DREADDs for clinical translation

药物是治疗各种神经和精神疾病的主要手段，但它们的有效性往往很低。它们相对不加选择地作用于涉及脑和脊髓功能不同方面的神经细胞。尽管在识别许多疾病中哪些神经细胞过度活跃或活动不足方面已经取得了很大进展，但通常不可能通过药物来纠正这些不平衡。基因疗法有可能克服这一障碍：通过将DNA插入不同的神经细胞群，可以改变它们的兴奋性，根据DNA编码的蛋白质的性质，使它们变得更容易或更不容易兴奋。这种疗法可以通过使用无法复制的病毒来靶向大脑或脊髓离散区域的特定神经细胞。尽管前景看好，但基因疗法因其不可逆性而受到阻碍：一旦DNA被插入，基因修饰就无法撤销。然而，一项重大突破是“化学遗传学”的发明，即DNA编码药物受体。受体的存在对神经细胞的特性没有影响，直到激活受体的药物被施用。这样，治疗效果可以按需调整或使用。我们率先将这项技术应用于一种特别严重的癫痫，这种癫痫不能用传统药物令人满意地治疗。我们的建议旨在使化学基因治疗更接近临床，特别是通过确保它可以与具有良好安全性的药物一起使用。我们设计了一种可以被苯海拉明激活的受体，苯海拉明是一种非常安全的药物，用于治疗晕动病和过敏的非处方药物。我们称这种受体为抑制性GRANPA（非处方药物激活的g蛋白偶联受体）。我们将验证它可用于按需抑制癫痫发作，并使用相同的原理来设计兴奋性GRANPA，以实现神经细胞活动的可调节增加。最后，由于一些受体的作用随着药物的长期激活而逐渐消失，我们将进一步修饰抑制性和兴奋性granpa，以尽量减少它们失去作用的趋势。虽然我们将在癫痫模型中验证我们的工具，这些工具具有快速读取和接近临床的优势，但它们可能在其他神经和精神疾病中有广泛的应用，这些疾病对社会和受影响的个体造成了巨大的负担。

Drugs are the mainstay of treatment for a very wide range of neurological and psychiatric disorders, but their effectiveness is often low. They act relatively indiscriminately on nerve cells involved in different aspects of brain and spinal cord function. Although much progress has been made in identifying which nerve cells are over- or underactive in many disorders, it is often not possible to correct these imbalances with medication. Gene therapy potentially overcomes this barrier: the excitability of different populations of nerve cells can be altered by inserting DNA into them, causing them to become intrinsically more or less excitable depending on the nature of the protein encoded by the DNA. The therapy can be targeted to specific nerve cells in discrete regions of the brain or spinal cord by the use of viruses that have been made unable to replicate. Although promising, gene therapy is hampered by its irreversible nature: once the DNA has been inserted, the genetic modification cannot be undone. However, a major breakthrough was the invention of 'chemogenetics', whereby the DNA encodes a receptor for a drug. The presence of the receptor has no effect on the nerve cell's properties until the drug that activates the receptor is administered. In this way the therapeutic effect can be adjusted or used on-demand. We have pioneered the application of this technology to an especially severe form of epilepsy that cannot be treated satisfactorily with conventional medication. Our proposal is aimed at bringing chemogenetic treatment closer to the clinic, specifically by ensuring that it can be used with a drug that has an excellent safety profile. We have designed a receptor that can be activated by diphenhydramine, a very safe drug that is used in over-the-counter remedies for motion sickness and allergies. We call the receptor an inhibitory GRANPA (G-protein coupled Receptor Activated by a Non-Prescription Agent). We will verify that it can be used to suppress seizures on demand, and use the same principles to design an excitatory GRANPA to achieve an adjustable increase in nerve cell activity. Finally, because the effects of some receptors wear off with prolonged drug activation, we will further modify the inhibitory and excitatory GRANPAs to minimise their tendency to lose effect. Although we will validate our tools in models of epilepsy, which have the advantage of rapid read-out and proximity to the clinic, they potentially have applications in a wide range of other neurological and psychiatric diseases that account for an enormous burden to society and to affected individuals.