A Quantitative Systems Pharmacology Model of Gaucher Disease Type 1 Provides Mechanistic Insight Into the Response to Substrate Reduction Therapy With Eliglustat.

Gaucher's disease type 1 (GD1) leads to significant morbidity and mortality through clinical manifestations, such as splenomegaly, hematological complications, and bone disease. Two types of therapies are currently approved for GD1: enzyme replacement therapy (ERT), and substrate reduction therapy (SRT). In this study, we have developed a quantitative systems pharmacology (QSP) model, which recapitulates the effects of eliglustat, the only first-line SRT approved for GD1, on treatment-naïve or patients with ERT-stabilized adult GD1. This multiscale model represents the mechanism of action of eliglustat that leads toward reduction of spleen volume. Model capabilities were illustrated through the application of the model to predict ERT and eliglustat responses in virtual populations of adult patients with GD1, representing patients across a spectrum of disease severity as defined by genotype-phenotype relationships. In summary, the QSP model provides a mechanistic computational platform for predicting treatment response via different modalities within the heterogeneous GD1 patient population.

Emergence of localized patterns in globally coupled networks of relaxation oscillators with heterogeneous connectivity.

Oscillations in far-from-equilibrium systems (e.g., chemical, biochemical, biological) are generated by the nonlinear interplay of positive and negative feedback effects operating at different time scales. Relaxation oscillations emerge when the time scales between the activators and the inhibitors are well separated. In addition to the large-amplitude oscillations (LAOs) or relaxation type, these systems exhibit small-amplitude oscillations (SAOs) as well as abrupt transitions between them (canard phenomenon). Localized cluster patterns in networks of relaxation oscillators consist of one cluster oscillating in the LAO regime or exhibiting mixed-mode oscillations (LAOs interspersed with SAOs), while the other oscillates in the SAO regime. Because the individual oscillators are monostable, localized patterns are a network phenomenon that involves the interplay of the connectivity and the intrinsic dynamic properties of the individual nodes. Motivated by experimental and theoretical results on the Belousov-Zhabotinsky reaction, we investigate the mechanisms underlying the generation of localized patterns in globally coupled networks of piecewise-linear relaxation oscillators where the global feedback term affects the rate of change of the activator (fast variable) and depends on the weighted sum of the inhibitor (slow variable) at any given time. We also investigate whether these patterns are affected by the presence of a diffusive type of coupling whose synchronizing effects compete with the symmetry-breaking global feedback effects.