Use of small RNAs for therapeutic gene silencing: risk versus benefit

Deliberate silencing of disease-associated genes using RNA interference (RNAi) has become a most powerful therapeutic option in the battle against cancer, infections and other human disorders. Yet, recent evidence suggests that over-dosing RNAi can have detrimental side effects on cells and tissues, and cause toxicities and lethalities in small animals. Unlike previously noted adverse effects, these new phenomena are unrelated to RNAi sequences but rather involve saturation of cellular gene silencing pathways. Considering the importance of these alarming findings for the clinical translation of RNAi technologies, we review the underlying mechanisms and discuss potential solutions.