Potschka Heidrun, Pérez-Pérez Daniel
Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-Universität (LMU) of Munich, Munich, Germany.
Epilepsia. 2025 Aug 6. doi: 10.1111/epi.18581.
Drug development for developmental and epileptic encephalopathies (DEEs) follows different strategies on one hand including disease-targeting precision medicine approaches considering the genetic variants and pathomechanisms in DEEs and on the other hand including therapeutic approaches with novel targets or second-generation drug candidates that may be of interest beyond selected DEEs. Although the first group of approaches can only be tested in dedicated DEE models, assessment in induced non-specific seizure and epilepsy models may provide valuable information if the mechanism of action implies a broader spectrum of efficacy. Data from such models can inform about general anti-seizure efficacy, efficacy against different seizure types including a possible broad-spectrum potential, dose range, and "therapeutic" plasma/brain concentrations. However, only dedicated DEE models will guide selection of the best candidates with a favorable efficacy and tolerability spectrum for specific DEEs. Several DEE models have already been used for preclinical testing of therapeutic approaches. Testing in these specific models can provide information about the effects on seizure generation; spread of seizure activity; epilepsy development; survival; behavioral, cognitive, and motor function; and about tolerability. On the other hand, we still face several limitations and challenges including lack of models for many DEEs, incomplete penetrance of the phenotype, high mortality, low throughput, limited knowledge concerning pharmacology and predictive validity, and species differences in development and disease course. In this review, we provide an overview of the preclinical efficacy data of approved orphan drugs in both model types and discuss the current state-of-knowledge concerning predictive validity. In conclusion, testing strategies need to be carefully tailored to the candidate drug or therapeutic approach. In this context, there is an urgent need for development of further specific DEE models and for a comprehensive characterization of the face and predictive validity of existing and future DEE models.
发育性和癫痫性脑病（DEEs）的药物研发一方面采用不同策略，包括针对疾病的精准医学方法，即考虑DEEs中的基因变异和发病机制；另一方面包括具有新靶点或第二代候选药物的治疗方法，这些方法可能对选定的DEEs之外的疾病也有意义。虽然第一类方法只能在专门的DEE模型中进行测试，但如果作用机制意味着更广泛的疗效谱，在诱导的非特异性癫痫发作和癫痫模型中的评估可能会提供有价值的信息。来自此类模型的数据可以提供关于一般抗癫痫疗效、对不同癫痫发作类型的疗效（包括可能的广谱潜力）、剂量范围以及“治疗性”血浆/脑浓度的信息。然而，只有专门的DEE模型才能指导选择对特定DEEs具有良好疗效和耐受性谱的最佳候选药物。几种DEE模型已经用于治疗方法的临床前测试。在这些特定模型中进行测试可以提供关于癫痫发作产生的影响、癫痫活动的传播、癫痫发展、生存、行为、认知和运动功能以及耐受性的信息。另一方面，我们仍然面临一些限制和挑战，包括许多DEEs缺乏模型、表型不完全外显、高死亡率、低通量、关于药理学和预测有效性的知识有限以及发育和疾病过程中的物种差异。在这篇综述中，我们概述了两种模型类型中已批准的孤儿药的临床前疗效数据，并讨论了关于预测有效性的当前知识状态。总之，测试策略需要根据候选药物或治疗方法进行精心调整。在这种情况下，迫切需要开发更多特定的DEE模型，并对现有和未来DEE模型的外观和预测有效性进行全面表征。
