With its ability to improve neuron health, experimental drug NU-9 has already shown promise in reversing amyotrophic lateral sclerosis (ALS). Now, the National Institute on Aging (NIA) has provided approximately $7.3 million to fund exploration into the Northwestern University-invented drug's effectiveness in other neurodegenerative diseases.
Like ALS, Alzheimer's disease and frontotemporal degeneration also result from misfolded proteins that damage brain health. Rather than treating symptoms from specific diseases, NU-9 instead addresses the underlying mechanisms. That gives scientists hope that the drug should demonstrate effectiveness in the common mechanisms that give rise to multiple neurogenerative diseases.
Invented by chemist Richard B. Silverman, NU-9 emerged as an important compound to potentially eliminate neurodegeneration through a cross-disciplinary collaboration between Silverman and neurologist P. Hande Ozdinler. Silverman, who previously invented pregabalin (Lyrica) to treat nerve pain and epilepsy, is the Patrick G. Ryan/Aon Professor in the Department of Chemistry at Northwestern's Weinberg College of Arts and Sciences. Ozdinler, who is an expert in ALS, is an associate professor of neurology at Northwestern University Feinberg School of Medicine. Both Silverman and Ozdinler are members of the Les Turner ALS Center and the Chemistry of Life Processes Institute.
"NU-9 acts on some of the shared causes of neurodegeneration, so we thought it may have a broader impact beyond ALS," said Ozdinler, who is principal investigator of the new NIA grant. "FTD and Alzheimer's disease share many cellular problems with ALS. For example, all three diseases affect mitochondria, the endoplasmic reticulum, brain inflammation and axon transport. If NU-9 is effective against those problems in ALS, it makes sense that it would also be effective in similar diseases."
Demonstrated success in animal models
In patients with neurodegenerative diseases, misfolded proteins clump together inside brain cells. The accumulation of misfolded proteins leads to toxicity and eventually triggers brain cells to die. In earlier studies, NU-9 successfully improved the health of diseased neurons. After 60 days of treatment in two different mouse models of ALS, the health of the diseased neurons became similar to those of healthy controls.
In a study published in 2022 in Scientific Reports, the researchers showed that NU-9 lengthened the axons of diseased upper motor neurons in an ALS mouse model. Connecting the brain to the spinal cord, axons make up the corticospinal tract, which degenerates in patients with ALS. In earlier work published in 2021 in Clinical and Translational Medicine, the researchers demonstrated the ability of NU-9 to improve the health of the mitochondria and endoplasmic reticulum in neurons. Treated neurons were more intact, their cell bodies were larger, and the dendrites were not riddled with holes.
"Improving the health of brain neurons is important for ALS and other motor neuron diseases," Ozdinler said.
Silverman founded Akava Therapeutics to carry out the safety studies needed for NU-9 (now called AKV9) to receive approval from the U.S. Food and Drug Administration (FDA). Last year, NU-9 received Investigational New Drug status from the FDA, which greenlit Phase I trials to evaluate safety and tolerability of NU-9 in healthy human subjects. Depending on the FDA response to the Phase I results, a Phase II trial to administer the drug to ALS patients will begin.
Drug can 'take out the garbage'
Although ALS, FTD and Alzheimer's disease affect different parts of the brain, protein aggregation is shared among all three diseases.
"The protein aggregates are like garbage inside a house," Ozdinler explained. "Imagine if you just stopped taking out the garbage. Eventually, you would not be able to tolerate living there. Similarly, the protein aggregates are like garbage inside a cell. The cells cannot clean up and eventually suffocate. NU-9 works by cleaning the house. Then neurons regain health within the brain circuitry."
For the new grant, Ozdinler and Silverman expanded their team to include Northwestern's William Klein, professor of neurobiology at Weinberg. An expert on Alzheimer's disease, Klein's work has led to a deeper understanding of Alzheimer's disease, earlier diagnoses and potential antibody-based therapeutics.
"It is a long process - possibly 10 to 12 years - to discover and bring a new drug to the market," Silverman said. "But this drug has us very excited and hopeful about its potential to improve the lives of ALS and other neurodegenerative disease patients who have been without hope for so long."
The project, "Investigations of the protein aggregation inhibitor NU-9 and its derivatives: Mode of action and impact on Alzheimer's disease and related dementias," is supported by the National Institutes of Health's National Institute on Aging (grant number 2R01AG061708-06).
Silverman, Ozdinler and Klein have affiliations with and financial interests in Akava Therapeutics. Northwestern University has financial interests (equities, royalties) in Akava Therapeutics.
