NIH BRAIN Initiative Backs Toolkit of 1,000+ Enhancer AAVs for Cell-Type Targeting in Brain Disorders

A consortium of researchers led by the Allen Institute, with collaborators from over two dozen U.S. institutions including Harvard, Broad, Duke, and Stanford, has released more than 1,000 enhancer AAV vectors—a new class of genetic tools designed to target specific brain cell types with high precision (Cell Press landing page). These adeno-associated viral vectors deliver tailored enhancers that can selectively activate or modulate gene expression in defined neural populations.

Published across eight studies in Cell, Neuron, Cell Reports Methods, and related journals, the toolkit offers the most expansive and experimentally validated resource to date for cell-type-specific access in the brain, spinal cord, and peripheral nervous system. 

Reported applications include modulation of behavior via targeted perturbations, labeling of rare neuronal subtypes such as sleep-regulating cells, and foundational work toward gene therapies for conditions like Dravet syndrome.

In one of the studies, scientists report that these enhancer AAV tools could be used to successfully modify cell behavior in the lab, a key proof-of-concept for their potential in developing targeted therapies. For example, Boaz Levi, Ph.D., associate investigator at the Allen Institute, noted that the precision offered by these tools may offer an alternative to current treatments that often carry broad neurological side effects, such as those used in epilepsy.

Allen Institute scientists Trygve Bakken, M.D., Ph.D., (left) and Jonathan Ting, Ph.D., (right) discuss research figures and data related to enhancer AAV tools. Photo by Jenny Burns / Allen Institute.

The effort forms part of the NIH’s Armamentarium for Precision Brain Cell Access, a flagship project within the BRAIN Initiative, which aims to scale and disseminate tools enabling molecular access to functionally relevant brain cells. The vectors and supporting datasets are available through the Allen Institute’s Genetic Tools Atlas and Addgene.

Researchers report that these tools were able to predictably influence brain activity and behavior in mice, offering a framework for translating enhancer AAVs to therapeutic contexts. The technology may help shift gene therapy from broad interventions to highly selective, circuit-level modulation.

The Armamentarium project’s findings were published across eight peer-reviewed studies in the Cell Press family of journals. Each paper details a different aspect of enhancer AAV vector development and application, spanning cortical, spinal, striatal, and vascular brain targets:

• Cell – A suite of enhancer AAVs and transgenic mouse lines for genetic access to cortical cell types
  https://doi.org/10.1016/j.cell.2025.05.002
   
• Cell Genomics – Evaluating Methods for the Prediction of Cell Type-Specific Enhancers in the Mammalian Cortex
  https://doi.org/10.1016/j.xgen.2025.100879
   
• Cell Reports – Enhancer AAVs for targeting spinal motor neurons and descending motor pathways in rodents and macaque
  https://doi.org/10.1016/j.celrep.2025.115730
   
• Cell Reports Methods – An AAV capsid proposed as microglia-targeting directs genetic expression in forebrain excitatory neurons
  https://doi.org/10.1016/j.crmeth.2025.101054
   
• Neuron – An enhancer-AAV toolbox to target and manipulate distinct interneuron subtypes
  https://doi.org/10.1016/j.neuron.2025.05.002
   
• Neuron – Machine learning identification of enhancers in the rhesus macaque genome
  https://doi.org/10.1016/j.neuron.2025.04.030
   
• Neuron – Enhancer AAV toolbox for accessing and perturbing striatal cell types and circuits
  https://doi.org/10.1016/j.neuron.2025.04.035
   
• Neuron – Specific targeting of brain endothelial cells using enhancer AAV vectors
  https://doi.org/10.1016/j.neuron.2024.12.025

Topics: Tools & Methods