Neuropathological Findings in Nonclinical Species Following Administration of Adeno-Associated Virus (AAV)-Based Gene Therapy Vectors.

Adeno-associated virus (AAV) gene therapy vectors are an accepted platform for treating severe neurological diseases. Test article (TA)-related and procedure-related neuropathological effects following administration of AAV-based vectors are observed in the central nervous system (CNS) and peripheral nervous system (PNS). Leukocyte accumulation (mononuclear cell infiltration > inflammation) may occur in brain, spinal cord, spinal nerve roots (SNRs), sensory and autonomic ganglia, and rarely nerves. Leukocyte accumulation may be associated with neuron necrosis (sensory ganglia > CNS) and/or glial changes (microgliosis and/or astrocytosis in the CNS, increased satellite glial cellularity in ganglia and/or Schwann cellularity in nerves). Axonal degeneration secondary to neuronal injury may occur in the SNR (dorsal > ventral), spinal cord (dorsal and occasionally lateral funiculi), and brainstem centrally and in nerves peripherally. Patterns of AAV-associated microscopic findings in the CNS and PNS differ for TAs administered into brain parenchyma (where tissue at the injection site is affected most) versus TAs delivered into cerebrospinal fluid (CSF) or systemically (which primarily impacts sensory ganglion neurons and their processes in SNR and spinal cord). Changes related to the TA and procedure may overlap. While often interpreted as adverse, AAV-associated neuronal necrosis and axonal degeneration of limited severity generally do not preclude clinical testing.