of moderate to severe pain. Though pain is subjective, multiple well-conducted clinical trials have demonstrated the high reproducibility of clear endpoints. Hence, pain clinical trials have a track record of demonstrating efficacy when they are well designed and executed. The prevalence of OUD, including high rates of overdose in the U.S. and toxicity profiles of currently available medications, underscore the need for a new strategy. Recognizing the need for novel non-opioid therapies, the National Institutes of Health (NIH) established the Helping to End Addiction Long-Term (HEAL) Initiative in 2018. This program’s financial, scientific, and commercialization support is an essential start toward pain relief innovation. The future towards the safer treatment of pain will come as biopharma, and investor communities appreciate the significant opportunities in supporting scientifically rigorous and clinically validated lead assets for the safer treatment of pain.

临床3期

100 项与 Nerve growth factor(Amgen, Inc.) 相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12620

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
阿尔茨海默症	临床3期	-	Chiron Corp.	-
阿尔茨海默症	临床3期	-	Amgen, Inc.	-
阿尔茨海默症	临床3期	-	Genentech, Inc.	-
阿尔茨海默症	临床3期	-	Ceregene, Inc.	-
糖尿病性神经病变	临床3期	-	Chiron Corp.	-
糖尿病性神经病变	临床3期	-	Ceregene, Inc.	-
糖尿病性神经病变	临床3期	-	Amgen, Inc.	-
糖尿病性神经病变	临床3期	-	Genentech, Inc.	-
单纯疱疹	临床3期	-	Ceregene, Inc.	-
单纯疱疹	临床3期	-	Chiron Corp.	-

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


ASCO2006	N/A	晚期非小细胞肺癌	451	Cisplatin and docetaxel	顧鑰觸繭鑰憲網築積衊(淵願觸繭築餘遞窪鬱壓) = 築廠鏇淵鹹糧夢積築衊壓遞顧廠艱醖糧壓觸構 (衊構蓋憲壓顧積積鹽範 )	-	2006-06-20
				nerve growth factor (NGF) (Controls)	顧鑰觸繭鑰憲網築積衊(淵願觸繭築餘遞窪鬱壓) = 簾顧築積淵鹹觸觸顧鏇壓遞顧廠艱醖糧壓觸構 (衊構蓋憲壓顧積積鹽範 )