Adeno-associated virus vectors and neurotoxicity—lessons from preclinical and human studies

Over 15 years after hepatotoxicity was first observed following administration of an adeno-associated virus (AAV) vector during a hemophilia B clinical trial, recent reports of treatment-associated neurotoxicity in animals and humans have brought the potential impact of AAV-associated toxicity back to prominence. In both pre-clinical studies and clinical trials, systemic AAV administration has been associated with neurotoxicity in peripheral nerve ganglia and spinal cord. Neurological signs have also been seen following direct AAV injection into the brain, both in non-human primates and in a clinical trial for late infantile Batten disease. Neurotoxic events appear variable across species, and preclinical animal studies do not fully predict clinical observations. Accumulating data suggest that AAV-associated neurotoxicity may be underdiagnosed and may differ between species in terms of frequency and/or severity. In this review, we discuss the different animal models that have been used to demonstrate AAV-associated neurotoxicity, its potential causes and consequences, and potential approaches to blunt AAV-associated neurotoxicity.