Verdura Edgard, Pérez-Cano Laura, Sabido-Vera Rubén, Guney Emre, Hyvelin Jean-Marc, Durham Lynn, Gomez-Mancilla Baltazar
Discovery and Data Science (DDS) Unit, Sociedad Limitada (STALICLA SL), Barcelona, Spain.
Research Programme on Biomedical Informatics, Hospital del Mar Medical Research Institute (IMIM), Departament de Ciències Experimentals i de la Salut (DCEXS), Pompeu Fabra University (UPF), Barcelona, Spain.
Front Psychiatry. 2021 Sep 30;12:722378. doi: 10.3389/fpsyt.2021.722378. eCollection 2021.
Fragile X syndrome (FXS) is the most frequent monogenic cause of autism or intellectual disability, and research on its pathogenetic mechanisms has provided important insights on this neurodevelopmental condition. Nevertheless, after 30 years of intense research, efforts to develop treatments have been mostly unsuccessful. The aim of this review is to compile evidence from existing research pointing to clinical, genetic, and therapeutic response heterogeneity in FXS and highlight the need of implementing precision medicine-based treatments. We comment on the high genetic and phenotypic heterogeneity present in FXS, as a contributing factor to the difficulties found during drug development. Given that several clinical trials have showed a non-negligeable fraction of positive responders to drugs targeting core FXS symptoms, we propose that success of clinical trials can be achieved by tackling the underlying heterogeneity in FXS by accurately stratifying patients into drug-responder subpopulations. These precision medicine-based approaches, which can be first applied to well-defined monogenic diseases such as FXS, can also serve to define drug responder profiles based on specific biomarkers or phenotypic features that can associate patients with different genetic backgrounds to a same candidate drug, thus repositioning a same drug for a larger number of patients with NDDs.
脆性X综合征（FXS）是自闭症或智力残疾最常见的单基因病因，对其发病机制的研究为这种神经发育疾病提供了重要见解。然而，经过30年的深入研究，开发治疗方法的努力大多未获成功。本综述的目的是汇集现有研究证据，指出FXS在临床、遗传和治疗反应方面的异质性，并强调实施基于精准医学的治疗方法的必要性。我们评论了FXS中存在的高度遗传和表型异质性，这是药物开发过程中遇到困难的一个促成因素。鉴于多项临床试验表明，针对FXS核心症状的药物有不可忽视比例的阳性反应者，我们建议，通过将患者准确分层为药物反应亚群来解决FXS潜在的异质性，临床试验有望取得成功。这些基于精准医学的方法可首先应用于如FXS这样明确的单基因疾病，也可用于根据特定生物标志物或表型特征定义药物反应者概况，这些特征可将具有不同遗传背景的患者与同一种候选药物联系起来，从而为更多神经发育障碍患者重新定位同一种药物。
