BACKGROUNDDepression is a prevalent nonmotor symptom in Parkinson disease and can greatly reduce the quality of life for patients; the dopamine receptors found in glutamatergic pyramidal cells in the medial prefrontal cortex (mPFC) play a role in regulating local field activity, which in turn affects behavioural and mood disorders. Given research showing that glial cell-derived neurotrophic factor (GDNF) may have an antidepressant effect, we sought to evaluate the impact of exogenous GDNF on depression-like behaviour in mouse models of Parkinson disease.METHODSWe used an established subacute model of Parkinson disease in mice involving intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), followed by brain stereotaxic injection of GDNF into the mPFC region. Subsequently, we assessed depression-like behaviour using the sucrose preference test, forced swimming test and tail suspension test, while also evaluating protein expression in the mPFC.RESULTSWe included 60 mice, divided into 3 groups, including a control group (saline injection), an MPTP plus saline injection group and an MPTP plus GDNF injection group. We found that exogenous GDNF injection into the mPFC led to an increase in dopamine receptor D1 (DRD1) protein levels. We also observed that activating the protein kinase A pathway through DRD1 produced a prolonged antidepressant response. Under GDNF stimulation, the expression of dopamine receptor D2 (DRD2) remained constant, suggesting that the DRD2 signal was ineffective in alleviating depression-like symptoms. Moreover, our investigation involved Golgi staining and Western blot techniques, which found enhanced synaptic plasticity, including increased dendritic branches, dendritic spines and retrograde protection after GDNF treatment in Parkinson disease models.LIMITATIONSA subtle motor phenotype became evident only toward the conclusion of the behavioural testing period. The study exclusively involved male mice, and no separate control group receiving only GDNF treatment was included in the experimental design.CONCLUSIONOur findings support a positive effect of exogenous GDNF on synaptic plasticity, mediated by DRD1 signalling in the mPFC, which could facilitate depression remission in Parkinson disease.

项与 GDNF 相关的新闻（医药）

2024-07-18

·药智网

恒瑞加码基因治疗

近日，恒瑞医药控股子公司瑞宏迪医药RGL-193注射液的临床试验申请获得NMPA受理，这是一款双基因AAV治疗药物，适应症为中晚期帕金森患者。值得注意的是，这不是恒瑞医药首款进入临床的基因治疗药物，早在今年4月，恒瑞医药mRNA基因治疗药物RGL-2102注射液获批临床，用于下肢缺血性疾病。如此紧凑的IND申报，可能是恒瑞医药药物创新策略转变的一个缩影，从更务实的视角来看，恒瑞医药快速加码基因治疗已经是“明牌”。从人力资源网站看到，恒瑞医药在大肆的招聘基因治疗相关人才，岗位下到基础的研究员，上至基因治疗公司CMO和COO，处于一个快速扩张的状态。过去，市场对于恒瑞医药的创新策略一直是“创新药仿制化”，两款基因治疗的IND后，或许让人们看到公司也在往更高风险的前沿领域进行探索。治疗下肢缺血性疾病的RGL-2102 RGL-2102是一款mRNA蛋白替代疗法药物，所谓蛋白替代疗法，就是通过劫持细胞机制，将人体细胞变成自身蛋白（治疗性分子）生产加工厂，从而治疗相关疾病。从机理出发，mRNA可以表达任何蛋白质，同时mRNA替代蛋白进行给药，具备成本低、可较容易通过序列修饰&改变载体来改变药代动力学参数等诸多优点，这些优点使得mRNA蛋白替代疗法有望取代部分蛋白药物市场，市场体量取决于蛋白替代疗法的发展。据中信证券研报测算，2025年蛋白药物市场规模2200亿美元计算，假设mRNA蛋白替代疗法替代率达到10%，对应市场规模为220亿美元。从全球范围内看，虽然最早的mRNA蛋白替代疗法可追溯至1992年，但实际应用到临床治疗中还有很长的一段路要走，以mRNA巨头莫德纳的布局为例，进度最快的治疗丙酸血症（PA）蛋白替代疗法mRNA-3927刚刚完成了I/II期临床试验并公布了结果，同时针对甲基丙二酸血症（MMA）和苯丙酮尿症（PKU）也正在临床开发当中。从全球的进度看，恒瑞医药今年拿到mRNA蛋白替代疗法药物的临床入场券并不算慢，并且公司指出：目前全球范围内尚无该mRNA蛋白替代药品的临床研究，潜台词是：我们是“First in class”。目前mRNA蛋白替代疗法主要通过静脉注射LNP-mRNA给药，恒瑞医药的RGL-2102同样是一款自主研发的由脂质体（LNP）包载的mRNA，管线的具体信息尚未披露，但下肢缺血性疾病却可能是大家的“老熟人”了。近日，CDE受理了首个治疗下肢缺血的国产基因药物诺思兰德的NL003，下肢缺血是属于外周动脉疾病范畴，严重者5年死亡率非常高，仅次于一些癌症。从市场空间和竞争格局看，国内患有严重下肢缺血的人群大约在500-600万人，尽管目前有不同的治疗手段，但机构预计基因治疗的渗透率普遍能达到5%以上，预计这是一个至少20亿起步的市场。目前，国内主要的竞争对手是诺思兰德和人福医药，各自的技术路线都有所差别，恒瑞医药虽然后发，但不一定是劣势。瞄准CNS的RGL-193 RGL-193则是一款候选双基因AAV治疗药物，采用立体定向技术注入患者脑内，提高左旋多巴的转化效率，降低使用药物剂量及剂量相关的不良反应，同时修复受损的多巴胺能神经元，以达到延缓疾病进展及减少口服抗帕金森药物剂量的效果。据瑞宏迪医药官媒报道，本月RGL-193的IIT研究已经完成首例患者给药，患者术后恢复良好，目前已经平安出院。 RGL-193在国内帕金森基因治疗药物中也算是第一梯队的研发管线，年初上海天泽云泰自研用于治疗原发性帕金森病和AADCD的AAV基因疗法获得CDE受理，其原理是递送功能的AADC为基础恢复多巴胺的生成，达到治疗帕金森病的长期疗效，而RGL-193是双基因AAV治疗药物，预计是AADC基因结合另一基因的组合（如GAD基因、GDNF基因等）。从创新性来说，全球范围内已上市的AAV基因治疗药物，均针对单一基因缺陷的疾病，尚未有双基因疗法上市，恒瑞医药的RGL-193走在了全球前列。虽说管线研发尝试走在了全球前列，但是市场投资者却对这款基因疗法的前景充满了疑惑和不解。目前，全球已有注射入脑的帕金森AAV单基因疗法上市，是一家美国药企PTC公司旗下的Upstaza，这是全球首款针对AADCD的AAV基因治疗产品，AAV2携带编码AADC酶的健康基因，以基因补偿的形式达到治疗效果，理论上一次给药长期有效。同时，Upstaza于2022年11月获批上市，Upstaza疗法在英国标价为300万英镑（约366万美元），是全球最贵的基因疗法之一。基因疗法的高定价导致商业化不及预期的案例，不在少数。比如，全球首个A型血友病AAV基因疗法Roctavian获批一年后（定价欧洲150万欧/美国290万美元），2023年仅有3名患者接受治疗；Bluebird的两款基因疗法Zynteglo、Skysona也由于“天价定价”，欧洲政府不愿意全价买单，最终公司携两款产品退出欧洲市场。那么恒瑞医药的RGL-193，未来在国内市场，该如何定价？商业化到底会是怎样的走向，市场投资者可能要打上一个大大的问号。结语：从本次恒瑞系研发的主体瑞宏迪医药来看，该主体成立于2021年8月，历经2年多的时间迅速将两款基因疗法推上临床，效率不俗（也不排除是原本恒瑞体内就开始研发，这样可能历时更长）。瑞宏迪医药在2022年进行了一次融资，认购机构均为恒瑞关联方，这也使得公司从恒瑞的全资子公司变为控股公司，这样做的目的可能是有效的隔离研发风险给上市公司带来的直接影响。除了瑞宏迪医药之外，其实恒瑞这种孵化模式也有不少，比如恒瑞源正、瑞石医药等，可以视为恒瑞对于前沿领域研发的分散押注布局。从恒瑞医药踏出做First in class或者全球创新的那一步开始，就意味公司脱离舒适圈进行“破圈”尝试。这对于恒瑞医药来说，显然是一个历史性的里程碑。命运的齿轮，正在慢慢转动。注：以上图片来源瞪羚社来源 | 瞪羚社（药智网获取授权转载）撰稿 | Kris. 责任编辑 | 八角声明：本文系药智网转载内容，图片、文字版权归原作者所有，转载目的在于传递更多信息，并不代表本平台观点。如涉及作品内容、版权和其它问题，请在本平台留言，我们将在第一时间删除。商务合作 | 王存星 19922864877（同微信）阅读原文，是昨天最受欢迎的文章哦

信使RNA基因疗法临床申请临床1期寡核苷酸

2024-06-25

·PipelineReview

AskBio Initiates Recruitment to its Phase 2 Parkinson's Disease Trial

RESEARCH TRIANGLE PARK, NC; USA I June 25, 2024 I Asklepios BioPharmaceutical, Inc. (AskBio), a gene therapy company wholly owned and independently operated as a subsidiary of Bayer AG, today announced initiation of recruitment to REGENERATE-PD, a Phase 2 clinical study assessing efficacy and safety of AB-1005, an investigational adeno-associated virus 2 (AAV2) glial cell line-derived neurotrophic factor (GDNF) gene therapy for the treatment of moderate-stage Parkinson’s disease. “By enhancing levels of a naturally occurring growth factor, glial cell line-derived neurotrophic factor (GDNF) gene therapy is intended to promote the survival and functioning of vulnerable brain cells that degenerate in Parkinson’s disease”, said Alan Whone, MD, PhD, Consultant Senior Lecturer in Movement Disorder, Bristol Medical School, and Honorary Consultant Neurologist at North Bristol Trust, UK. “The advancement of AB-1005 is a significant milestone in the development of a gene therapy for Parkinson’s disease and has the potential to bring an effective treatment one step closer to patients”. Dr Whone will act as European Lead Principal Investigator (PI) on REGENERATE-PD once the program becomes active in the UK. According to the Parkinson’s Foundation, more than 10 million people worldwide suffer from Parkinson’s disease. 1 “Following the encouraging results from the Phase 1b study and the presentation of 18-month data at the American Association of Neurology (AAN) meeting in April, we are excited to be progressing AB-1005 to this larger, Phase 2 study,” said Krystof Bankiewicz, MD, PhD, Scientific Chair, Parkinson’s and MSA, AskBio. “This latest advancement highlights our confidence in the potential of AB-1005 to provide a transformative impact for patients with Parkinson’s disease.” In January, AskBio announced that the Phase 1b trial of AB-1005 met its primary endpoint, which was to evaluate the safety of a one-time bilateral delivery of AB-1005 directly to the putamen. The investigational gene therapy for the treatment of Parkinson’s disease was well tolerated with no serious adverse events that were considered related to AB-1005 in all 11 patients at 18 months. 2 AskBio is also exploring GDNF therapy beyond Parkinson’s disease and is currently enrolling patients in the US with the parkinsonian subtype of multiple system atrophy (MSA-P) in a Phase 1 trial to assess the preliminary safety, tolerability, and efficacy of GDNF therapy for this rapidly progressing condition. 3 AB-1005 is an investigational gene therapy that has not been approved by any regulatory authority, and its efficacy and safety have not been established or fully evaluated. About Parkinson’s disease Parkinson’s disease is a progressive neurodegenerative disorder caused by the death of nerve cells in the brain, leading to decreased dopamine levels. 4 At diagnosis, it is estimated that patients have already lost 50-80% of their dopaminergic neurons. 5 The loss of these neurons leads to a progressive loss of motor function and symptoms such as tremors, muscle rigidity, and slowness of movement. 6 Even with medication, the symptoms of Parkinson’s disease can fluctuate during the course of the day. According to the Parkinson’s Foundation, more than 10 million people worldwide suffer from Parkinson’s disease, with approximately one million living in the United States. 1 There is no cure, and the effectiveness of current treatments frequently decreases over time. 7 About REGENERATE-PD REGENERATE-PD is a Phase 2, randomized, double-blind, surgery-controlled study of the efficacy and safety of intraputaminal AAV2-GDNF in the treatment of adults (45-75 years) with moderate stage Parkinson’s disease. Subjects will receive either bilateral image-guided infusion of AAV2-GDNF into the putamen, single dose (active treatment arm), or bilateral partial burr/twist holes (control arm). The trial will include an estimated 87 subjects with study sites located in the United States, UK and Europe. For more information about the REGENERATE-PD clinical trial, visit clinicaltrials.gov (NCT06285643), or visit www.askbio.com . About AB-1005 AB-1005 is an investigational gene therapy based on adeno-associated viral vector serotype 2 (AAV2) containing the human glial cell line-derived neurotrophic factor (GDNF) transgene, which allows for stable and continuous expression of GDNF in localized regions of the brain after direct neurosurgical injection with MRI-monitored convection enhanced delivery 8,9 GDNF is a homodimer that is a distantly related member of the transforming growth factor-β superfamily. In midbrain neuronal cell cultures, recombinant human GDNF promoted the survival and morphological differentiation of dopaminergic neurons and increased their high-affinity dopamine uptake. GDNF has long been evaluated as a potential treatment for diseases, such as Parkinson’s, marked by progressive degeneration of midbrain dopaminergic neurons. 10 About AskBio Asklepios BioPharmaceutical, Inc. (AskBio), a wholly owned and independently operated subsidiary of Bayer AG, is a fully integrated gene therapy company dedicated to developing life-saving medicines and changing lives. The company maintains a portfolio of clinical programs across a range of neuromuscular, central nervous system, cardiovascular, and metabolic disease indications with a clinical-stage pipeline that includes therapeutics for congestive heart failure, Huntington’s disease, limb-girdle muscular dystrophy, multiple system atrophy, Parkinson’s disease, and Pompe disease. AskBio’s gene therapy platform includes Pro10™, an industry-leading proprietary cell line manufacturing process, and an extensive capsid and promoter library. With global headquarters in Research Triangle Park, North Carolina, and European headquarters in Edinburgh, Scotland, the company has generated hundreds of proprietary capsids and promoters, several of which have entered pre-clinical and clinical testing. An early innovator in the gene therapy field, with over 900 employees in five countries, the company holds more than 800 patents and patent applications in areas such as AAV production and chimeric capsids. Learn more at www.askbio.com or follow us on LinkedIn. About Bayer Bayer is a global enterprise with core competencies in the life science fields of health care and nutrition. In line with its mission, “Health for all, Hunger for none,” the company’s products and services are designed to help people and the planet thrive by supporting efforts to master the major challenges presented by a growing and aging global population. Bayer is committed to driving sustainable development and generating a positive impact with its businesses. At the same time, the Group aims to increase its earning power and create value through innovation and growth. The Bayer brand stands for trust, reliability and quality throughout the world. In fiscal 2023, the Group employed around 100,000 people and had sales of 47.6 billion euros. R&D expenses before special items amounted to 5.8 billion euros. For more information, go to www.bayer.com . References [1] Parkinson’s Foundation. Who has Parkinson’s? Available at: https://www.parkinson.org/understanding-parkinsons/statistics . Accessed: June 2024. [2] Asklepios BioPharmaceutical, Inc. (January 2024). AskBio Phase Ib trial of AB-1005 gene therapy in patients with Parkinson’s disease meets primary endpoint [Press Release]. https://www.askbio.com/askbio-phase-ib-trial-of-ab-1005-gene-therapy-in-patients-with-parkinsons-disease-meets-primary-endpoint [3] ClinicalTrials.gov. GDNF Gene Therapy for Multiple System Atrophy. Available at: https://clinicaltrials.gov/study/NCT04680065 . Accessed: June 2024. [4] Michael J. Fox Foundation. Parkinson’s 101 – What is Parkinson’s disease? Available at: https://www.michaeljfox.org/parkinsons-101 . Accessed: June 2024. [5] DeMaagd G, Philip A. Parkinson’s Disease and Its Management: Part 1: Disease Entity, Risk Factors, Pathophysiology, Clinical Presentation, and Diagnosis. P T. 2015 Aug;40(8):504-32. PMID: 26236139; PMCID: PMC4517533. [6] Parkinson’s Foundation. Motor-fluctuations. Available at: https://www.parkinson.org/library/fact-sheets/motor-fluctuations . Accessed: June 2024. [7] Mayo Clinic. Parkinson’s disease. Available at: https://www.mayoclinic.org/diseases-conditions/parkinsons-disease/diagnosis-treatment/drc-20376062 . Accessed: June 2024. [8] Heiss JD, Lungu C, Hammoud DA, Herscovitch P, Ehrlich DJ, Argersinger DP, Sinharay S, Scott G, Wu T, Federoff HJ, Zaghloul KA, Hallett M, Lonser RR, Bankiewicz KS. Trial of magnetic resonance-guided putaminal gene therapy for advanced Parkinson’s disease. Mov Disord. 2019 Jul;34(7):1073-1078. [9] Kells AP, Eberling J, Su X, Pivirotto P, Bringas J, Hadaczek P, Narrow WC, Bowers WJ, Federoff HJ, Forsayeth J, Bankiewicz KS. Regeneration of the MPTP-lesioned dopaminergic system after convection-enhanced delivery of AAV2-GDNF. J Neurosci. 2010 Jul 14;30(28):9567-77. [10] Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F. GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science. 1993;260(5111):1130-1132. SOURCE: Asklepios BioPharmaceutical

临床1期临床2期基因疗法临床结果

2024-06-21

·奇点网

《科学》：科学家首次发现，乳腺癌细胞竟会沿椎体血管贯穿颅骨爬进大脑，并劫持巨噬细胞为自己供养，难怪乳腺癌容易软脑膜转移

*仅供医学专业人士阅读参考乳腺癌很容易脑转移。乳腺癌软脑膜（LM）转移患者的预后很差，诊断后中位生存期不足6个月。但是癌细胞是如何钻进大脑的呢？按理说大脑有血脑屏障的存在，安保措施应该还算是比较严格的。今日，《科学》杂志发表了来自杜克大学科学团队的论文，研究者们发现了一条全新的癌细胞迁移通路。原来，乳腺癌细胞（BCC）竟会沿着椎体血管外表面攀爬，并一路顺着贯穿颅骨的导静脉（EV）进入软脑膜。这还没完，进入软脑膜的癌细胞还会劫持巨噬细胞，利用它们分泌的神经胶质细胞衍生神经营养因子（GDNF），在营养贫瘠的软脑膜环境中茁壮生长。这种近道都被癌细胞发现了，真是一点也不能放心啊！论文题图我们对乳腺癌软脑膜转移的机制了解非常有限，虽然有研究发现，乳腺癌细胞可以通过破坏脉络膜丛的血-脑脊液屏障在软脑膜上定植，但是很多软脑膜转移乳腺癌患者并未发现脉络膜丛累及。这说明，乳腺癌细胞一定还有别的路线突破大脑。研究者从白血病相关的研究中得到了灵感。白血病细胞可以沿着富含层粘连蛋白（laminin）的血管外表面，从脊椎或颅骨骨髓迁移至软脑膜，从而避开血脑屏障。这条通路免疫细胞也经常往来。说不定，乳腺癌细胞抄的也是这条近道。由于一般的异种移植乳腺癌模式小鼠其实不怎么发生软脑膜转移，研究者专门研发了相应的模型，1833-P和EO-LM2小鼠。对两种小鼠进行颅骨成像，果然发现乳腺癌软脑膜转移小鼠连接软脑膜、颅骨骨髓和椎管的静脉骨通道平均直径增加。静脉骨通道平均直径增加在活体显微镜下，研究者也观察到了癌细胞与血管的亲密接触，并排除了其来自脑转移瘤的可能性。机制上，研究者分析了两种小鼠中软脑膜转移癌细胞的表达，发现整合素α6高表达，这是层粘连蛋白的受体。由此我们可以判断，乳腺癌细胞通过表达整合素α6，与血管表面的层粘连蛋白结合，获得了沿血管迁徙的能力。在实验中，研究者注意到，软脑膜实际上营养相当匮乏，乳腺癌细胞想要在其中顺利发展，必然还有其他帮助。 RNA测序结果显示，神经细胞粘附分子（NCAM）是软脑膜转移癌细胞中上调最多的转录物之一。敲除NCAM会显著影响癌细胞的增殖、延长小鼠的生存。敲除NCAM小鼠延长生存 NACM可作为GDNF的受体发挥作用。在健康的成人大脑和软脑膜中，GDNF表达极少，但是在中风或其他脑损伤发生时，反应性小胶质细胞和巨噬细胞会分泌GDNF，阻断凋亡神经元的应激反应。研究者发现，进入软脑膜的乳腺癌细胞正是利用了GDNF，在营养匮乏的环境中避免细胞死亡，顽强地生存了下来。癌细胞靠GDNF顽强生存在乳腺癌软脑膜转移患者中，研究者也发现了整合素α6和NCAM的广泛表达。与此同时，GDNF和CD68表达的显著增加也说明，巨噬细胞是患者GDNF的主要来源。其实不仅乳腺癌，肺癌、黑色素瘤也常见软脑膜转移，其中整合素α6/NCAM或许也发挥着类似的作用。针对这些信号寻找靶点，或许能够解决临床上软脑膜转移治疗不足的问题。参考资料： [1]https://www.science.org/doi/10.1126/science.adh5548 [2]https://www.science.org/doi/10.1126/science.adq4019 本文作者丨代丝雨

100 项与 GDNF 相关的药物交易

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