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

Interaction of alcohol intake and cofactors on the risk of cirrhosis

Objective: Evaluation of the interaction between alcohol intake and cofactors [hepatitis B virus (HBV), hepatitis C virus (HCV), body mass index] and coffee consumption on the risk of cirrhosis. Design: Seven hundred and forty-nine consecutive patients with chronic liver disease referring to units for liver or alcohol diseases in Italy during a 6-months period. Teetotalers were excluded. The odds ratios (OR) for cirrhosis were evaluated using chronic hepatitis cases as the control group. Results: An alcohol intake of more than 3 units/day resulted associated with the likelihood of cirrhosis both in males (OR 4.3; 95% CI=2.5-7.3) and in females (OR 5.7; 95% CI=2.3-14.5). A multiplicative interaction on the risk of cirrhosis between risky alcohol intake and HBsAg or HCV-Ab/HCV-RNA positivity was observed. A reduction of cirrhosis risk was observed in subjects consuming more than 3 alcohol units/day with increasing coffee intake. The OR for the association with cirrhosis decreased from 2.3 (95% CI=1.2-4.4) in subjects drinking 0-2 cups of coffee/day to 1.4 (95% CI=0.6-3.6) in those drinking more than 2 cups/day. Conclusions: In subjects with an alcohol intake >3 units/day the coexistence of HBV or HCV multiplies the risk of cirrhosis. Coffee represents a modulator of alcoholic cirrhosis risk