Experimental ALS drug may be more effective than existing drugs

Summary: NU-9, an experimental drug, appears to be more effective in treating ALS than existing drugs.

Source: Northwestern University

New research on the experimental drug NU-9, invented and developed by two scientists at Northwestern University to treat ALS (amyotrophic lateral sclerosis), shows it to be more effective than existing FDA-approved drugs for the disease.

More importantly, NU-9 has an enhanced effect when given in combination with those drugs, riluzole and edaravone. The drug was invented by Richard B. Silverman, the Patrick G. Ryan/Aon Professor at Northwestern, and animal studies were conducted by P. Hande Ozdinler, an associate professor of neurology at Northwestern University Feinberg School of Medicine.

The study, recently published in Scientific Reports, showed that NU-9 elongated the axons of diseased upper motor neurons in a SOD1 ALS mouse model. This new finding on the lengthening of axons of diseased neurons further illustrates the benefits of NU-9.

The axon is the segment of the upper motor neuron that connects the brain to the spinal cord and makes the corticospinal tract, which degenerates in ALS patients. Deteriorating axons contribute to the rapid and fatal paralysis of ALS patients.

“For a drug to be effective, it’s important that that drug improves axon outgrowth and axon health,” said co-lead researcher Ozdinler. “This is very important for connecting the brain and spinal cord and for revitalizing the motor neuron circuit that degenerates in patients.”

In ALS, movement initiatives of nerve cells in the brain (upper motor neurons) and muscle-regulating nerve cells in the spinal cord (lower motor neurons) die.

In research published last year, Northwestern scientists showed that NU-9 improved two key factors that cause upper motor neurons to become diseased in ALS: protein misfolding and protein aggregation in the cell. Both factors become neuron toxic and are common in ALS patients and neurodegeneration in general.

That study showed that the NU-9 compound prevented neurons from degenerating to such an extent that the diseased neurons became equal to healthy control neurons after 60 days of treatment in two different mouse models of ALS.

NU-9 heading for clinical trials

NU-9 is headed for clinical trials. The company, AKAVA Therapeutics, started last year by Silverman, is conducting animal safety studies necessary for the drug (now called AKV9 in the company) to gain FDA approval to become an Investigational New Drug. Those studies include determining the dose level and toxic effects.

When mixed cortical cultures are established on P3, UMNs are labeled by eGFP expression in UCHL1-eGFP reporter mice and express disease-causing proteins in reporter lines of mouse models of amyotrophic lateral sclerosis (ALS) (ac) Generation of hSOD1G93A-UeGFP and WT- UeGFP littermate control mice. (de) UMNs in layer 5 of the primary motor cortex express eGFP at postnatal day P3 of WT-UeGFP mice. (e) B8H10 antibody detects misfolded SOD1 protein in the primary motor cortex of hSOD1G93A-UeGFP mice, but not the control WT-UeGFP mice at P3. Scale bars = 200 µm in low mag, 50 µm in high mag panels. Credit: Barış Genç et al

“If all goes well, we hope to start a Phase 1 clinical trial with healthy volunteers in early 2023,” said co-lead researcher Silverman.

Depending on the FDA’s response to the Phase 1 results, a Phase II trial could begin in early 2024 to administer the drug to ALS patients.

“NU-9 has a novel mechanism of action and it needs to be tested in humans for its efficacy in treating ALS,” said Silverman.

“It’s a long process — potentially 10 to 12 years — to discover and bring a new drug to market,” Silverman said. “But this drug makes us very excited and hopeful about its potential to improve the lives of ALS patients who have had no hope for so long.”

Other northwestern authors include Barış Genç, Mukesh Gautam, Benjamin Helmold, Nuran Koçak, Aksu Günay, and Gashaw Goshu.

About this research news on ALS and neuropharmacology

Writer: Marla Paul
Source: Northwestern University
Contact: Press Office – Northwestern University
Image: The statue is attributed to Barış Genç et al

Original research: Open access.
“NU-9 improves the health of hSOD1G93A mouse upper motor neurons in vitro, especially in combination with riluzole or edaravone” by Barış Genç et al. Scientific Reports


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NU-9 improves health of hSOD1G93A mouse upper motor neurons in vitro, especially when combined with riluzole or edaravone

Although amyotrophic lateral sclerosis (ALS) is a disease of the upper and lower motor neurons, to date none of the compounds have been tested in clinical trials to improve the health of diseased upper motor neurons (UMNs).

There is an urgent need to develop preclinical tests that include UMN health as a readout. Since ALS is a complex disease, combinatorial treatment strategies will be needed to address the disrupted mechanisms in patients.

Here we describe a novel in vitro platform utilizing a UMN reporter line in which UMNs are genetically labeled with fluorescence and misfolded SOD1 toxicity.

We report that NU-9, an analog of the cyclohexane-1,3-dione family of compounds, improves the health of UMNs with misfolded SOD1 toxicity more effectively than riluzole or edaravone, the only two FDA-approved ALS- drugs to date.

Interestingly, when NU-9 is applied in combination with riluzole or edaravone, there is an additive effect on UMN health, as they elongate axons and exhibit enhanced branching and arborization, two important features of healthy UMNs in vitro.

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