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

Sport and early osteoarthritis: the role of sport in aetiology, progression and treatment of knee osteoarthritis

Sports activities are considered favourable for general health; nevertheless, a possible influence of sports practice on the development of early osteoarthritis (OA) is a cause for concern. A higher incidence of OA in knees and ankles of former high-impact sports players than in those of the normal population has been shown and it is still debatable whether the cause is either to be recognized generically in the higher number of injuries or in a joint overload. The possibility to address knee OA in its early phases may be strictly connected to the modification of specific extrinsic or intrinsic factors, related to the patient in order to save the joint from further disease progression; these include sport practice, equipment and load. Non-surgical therapies such as continuative muscles reinforce and training play a strong role in the care of athletes with early OA, particularly if professional. There is an overall agreement on the need of an early restoring of a proper meniscal, ligament and cartilage integrity in order to protect the knee and resume sports safely, whereas alignment is a point still strongly debatable especially for professional athletes. Remaining questions still to be answered are the risks of different sports in relation to one another, although an actual protective effect of low-impact sports, such as walking, swimming or cycling, has been recognized on the appearance or worsening of OA, the effect of continuing or ceasing to practice a sport on the natural history of early OA, and even following appropriate treatment is still unknown.info:eu-repo/semantics/publishedVersio