Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in Drosophila

G4C2 repeat expansions within the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The repeats undergo repeat-associated non-ATG translation to generate toxic dipeptide repeat proteins. Here, we show that insulin/Igf signalling is reduced in fly models of C9orf72 repeat expansion using RNA-sequencing of adult brain. We further demonstrate that activation of insulin/Igf signalling can mitigate multiple neurodegenerative phenotypes in flies expressing either expanded G4C2 repeats or the toxic dipeptide repeat protein poly-GR. Levels of poly-GR are reduced when components of the insulin/Igf signalling pathway are genetically activated in the diseased flies, suggesting a mechanism of rescue. Modulating insulin signalling in mammalian cells also lowers poly-GR levels. Remarkably, systemic injection of insulin improves the survival of flies expressing G4C2 repeats. Overall, our data suggest that modulation of insulin/Igf signalling could be an effective therapeutic approach against C9orf72 ALS/FTD

Impact of predictive medicine on therapeutic decision making: a randomized controlled trial in congenital heart disease

Computational modelling has made significant progress towards clinical application in recent years. In addition to providing detailed diagnostic data, these methods have the potential to simulate patient-specific interventions and to predict their outcome. Our objective was to evaluate to which extent patient-specific modelling influences treatment decisions in coarctation of the aorta (CoA), a common congenital heart disease. We selected three cases with CoA, two of which had borderline indications for intervention according to current clinical guidelines. The third case was not indicated for intervention according to guidelines. For each case, we generated two separate datasets. First dataset included conventional diagnostic parameters (echocardiography and magnetic resonance imaging). In the second, we added modelled parameters (pressure fields). For the two cases with borderline indications for intervention, the second dataset also included pressure fields after virtual stenting simulations. All parameters were computed by modelling methods that were previously validated. In an online-administered, invitation-only survey, we randomized 178 paediatric cardiologists to view either conventional (control) or add-on modelling (experimental) datasets. Primary endpoint was the proportion of participants recommending different therapeutic options: (1) surgery or catheter lab (collectively, “intervention”) or (2) no intervention (follow-up with or without medication). Availability of data from computational predictive modelling influenced therapeutic decision making in two of three cases. There was a statistically significant association between group assignment and the recommendation of an intervention for one borderline case and one non-borderline case: 94.3% vs. 72.2% (RR: 1.31, 95% CI: 1.14–1.50, p = 0.00) and 18.8% vs. 5.1% (RR: 3.09, 95% CI: 1.17–8.18, p = 0.01) of participants in the experimental and control groups respectively recommended an intervention. For the remaining case, there was no difference between the experimental and control group and the majority of participants recommended intervention. In sub-group analyses, findings were not affected by the experience level of participating cardiologists. Despite existing clinical guidelines, the therapy recommendations of the participating physicians were heterogeneous. Validated patient-specific computational modelling has the potential to influence treatment decisions. Future studies in broader areas are needed to evaluate whether differences in decisions result in improved outcomes (Trial Registration: NCT02700737)

Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in Drosophila

G4C2 repeat expansions within the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The repeats undergo repeat-associated non-ATG translation to generate toxic dipeptide repeat proteins. Here, we show that insulin/Igf signalling is reduced in fly models of C9orf72 repeat expansion using RNA-sequencing of adult brain. We further demonstrate that activation of insulin/Igf signalling can mitigate multiple neurodegenerative phenotypes in flies expressing either expanded G4C2 repeats or the toxic dipeptide repeat protein poly-GR. Levels of poly-GR are reduced when components of the insulin/Igf signalling pathway are genetically activated in the diseased flies, suggesting a mechanism of rescue. Modulating insulin signalling in mammalian cells also lowers poly-GR levels. Remarkably, systemic injection of insulin improves the survival of flies expressing G4C2 repeats. Overall, our data suggest that modulation of insulin/Igf signalling could be an effective therapeutic approach against C9orf72 ALS/FTD