Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects

Over the last decade, pioneering liver-directed gene therapy trials for haemophilia B have achieved sustained clinical improvement after a single systemic injection of adeno-associated virus (AAV) derived vectors encoding the human factor IX cDNA. These trials demonstrate the potential of AAV technology to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Indeed, with more than ten ongoing or planned clinical trials for haemophilia A and B and dozens of trials planned for other inherited genetic/metabolic liver diseases, clinical translation is expanding rapidly. Gene therapy is likely to become an option for routine care of a subset of severe inherited genetic/metabolic liver diseases in the relatively near term. In this review, we aim to summarise the milestones in the development of gene therapy, present the different vector tools and their clinical applications for liver-directed gene therapy. AAV-derived vectors are emerging as the leading candidates for clinical translation of gene delivery to the liver. Therefore, we focus on clinical applications of AAV vectors in providing the most recent update on clinical outcomes of completed and ongoing gene therapy trials and comment on the current challenges that the field is facing for large-scale clinical translation. There is clearly an urgent need for more efficient therapies in many severe monogenic liver disorders, which will require careful risk-benefit analysis for each indication, especially in paediatrics

Fitzpatrick\u27s color atlas & synopsis of clinical dermatology

In the present paper, the observation and characterization of isolated response curves (IRCs) are experimentally reported in the case of a nonlinear system consisting of two masses sliding on an horizontal guide. Transverse springs are attached to one mass to provide the nonlinear restoring force, and a harmonic motion of the complete system is imposed by prescribing the displacement of their supports. The existence of an IRC is related to a 3:1 internal resonance between the two modes of the system. The observed IRC is studied in detached and merged conditions using swept-sine excitations and system perturbations

Prediction of isolated resonance curves using nonlinear normal modes

Isolated resonance curves are separate from the main nonlinear forced-response branch, so they can easily be missed by a continuation algorithm and the resonant response might be underpredicted. The present work explores the connection between these isolated resonances and the nonlinear normal modes of the system and adapts an energy balance criterion to connect the two. This approach provides new insights into the occurrence of isolated resonances as well as a method to find an initial guess to compute the isolated resonance curve using numerical continuation. The concepts are illustrated on a finite element model of a cantilever beam with a nonlinear spring at its tip. This system presents jumps in both frequency and amplitude in its response to a swept sinusoidal excitation. The jumps are found to be the result of a modal interaction that creates an isolated resonance curve that eventually merges with the main resonance branch as the excitation force increases. Excellent insight into the observed dynamics is provided with the NNM theory, which supports that NNMs can also be a useful tool for predicting isolated resonance curves and other behaviors in the damped, forced response.</jats:p

Model reduction concepts and substructuring approaches for nonlinear systems

This chapter reviews common nonlinearities that are encountered in engineering structures, with a particular emphasis on geometric nonlinearity. Popular ways to construct reduced order models for geometrically nonlinear problems are discussed. The concept of nonlinear normal modes is presented to help understand the dynamics of these structures, and some recently presented substructuring methods are reviewed