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Title: “Dendrimer Nanoparticles for Microglia-Targeted Drug Delivery in Parkinson's Disease”

Advisory Committee: Xue Han, PhD – BU BME (Chair) Tim O’Shea, PhD – BU BME (Advisor) Wilson Wong, PhD – BU BME Michelle Teplensky, PhD – BU BME Ludy Shih, MD – Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School

Abstract: Parkinson’s disease (PD) is currently the second most common neurodegenerative disorder, and its pathology has been characterized by loss of dopaminergic neurons in the substantia nigra (SN). Glial cells, especially microglia and astrocytes, are essential to support healthy neuron function. Microglia, in particular, are responsible for clearance of protein build up and excess cell debris in the brain. In the early stages of PD, microglia homeostatic phenotypes and functions are altered resulting in an increased burden of neuron-released alpha synuclein (αSyn) that cannot be readily cleared, amplifying neuroinflammation and neuronal loss. Microglial dysfunction occurs years prior to neuronal death and motor symptoms in PD. Therefore, it is critical to understand the role of microglia in PD and innovate mechanism-based strategies to target microglia for therapy. Synthetic nanoparticle (NP)-based approaches represent a potentially safer and more versatile approach for drug delivery to microglia compared to viral vector methods, but there is an unmet need for new NPs that target microglia with high specificity. My main objectives are to optimize NP formulations and uncover mechanisms to target microglia in the brain, evaluate delivery efficiency and specificity, and to use targeted NP to modulate microglia states in the early stages of PD pathology. Dendrimers offer a promising platform to design synthetic NPs with cell specific targeting due to the tunable structure and multivalent presentation of endcaps. I hypothesize that local neural tissue injection of NPs containing multivalent presentation of microglia specific ligands will enable preferential uptake of NPs, and its drug cargo, into microglia, enabling highly specific mRNA therapeutic delivery to these cells to modify dysfunction induced by neuroinflammation and PD. To identify ligands that could be used for microglia specific targeting, I completed an in silico unsupervised analysis of published neuronal and glial transcriptomes. I evaluated microglia specific expression of surfaceome genes and have identified several candidates for targeting. For proof of concept, I selected one of these candidates to pursue, the cell surface fructose transporter, Glut5 (Slc2a5), that is uniquely and highly expressed by microglia. I have also established a synthesis scheme for making dendrimer NPs and have developed a library of dendrimer NP formulations. To investigate my hypothesis, I will optimize synthetic dendrimer NPs that are functionalized with multivalent presentation of fructose and ionizable amines for (1) optimization of NP formulation for in vitro mRNA delivery, (2) to test the delivery efficacy and specificity to microglia in the healthy and neuroinflammatory murine brain in vivo, and (3) to determine how microglia modulation via mRNA delivery affects PD pathology in an αSyn overexpression mouse model. This work will introduce a novel, cell-specific drug delivery method, enhance our understanding of the microglia role in PD pathology, and expand our knowledge on how to deliver mRNA therapies to microglia in vivo. This work lays the foundations to investigate new cell targeting modalities and mRNA therapies for PD in future work.