# Investigating Mechanisms of Viral Impairment of Neurogenesis Using Recombinant AAV

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $438,630

## Abstract

PROJECT SUMMARY
 There is growing evidence that viral infections of the central nervous system (CNS) contribute to chronic
brain disease. During development, multiple viruses including cytomegalovirus, herpes simplex virus, rubella
virus, human immunodeficiency virus, and Zika virus annually cause thousands of cases of microcephaly —
small head size resulting from impaired neurogenesis within the cerebral cortex. The sequalae of these viruses
later in neurodevelopment and adulthood are less understood, but here they also disrupt neurogenesis and have
been implicated in disease. These viruses share a common ability to eliminate neural progenitor cells (NPCs) in
the developing and adult brain. However, the complex biology of these viruses has precluded our ability to identify
a precise mechanism by which these infectious agents ablate neurogenesis.
 We recently discovered that the widely used recombinant adeno-associated virus (rAAV) rapidly kills
dividing NPCs and early post-mitotic neurons in the adult murine dentate gyrus (DG) in a dose-dependent
manner. Unlike the other viruses described above, rAAV is replication defective and is not known to cause
significant pathology. This has resulted in its wide use as a vector in both experimental biology and human gene
therapy. However, evidence is mounting that rAAV-based gene therapies are not without significant risk, with at
least 7 rAAV-related deaths and numerous adverse outcomes reported in pediatric rAAV trials during the past
three years alone. While some of these adverse effects are thought to be caused by immune reactions to the
capsid or transgene, increasing evidence indicates that the rAAV genome, which contains two 145-base pair
DNA segments named inverted terminal repeats (ITRs), is a major source of rAAV toxicity. Our preliminary
experiments indicate that rAAV ITRs bind to and deplete Parp1, a first responder in cellular DNA damage
response (DDR) within the nucleus. Moreover, rAAV toxicity mimics pharmacological inhibition of Parp1, inducing
cell cycle arrest and cell death, and can be partially reversed by Parp1 activation. We aim to capitalize on these
findings to identify the cellular pathways that mediate ITR-induced toxicity and discern whether
therapeutic targets within these pathways are shared among viruses that cause microcephaly.

## Key facts

- **NIH application ID:** 10660863
- **Project number:** 1R01NS126680-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Matthew Shtrahman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $438,630
- **Award type:** 1
- **Project period:** 2023-03-15 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10660863

## Citation

> US National Institutes of Health, RePORTER application 10660863, Investigating Mechanisms of Viral Impairment of Neurogenesis Using Recombinant AAV (1R01NS126680-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10660863. Licensed CC0.

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