A Randomized, Double-Blind, Placebo Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of QPI-1002 for the Prevention of Major Adverse Kidney Events (MAKE) in Subjects at High Risk for Acute Kidney Injury (AKI) Following Cardiac Surgery

This trial is designed to evaluate QPI-1002 versus placebo for the prevention of Major Adverse Kidney Events (MAKE) in subjects at high risk for acute kidney injury following cardiac surgery. Half of the participants will receive QPI-1002 while the other half will receive placebo.

开始日期2018-06-29

申办/合作机构

Quark Pharmaceuticals, Inc.

NCT02610296

/ Completed临床3期

A Phase 3, Randomized, Double-blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of QPI-1002 for Prevention of Delayed Graft Function in Recipients of a Donation After Brain Death Older Donor Kidney Transplant

The purpose of this trial is to evaluate the reduction in incidence and severity of delayed graft function with kidney allografts from donors >45 years after brain death (DBD).

开始日期2016-03-01

申办/合作机构

Quark Pharmaceuticals, Inc.

NCT02610283

/ Completed临床2期

A Randomized, Double-Blind, Placebo Controlled , Phase 2 Study to Evaluate the Efficacy and Safety of QPI-1002 for the Prevention of Acute Kidney Injury in Subjects at High Risk for AKI Following Cardiac Surgery

This trial is designed to evaluate QPI-1002 versus placebo for the prevention of AKI in subjects who are at high risk for AKI following cardiac surgery. Half of the participants will receive QPI-1002 while the other half will receive placebo.

开始日期2015-12-01

申办/合作机构

Quark Pharmaceuticals, Inc.

100 项与 Teprasiran 相关的临床结果

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100 项与 Teprasiran 相关的转化医学

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100 项与 Teprasiran 相关的专利（医药）

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项与 Teprasiran 相关的文献（医药）

2025-08-01·CLINICAL TRANSPLANTATION

Emerging Therapeutic Strategies for Renal Ischemia‐Reperfusion Injury in Kidney Transplantation: Progress and Challenges—A Systematic Review

Review

作者: Cogua, Laura M. ; Zuluaga, Dayanna ; Ratner, Lloyd E. ; Wang, Harvey ; Khan, Sohail ; Ortiz, Jorge

ABSTRACT:

Introduction:

Ischemia‐reperfusion injury (IRI) contributes to delayed graft function (DGF) and long‐term allograft loss in kidney transplantation (KTx). Despite decades of investigation, no pharmacologic strategy has achieved clinical translation. This systematic review evaluates investigational therapies for renal IRI (RIRI) reported since 2000.

Methods:

Following the PRISMA 2020 guidelines, a systematic search of PubMed, ClinicalTrials.gov, and the European Union Clinical Trials Register (EUCTR) was conducted for articles published between January 1, 2000, and March 31, 2025. Eligible records included preclinical and clinical investigations evaluating pharmacologic interventions for RIRI in KTx. Narrative reviews, pediatric‐only, in silico‐only, and in vitro‐only records were excluded. A total of 76 full‐text reports were assessed for eligibility, with 43 meeting the inclusion criteria. Meta‐analysis was not performed due to heterogeneity. Included reports were synthesized by the mechanism of action, developmental stage, and translational status. Risk of bias was qualitatively assessed. This review was not prospectively registered, no formal protocol was prepared, and no external funding was received.

Results:

Legacy agents, Diannexin, YSPSL, and I5NP demonstrated initial promise but failed to achieve late‐phase clinical efficacy. More recent agents, particularly alkaline phosphatase, complement‐targeting biologics, and mesenchymal stem cell (MSC)‐derived exosomes, offer mechanistically diverse strategies to attenuate RIRI, though most remain in early development.

Conclusion:

Most available data remain preclinical and are limited by inconsistent outcome measures and translational bottlenecks. Future efforts should prioritize harmonized animal models, biomarker‐defined endpoints, and strategic investment in promising candidates to integrate them into kidney transplant care.

2025-06-01·Anesthesiology clinics

Cardiac Surgery-Associated Acute Kidney Injury

Review

作者: Leaf, David E ; Jacob, Kirolos A

Acute kidney injury (AKI) is a frequent and often severe postoperative complication following cardiac surgery, which is associated with poor outcomes in both the short and long terms. Numerous randomized clinical trials have been conducted to investigate various strategies for prevention of cardiac surgery-associated AKI. Unfortunately, most trials conducted to date have been negative. However, encouraging results have been reported with several interventions, including preoperative implementation of oxygen delivery-directed perfusion, novel drugs such as teprasiran and amino acids. Many of these studies, however, require validation in larger, multicenter trials, before their routine use in clinical practice can be recommended.

2021-10-05·Circulation1区 · 医学

Teprasiran, a Small Interfering RNA, for the Prevention of Acute Kidney Injury in High-Risk Patients Undergoing Cardiac Surgery: A Randomized Clinical Study

1区 · 医学

Article

作者: Lukas J. Lehner ; Shai Erlich ; Bruce Molitoris ; David Corteville ; Gabor Szabo ; Craig D. Brown ; Nicolas Noiseux ; Andre Lamy ; Matthias Thielmann ; Elizabeth C. Squiers ; Madhav Swaminathan ; Mohamed G. Atta ; Daniel Rothenstein ; C. David Mazer

Background::

Acute kidney injury (AKI) affects up to 30% of patients undergoing cardiac surgery, leading to increased in-hospital and long-term morbidity and mortality. Teprasiran is a novel small interfering RNA that temporarily inhibits p53-mediated cell death that underlies AKI.

Methods::

This prospective, multicenter, double-blind, randomized, controlled phase 2 trial evaluated the efficacy and safety of a single 10 mg/kg dose of teprasiran versus placebo (1:1), in reducing the incidence, severity, and duration of AKI after cardiac surgery in high-risk patients. The primary end point was the proportion of patients who developed AKI determined by serum creatinine by postoperative day 5. Other end points included AKI severity and duration using various prespecified criteria. To inform future clinical development, a composite end point of major adverse kidney events at day 90, including death, renal replacement therapy, and ≥25% reduction of estimated glomerular filtration rate was assessed. Both serum creatinine and serum cystatin-C were used for estimated glomerular filtration rate assessments.

Results::

A total of 360 patients were randomly assigned in 41 centers; 341 dosed patients were 73±7.5 years of age (mean±SD), 72% were men, and median European System for Cardiac Operative Risk Evaluation score was 2.6%. Demographics and surgical parameters were similar between groups. AKI incidence was 37% for teprasiran- versus 50% for placebo-treated patients, a 12.8% absolute risk reduction, P =0.02; odds ratio, 0.58 (95% CI, 0.37–0.92). AKI severity and duration were also improved with teprasiran: 2.5% of teprasiran- versus 6.7% of placebo-treated patients had grade 3 AKI; 7% teprasiran- versus 13% placebo-treated patients had AKI lasting for 5 days. No significant difference was observed for the major adverse kidney events at day 90 composite in the overall population. No safety issues were identified with teprasiran treatment.

Conclusions::

The incidence, severity, and duration of early AKI in high-risk patients undergoing cardiac surgery were significantly reduced after teprasiran administration. A phase 3 study with a major adverse kidney event at day 90 primary outcome that has recently completed enrollment was designed on the basis of these findings (NCT03510897).

Registration::

URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02610283.

项与 Teprasiran 相关的新闻（医药）

2026-04-21

·Intensive Care Medicine

治疗急性肾损伤的新药

治疗急性肾损伤的新药 New drugs for acute kidney injury Citation: Hariri G, Legrand M. New drugs for acute kidney injury. J Intensive Med. 2024;5(1):3–11. doi: 10.1016/j.jointm.2024.08.001. 核心结论急性肾损伤（AKI）在重症及围术期患者中发病率高达30%-60%，目前仍无高级别证据支持的预防或治疗药物。本文系统综述了基于最新病理生理机制（炎症应答、代谢重编程、血流动力学调节、补体活化及细胞凋亡/修复）的在研新药，涵盖碱性磷酸酶、Reltecimod、血管紧张素II、维生素B3类、CD39重组蛋白、Ravulizumab、siRNA QPI-1002及间充质干细胞等。多项II/III期临床试验正在评估其疗效，为降低AKI发生率及严重程度带来新希望。正文急性肾损伤（AKI）是全球性健康问题，每年影响超过1300万人，并导致约170万例死亡[1]。从病理生理角度看，AKI以肾小球滤过率（GFR）快速下降为特征，数小时或数日内表现为血清肌酐急剧升高。2004年之前由于缺乏统一定义，AKI的诊断标准从轻度肌酐升高至需要肾脏替代治疗（RRT）范围广泛[2]。RIFLE、AKIN及KDIGO分级系统的建立，依据血清肌酐和尿量变化提供了结构化诊疗路径，实现了早期识别与干预[3-5]。在重症监护环境中，AKI发病率异质性较大（15%-60%），且与死亡率升高、住院时间延长及慢性肾脏病（CKD）风险增加密切相关[6-8]。尽管过去二十年危重症患者管理取得显著进步，但预防或治疗AKI的有效药物干预仍十分缺乏。近期对AKI病理生理机制的深入理解揭示了炎症、代谢紊乱及细胞修复障碍等共同通路，为新型药物研发提供了方向（图1，表1）。图1：重症及围术期急性肾损伤预防或治疗新药的作用机制概览。HGF: 肝细胞生长因子；MSC: 间充质干细胞。基于上述机制，目前处于研发阶段的药物涵盖了免疫调节、血流动力学优化、细胞能量代谢支持、补体抑制及抗凋亡/促修复等多个维度。下文按照靶点分类逐一阐述代表性药物的临床证据。1. 炎症调控碱性磷酸酶（ALP）可通过去磷酸化脂多糖（LPS）及胞外ATP/ADP，减轻Toll样受体介导的先天免疫反应。STOP-AKI试验（n=301）中，重组ALP（ilofotase alfa）虽未改善7天肾功能，但28天肌酐清除率提升18.5 mL/min（95%CI: 5.3-31.7），死亡率降低（14.4% vs 26.7%）[18]。然而后续III期REVIVAL试验（n=655）未显示28天全因死亡率获益，但MAKE90复合终点（56.7% vs 64.6%, P=0.02）提示可能降低RRT需求[19]。针对CSA-AKI的II期预防试验（NCT06168799）正在进行。 Reltecimod是一种靶向T细胞表面CD28的肽类，可调节脓毒症免疫应答。在坏死性软组织感染III期试验中虽未达到主要复合终点，但第14天SOFA评分改善（65.1% vs 52.6%, P=0.04）[24]。目前针对KDIGO 2-3期AKI合并腹腔脓毒症的III期试验（NCT03403751）正在评估28天AKI恢复率。活性维生素D（骨化三醇）可通过下调核因子κB减轻炎症。但ACTIVATE-AKI试验（NCT02962102）未显示7天内死亡或RRT需求的显著差异。RBT-1（锡原卟啉+蔗糖铁）通过上调HO-1、铁蛋白发挥预适应保护，PROTECT III期研究（n=400）正在进行，主要终点为死亡、透析需求、ICU住院日及30天再入院复合指标。 TIN816（重组CD39）可水解胞外ATP/ADP，抑制炎症及血小板聚集。针对SA-AKI的II期试验（NCT05996835）以第1-8天时间校正肌酐清除率曲线下面积为主要终点；CSA-AKI预防试验（NCT05524051）计划纳入120例患者。2. 血流动力学调节血管紧张素II选择性收缩肾出球小动脉，提升GFR。ATHOS-3试验显示，血管紧张素II显著提高顽固性血管扩张性休克患者3小时平均动脉压（69.9% vs 23.4%, OR=7.95）[46]，且在需RRT的亚组中28天生存率更高（53% vs 30%）[47]。预防CSA-AKI的可行性研究提示AKI发生率降低（25% vs 38%, P=0.31），III期试验（NCT05199493）正在开展。血管加压素：心脏术后血管麻痹性休克患者中，血管加压素较去甲肾上腺素显著降低CSA-AKI（10.3% vs 35.8%, P<0.0001）[52]；但在脓毒性休克中未显示AKI预防获益。个体患者数据Meta分析提示可能降低RRT需求（RR=0.86）。两项RCT（NCT04602767, NCT06125184）将进一步明确。左西孟旦：钙增敏剂兼有入球小动脉扩张作用。心脏手术Meta分析显示可减少CSA-AKI（OR=0.51）及RRT（OR=0.43），但大型RCT未证实获益[57]。LEVO-AKI试验（NCT02531724）正在评估已发生CSA-AKI的治疗效果。3. 细胞代谢与线粒体功能维生素B3类（烟酰胺、烟酰胺核糖）通过补充NAD+保护肾小管。心脏手术II期试验显示烟酰胺使AKI发生率降低35%[59]。多项RCT正在验证其预防CSA-AKI（NCT04750616）、肾移植后移植物功能（NCT05513807）及脓毒性休克相关AKI（NCT04589546）的疗效。ASP1128（PPARδ调节剂）在心脏手术高危患者中未减少AKI发生率（24.6% vs 21%, P=0.595）[62]。SIRT1激活剂NRPT（烟酰胺核糖+紫檀芪）II期试验（NCT04342975）正在主动脉弓置换患者中评估预防效果。表1：重症及围术期急性肾损伤预防/治疗新药汇总药物机制靶点相关临床试验研究人群 Angiotensin II 血流动力学肾出球小动脉 NCT05199493 预防CSA-AKI Angiotensin II 血流动力学肾出球小动脉 NCT04592744 肝移植后AKI预防 Angiotensin II 血流动力学肾出球小动脉 NCT04901169 肝移植后AKI预防 Vasopressin 血流动力学 V1a受体 NCT04602767 预防CSA-AKI Vasopressin 血流动力学 V1a受体 NCT06125184 预防SA-AKI(脓毒性休克) Levosimendan 血流动力学/正性肌力肾入球小动脉 NCT02531724 CSA-AKI治疗 Reltecimod 免疫调节 CD28 NCT03403751 SA-AKI(腹腔脓毒症) Activated vitamin D 免疫调节 NF-κB NCT02962102 高危患者AKI预防 ALP (Ilofotase alfa) 免疫调节 TLR-4/LPS NCT06168799 预防CSA-AKI RBT-1 缺血预适应 HO-1/铁蛋白 PROTECT study 预防CSA-AKI TIN816 ATP/ADP水解 CD39 NCT05996835 SA-AKI TIN816 ATP/ADP水解 CD39 NCT05524051 预防CSA-AKI Vitamin B3 (Nicotinamide) 细胞代谢 NAD+合成 NCT04750616 预防CSA-AKI Nicotinamide 细胞代谢 NAD+ NCT05513807 肾移植后移植物功能延迟 NR (Nicotinamide riboside) NAD+前体 SIRT1 NCT04818216 COVID-19相关AKI ASP1128 PPARδ激动剂脂肪酸氧化 II期(已停止) CSA-AKI高危 NRPT (NR+Pterostilbene) SIRT1激活 NAD+/SIRT1 NCT04342975 主动脉弓置换后AKI预防 Ravulizumab 补体C5抑制剂 C5 NCT05746559 预防CSA-AKI siRNA QPI-1002 抗凋亡 p53 NCT02610296 肾移植后移植物功能延迟 HGF-mimetic (BB3) 细胞修复/抗凋亡 cMet/Bcl-2 NCT02771509 预防CSA-AKI Mesenchymal Stem Cells 免疫调节/修复多靶点 NCT04445220 COVID-19合并RRT Umbilical cord MSC 组织修复多靶点 NCT04194671 AKI治疗补体抑制剂Ravulizumab（长效C5单抗）在COVID-19相关AKI的小样本试验中显示透析需求降低（P=0.03），III期ARTEMIS试验（NCT05746559）正在心脏手术CKD患者中验证其预防CSA-AKI的效果。4. 凋亡抑制与细胞修复 siRNA药物QPI-1002（靶向p53）在心脏手术高危患者中使AKI发生率降低13%（37% vs 50%, P=0.02）[75]，但MAKE90无差异；III期预防试验因无效而终止。HGF模拟物BB3在肾移植后未改善360天eGFR（P=0.32）[80]，GUARD试验（NCT02771509）正在评估其对CSA-AKI的预防效果。间充质干细胞（MSC）在CSA-AKI的II期试验中未显示获益，但体外扩增MSC可能具有免疫修复潜力，相关试验仍在进行（NCT04445220, NCT04194671）。综上所述，目前尚无获批的AKI特效药，但基于精准病理生理靶点的多种药物已进入后期临床试验阶段，为改善重症及手术患者AKI结局带来了切实希望。参考文献 Mehta R.L., Cerdá J., Burdmann E.A., Tonelli M., García-García G., Jha V., et al. International Society of Nephrology's 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): a human rights case for nephrology. Lancet. 2015;385:2616–2643. doi: 10.1016/S0140-6736(15)60126-X. Ricci Z., Cruz D.N., Ronco C. Classification and staging of acute kidney injury: beyond the RIFLE and AKIN criteria. Nat Rev Nephrol. 2011;7(4):201–208. doi: 10.1038/nrneph.2011.14. Bellomo R., Ronco C., Kellum J.A., Mehta R.L., Palevsky P. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8(4):R204–R212. doi: 10.1186/cc2872. Mehta R.L., Kellum J.A., Shah S.V., Molitoris B.A., Ronco C., Warnock D.G., et al. Acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11(2):R31. doi: 10.1186/cc5713. Kellum J.A., Lameire N., Aspelin P., Barsoum R.S., Burdmann E.A., Goldstein S.L., et al. Kidney disease: improving global outcomes (KDIGO) acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl. 2012;2:1–138. doi: 10.1038/kisup.2012.1. Hoste E., Kellum J.A., Selby N.M., Zarbock A., Palevsky P.M., Bagshaw S.M., et al. Global epidemiology and outcomes of acute kidney injury. Nat Rev Nephrol. 2018;14(10):607–625. doi: 10.1038/s41581-018-0052-0. Chaïbi K., Ehooman F., Pons B., Martin-Lefevre L., Boulet E., Boyer A., et al. Long-term outcomes after severe acute kidney injury in critically ill patients: the SALTO study. Ann Intensive Care. 2023;13(1):18. doi: 10.1186/s13613-023-01108-x. Pickkers P., Darmon M., Hoste E., Joannidis M., Legrand M., Ostermann M., et al. Acute kidney injury in the critically ill: an updated review on pathophysiology and management. Intensive Care Med. 2021;47(8):835–850. doi: 10.1007/s00134-021-06454-7. Wang Y., Bellomo R. Cardiac surgery-associated acute kidney injury: risk factors, pathophysiology and treatment. Nat Rev Nephrol. 2017;13(11):697–711. doi: 10.1038/nrneph.2017.119. Legrand M., Bagshaw S.M., Bhatraju P.K., Bihorac A., Caniglia E., Khanna A.K., et al. Sepsis-associated acute kidney injury: recent advances in enrichment strategies, sub-phenotyping and clinical trials. Crit Care. 2024;28(1):92. doi: 10.1186/s13054-024-04877-4. Perazella M.A., Rosner M.H. Drug-Induced Acute Kidney Injury. Clin J Am Soc Nephrol. 2022;17(8):1220–1233. doi: 10.2215/CJN.11290821. Rabb H., Griffin M.D., McKay D.B., Swaminathan S., Pickkers P., Rosner M.H., et al. Inflammation in AKI: current understanding, key questions, and knowledge gaps. J Am Soc Nephrol. 2016;27(2):371–379. doi: 10.1681/ASN.2015030261. McWilliam S.J., Wright R.D., Welsh G.I., Tuffin J., Budge K.L., Swan L., et al. The complex interplay between kidney injury and inflammation. Clin Kidney J. 2021;14(3):780–788. doi: 10.1093/ckj/sfaa164. Schenck E.J., Ma K.C., Murthy S.B., Choi A. Danger signals in the ICU. Crit Care Med. 2018;46(5):791–798. doi: 10.1097/CCM.0000000000003007. Bentala H., Verweij W.R., Huizinga-Van der Vlag A., van Loenen-Weemaes A.M., Meijer D.K., Poelstra K. Removal of phosphate from lipid A as a strategy to detoxify lipopolysaccharide. Shock. 2002;18(6):561–566. doi: 10.1097/00024382-200212000-00013. Wy C.A., Goto M., Young R.I., Myers T.F., Muraskas J. Prophylactic treatment of endotoxic shock with monophosphoryl lipid A in newborn rats. Biol Neonate. 2000;77(3):191–195. doi: 10.1159/000014215. Peters E., Heemskerk S., Masereeuw R., Pickkers P. Alkaline phosphatase: a possible treatment for sepsis-associated acute kidney injury in critically ill patients. Am J Kidney Dis. 2014;63(6):1038–1048. doi: 10.1053/j.ajkd.2013.11.027. Pickkers P., Mehta R.L., Murray P.T., Joannidis M., Molitoris B.A., Kellum J.A., et al. Effect of human recombinant alkaline phosphatase on 7-day creatinine clearance in patients with sepsis-associated acute kidney injury: a randomized clinical trial. JAMA. 2018;320(19):1998–2009. doi: 10.1001/jama.2018.14283. Pickkers P., Angus D.C., Bass K., Bellomo R., van den Berg E., Bernholz J., et al. Phase-3 trial of recombinant human alkaline phosphatase for patients with sepsis-associated acute kidney injury (REVIVAL) Intens Care Med. 2024;50(1):68–78. doi: 10.1007/s00134-023-07271-w. Ramachandran S., Subramanian V., Mohanakumar T. Immune responses to self-antigens (autoimmunity) in allograft rejection. Clin Transpl. 2012:261–272. Ramachandran G., Kaempfer R., Chung C.S., Shirvan A., Chahin A.B., Palardy J.E., et al. CD28 homodimer interface mimetic peptide acts as a preventive and therapeutic agent in models of severe bacterial sepsis and gram-negative bacterial peritonitis. J Infect Dis. 2015;211(6):995–1003. doi: 10.1093/infdis/jiu556. Edgar R., Tarrio M.L., Maislin G., Chiguang F., Kaempfer R., Cross A., et al. Treatment with one dose of Reltecimod is superior to two doses in mouse models of lethal infection. Int J Pept Res Ther. 2020;26:1669–1683. doi: 10.1007/s10989-019-09974-5. Bulger E.M., Maier R.V., Sperry J., Joshi M., Henry S., Moore F.A., et al. A novel drug for treatment of necrotizing soft-tissue infections: a randomized clinical trial. JAMA Surg. 2014;149(6):528–536. doi: 10.1001/jamasurg.2013.4841. Bulger E.M., May A.K., Robinson B., Evans D.C., Henry S., Green J.M., et al. A novel immune modulator for patients with necrotizing soft tissue infections (NSTI): results of a multicenter, phase 3 randomized controlled trial of reltecimod (AB 103) Ann Surg. 2020;272(3):469–478. doi: 10.1097/SLA.0000000000004102. Keung L., Perwad F. Vitamin D and kidney disease. Bone Rep. 2018;9:93–100. doi: 10.1016/j.bonr.2018.07.002. Al-Badr W., Martin K.J. Vitamin D and kidney disease. Clin J Am Soc Nephrol. 2008;3(5):1555–1560. doi: 10.2215/CJN.01150308. Graidis S., Papavramidis T.S., Papaioannou M. Vitamin D and acute kidney injury: a two-way causality relation and a predictive, prognostic, and therapeutic role of vitamin D. Front Nutr. 2021;7 doi: 10.3389/fnut.2020.630951. Xu S., Chen Y.H., Tan Z.X., Xie D.D., Zhang C., Zhang Z.H., et al. Vitamin D3 pretreatment regulates renal inflammatory responses during lipopolysaccharide-induced acute kidney injury. Sci Rep. 2015;5:18687. doi: 10.1038/srep18687. Vervloet M.G., Hsu S., de Boer I.H. Vitamin D supplementation in people with chronic kidney disease. Kidney Int. 2023;104(4):698–706. doi: 10.1016/j.kint.2023.07.010. Zhang H., Jiang Y., Shi N., Lu Y.Q. Serum vitamin D levels and acute kidney injury: a systemic review and meta-analysis. Sci Rep. 2022;12(1):20365. doi: 10.1038/s41598-022-24560-4. Leaf D.E., Jacob K.A., Srivastava A., Chen M.E., Christov M., Jüppner H., et al. Fibroblast growth factor 23 levels associate with AKI and death in critical illness. J Am Soc Nephrol. 2017;28(6):1877–1885. doi: 10.1681/ASN.2016080836. Eltzschig H.K., Eckle T. Ischemia and reperfusion–from mechanism to translation. Nat Med. 2011;17(11):1391–1401. doi: 10.1038/nm.2507. Huang Y., Rabb H., Womer K.L. Ischemia-reperfusion and immediate T cell responses. Cell Immunol. 2007;248(1):4–11. doi: 10.1016/j.cellimm.2007.03.009. Li C., Jackson R.M. Reactive species mechanisms of cellular hypoxia-reoxygenation injury. Am J Physiol Cell Physiol. 2002;282(2):C227–C241. doi: 10.1152/ajpcell.00112.2001. Zhang M., Liu Q., Meng H., Duan H., Liu X., Wu J., et al. Ischemia-reperfusion injury: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther. 2024;9(1):12. doi: 10.1038/s41392-023-01688-x. Lamy A., Chertow G.M., Jessen M., Collar A., Brown C.D., Mack C.A., et al. Effects of RBT-1 on preconditioning response biomarkers in patients undergoing coronary artery bypass graft or heart valve surgery: a multicentre, double-blind, randomised, placebo-controlled phase 2 trial. EClinicalMedicine. 2024;68 doi: 10.1016/j.eclinm.2023.102364. Priyan V. Renibus begins subject dosing in phase III trial of RBT-1. Clinical Trials Arena. 2023 Cauwels A., Rogge E., Vandendriessche B., Shiva S., Brouckaert P. Extracellular ATP drives systemic inflammation, tissue damage and mortality. Cell Death Dis. 2014;5(3):e1102. doi: 10.1038/cddis.2014.70. Woulfe D., Yang J., Brass L. ADP and platelets: the end of the beginning. J Clin Invest. 2001;107:1503–1505. doi: 10.1172/JCI13361. Eltzschig H.K., Köhler D., Eckle T., Kong T., Robson S.C., Colgan S.P. Central role of Sp1-regulated CD39 in hypoxia/ischemia protection. Blood. 2009;113(1):224–232. doi: 10.1182/blood-2008-06-165746. Hayes G.M., Cairns B., Levashova Z., Chinn L., Perez M., Theunissen J.W., et al. CD39 is a promising therapeutic antibody target for the treatment of soft tissue sarcoma. Am J Transl Res. 2015;7(6):1181–1188. Granja T., Körner A., Glück C., Hohmann J.D., Wang X., Köhler D., et al. Targeting CD39 toward activated platelets reduces systemic inflammation and improves survival in sepsis: a preclinical pilot study. Crit Care Med. 2019;47(5) doi: 10.1097/CCM.0000000000003682. e420-420e427. Bellomo R., Forni L.G., Busse L.W., McCurdy M.T., Ham K.R., Boldt D.W., et al. Renin and survival in patients given angiotensin II for catecholamine-resistant vasodilatory shock. A clinical trial. Am J Respir Crit Care Med. 2020;202(9):1253–1261. doi: 10.1164/rccm.201911-2172OC. Küllmar M., Saadat-Gilani K., Weiss R., Massoth C., Lagan A., Cortés M.N., et al. Kinetic changes of plasma renin concentrations predict acute kidney injury in cardiac surgery patients. Am J Respir Crit Care Med. 2021;203(9):1119–1126. doi: 10.1164/rccm.202005-2050OC. Chawla L.S., Busse L., Brasha-Mitchell E., Davison D., Honiq J., Alotaibi Z., et al. Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): a pilot study. Crit Care. 2014;18(5):534. doi: 10.1186/s13054-014-0534-9. Khanna A., English S.W., Wang X.S., Ham K., Tumlin J., Szerlip H., et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med. 2017;377(5):419–430. doi: 10.1056/NEJMoa1704154. Tumlin J.A., Murugan R., Deane A.M., Ostermann M., Busse L.W., Ham K.R., et al. Outcomes in patients with vasodilatory shock and renal replacement therapy treated with intravenous angiotensin II. Crit Care Med. 2018;46(6):949–957. doi: 10.1097/CCM.0000000000003092. Bokoch M.P., Tran A.T., Brinson E.L., Marcus S.G., Reddy M., Sun E., et al. Angiotensin II in liver transplantation (AngLT-1): protocol of a randomised, double-blind, placebo-controlled trial. BMJ Open. 2023;13(11) doi: 10.1136/bmjopen-2023-078713. Coulson T.G., Miles L.F., Serpa Neto A., Pilcher D., Weinberg L., Landoni G., et al. A double-blind randomised feasibility trial of angiotensin-2 in cardiac surgery( Anaesthesia. 2022;77(9):999–1009. doi: 10.1111/anae.15802. Finley J.J., 4th, Konstam M.A., Udelson J.E. Arginine vasopressin antagonists for the treatment of heart failure and hyponatremia. Circulation. 2008;118(4):410–421. doi: 10.1161/CIRCULATIONAHA.108.765289. Okazaki N., Iguchi N., Evans R.G., Hood S.G., Bellomo R., May C.N., et al. Beneficial effects of vasopressin compared with norepinephrine on renal perfusion, oxygenation, and function in experimental septic acute kidney injury. Crit Care Med. 2020;48(10) doi: 10.1097/CCM.0000000000004511. e951-951e958. Hajjar L.A., Vincent J.L., Barbosa Gomes Galas F.R., Rhodes A., Landoni G., Osawa E.A., et al. Vasopressin versus norepinephrine in patients with vasoplegic shock after cardiac surgery: the VANCS randomized controlled trial. Anesthesiology. 2017;126(1):85–93. doi: 10.1097/ALN.0000000000001434. Gordon A.C., Mason A.J., Thirunavukkarasu N., Perkins G.D., Cecconi M., Cepkova M., et al. Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: the VANISH randomized clinical trial. JAMA. 2016;316(5):509–518. doi: 10.1001/jama.2016.10485. Hajjar L.A., Zambolim C., Belletti A., de Almeida J.P., Gordon A.C., Oliveira G., et al. Vasopressin versus norepinephrine for the management of septic shock in cancer patients: the VANCS II randomized clinical trial. Crit Care Med. 2019;47(12):1743–1750. doi: 10.1097/CCM.0000000000004023. Pan J., Yang Y.M., Zhu J.Y., Lu Y.Q. Multiorgan drug action of levosimendan in critical illnesses. Biomed Res Int. 2019;2019 doi: 10.1155/2019/9731467. Zhou C., Gong J., Chen D., Wang W., Liu M., Liu B. Levosimendan for prevention of acute kidney injury after cardiac surgery: a meta-analysis of randomized controlled trials. Am J Kidney Dis. 2016;67:408–416. doi: 10.1053/j.ajkd.2015.09.015. Landoni G., Lomivorotov V.V., Alvaro G., Lobreglio R., Pisano A., Guarracino F., et al. Levosimendan for hemodynamic support after cardiac surgery. N Engl J Med. 2017;376(21):2021–2031. doi: 10.1056/NEJMoa1616325. Gordon A.C., Perkins G.D., Singer M., McAuley D.F., Orme R.M., Santhakumaran S., et al. Levosimendan for the prevention of acute organ dysfunction in sepsis. N Engl J Med. 2016;375(17):1638–1648. doi: 10.1056/NEJMoa1609409. Poyan Mehr A., Tran M.T., Ralto K.M., Leaf D.E., Washco V., Messmer J., et al. De novo NAD(+) biosynthetic impairment in acute kidney injury in humans. Nat Med. 2018;24(9):1351–1359. doi: 10.1038/s41591-018-0138-z. Gao J., Gu Z. The role of peroxisome proliferator-activated receptors in kidney diseases. Front Pharmacol. 2022;13 doi: 10.3389/fphar.2022.832732. Taniuchi Y., van Till J.W.O., Wojtkowski T., Toyoshima J., Koibuchi A., Sargent B., et al. Single- and multiple-dose safety, tolerability, pharmacokinetics, and pharmacodynamics of ASP1128, a novel peroxisome proliferator-activated receptor δ modulator, in healthy participants. Clin Pharmacol Drug Dev. 2023;12:810–818. doi: 10.1002/cpdd.1236. van Till J.W.O., Nojima H., Kameoka C., Hayashi C., Sakatani T., Washburn T.B., et al. The effects of peroxisome proliferator-activated receptor-delta modulator ASP1128 in patients at risk for acute kidney injury following cardiac surgery. Kidney Int Rep. 2023;8:1407–1416. doi: 10.1016/j.ekir.2023.04.004. Guan Y., Wang S.R., Huang X.Z., Xie Q.H., Xu Y.Y., Shang D., et al. Nicotinamide mononucleotide, an NAD+ precursor, rescues age-associated susceptibility to AKI in a Sirtuin 1–dependent manner. J Am Soc Nephrol. 2017;28:2337–2352. doi: 10.1681/ASN.2016040385. Guan Y., Hao C.M. SIRT1 and kidney function. Kidney Dis (Basel) 2016;1:258–265. doi: 10.1159/000440967. Peasley K., Chiba T., Goetzman E., Sims-Lucas S. Sirtuins play critical and diverse roles in acute kidney injury. Pediatr Nephrol. 2021;36:3539–3546. doi: 10.1007/s00467-020-04866-z. Simic P., Vela Parada X.F., Parikh S.M., Dellinger R., Guarente L.P., Rhee E.P. Nicotinamide riboside with pterostilbene (NRPT) increases NAD+ in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI. BMC Nephrol. 2020;21:342. doi: 10.1186/s12882-020-02006-1. Fakhouri F., Schwotzer N., Golshayan D., Frémeaux-Bacchi V. The rational use of complement inhibitors in kidney diseases. Kidney Int Rep. 2022;7:1165–1178. doi: 10.1016/j.ekir.2022.02.021. Sheridan D., Yu Z.X., Zhang Y., Patel R., Sun F., Lasaro M.A., et al. Design and preclinical characterization of ALXN1210: a novel anti-C5 antibody with extended duration of action. PLoS ONE. 2018;13 doi: 10.1371/journal.pone.0195909. Memon A.A., Ahmed H., Li Y., Wongboonsin J., Hundert J., Benoit S., et al. A randomized control trial of ravulizumab for treatment of patients with COVID-19 infection and kidney injury. Kidney Int Rep. 2022;7:2714–2717. doi: 10.1016/j.ekir.2022.09.003. Olsen T.S., Olsen H.S., Hansen H.E. Tubular ultrastructure in acute renal failure in man: epithelial necrosis and regeneration. Virchows Arch A Pathol Anat Histopathol. 1985;406:75–89. doi: 10.1007/BF00710559. Sanz A.B., Sanchez-Niño M.D., Ramos A.M., Ortiz A. Regulated cell death pathways in kidney disease. Nat Rev Nephrol. 2023;19:281–299. doi: 10.1038/s41581-023-00694-0. Tang C., Ma Z., Zhu J., Liu Z., Liu Y., Liu Y., et al. P53 in kidney injury and repair: mechanism and therapeutic potentials. Pharmacol Ther. 2019;195:5–12. doi: 10.1016/j.pharmthera.2018.10.013. Wei Q., Dong G., Yang T., Megyesi J., Price P.M., Dong Z. Activation and involvement of p53 in cisplatin-induced nephrotoxicity. Am J Physiol Renal Physiol. 2007;293:F1282–F1291. doi: 10.1152/ajprenal.00230.2007. Peddi V.R., Ratner L., Cooper M., Gaber O., Feng S., Tso P., et al. Treatment with QPI-1002, a short interfering (SI) RNA for the prophylaxis of delayed graft function.: abstract# 2967. Transplantation. 2014;98:153. doi: 10.1097/00007890-201407151-00467. Thielmann M., Corteville D., Szabo G., Swaminathan M., Lamy A., Lehner L.J., et al. Teprasiran, a small interfering RNA, for the prevention of acute kidney injury in high-risk patients undergoing cardiac surgery: a randomized clinical study. Circulation. 2021;144:1133–1144. doi: 10.1161/CIRCULATIONAHA.120.053029. Kawaida K., Matsumoto K., Shimazu H., Nakamura T. Hepatocyte growth factor prevents acute renal failure and accelerates renal regeneration in mice. Proc Natl Acad Sci U S A. 1994;91:4357–4361. doi: 10.1073/pnas.91.10.4357. Zhou D., Tan R.J., Lin L., Zhou L., Liu Y. Activation of hepatocyte growth factor receptor, c-met, in renal tubules is required for renoprotection after acute kidney injury. Kidney Int. 2013;84:509–520. doi: 10.1038/ki.2013.102. Narayan P., Duan B., Jiang K., Li J., Paka L., Yamin M.A., et al. Late intervention with the small molecule BB3 mitigates postischemic kidney injury. Am J Physiol Renal Physiol. 2016;311:F352–F361. doi: 10.1152/ajprenal.00455.2015. Bromberg J.S., Weir M.R., Gaber A.O., Yamin M.A., Goldberg I.D., Mayne T.J., et al. Renal function improvement following ANG-3777 treatment in patients at high risk for delayed graft function after kidney transplantation. Transplantation. 2021;105:443–450. doi: 10.1097/TP.0000000000003255. Vincenti F., Bromberg J., Kim J., Faravardeh A., Leca N., Alperovich G., et al. The hepatocyte growth factor mimetic, ANG-3777, in kidney transplant recipients with delayed graft function: results from a randomized phase 3 trial. Am J Transplant. 2024 doi: 10.1016/j.ajt.2024.02.014. S1600-6135(24)00156-4. Ayad S., Neylan J.F., Mayne T.J., Gouveia D., Swaminathan M. Hepatocyte growth factor mimetic ANG-3777 for cardiac surgery-associated acute kidney injury. Kidney Int Rep. 2020;5(12):2325–2332. doi: 10.1016/j.ekir.2020.09.031. Allinson C.S., Pollock C.A., Chen X. Mesenchymal stem cells in the treatment of acute kidney injury (AKI), chronic kidney disease (CKD) and the AKI-to-CKD transition. Intgr Med Nephrol Androl. 2023;10:e00014. doi: 10.1097/IMNA-D-22-00014. Swaminathan M., Stafford-Smith M., Chertow G.M., Warnock D.G., Paragamian V., Brenner R.M., et al. Allogeneic mesenchymal stem cells for treatment of AKI after cardiac surgery. J Am Soc Nephrol. 2018;29:260–267. doi: 10.1681/ASN.2016101150. Swaminathan M., Kopyt N., Atta M.G., Radhakrishnan J., Umanath K., Nguyen S., et al. Pharmacological effects of ex vivo mesenchymal stem cell immunotherapy in patients with acute kidney injury and underlying systemic inflammation. Stem Cell Transl Med. 2021;10:1588–1601. doi: 10.1002/sctm.21-0043. 如果这篇文献综述对您的临床工作有所帮助，欢迎点击文末的“赞”与“推荐(小爱心)”，或转发分享至科室群，让更多同道看到本文；也期待您在留言区留下宝贵见解，与我们交流临床实践中的类似挑战。【获取完整版原文】请点击左下角「阅读原文」下载完整 PDF 文件。

2023-10-25

·SYNAPSE

Analysis on the Research Progress of p53 inhibitors

p53 inhibitors are a class of chemical compounds that target and inhibit the function of the p53 protein. The p53 protein, also known as the tumor protein 53, is a critical regulator of cell cycle progression, DNA repair, and apoptosis (programmed cell death). It acts as a tumor suppressor by preventing the proliferation of cells with damaged DNA or mutations that could lead to cancer development. In normal conditions, the p53 protein is tightly regulated and maintained at low levels in the cell. However, in response to various stress signals such as DNA damage, oncogene activation, or hypoxia, the levels and activity of p53 can increase. Activated p53 induces cell cycle arrest, allowing time for DNA repair, or triggers apoptosis if the DNA damage is irreparable. This mechanism helps to maintain genomic stability and prevent the survival and propagation of cells with potentially harmful mutations. p53 inhibitors interfere with the normal function of the p53 protein and are primarily used as research tools to study the biological effects of p53 inactivation. By inhibiting p53, these chemicals allow researchers to investigate the consequences of p53 loss or reduced activity in cellular processes and disease models. There are several types of p53 inhibitors, and they can target different aspects of p53 function. One common approach is to disrupt the interaction between p53 and its negative regulator, MDM2 (mouse double minute 2). MDM2 binds to p53 and promotes its degradation, thereby regulating its levels in the cell. Inhibitors that interfere with the p53-MDM2 interaction prevent MDM2 from tagging p53 for degradation, leading to increased levels and activity of p53. Overall, the p53 pathway is highly complex and involves numerous interactions with other proteins and regulatory mechanisms. Many p53 inhibitors bind directly to the p53 protein and disrupt it's interaction with other proteins involved in p53 signaling pathways. These inhibitors can also interfere with the ability of p53 to activate downstream genes involved in cell cycle arrest or apoptosis. p53 is a crucial protein that plays a vital role in maintaining the integrity of the human body. It acts as a tumor suppressor by regulating cell division and preventing the formation of cancerous cells. p53 monitors DNA damage and initiates repair mechanisms, halting cell division if the damage is irreparable. Additionally, it promotes programmed cell death (apoptosis) to eliminate cells with severe DNA damage. p53 also regulates various cellular processes, including metabolism, angiogenesis, and immune response. Its significance in preventing cancer and maintaining genomic stability makes p53 an essential protein in the human body. p53 Competitive LandscapeAccording to Patsnap Synapse, as of 5 Oct 2023, there are a total of 136 p53 drugs worldwide, from 154 organizations, covering 107 indications, and conducting 211 clinical trials. 👇Please click on the picture link below for free registration or login directly if you have freemium accounts, you can browse the latest research progress on drugs , indications, organizations, clinical trials, clinical results, and drug patents related to this target. The analysis of the current competitive landscape and future development of target p53 reveals a diverse and dynamic pharmaceutical industry. Aprea Therapeutics, Inc. is a key player in the development of drugs targeting p53, with a strong focus on advancing their drugs through clinical trials. The indications for target p53 cover a wide range of diseases and conditions, indicating its potential in various therapeutic areas. The presence of multiple drug types and the intense competition around biosimilars suggest a diverse and innovative approach to targeting p53. China, the United States, and other countries/locations are actively involved in the development of drugs targeting p53, with China showing significant progress. Overall, the future development of target p53 holds promise for advancements in the treatment of various diseases and conditions. Key drug：TeprasiranTeprasiran is a small interfering RNA (siRNA) drug that targets the p53 protein. It is being developed by Silence Therapeutics Plc, a pharmaceutical company specializing in RNA interference (RNAi) therapeutics. The drug is currently in Phase 3, which is the final stage of clinical trials before seeking regulatory approval. Teprasiran is primarily being investigated for its potential use in treating urogenital diseases and other diseases. Specifically, it is being studied for its efficacy in treating acute kidney injury and delayed graft function. These conditions are characterized by damage to the kidneys, which can lead to impaired kidney function and potentially life-threatening complications. 👇Please click on the image below to directly access the latest data (R&D Status | Core Patent | Clinical Trial | Approval status in Global countries) of this drug. One notable aspect of Teprasiran is its regulatory status as an orphan drug. Orphan drugs are medications developed to treat rare diseases or conditions that affect a small number of patients. The designation provides certain incentives and benefits to the drug developer, such as extended market exclusivity and financial support for clinical trials. siRNA drugs like Teprasiran work by interfering with the expression of specific genes, in this case, the p53 gene. The p53 protein is known as the "guardian of the genome" and plays a crucial role in regulating cell growth and preventing the formation of tumors. By targeting p53, Teprasiran aims to modulate its activity and potentially provide therapeutic benefits in the treatment of urogenital diseases and other conditions. As Teprasiran is currently in Phase 3, it is undergoing rigorous testing to evaluate its safety and efficacy in a larger patient population. The results of these trials will determine whether the drug can proceed to regulatory approval and ultimately be made available to patients. In summary, Teprasiran is a siRNA drug developed by Silence Therapeutics Plc that targets the p53 protein. It is being investigated for its potential use in treating urogenital diseases and other conditions, specifically acute kidney injury and delayed graft function. With its orphan drug designation and current Phase 3 status, Teprasiran holds promise as a potential therapeutic option for patients in need.

2022-07-29

·行舟Drug

独家原创|全球基因治疗药物研发现状分析

点击上方的行舟Drug ▲ 添加关注全球基因治疗药物研发现状分析 PPS 朱凌峰，王中健*（药融云数字科技（成都）有限公司，四川成都610000）[摘要]随着DNA重组、基因克隆等技术的逐步成熟，基因治疗这一具有革命性的医疗技术不断发展，改变了单基因遗传病的治疗现状，为肿瘤、遗传性疾病、自身免疫性疾病等带来了新的选择。截至2022年2月，全球已有37款基因治疗药物获批上市。通过对1998年至2022年2月全球范围内获批上市的基因治疗药物进行数据监控与分析，包括药物分类、药物名称、适应证、批准日期、批准国家、研发公司等，并且对全球在研基因治疗药物的研发现状进行分析总结，以期为基因治疗药物的立项与研发提供参考。1基因治疗药物概述1968年，美国科学家迈克尔·布莱泽发表了《改变基因缺损：医疗美好前景》的文章，首次在医学界提出了基因治疗的概念[1]。基因治疗是以改变人的遗传物质为基础的生物医学治疗手段，是指将外源正常基因导入靶细胞，以纠正或补偿因基因缺陷或基因表达异常引起的疾病，从而达到治疗疾病的目的[2]。美国食品药品监督管理局（Food and Drug Administration，FDA）对基因治疗定义为：基因治疗是一种通过改变人的基因来治疗或治愈疾病的技术。基因治疗可以通过以下几种机制发挥作用：1）用一个正常基因来替换致病基因；2）使不能正常发挥作用的致病基因失活；3）将一种新的或经过修饰的基因导入体内以帮助治疗疾病。基因治疗药物，是指经过药物监管机构批准的用于治疗人体相关疾病的基因类产品[3]。从1998年全球首款基因治疗药物上市到2015年期间，断断续续有少量基因治疗药物获批；从2016年开始，每年都有多款基因治疗药物获批上市。截至2022年2月，全球共有37款基因治疗药物获批上市，从1998年到2022年2月，每年基因治疗药物获批上市的数量如图1所示。基因治疗药物按照结构可划分为核酸类药物、重组病毒类药物以及细胞治疗类药物。其中核酸药物按照种类又可划分为DNA药物（裸质粒等）、RNA药物[干扰RNA（RNAi）等]及反义寡核苷酸药物，其作用原理是借助一定载体将核酸药物传送进细胞内并进行复制转录继而从基因层面起到治疗效果；重组病毒类药物是利用人工修饰过的病毒选择性进攻人体病灶部位，以起到治疗疾病的目的，该类药物目前大多用于治疗癌症；细胞治疗类药物以细胞为主体通过基因工程技术对相关功能细胞进行改造，改造后的细胞直接输送回病人体内用以治疗相关疾病。已上市37款基因治疗药物中，核酸类药物共计15款，其中裸质粒2款，反义寡核苷酸9款，RNAi4款；重组病毒类药物9款；细胞治疗类药物13款（见图2）。从获批药物的疾病领域来看，近一半是罕见病，其次是肿瘤（见图3）。针对肿瘤的基因治疗主要是嵌合抗原受体T细胞免疫疗法（chimeric antigen receptor T-Cell immunotherapy，CAR-T）药物和溶瘤病毒药物。从获批药物使用的载体来看，裸质粒/寡核苷酸最多，其次是慢病毒和逆转录病毒载体（见图4）。本文将分别按照核酸类药物、重组病毒类药物和细胞治疗类药物对目前已经上市的基因治疗药物以及全球研发现状进行介绍。2核酸类药物2.1裸质粒截至2022年2月，全球共有2个裸质粒药物获批上市，分别为2011年在俄罗斯上市的Neovasculgen（cambiogenplasmid）和2019年在日本上市的Collategene（beperminogene perplasmid）（见表1）。Neovasculgen是一个编码血管内皮生长因子基因的质粒，注射到人体内后，表达出的血管内皮生长因子能够促进血管的生成，从而改善患者的生活质量[4]。Collategene是一种编码肝细胞生长因子基因的质粒，注射到人体内后，表达出的肝细胞生长因子能够促进血管的生成，从而治疗缺血性疾病。相关研究表明[5-6]，病毒载体介导的促血管生成因子基因的传递诱导了小鼠心脏血管瘤的形成，将表达血管内皮生长因子的基因工程细胞注入到正常肌肉中，术后24d后也可以观察到血管瘤的形成。因此，为避免促血管生成因子的长期表达，裸质粒是一个很好的选择。目前裸质粒的主要开发方向就是编码促血管生成因子基因。截至2022年2月，全球处于已上市及在研状态的裸质粒基因治疗药物共计39个（见图5）。目前处于Ⅲ期临床的2款药物的相关信息如表2所示。重组质粒-肝细胞生长因子注射液（pUDK-HGF）是由中国人民解放军军事医学科学院放射与辐射医学研究所研发，人福医药合作开发的裸质粒药物。其治疗严重下肢缺血性疾病导致的肢体静息痛的Ⅲ期临床试验（CTR20181274）正在进行中，首次公示日期为2018年8月9日，主要临床机构为首都医科大学宣武医院。由Helixmith公司研发的重组人肝细胞生长因子裸质粒注射液（NL-003）目前正在全球范围内开展临床试验，其在中国的开发由北京诺思兰德生物技术股份有限公司进行，目前治疗下肢缺血性疾病的Ⅲ期临床试验（CTR20190746和CTR20190750）正在进行中，首次公示日期为2019年4月17日，主要临床机构为北京协和医院。2.2 反义寡核苷酸反义寡核苷酸是一种单链寡核苷酸分子，通常包含15~25个核苷酸残基。其进入细胞后在核糖核酸酶H1的作用下通过碱基互补配对原则同与其互补的靶信使核糖核酸（messenger RNA，mRNA）结合，抑制靶基因的表达。截至2022年2月，全球共有9款反义寡核苷酸药物获批上市（见表3）。1998年，美国FDA批准了首款基因治疗药物Vitravene（fomivirsen），Vitravene是一种反义寡核苷酸，可用于治疗局部免疫缺陷患者（包括获得性免疫缺陷综合征患者）的巨细胞病毒视网膜炎，但是，由于更高效抗逆转录病毒治疗药物的开发，Vitravene于2002年退出欧洲市场，并于2006年退出美国市场[7]。2013年，美国FDA批准了一款包含载脂蛋白B-100的反义寡核苷酸药物Kynamro（mipomersen）用于治疗纯合子家族性高胆固醇血症[8]。2016年，有2个反义寡核苷酸药物获得美国FDA批准，分别为Spinraza（nusinersen）和Exondys51（eteplirsen）。Spinraza用于治疗脊髓性肌萎缩，Exondys51用于治疗杜氏肌营养不良症[9-10]。2018年7月，Tegsedi（inotersen）作为一款反义寡核苷酸药物获得欧盟药品管理局（European Medicines Agency，EMA）的批准，用于治疗遗传性甲状腺淀粉样变性[11]。2019年，Waylivra（volanesorsen）获得了EMA批准用于治疗成年人家族性乳糜微粒血症综合征[12]。Vyondys53（golodirsen）获得了FDA批准用于治疗杜氏肌营养不良症[13]。2020年，日本独立行政法人医药品医疗器械综合机构（Pharmaceuticals and Medical Devices Agency，PMDA）批准了Viltepso（viltolarsen），用于治疗杜氏肌营养不良症[14]。2021年，FDA批准了Amondys45（casimersen）用于治疗杜氏肌营养不良症[15]。从治疗领域来看，除了已经退市的Vitravene外，全部是罕见病治疗领域，其中有4个适应证为杜氏肌营养不良症。从开发公司来看，小核酸药物研发公司Ionis公司占5个，Sarepta公司占3个。截至2022年2月，全球处于已上市及在研状态的反义寡核苷酸基因治疗药物共计345个，临床前180个，进入临床阶段的共计90个（见图6）。其中，目前处于Ⅲ期临床的13款药物如表4所示。Alicaforsen是细胞间黏附分子-1的反义抑制剂，最新的针对结肠袋炎的Ⅲ期临床效果不佳，未达到预期主要终点，经内窥镜评估缓解率，与安慰剂相比并无改善（4.6% vs. 4.9%）。Sepofarsen是一种旨在解决CEP290基因中p.Cys998X突变引起的莱伯先天性黑内障的反义寡核苷酸，p.Cys998X突变会导致mRNA的异常剪接和中心体蛋白290（centrosomal protein of 290 kDa，CEP290）失去功能，sepofarsen通过结合到pre-mRNA的突变位置，使得产生正常的CEP290[16]。Imetelstat是一种端粒酶抑制剂，在治疗骨髓增生异常综合征的Ⅱ/Ⅲ期临床试验IMerge中，imetelstat取得了积极的临床效果，持续8周输血不依赖率达到34.3%，而其中未接受过低甲基化药物或来那度胺治疗，且无染色体5q缺失的持续8周输血不依赖率达到53.8%[17]。AKCEA-APOCIII-LRx是由Ionis公司专有的配体共轭反义技术平台开发的反义寡核苷酸药物，能够抑制载脂蛋白C-Ⅲ（apolipoprotein C-Ⅲ，ApoC Ⅲ）的产生。ApoC Ⅲ是一种在肝脏中产生的蛋白质，在血清三酰甘油的调节中发挥着核心作用。Trabedersen是TGF-β2基因mRNA区域的反义互补物，通过下调TGF-β2mRNA发挥抑制作用。在Ⅱ期临床研究中，与标准化疗治疗相比，使用10mmol·L-1trabedersen治疗的复发/难治性晚期胶质瘤患者的2年生存率更高。亨廷顿舞蹈症的主要机制为患者4号染色体上的亨廷顿基因CAG三核苷酸重复扩增，从而导致亨廷顿蛋白质具有延伸的聚谷氨酰胺束，并在细胞内积聚成大分子团，影响神经元的正常功能[18]。Tominersen可以在核糖核酸酶H1的作用下通过碱基互补配对原则与其互补的靶mRNA结合，抑制靶基因的表达。基于这一原理，tominersen可靶向相应的mRNA以防止蛋白质产生，基于非盲独立数据监测委员会对受试者的潜在风险/收益比提出了意见，罗氏于2021年3月宣布终止tominersen治疗显性亨廷顿舞蹈症的Ⅲ期GENERATION HD1临床的给药工作。携带肉瘤融合基因（fused in sarcoma，FUS）突变的患者会发展成罕见形式的肌萎缩侧索硬化症（amyotrophic lateral sclerosis，ALS），即FUS-ALS，FUS基因突变是青少年ALS最常见的病因。ION-363是一种靶向FUS mRNA的反义药物，以减少FUS蛋白质的产生。在FUS-ALS小鼠模型中，反义介导的突变FUS蛋白质减少可以防止运动神经元丢失。通过靶向FUS-ALS的根本病因，ION-363有潜力减少或防止患者的病情进展。Aganirsen可抑制胰岛素受体底物1（insulin receptor substrate 1，IRS1）的表达，被研究用于角膜和视网膜新生血管的治疗。Tofersen是一种反义寡核苷酸药物，旨在降低超氧化物歧化酶1（superoxide dismutase1，SOD1）的mRNA，从而降低SOD1蛋白，在对SOD1-ALS的Ⅲ期临床试验VALOR中，与安慰剂相比，tofersen在其主要终点上并没有取得统计上显著的改善。Eplontersen是一种靶向转甲状腺素的反义寡核苷酸药物。Pelacarsen是首个靶向脂蛋白（a）[lipoprotein（a），Lp（a）]的反义寡核苷酸降脂药，pelacarsen的Ⅱb期临床试验研究显示，98%的患者Lp（a）水平降至50mg·dL-1以下的适宜水平。ION-373是一种靶向胶质纤维酸性蛋白mRNA的反义寡核苷酸药物，FDA已授予ION-373孤儿药资格认定。Donidalorsen是一种抑制前激肽释放酶产生的反义寡核苷酸药物，前激肽释放酶在遗传性血管性水肿急性发作相关的炎症介质激活中起关键作用，该药物治疗遗传性血管性水肿的Ⅲ期临床正在进行中，Ⅱ期临床试验研究显示，与安慰剂组相比，donidalorsen可减少遗传性血管性水肿的发作。2.3 RNA干扰药物截至2022年2月，全球共有4款RNAi药物获批上市（见表5），4款RNAi药物都是小干扰RNA（small interfering RNA，siRNA）药物，siRNA进入细胞后，与解旋酶和其他因子结合，形成RNA诱导沉默复合物（RNA-induced silencing complex，RISC），RISC与mRNA结合，使得mRNA降解。2018年，Onpattro（patisiran）作为首个RNAi药物获得FDA和EMA的许可，用于治疗淀粉样变性[19]。2019年，Givlaari（givosiran）获得FDA批准用于治疗肝卟啉病。2020年，2款RNAi药物获批上市，Oxlumo（lumasiran）获得EMA和FDA批准用于治疗高草酸尿症[20]，Leqvio（inclisiran）获得EMA批准用于治疗高胆固醇血症。Leqvio的获批上市，也使得RNAi疗法的疾病领域不仅局限于罕见病[21]。载体上，除了Onpattro使用的纳米脂质体，后续3个药物都是使用靶向肝细胞的N-乙酰半乳糖胺（N-acetylgalactosamine，GalNAc）修饰。截至2022年2月，全球处于已上市及在研状态的RNAi基因治疗药物共计235项（见图7），其中临床前131项。已提交上市申请和Ⅲ期临床试验的7款药物如表6所示。RNAi疗法药物vutrisiran靶向和沉默特定的mRNA，从而阻止野生型和突变型甲状腺素转运蛋白（transthyretin，TTR）的产生，在Ⅲ期临床试验HELIOS-A中取得积极的临床结果，2021年6月，Alnylam宣布FDA已受理vutrisiran的新药申请[22]。Fitusiran使用siRNA来靶向并减少抗凝血酶，从而促进血友病A或B的患者有足够的凝血酶生成，以恢复止血功能和防止出血。然而于2020年11月，因发现新的不良反应事件，赛诺菲宣布fitusiran的研究暂时搁置。Tivanisiran是一种靶向香草酸受体（transient receptor potential cation channel subfamily V member 1，TRPV1）的小分子RNAi疗法药物，Sylentis公司发布的Ⅲ期临床试验HELIX显示，中央角膜染色的减少有改善（P=0.035）。Cosdosiran是一种靶向细胞凋亡相关基因caspase-2的mRNA的siRNA药物，拟用于治疗视网膜神经节细胞死亡相关的疾病。目前，cosdosiran用于非动脉性缺血性视神经病变治疗的Ⅱ/Ⅲ期临床试验已于2019年6月终止，原因是中期分析的结果不足以支持后续的患者入组。Teprasiran可通过暂时抑制P53介导的细胞死亡，减少急性肾损伤（acute kidney injury，AKI）发生，41个临床试验中心共360例患者随机分为给药组（10mg·kg-1）和安慰剂组，给药方式为术后4h内单次静脉推注，术后7d内每日随访，第30、90和365d时再进行3次随访观察。结果显示，teprasiran可显著降低心脏术后患者AKI的发生率、严重程度及持续时间，90d内主要不良事件的发生率与安慰剂组无统计学差异[23]。Nedosiran是一种正在开发用于原发性高草酸尿症（primary hyperoxaluria，PH）1、PH2和PH3型的RNAi候选药物，旨在抑制肝乳酸脱氢酶（lactate dehydrogenase，LDH）的产生，该酶可催化乙醛酸代谢途径的最后一步，可以导致PH1、PH2或PH3患者草酸过量产生，在治疗PH患者中的关键临床试验PHYOX2中取得了积极顶线结果。ARO-APOC3是一种靶向ApoC Ⅲ的RNAi药物，其治疗家族性乳糜微粒血症的Ⅲ期临床试验正在进行中。3重组病毒类药物病毒因其良好的感染效率和在体内外靶细胞中持久表达的潜力被用于生物研究领域重组细胞的构建以及作为医药领域基因治疗技术的重要载体。而现在，病毒除了可以作为细胞和基因治疗药物的主要工具外，重组病毒也已经作为一类药物进入临床使用[24]。目前，主要应用的病毒包括腺病毒及腺相关病毒、逆转录病毒、单纯疱疹病毒等。截至2022年2月，全球共有9款重组病毒类基因治疗药物获批上市（见表7）。2003年，我国批准一款重组腺病毒载体表达p53治疗头颈癌的基因治疗药物——今又生（重组人p53腺病毒注射液）。今又生被认为是我国首个商品化的基因治疗药物[25]。2005年，我国批准了用于治疗鼻咽癌的世界首个溶瘤病毒药物安柯瑞（重组人5型腺病毒注射液）[26]。2007年，菲律宾批准了Rexin-G（Mx-dnG1）用于治疗软组织肉瘤和骨肉瘤，Rexin-G也是一种溶瘤病毒药物，所用的病毒载体为逆转录病毒[27]。2009年，拉脱维亚批准了Rigvir（VirusECHO-7）用于治疗黑色素瘤，Rigvir也是一款溶瘤病毒药物，所用的病毒载体为ECHO-7肠道病毒[28]。2012年，EMA批准了Glybera（alipogene tiparvovec）用于治疗家族性脂蛋白脂酶缺乏症，Glybera所用的载体为重组腺相关病毒。Glybera的获批上市是整个基因治疗领域的里程碑，促进了基因治疗的发展。但是，由于高昂的价格以及市场需求有限，Glybera已经撤市[29]。2015年，Imlygic（talimogene laherparepvec）获得FDA批准用于治疗黑色素瘤，这是FDA批准的首个溶瘤病毒药物，使用的载体为单纯疱疹病毒[30]。2017年，腺相关病毒载体药物Luxturna（voretigene neparvovec-rzyl）获得FDA批准上市用于治疗经证实的双等位基因RPE65突变相关的视网膜营养障碍性疾病[31]。2019年，美国FDA批准Zolgensma（onasemnogene abeparvovec-xioi）用于治疗脊髓性肌萎缩症[32]。2021年6月，PMDA宣布授予Delytact（teserpaturev）许可，在一定的条件及时限内，允许被应用于治疗恶性胶质瘤患者。目前已上市的9款重组病毒类药物中，5款为溶瘤病毒，说明这种借由病毒的“以毒攻毒”的溶瘤病毒疗法已经逐渐取得成功。治疗领域来看，肿瘤治疗有6款，罕见病治疗有3款。使用最多的载体为腺相关病毒载体。截至2022年2月，全球处于已上市及在研状态的病毒载体药物共计980项，其中临床前570项，药物发现147项，临床阶段共计250项（见图8）。溶瘤病毒疗法已上市及在研状态共计212项（占全部重组病毒的21.6%），其中临床前101项（占临床前重组病毒的17.8%），药物发现38项（占比25.9%），临床阶段68项（占临床阶段重组病毒的27.2%）。目前提交上市申请的4款药物如表8所示。Lenadogene nolparvovec是一款重组腺相关病毒的基因治疗药物，病毒内包含编码人野生型线粒体烟酰胺腺嘌呤二核苷酸脱氢酶4蛋白（nicotinamide adenine dinucleotide dehydrogenase4，ND4）的基因，该化合物专为治疗ND4基因突变相关的Leber遗传性视神经病变而开发。GenSight公司根据Ⅰ/Ⅱa期临床试验研究（CLIN-01）、2项关键性Ⅲ期的有效性研究（CLIN-03A：RESCUE和CLIN-03B：REVERSE）以及RESCUE和REVERSE的长期随访研究，同时结合统计学的间接比较方法，确立基因疗法与自然病史对比的药效和获益-风险比，并以此为基础提交上市申请[33]。Valoctocogene roxaparvovec是一种使用腺相关病毒来递送凝血因子Ⅷ功能基因，用以恢复凝血因子Ⅷ的产生，从而起到治疗A型血友病的基因治疗药物，Ⅲ期临床研究结果显示，年化出血率下降84%。Eladocagene exuparvovec是一种基于腺相关病毒提供芳香族L-氨基酸脱羧酶（amino acid decarboxylase，AADC）基因的基因治疗药物[34]。Nadofaragene firadenovec是一款重组腺病毒的基因治疗药物，含有干扰素α-2b基因，每3个月1次通过导管灌注膀胱。腺病毒进入膀胱壁细胞后，释放出活性基因，经转录和翻译后，使膀胱壁细胞分泌大量的干扰素α-2b蛋白，从而增强抗肿瘤活性[35]。4细胞治疗4.1自体细胞治疗细胞治疗是利用患者自体或异体的成体细胞或干细胞对组织、器官进行修复的治疗方法。FDA对来自于患者自体的细胞基因治疗的定义是：从患者体内取出细胞、基因改造（通常使用病毒载体），然后回输到患者体内。细胞治疗给患有无法治愈的疾病的患者带来了希望。截至2022年2月，全球共有11款自体细胞基因治疗药物获批上市（见表9）。2016年，EMA批准Strimvelis用于治疗由于腺苷脱氨酶缺失导致的重症联合免疫缺陷。Strimvelis是一种表达人腺苷脱氨酶的CD34+自体细胞，是全球首个获批上市的细胞基因治疗药物[36]。2017年，FDA批准了全球首款及第2款CAR-T产品Kymriah（tisagenlecleucel）和Yescarta（axicabtagene ciloleucel）。2款药物都是在体外将CD19基因导入到患者自体的T细胞中。Kymriah可用于治疗25岁以下的复发或难治性B细胞急性淋巴细胞白血病；Yescarta被用来治疗成年患者复发或难治愈的大B细胞淋巴瘤[37-38]。2019年，EMA批准了Zynteglo用于治疗12岁及以上的输血依赖性β-地中海贫血症，Zynteglo是一种含有造血干细胞的用慢病毒载体转导了βA-T87Q球蛋白基因的CD34+自体细胞[39]。2020年，2款自体细胞治疗药物上市，分别为FDA批准的用于治疗套细胞淋巴瘤的CAR-T产品Tecartus（brexucabtagene autoleucel）以及EMA批准的用于治疗异染性脑白质营养不良的药品Libmedly。Libmedly是一种含有造血干细胞和祖细胞的用慢病毒载体转导了人芳基硫酸酯酶A基因的CD34+自体细胞[40]。2021年，3款CAR-T产品和1款自体细胞治疗药物获得批准上市，FDA批准了用于治疗弥漫性大B细胞淋巴瘤的Breyanzi（lisocabtagene maraleucel）和治疗多发性骨髓瘤的Abecma（idecabtagene vicleucel）[41-42]，我国批准了倍诺达（瑞基奥仑赛注射液）用于治疗经过二线或以上系统性治疗后复发或难治性大B细胞淋巴瘤的成人患者，倍诺达成为我国首个获批为1类生物制品的CAR-T产品。EMA批准了Skysona用于治疗携带ABCD1基因突变的、18岁以下的早期脑性肾上腺脑白质营养不良患者。2022年2月28日，FDA批准Carvykti（ciltacabtagene autoleucel）用于复发或难治性多发性骨髓瘤患者，Carvykti是一款靶向B细胞成熟抗原（B-cell maturation antigen，BCMA）的CAR-T产品，Carvykti是首款由我国自主研发获得FDA批准上市的CAR-T产品[43]。截至2022年2月，全球处于已上市及在研状态的CAR-T药物共计797项，临床阶段共计376项（见图9），适应证以肿瘤为主。4.2 异体细胞治疗在异体细胞基因治疗中，提供基因修饰细胞的供体与接受基因修饰细胞的受体是不同的人。从生产制造的角度来看，异体细胞治疗产品可以形成商业化的现成品，相较于自体细胞治疗，这可以大大降低生产成本[44]。截至2022年2月，全球共有2款异体细胞基因治疗产品获批上市（见表10）。2016年，EMA批准Zalmoxis（nalotimagene carmaleucel）用于造血干细胞移植后辅助恢复患者的免疫系统。2017年，韩国批准Invossa（tissuegene-c）治疗中度骨性关节炎，这是韩国的首款基因治疗药物[45-46]。5结语与展望目前已上市基因治疗药物包括核酸类药物、重组病毒类药物和细胞治疗类药物，核酸类药物细分为裸质粒、反义寡核苷酸和RNAi。裸质粒药物目前的主要应用方向为编码促血管生成因子基因，进一步优化方向为提高其在体内的稳定性与利用度。反义寡核苷酸药物近年来取得了良好的市场表现，美国渤健公司年报披露，2021年Spinraza全球销售额达到20.52亿美元，2021年12月3日该品种正式纳入我国医保，进入医保后，Spinraza在我国的市场规模预计达到30亿元人民币。已上市反义寡核苷酸药物适应证主要是罕见病，我国因人口基数庞大，罕见病人数相对较多，市场需求较高，反义寡核苷酸药物在我国具有相当大的市场潜力。RNAi药物起步较晚，首个药物于2018年获批，RNAi药物对于载体的要求较高，因此构建载体技术平台是开发RNAi药物的关键。重组病毒药物已为肿瘤及罕见病带来突破性的疗效，诺华的Zolgensma只要注射1次就可治愈脊髓性肌萎缩症，展现出基因治疗药物巨大的优势，诺华年报披露2021年Zolgensma全球销售额达到13.51亿美金。细胞治疗药物中自体细胞治疗药物开发较多，异体细胞治疗药物开发较少，然而从生产成本的角度考虑，使用自体细胞生产流程较长，成本远远高于异体细胞，但是使用异体细胞目前效果不佳且副作用较大，仍需技术上的突破。从发展阶段来看，基因治疗正处迅速发展期，越来越多的基因治疗药物进入到临床试验阶段。相信在不久的将来，基因治疗会给更多的疾病带来颠覆的解决方案，给患者带来更多的用药选择。数据说明本文中的上市药物数据和研发管线数据主要来源于：1）全球权威期刊所发表的与基因治疗相关学术文献，该部分已分别标注于文中；2）中国国家药品监督管理局网站（www.nmpa.gov.cn）、美国食品药品监督管理局网站（www.fda.gov）、欧洲药品管理局网站（www.ema.europa.eu）、英国药品与保健品监管局网站（http://www.mca.gov.uk/home.htm）、日本药品与医疗器械管理局网站（www.pmda.go.jp）等；3）中国临床试验登记与信息公开平台（www.chinadrugtrials.org.cn）、美国临床试验（clinicaltrials.gov）、澳大利亚临床试验（www.australianclinicaltrials.gov.au）等；4）国内外制药企业官网：辉瑞（www.pfizer.com）、诺华（www.novartis.com）、百济神州（www.beigene.com）、人福医药（www.humanwell.com.cn）等；5）各大综合类及医药类新闻网站，如美通社（www.prnasia.com）、商业资讯（services.businesswire.com）、世界医药新闻（www.worldpharmanews.com）、Drugs.com（www.drugs.com）、新浪医药新闻（med.sina.com）。基于上述数据源，以医药知识为核心，结合药融云公司人工智能团队，利用 Python 语言的数据采集与数据分析功能建立了药融云数据库，实时监控了全球范围内已上市、临床、临床前、药物发现各阶段的基因治疗药物信息，同时通过医药专业人员对智能化监控的数据进行了标准化处理、统计、分析和校对。参考文献：[1] 邓洪新 , 魏于全 . 肿瘤基因治疗的研究现状和展望 [J]. 中国肿瘤生物治疗杂志 , 2015, 22(2): 170-176.[2] Gruntman A M, Flotte T R. The rapidly evolving state of gene therapy[J]. FASEB J, 2018, 32(4): 1733-1740.[3] Mariot V, Guiner C L, Barthélémy I, et al. Myostatin is a quantifiable biomarker for monitoring pharmaco-gene therapy in duchenne muscular dystrophy[J/OL]. Mol Ther Methods Clin Dev, 2020, 18: 415-421[2022-03-01]. https://doi.org/10.1016/j.phrs.2020.104999.[4] Burleva E P, Babushkina Y V. Administration of neovasculgen agent for treatment of a patient with neuroischaemic form of diabetic foot syndrome[J]. Angiol Sosud Khir, 2016, 22(2): 47-51.[5] Sanada F, Taniyama Y, Kanbara Y, et al. Gene therapy in peripheral artery disease[J]. Expert Opin Biol Ther, 2015, 15(3): 381-390.[6] Shimamura M, Morishita R. Naked plasmid DNA for gene therapy[J/ OL]. Curr Gene Ther, 2011, 11(6): 433[2022-03-01]. https://www. eurekaselect.com/article/20619. DOI: 10.2174/156652311798192824.[7] Holmlund J T. Applying antisense technology: Affinitak and other antisense oligonucleotides in clinical development[J]. Ann N Y Acad Sci, 2010, 1002(1): 244-251.[8] Crooke S T, Geary R S. Clinical pharmacological properties of mipomersen (Kynamro), a second generation antisense inhibitor of apolipoprotein b[J]. Br J Clin Pharmacol, 2013, 76(2): 269-276.[9] Ohmura T, Saeki S, Ogiwara K, et al. Pharmacological and clinical profile of spinal muscular atrophy (SMA) therapeutic drug nusinersen (Spinraza ®) [J]. Nihon Yakurigaku Zasshi, 2018, 152(3): 147-159.[10] Young C S, Pyle A D. Exon skipping therapy[J]. Cell, 2016, 167(5): 1144[2022-03-01]. https://doi.org/10.1016/j.cell.2016.10.050.[11] Coelho T, Yarlas A, Waddington-Cruz M, et al. Inotersen preserves or improves quality of life in hereditary transthyretin amyloidosis[J]. J Neurol, 2020, 267(4): 1070-1079.[12] Valéro R, Charriere S. Prise en charge des hypertriglycéridémies sévères[J]. Ann Endocrinol, 2020, 81(4): 140-141.[13] Scaglioni D, Catapano F, Ellis M, et al. The administration of antisense oligonucleotide golodirsen reduces pathological regeneration in patients with duchenne muscular dystrophy[J/OL]. Acta Neuropathol Commun, 2021, 9(1): 7[2022-03-01]. https://doi. org/10.1186/s40478-020-01106-1.[14] Dhillon S. Viltolarsen: first approval[J]. Drugs, 2020, 80(10): 1027- 1031.[15] Shirley M. Casimersen: first approval[J]. Drugs, 2021, 81(7): 875- 879.[16] Xue K, MacLaren R E. Antisense oligonucleotide therapeutics in clinical trials for the treatment of inherited retinal diseases[J]. Expert Opin Investig Drugs, 2020, 29(10): 1163-1170.[17] Mascarenhas J, Komrokji R S, Palandri F, et al. Randomized, single-blind, multicenter phase II study of two doses of imetelstat in relapsedor refractory myelofibrosis[J]. J Clin Oncol, 2021, 39(26): 2881-2892.[18] Bogdahn U, Hau P, Stockhammer G, et al. Targeted therapy for high[1]grade glioma with the TGF-β2 inhibitor trabedersen: results of a randomized and controlled phase IIb study[J]. Neuro Oncol, 2011, 13(1): 132-142.[19] Müschen L H, Krner G, Gingele S, et al. Treatment with patisiran of a patient with hereditary transthyretin-mediated amyloidosis with stage 3 polyneuropathy[J]. Muscle Nerve, 2021, 64(3): E11-E13.[20] Shah V N, Pyle L. Lumasiran, an RNAi therapeutic for primary hyperoxaluria type 1[J]. N Engl J Med, 2021, 384(13): 1216-1226.[21] Nambi V, Agha A. Inclisiran: a game changer in a changing game? [J]. J Am Coll Cardiol, 2021, 77(9): 1194-1196.[22] Benbrahim M, Norman K, Sanchorawala V, et al. A review of novel agents and clinical considerations in patients with attrcardiac amyloidosis[J]. J Cardiovasc Pharmacol, 2021, 77(5): 544-548.[23] Thielmann M, Corteville D, Szabo G, et al. Teprasiran, a small interfering RNA, for the prevention of acute kidney injury in high-risk patients undergoing cardiac surgery: a randomized clinical study[J]. Circulation, 2021, 144(14): 1133-1144.[24] Ginn S L, Alexander I E, Edelstein M L, et al. Gene therapy clinical trials worldwide to 2012 – an update[J]. J Gene Med, 2013, 15(2): 65-77.[25] Peng Z H. Current status of gendicine in China: recombinant human Ad-p53 agent for treatment of cancers[J]. Hum Gene Ther, 2005, 16(9): 1016-1027.[26] Liang M. Oncorine, the world first oncolytic virus medicine and its update in China[J]. Curr Cancer Drug Targets, 2018, 18(2): 171-176.[27] Gordon E M, Hall F L. Rexin-G, a targeted genetic medicine for cancer[J]. Expert Opin Biol Ther, 2010, 10(5): 819-832. [28] Doniņa S, Strēle I, Proboka G, et al. Adapted ECHO-7 virus rigvir immunotherapy (oncolytic virotherapy) prolongs survival in melanoma patients after surgical excision of the tumour in a retrospective study[J]. Melanoma Res, 2015, 25(5): 421-426.[29] Ferreira V, Petry H, Salmon F. Immune responses to AAV-vectors, the glybera example from bench to bedside[J/OL]. Front Immunol, 2014, 5: 82[2022-03-01]. https://doi.org/10.3389/fimmu.2014.00082.[30] Garnock-Jones K P. Talimogene laherparepvec: a review in unresectable metastatic melanoma[J]. BioDrugs, 2016, 30(5): 461- 468.[31] Prado D A, Acosta-Acero M, Maldonado R S. Gene therapy beyond luxturna: a new horizon of the treatment for inherited retinal disease[J]. Curr Opin Ophthalmol, 2020, 31(3): 147-154.[32] Cappella M, Ciotti C, Cohen-Tannoudji M, et al. Gene therapy for ALS—a perspective[J]. Int J Mol Sci, 2019, 20(18): 4388[2022-03- 01]. https://doi.org/10.3390/ijms20184388.[33] Biousse V, Newman N J, Yu-Wai-Man P, et al. Long-term follow-up after unilateral intravitreal gene therapy for leber hereditary optic neuropathy: the restore study[J]. J Neuroophthalmol, 2021, 41(3): 309-315.[34] Tai C H, Lee N C, Chien Y H, et al. Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency[J]. Mol Ther, 2022, 30(2): 509-518.[35] Boorjian S A, Alemozaffar M, Konety B R, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial[J]. Lancet Oncol, 2021, 22(1): 107-117.[36] Schimmer J, Breazzano S. Investor outlook: rising from the ashes; GSK's European approval of strimvelis for ADA-SCID[J]. Hum Gene Ther Clin Dev, 2016, 27(2): 57-61.[37] Morrow T. Novartis's kymriah: harnessing immune system comes with worry about reining in costs[J]. Manag Care, 2017, 26(10): 28- 30.[38] Arabi F, Torabi-Rahvar M, Shariati A, et al. Antigenic targets of CAR T cell therapy. A retrospective view on clinical trials[J]. Exp Cell Res, 2018, 369(1): 1-10. [39] Schuessler-Lenz M, Enzmann H, Vamvakas S. Regulators' advice can make a difference: European Medicines Agency approval of zynteglo for beta thalassemia[J]. Clin Pharmacol Ther, 2020, 107(3): 492-494.[40] Han D L, Xu Z H, Zhuang Y, et al. Current progress in CAR-T cell therapy for hematological malignancies[J]. J Cancer, 2021, 12(2): 326-334.[41] Abramson J S, Siddiqi T, Garcia J, et al. Cytokine release syndrome and neurological event costs in lisocabtagene maraleucel–treated patients in the transcend NHL 001 trial[J]. Blood Adv, 2021, 5(6): 1695-1705.[42] Munshi N C, Anderson L D, Shah N. Idecabtagene vicleucel in relapsed and refractory multiple myeloma[J]. N Engl J Med, 2021, 384(8): 705-716.[43] Berdeja J G, Madduri D, Usmani S Z, et al. Ciltacabtagene autoleucel, a b-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (cartitude-1): a phase 1b/2 open-label study[J]. Lancet, 2021, 398(10297): 314-324.[44] Harrison R P, Zylberberg E, Ellison S, et al. Chimeric antigen receptor-T cell therapy manufacturing: modelling the effect of offshore production on aggregate cost of goods[J]. Cytotherapy, 2019, 21(2): 224-233.[45] Farkas A M, Segundo M, Stoyanova-Beninska V, et al. Advanced therapy medicinal products for rare diseases: state of play of incentives supporting development in Europe[J]. Front Med, 2017, 4: 53[2022-03-01]. https://doi.org/10.3389/fmed.2017.00053.[46] Lee H, Kim H, Seo J, et al. Tissuegene-c promotes an anti[1]inflammatory micro-environment in a rat monoiodoacetate model of osteoarthritis via polarization of m2 macrophages leading to pain relief and structural improvement[J]. Inflammopharmacology, 2020, 28(5): 1237-1252文章信息源于公众号药学进展，登载该文章目的为更广泛的传递行业信息，不代表赞同其观点或对其真实性负责。文章版权归原作者及原出处所有，文章内容仅供参考。本网拥有对此声明的最终解释权，若无意侵犯版权，请联系小编删除。学如逆水行舟，不进则退；心似平原走马，易放难收。行舟Drug每日更新欢迎订阅+医药大数据|行业动态|政策解读

基因疗法寡核苷酸信使RNA细胞疗法免疫疗法

100 项与 Teprasiran 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15064

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
急性肾损伤	临床3期	美国	Quark Pharmaceuticals, Inc.	2018-06-29
急性肾损伤	临床3期	澳大利亚	Quark Pharmaceuticals, Inc.	2018-06-29
急性肾损伤	临床3期	奥地利	Quark Pharmaceuticals, Inc.	2018-06-29
急性肾损伤	临床3期	比利时	Quark Pharmaceuticals, Inc.	2018-06-29
急性肾损伤	临床3期	加拿大	Quark Pharmaceuticals, Inc.	2018-06-29
急性肾损伤	临床3期	捷克	Quark Pharmaceuticals, Inc.	2018-06-29
急性肾损伤	临床3期	法国	Quark Pharmaceuticals, Inc.	2018-06-29
急性肾损伤	临床3期	德国	Quark Pharmaceuticals, Inc.	2018-06-29
急性肾损伤	临床3期	新西兰	Quark Pharmaceuticals, Inc.	2018-06-29
急性肾损伤	临床3期	西班牙	Quark Pharmaceuticals, Inc.	2018-06-29

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临床结果

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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


NCT02610283 (Pubmed \| J Am Coll Cardiol \| Circulation) 人工标引	临床3期	急性肾损伤	341	Teprasiran	繭顧鹽醖築齋壓範壓齋(鬱鹽選襯鏇鏇選鹽觸願) = 襯鏇願製繭淵夢範艱衊糧鑰餘範夢廠醖構鹹選 (壓夢齋鹽製糧獵衊鹽衊 ) 更多	积极	2021-10-05
				Placebo	繭顧鹽醖築齋壓範壓齋(鬱鹽選襯鏇鏇選鹽觸願) = 窪製繭鹹餘醖艱憲艱艱糧鑰餘範夢廠醖構鹹選 (壓夢齋鹽製糧獵衊鹽衊 ) 更多
NCT02610283 (ASN2018)	临床2期	急性肾损伤 SCysC \| SCr \| eGFRCys ... 更多	341	QPI-1002	鏇衊淵簾簾觸構網鹽壓(簾壓蓋觸艱觸壓廠鏇蓋) = 糧鬱簾簾憲艱網廠衊獵顧鏇糧網醖鬱願夢鹹鏇 (顧憲觸膚顧壓蓋選膚簾 )	积极	2018-10-23
				Placebo	鏇衊淵簾簾觸構網鹽壓(簾壓蓋觸艱觸壓廠鏇蓋) = 憲衊淵鑰顧遞廠糧獵廠顧鏇糧網醖鬱願夢鹹鏇 (顧憲觸膚顧壓蓋選膚簾 )
NCT00554359 (Pubmed \| Kidney Int Rep) 人工标引	临床1期	急性肾损伤	16	Teprasiran	簾製鑰淵觸憲艱繭醖遞(鹽鹽鏇構鏇構顧積夢蓋) = 窪製範艱構衊窪鏇簾憲遞壓觸鑰壓艱廠夢繭壓 (鹽廠夢簾製鹽觸鹹衊選 )	积极	2017-04-25
				Placebo	簾製鑰淵觸憲艱繭醖遞(鹽鹽鏇構鏇構顧積夢蓋) = 糧蓋壓鹹蓋鑰憲簾築膚遞壓觸鑰壓艱廠夢繭壓 (鹽廠夢簾製鹽觸鹹衊選 )