Improvement of synaptic plasticity and cognitive function in RASopathies—a monocentre, randomized, double-blind, parallel-group, placebo-controlled, cross-over clinical trial (SynCoRAS)

Abstract

Background Cognitive impairment is a common medical issue in rat sarcoma (RAS) pathway disorders, so-called RASopathies, like Neurofibromatosis type 1 (NF1) or Noonan syndrome (NS). It is presumed to be caused by impaired synaptic plasticity. In animal studies, pathway-specific pharmacological interventions with lovastatin (LOV) and lamotrigine (LTG) have been shown to improve synaptic plasticity as well as cognitive function. The aim of this clinical trial is to translate the findings of animal studies to humans and to probe the effect of lovastatin (NS) and lamotrigine (NS and NF1) on synaptic plasticity and cognitive function/alertness in RASopathies. Methods Within this phase IIa, monocentre, randomized, double-blind, parallel-group, placebo-controlled, cross-over clinical trial (syn. SynCoRAS), three approaches (approaches I–III) will be carried out. In patients with NS, the effect of LTG (approach I) and of LOV (approach II) is investigated on synaptic plasticity and alertness. LTG is tested in patients with NF1 (approach III). Trial participants receive a single dose of 300 mg LTG or placebo (I and III) and 200 mg LOV or placebo (II) daily for 4 days with a cross-over after at least 7 days. Synaptic plasticity is investigated using a repetitive high-frequency transcranial magnetic stimulation (TMS) protocol called quadri-pulse theta burst stimulation (qTBS). Attention is examined by using the test of attentional performance (TAP). Twenty-eight patients are randomized in groups NS and NF1 with n = 24 intended to reach the primary endpoint (change in synaptic plasticity). Secondary endpoints are attention (TAP) and differences in short interval cortical inhibition (SICI) between placebo and trial medication (LTG and LOV). Discussion The study is targeting impairments in synaptic plasticity and cognitive impairment, one of the main health problems of patients with RASopathies. Recent first results with LOV in patients with NF1 have shown an improvement in synaptic plasticity and cognition. Within this clinical trial, it is investigated if these findings can be transferred to patients with NS. LTG is most likely a more effective and promising substance improving synaptic plasticity and, consecutively, cognitive function. It is expected that both substances are improving synaptic plasticity as well as alertness. Changes in alertness may be a precondition for improvement of cognition. Trial registration The clinical trial is registered in ClinicalTrials.gov (NCT03504501; https://www.clinicaltrials.gov; date of registration: 04/11/2018) and in EudraCT (number 2016–005022-10).

Synergistic Suppression of NF1 Malignant Peripheral Nerve Sheath Tumor Cell Growth in Culture and Orthotopic Xenografts by Combinational Treatment with Statin and Prodrug Farnesyltransferase Inhibitor PAMAM G4 Dendrimers

“…Statins are increasingly being considered for the treatment of a variety of medical conditions, in addition to dyslipidemia. For example, lovastatin and simvastatin have been extensively examined in NF1 patients for their potential abilities to improve synaptic plasticity, behavioral and cognitive functions, as well as phasic alertness [ 46 , 47 , 48 , 49 , 50 ]. Another broad use of statins is in both the mono and combinational treatment of a variety of cancers [ 51 , 52 , 53 , 54 ].…”

Statins in Children with Neurofibromatosis Type 1: A Systematic Review of Randomized Controlled Trials

“…Several studies focused on deficits in synaptic plasticity and cognitive impairment, two of the most significant health issues in patients with RASopathies [ 40 ]. Recent results for lovastatin in patients with NF1 have shown an improvement in synaptic plasticity and cognition [ 40 ].…”

“…Several studies focused on deficits in synaptic plasticity and cognitive impairment, two of the most significant health issues in patients with RASopathies [ 40 ]. Recent results for lovastatin in patients with NF1 have shown an improvement in synaptic plasticity and cognition [ 40 ]. During synaptic plasticity and memory formation, several signaling pathways regulate gene transcription in crucial ways [ 15 ], such as the NF1 mutations anticipated that interfere with memory-related gene expression.…”

Statins—From Fungi to Pharmacy

“…Selected clinical trials regarding the beneficial and pleiotropic effects of statins are presented in Table 2. reduction of LDL cholesterol level/NCT03242499 [111], NCT04359823 [112] the effect on synaptic plasticity, cognitive function, and attention in patients with RASopathies/NCT03504501 [113] improvement in the treatment of diffuse superficial actinic porokeratosis/NCT04359823 [112] modulation of cortical inhibition in neurofibromatosis type 1 (NF1)/NCT03826940 [114] reduction of motor symptoms in patients with early-stage Parkinson's/NCT03242499 [111] pravastatin reduction of LDL cholesterol level/ACTRN12616000535471 [115] prevention of pre-eclampsia in pregnant women/NCT01717586 [116] biomarker for monitoring the clinical benefit of statin treatment in secondary prevention/ ACTRN12616000535471 [115] prevention of the occurrence of atherothrombotic brain infarction in noncardioembolic infarction patients/NCT00361530 [117] reducing the incidence of lacunar stroke/NCT00221104 [118] reduction in levels of lipoprotein subclasses/NCT03073018 [119] reduction of vascular inflammation in non-cardiogenic ischemic stroke/NCT00361699 [120] simvastatin inhibition of 3-hydroxy-3-methyl-glutaryl-CoA reductase/ NCT00529139 [121] reduction in serum LDL concentration/NCT00939822 [122], NCT01061671 [123] activation of PI3K-kinase/NCT00676897 [121] positive effect on emotions/NCT04652089 [124] improved survival in ever-smokers with extensive disease (ED)-small cell lung cancer (SCLC)/NCT01441349 [125] reductions in total cholesterol, lipoprotein, and triglycerides observed in children with type 1 diabetes mellitus/NCT03660293 [126] anti-inflammatory and neuroprotective effects/NCT01999309 [127] prevention of decompensation in patients with compensated cirrhosis/NCT03654053 [128] Type II-synthetically derived statins fluvastatin reduction in blood lipid levels/ ChiCTR-TRC-12002642 [129] decrease in LDL-level/NCT00421005 [130] decrease of inflammatory index, ultrasonic index and electrocardiographic measurement results in atrial fibrillation/ChiCTR-TRC-12002642 [129] normalization of bilirubin levels and reduced blood ...…”