Monday, April 29, 2024
4/29/2024
Microglia and astrocytes are glial cell types in the brain that interact directly with neurons to maintain neural tissue homeostasis. We are beginning to understand that glial cell dysfunctions contribute to the early damage of neural circuits that manifests disease symptoms in many neurodegenerative disorders. Despite the contributions of glia to CNS disorder progression, we currently have limited approaches to target these cells preferentially for therapy. Viral vectors are used routinely in preclinical CNS models for cell specific targeting, but there are limitations with these technologies including poor transduction efficiency in glia, low specificity, immune activation, and off-target effects. The emergence of comprehensive glial cell specific transcriptomics information has enabled the identification of unique molecular features on the surface of different glial cells that can be used to develop innovative targeted non-viral drug delivery approaches. With the overall goal of developing effective nanoparticle-based strategies to deliver therapies to specific glial cell types to correct dysfunctions that cause CNS disease, this project’s main objectives are to: 1) optimize dendrimer nanoparticles with multivalent functionalization of ligands for specific cell surface transporters that are uniquely and highly expressed on microglia and astrocytes, and 2) test the glial cell specific delivery of mRNA afforded by these nanoparticles when injected locally into different brain regions or neuroinflammatory states. Our hypothesis is that intracerebral injection of nanoparticles with multivalent presentation of specific ligands will enable preferential binding and subsequent uptake of nanoparticles into the glial cells that uniquely express the transporter for that ligand, thereby enabling highly specific mRNA delivery. In the first aim, we will optimize dendrimer nanoparticles with multivalent presentation of microglia and astrocyte targeting molecules and ionizable tertiary amines for mRNA loading. Using an in silico unsupervised analysis of published glia transcriptomes we have identified specific cell surface transporters that are uniquely and highly expressed on microglia and astrocytes respectively that can be targeted with known ligands that we can readily conjugate to dendrimer nanoparticles. We will use several in vitro screening assays to optimize dendrimers for mRNA loading and delivery. In the second aim, we will test glial cell targeting of dendrimer nanoparticles in the mouse brain under healthy and neuroinflammation states and use functional delivery of Cre recombinase mRNA in Ai14 transgenic reporter mice to determine efficacy. Through this project, we will provide new insights into the biology of transporters and their involvement in trafficking and uptake mechanisms in glia that can be used to improve drug delivery outcomes. This work will also enable innovations in nanoparticle design for exogenous targeting of therapies in the CNS that will have broad implications for treating neurological disease.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
