Recent publications in Molecular Therapy 1 and Human Gene Therapy 2 identify acute toxicity of adeno-associated virus (AAV)-mediated survival of motor neuron (SMN) or GFP expression, which warrants careful consideration to better understand the observation as well as the need to perform well-controlled studies to address this finding. However, these findings should be viewed in the context of an initial observation in a basic proof-of-concept study and not in relationship to established practices for rational and patient-centered drug development, which follow guidance from the International Committee on Harmonization (ICH) for Good Clinical Practice (GCP). 3 The purpose of this commentary is to address the basis by which gene therapy medicinal products are evaluated in non-clinical studies to best inform us of the risk-benefit profile of a given product under development for a specific indication. The findings of the two publications can be summarized as preliminary studies to develop an approach to spinal muscular atrophy (SMA) using variants of AAV9. The first study tested these vectors in piglets and non-human primates (NHPs) with a finding of acute toxicity in one NHP and neural inflammation in the piglets. The second study showed a single animal with the AAV9 variant, PHP. B, which developed an acute coagulopathy. 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.” 1, 2 Platform technology studies are important to understanding basic behavior of AAV-vectors in vivo. However, in order to develop therapies aimed at treating human disease, it is imperative that investigators follow the guidance agreed to by Federal Drug Administration (FDA) and European Medicines Agency (EMA) which oversee human clinical research conducted under the principles of GCP. The non-clinical and clinical data supporting nine active clinical studies should also be considered in evaluating the clinical application of AAV9 vectors.

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. Therefore, any anticipated risk should be established in light of the potential benefit for the subject. This principle is further emphasized in research involving children, the greatest proportion of those with severe genetic conditions amenable to gene therapy, where the prospect of direct benefit is required to conduct a pediatric study. Because of these principles, all available non-clinical and clinical data for an investigational product should directly support the proposed clinical use. The guidelines provide specific recommendations on how the investigator, institutional review