TY - JOUR T1 - Considerations for Clinical Therapeutic Development of Statins for Neurodevelopmental Disorders JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0392-19.2020 VL - 7 IS - 2 SP - ENEURO.0392-19.2020 AU - Myrthe J. Ottenhoff AU - Lianne C. Krab AU - Ype Elgersma Y1 - 2020/03/01 UR - http://www.eneuro.org/content/7/2/ENEURO.0392-19.2020.abstract N2 - The 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase) inhibitors lovastatin and simvastatin have both been investigated in clinical trials designed to treat the cognitive deficits associated with neurodevelopmental disorders such as neurofibromatosis type 1, fragile X and autism. In a recent study, the therapeutic efficacy of lovastatin and simvastatin were compared in a fragile X (Fmr1) mouse model. The authors concluded that lovastatin was superior to simvastatin in rescuing the Fmr1 phenotypes, and cautioned against considering simvastatin as treatment for neurodevelopmental disorders. We discuss these findings in the context of published literature and argue that more support is needed for this potentially far-reaching conclusion. We further provide recommendations to improve the translation of pre-clinical studies of cognitive disorders into the clinical domain. The potential use of statins for antagonizing RAS (rat sarcoma viral oncogene homolog) signaling was first recognized nearly three decades ago (Mendola and Backer, 1990; Sebti et al., 1991). Functional RAS requires post-translational farnesylation to become membrane bound and active. Since farnesyl (like cholesterol) is a product of the mevalonate synthesis pathway, its synthesis can be reduced by interfering with the rate-limiting enzyme, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase). Statins, designed as high-affinity HMG-CoA reductase inhibitors, are commonly prescribed for hypercholesterolemia. Over the past several decades, various types of statins have been extensively investigated as potential cancer therapeutics using cellular models, mouse studies, and human clinical trials (Gazzerro et al., 2012; Pisanti et al., 2014; Sopková et al., 2017). On the basis of these findings, Alcino Silva and colleagues explored whether statins might have efficacy in the treatment of RASopathies, a group of neurodevelopmental disorders resulting from mutations that lead to … ER -