ABSTRACT
There are no effective treatment options for neurodegenerative diseases. There is an imminent need to expedite
drug discovery efforts for Alzheimer’s disease (AD) and its related dementias, such as frontotemporal dementia
(FTD). Even though different neuron populations display selective vulnerability and progressive degeneration in
different diseases, building evidence reveals the presence of numerous common causes that act as the
“converging path” responsible for neuronal death. Therefore, drug discovery efforts now focus not on the
“disease” per se, but on the cellular mechanisms that cause disease pathology. For example, even though
different proteins aggregate, the protein aggregation problem is shared among different diseases. Likewise,
problems with mitochondria, endoplasmic reticulum, neuroinflammation, and axonal transport defects have all
been identified to be converging paths, which allow development of treatment strategies that might more broadly
help patients who share common cellular problems but diagnosed with different diseases. During our parent
R01 application, we identified NU-9 to be the first compound that improves the health of upper motor neurons
diseased due to misfolded SOD1 toxicity and TDP-43 pathology, two different and unrelated causes of
neurodegeneration. NU-9 reduces protein aggregation, improves the integrity of mitochondria and endoplasmic
reticulum, and enhances cytoarchitectural stability in diseased upper motor neurons. Interestingly, it also
enhances axon outgrowth and branching in vitro, and even more so when applied together with two of the FDA
approved drugs riluzole and edaravone. NU-9 is not toxic and the IND application to the FDA was approved in
early June 2023, with the plan to initiate Phase 1 clinical trials in healthy volunteers in year 2023.
Results of our parent R01 and initial findings with Dr. Klein lay a very strong foundation to further
investigate NU-9 and its potential impact on AD and its related dementias, which share many of the common
causes of neurodegeneration. Therefore, we formed a very strong team for our R01 renewal application to
investigate the impact of NU-9 on improving the health of neurons that degenerate in AD and FTD and how that
contributes to neuronal health, overall function, behavior and survival. Although our proposal will focus on NU-
9 with best characterized model systems of the diseases, we will continue to generate new derivatives of NU-9
to investigate whether NU-9 can be further improved. We also will identify the target(s) of NU-9. This is a
comprehensive, multi-PI team grant, focusing on cellular, molecular, and mechanism-based treatment strategies
for AD and FTD, with a special focus on NU-9, a compound that was shown to overcome many of the common
and shared paths to neurodegeneration.
