A Novel Therapeutic Nano-Vesicle for the Clearance of Axonal Blocks to Prevent Alzheimer's
With rising life expectancies and an aging baby boomer generation, Alzheimer’s disease (AD) has become widespread and it is one of the leading causes of death in the U.S. Treating AD has proven difficult, as current treatments are only able to target the late stage of disease, with many adverse side effects. Currently, there are no cures for AD. The challenge is to develop treatments that are able to specifically target affected neurons at early stages of disease initiation. We will use a highly innovative approach to develop synthetic biomolecules that will deliver therapeutics to specific sites within the brain, to modify defects that activate disease pathways.
Summary: As our aging population increases there is an urgent need to develop effective cures for Alzheimer’s disease (AD). While there are no cures, current treatment strategies target pathologies that occur late in AD progression, and often impart side effects that negatively affect patients. Therefore, our aim is to develop therapeutics that target early insults during disease so as to stop the activation of deleterious pathways and the progression of disease. As a first step towards this aim, we will use an integrated approach that combines engineering, chemistry, and neuroscience, in a highly innovative, transformative project that seeks to test a synthetic functional nano-vesicle in human AD neurons. This synthetic nano-vesicle will have the potential to function as a novel therapeutic device that can modify early defects within nerve cells to stop cell death and halt the progression of neurodegeneration seen in AD.
Details: Within axons, essential components packaged into vesicles are transported on microtubules (MTs), (the highways), from the cell body, where proteins are made, to distal ends of the axon (synapse) where they are used. Recent work has shown that defects in transport (observed as axonal blocks) occur early in disease, before pathological or behavioral phenotypes are observed. Our long-term goal is to understand the mechanisms of how problems in axonal transport initiate disease pathways and to develop modifiers that restore transport. The objective here is to examine the potential of a synthetic nano-vesicle for targeted modification of axonal blocks induced by excess mutant APP. Our central hypothesis is that engineered synthetic nano-vesicles will move on MTs to axonal blocks via associations with endogenous motor proteins. Our goals are 1) to evaluate the motility behavior of the synthetic nano-vesicle in human AD and normal neurons differentiated from AD and normal iPSCs, and 2) to identify how a modifier caged inside the porous surface of the synthetic nano-vesicle modifies axonal blocks in human AD neurons. The rationale for the proposed work is that targeting therapeutic interventions to an early defect seen in AD will eliminate downstream deleterious effects that propagate disease and cell death. Such a strategy will have the ability to stop the initial progression of AD, which for the first time will lead to a cure, since the FDA-approved treatments that currently exists only reduce disease symptoms.
About the Researcher
Shermali Gunawardena PhD, is an associate professor in the Department of Biological Sciences and in the Institute for Lasers, Photonics and Biophotonics at the State University of New York at Buffalo, Buffalo, NY. She received her BS degree in biology and her MS degree in genetics from the University of Arizona. She continued her graduate research at the same institution and received her PhD in genetics and cell biology (Flinn Foundation fellow). Gunawardena performed her postdoctoral studies at the University of California San Diego (a Wills Foundation Postdoctoral Fellow, an Ellison Medical Foundation/AFAR Senior Postdoctoral Fellow). As an assistant project scientist at the University of California, San Diego, she was funded by a New Investigator Research Grant from the Alzheimer Association. Gunawardena started her independent career as an assistant professor in the Department of Biological Sciences at the State University of New York at Buffalo in 2008. Her research is focused on understanding the cellular and molecular mechanisms of the Alzheimer's disease proteins amyloid precursor protein (APP) and Presenilin (PS), and the Huntington's disease protein Huntingtin (HTT), with the rationale of unraveling how disease is initiated.
From a young age, I have been intrigued by the complexities of nature and how it works. Curiosity to discover the unknown intricacies has led to my passion in uncoupling the mechanisms of how normal disease proteins function so that we can better understand how these proteins can cause disease states. My laboratory seeks to use innovative in vivo research strategies to not only isolate mechanisms of function but also to develop targeted therapeutic strategies to rescue defects seen in normal functions. The financial support from the BrightFocus Foundation enables us to conduct high risk/high gain research, which is too risky to be funded by conventional funding agencies. Thus we are extremely grateful to the donors of the BrightFocus Foundation for recognizing the importance of the research undertaken by my group, and for their generosity and support of such work so that we can explore avenues to better understand and target directed treatments for Alzheimer’s patients.
Hansen T, Thant C, White JA 2nd, Banerjee R, Thuamsang B, Gunawardena S. Excess active P13K rescues huntingtin-mediated neuronal cell death but has no effect on axonal transport defects. Apoptosis. 2019 Feb 6. doi: 10.1007/s10495-019-01520-4. [Epub ahead of print] PubMed PMID: 30725352 axonal transport defects. Apoptosis. 2019 Feb 6. doi:10.1007/s10495-019-01520-4. [Epub ahead of print] PubMed PMID: 30725352
First published on: June 27, 2018
Last modified on: February 13, 2019