AAV-Induced Ablation of Neurogenesis

In the developing and adult brain, there is strong evidence that several viruses can kill neural progenitor cells (NPCs) and impair neurogenesis, resulting in a number of neurodevelopmental abnormalities including microcephaly or small head size. We recently discovered that the widely used recombinant adeno associated virus (rAAV) kills dividing NPCs and early post-mitotic neurons in the dentate gyrus of adult mice in a dose dependent fashion. Unlike other viruses that impair neurogenesis, rAAV is replication defective and typically does not cause disease. This has resulted in its wide use as a vector in both experimental biology and human gene therapy, including two FDA-approved treatments for diseases of the central nervous system (CNS). This recombinant virus’ lack of virulence is in part due to its minimal genome, which contains only two 145-base pair DNA segments, named inverted terminal repeats (ITRs). However, our experiments indicate that these GC-rich ITR DNA sequences are toxic to dividing NPCs in a cell-autonomous manner. We are currently working to discern the cellular pathways that mediate rAAV ITR toxicity in order to identify a universal mechanism for viral-induced toxicity in NPCs and other neuronal cell populations.