Importantly, the severe findings in a limited number of animals in these studies should not be confused with low-grade laboratory findings in clinical studies that are self-limited. Since these studies are related to variants of AAV9 vectors given systemically, the focus of this commentary will be limited to active clinical programs using AAV serotype 9, both by systemic and regional delivery, since the one conclusion of Hinderer et al.2 is that, “The present results and those of another recent study utilizing a different AAV9 variant and transgene indicate that systemic and sensory neuron toxicity may be general properties of intravenous delivery of AAV vectors at high doses irrespective of the capsid serotype or transgene.” GCP guidance is based on the ethical principles established in the Declaration of Helsinki in which the rights, safety, and well-being of trial subjects are the most important and overriding considerations in the design and conduct of research involving human subjects. ...any anticipated risk should be established in light of the potential benefit for the subject. The IB provides information on the characteristics of the investigational product and the non-clinical studies which support the clinical use. ...a comparison of the cumulative findings from IBs which support active AAV9 studies to the current non-clinical studies by Hordeux et al.1 and Hinderer et al.2 is warranted. Immuno-toxicity can in fact be managed by immune modulation which would allow for incremental dosing.7,8 An additional challenge is that the vector production and quantification was accomplished by a different method than established for other clinical programs which followed Good Laboratory Practice (GLP) guidance, especially related to a qualified assay for characterization of vector quantity. ...reliance on the results of these studies should be limited to understanding the means by which an acute response leading to coagulopathy can be explained in NHPs and the unique finding of strain specific murine receptor for AAV PHP.B.