# Cell type specific AAVs to study reward and cognition

> **NIH NIH UF1** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $6,850,168

## Abstract

Adeno-Associated Viruses (AAVs) are potent gene delivery vectors for neuroscience studies and gene therapy
applications. However, naturally occurring AAVs are not cell type specific: they must be combined with other
technologies, such as transgenic animals, to achieve cell type specific gene expression. This requirement limits
the use genetically coded ‘circuit-breaking’ tools to study behavior in nonhuman primates (NHPs) – the
experimental animal model with the greatest similarity to humans – and hinders development of cell type specific
targeting strategies for achieving direct clinical benefits. To expand cell type specific access in NHPs and lay the
foundation for circuit specific gene therapy, we propose to create, test, and validate next generation, cell type
specific AAVs. First, we will define cell type specific enhancers – distal regulatory elements that have
demonstrated considerable promise as cell type specific AAV drivers. In preliminary data, we collected
transcriptomic and chromatin accessibility (i.e. “multi-omic”) single cell data from the striatum, dorsolateral
prefrontal cortex (dlPFC), primary motor cortex (M1), insula, and ventral midbrain of 2 rhesus macaque monkeys.
We combined the rhesus monkey data set with existing human and mouse data and used convolutional neural
networks (CNNs) to rank open chromatin sequences according to their potential as cell type specific enhancers.
We packaged AAVs with the top candidate enhancers, injected them into NHP striatum, and we have observed
cell type specific, enhancer driven expression in striosomes – a cell type specific striatal compartment related to
reward processing. To broadly advance this agenda and develop AAVs that drive robust, cell type-specific
expression, we propose to expand our multi-omic single cell database with additional data from macaque and
marmoset. We will leverage this updated, sex-balanced database, with will include data from 8 NHPs to identify
cell type specific enhancers that are likely to drive robust expression in primates. In parallel, we will use our
validated scAAVengr pipeline to screen AAV capsid mutants for cell-type biased infection patterns in the NHP
cognitive and reward systems. We will combine the top cell type specific enhancers with the most biased AAV
capsids to generate new, cell type specific AAVs for targeting neurons in the NHP cognitive and reward systems.
We will validate AAV specificity using Fluorescent in situ hybridization (FISH). This data will be combined with
ultra-high resolution MRI scans to create a rhesus macaque brain atlas, and the validated vectors will be stored
and distributed by The University of Pittsburgh BioForge Initiative. NHPs are critical for studying human cognition
and disease, and thus there is a pressing need to define the molecular properties of NHP cell types and study
their behavioral functions. This proposal will generate a unique NHP multi-omic single cell database, provide cell
type specific AAVs for ...

## Key facts

- **NIH application ID:** 10517904
- **Project number:** 1UF1MH130881-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Leah Byrne
- **Activity code:** UF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $6,850,168
- **Award type:** 1
- **Project period:** 2022-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10517904

## Citation

> US National Institutes of Health, RePORTER application 10517904, Cell type specific AAVs to study reward and cognition (1UF1MH130881-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10517904. Licensed CC0.

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