Multifarious variables causing unpredictable responses to AAV gene therapy. Many variables, known and unknown, contribute to the success of AAV gene therapy and define the benefit-risk balance for individuals and for disease populations.^3,5 The manufacturing process remains poorly defined, with lot-to-lot variability and inconsistent scale-up. Each recipient has a unique phenotype based upon their genetics and epigenetic influences. Collectively, these variables dictate the range of individual response to gene therapy, from durable therapeutically beneficial effects to suboptimal responses and durability. Predictability of individual responses is not yet possible because biomarkers for host hepatocyte condition and host defenses are not well established. Professional illustration by Patrick Lane, ScEYEnce Studios.