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Preclinical Development: Overview01:28

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Preclinical development consists of a series of tests that ensure the safety and efficacy of a new therapeutic compound before it is tested in humans. There are four main phases to this process. First, safety pharmacology tests are conducted to ensure the drug does not produce any acutely harmful effects. These tests examine parameters such as bronchoconstriction, cardiac dysrhythmias, blood pressure changes, and ataxia. Next, preliminary toxicological testing is performed to determine the...
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Clinical development focuses on how the drug will interact with the human body and encompasses four key phases of clinical trials, each serving a specific purpose in assessing the safety and effectiveness of new drugs. These phases overlap and build upon one another. Phase I involves a small group of healthy volunteers (typically 20-80 individuals) or, in cases where significant toxicity is expected, patients with the targeted disease, such as cancer or AIDS. The volunteers are tested for...
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Drug discovery is a multifaceted process involving extensive screening, testing, and optimization of lead compounds to identify potential new drugs for therapeutic use. It combines several approaches, including screening large numbers of natural products, chemical modification of known active molecules, identification of new drug targets, and rational design based on biological mechanisms and drug-receptor structure. These approaches are carried out in both academic research laboratories and...
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Drugs, the chemical agents used in diagnosing, treating, or preventing diseases, undergo a four-phase process of development: pharmaceutic, pharmacokinetics, pharmacodynamics, and therapeutic.
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In vitro dissolution and drug release tests assess how quickly and how much of a drug is released from its dosage form into an aqueous medium under standardized laboratory conditions. These tests are essential tools in pharmaceutical development and quality assurance, offering insight into the drug's performance before clinical use.During formulation development, dissolution testing identifies incomplete or inconsistent drug release issues. It also supports decisions on selecting the optimal...
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药物开发 药物开发

Maxine R Nelson1, Marina Kovaliov1, Priyanka Singh1

  • 1Switch Therapeutics, South San Francisco, CA, USA.

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PubMed
概括
此摘要是机器生成的。

一种新的条件激活siRNA (CASi) 在阿尔茨海默病 (AD) 模型中有效降低大脑Apolipoprotein E (APOE) mRNA. 这种有针对性的方法节省了外围APOE和胆固醇,为APOE*ε4载体提供了有前途的治疗方法.

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科学领域:

  • 神经科学是一个神经科学.
  • 遗传学 是一个遗传学.
  • 药理学 药理学是指药理学的学科.

背景情况:

  • 阿波脂蛋白E (APOE) * ε4等位基因是晚发性阿尔茨海默病 (AD) 的主要遗传风险因素.
  • 临床前研究表明,降低APOE4mRNA水平可以减轻AD病理.
  • 开发针对APOE*ε4携带轻度认知障碍 (MCI) 或AD携带者的向疗法至关重要,需要在保持全身功能的同时进行脑特异性APOE减少.

研究的目的:

  • 开发和评估一种新的,强效的,有条件激活的siRNA (CASi),旨在专门针对和减少大脑中的APOE mRNA.
  • 在临床前模型中评估CASi的安全性和有效性,重点关注大脑APOE的减少,而不影响外围APOE水平或胆固醇代谢.

主要方法:

  • 一个针对APOE的CASi分子库被设计并测试在诱导多能干细胞 (iPSC) 衍生天体细胞中.
  • 活体内疗效在人类APOE4转基因 (hE4) 小鼠中评估了剂量范围,评估了APOE mRNA和蛋白质水平在大脑区域和肝脏.
  • 领先的CASi候选者进一步通过内给药在非人类灵长类动物 (NHPs) 中进行了测试,在脑脊液 (CSF),大脑组织和血中测量了APOE水平.

主要成果:

  • CASi分子在iPSC星球细胞中表现出高强度 (<20pM),并在10nmol剂量时在EHE4小鼠的海马中实现60-85%的APOE mRNA减少.
  • CASi在小鼠中耐受良好,没有观察到肝脏中的APOE敲击,并且没有改变周围胆固醇水平.
  • NHP研究表明,中枢神经液中持续50-75%的APOE蛋白被击倒,并显著减少了内腔皮层和海马体,而不会影响肝脏或血APOE.

结论:

  • 确定了一种强大的CASi向大脑APOE,证明了显著的疗效和良好的安全性,对肝脏APOE或外围胆固醇没有不良影响.
  • 这种CASi代表了MCI/AD的APOE*ε4载体的有希望的治疗候选者,特别是那些不能容忍当前免疫疗法的人.