Compound stops neuron degeneration

Potential relevance for HSP, PLS, MND

Hande Ozdinler

The team of Dr Hande Ozdinler at Northwestern University in Chicago has identified a compound that improves the health of diseased upper motor neurons by stopping degeneration.

This has potential relevance to upper motor neuron diseases such as HSP, Primary Lateral Sclerosis and Motor Neurone Disease.

The study was initiated after Prof. Richard Silverman identified a compound, NU-9, developed in his lab for its ability to reduce protein misfolding in critical cell lines. The compound is not toxic and crosses the blood brain barrier. The results in mice were positive. Scientists next performed experiments to reveal how and why the diseased upper motor neurons regained their health. After administering NU-9, both the mitochondria (the cell’s energy producer) and the endoplasmic reticulum (the cell’s protein producer) began to regain their health and integrity, resulting in improved neuron health. The upper motor neurons were more intact, their cell bodies were larger and the dendrites were not riddled with holes. They stopped degenerating so much that the diseased neurons became similar to healthy control neurons after 60 days of NU-9 treatment.

“Improving the health of brain neurons is important for ALS and other motor neuron diseases,” Ozdinler said.

Ozdinler and colleagues will now complete more detailed toxicology and pharmacokinetic studies prior to initiating a Phase 1 clinical trial.

Read the entire article

Dr Ozdinler recently presented the first 2021 SPF virtual conference.

Background: Upper motor neurons (UMNs) are a key component of motor neuron circuitry. Their degeneration is a hallmark for diseases, such as hereditary spastic paraplegia (HSP), primary lateral sclerosis (PLS), and amyotrophic lateral sclerosis (ALS). Currently there are no preclinical assays investigating cellular responses of UMNs to compound treatment, even for diseases of the UMNs. The basis of UMN vulnerability is not fully understood, and no compound has yet been identified to improve the health of diseased UMNs: two major roadblocks for building effective treatment strategies.

Methods: Novel UMN reporter models, in which UMNs that are diseased because of misfolded superoxide dismutase protein (mSOD1) toxicity and TDP-43 pathology are labeled with eGFP expression, allow direct assessment of UMN response to compound treatment. Electron microscopy reveals very precise aspects of endoplasmic reticulum (ER) and mitochondrial damage. Administration of NU-9, a compound initially identified based on its ability to reduce mSOD1 toxicity, has profound impact on improving the health and stability of UMNs, as identified by detailed cellular and ultrastructural analyses.

Results: Problems with mitochondria and ER are conserved in diseased UMNs among different species. NU-9 has drug-like pharmacokinetic properties. It lacks toxicity and crosses the blood brain barrier. NU-9 improves the structural integrity of mitochondria and ER, reduces levels of mSOD1, stabilizes degenerating UMN apical dendrites, improves motor behavior measured by the hanging wire test, and eliminates ongoing degeneration of UMNs that become diseased both because of mSOD1 toxicity and TDP-43 pathology, two distinct and important overarching causes of motor neuron degeneration.

Conclusions: Mechanism-focused and cell-based drug discovery approaches not only addressed key cellular defects responsible for UMN loss, but also identified NU-9, the first compound to improve the health of diseased UMNs, neurons that degenerate in ALS, HSP, PLS, and ALS/FTLD patients.

SOURCE:  Clin Transl Med. 2021 Feb;11(2):e336. doi: 10.1002/ctm2.336. PMID: 33634973 © 2021 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.

Improving mitochondria and ER stability helps eliminate upper motor neuron degeneration that occurs due to mSOD1 toxicity and TDP-43 pathology

Barış Genç  1 Mukesh Gautam  1 Öge Gözütok  1 Ina Dervishi  1 Santana Sanchez  1 Gashaw M Goshu  2 Nuran Koçak  1 Edward Xie  1 Richard B Silverman  2   3   4   5 P Hande Özdinler  1   3   5   6   7

1. Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

2. Department of Chemistry, Northwestern University, Evanston, Illinois, USA.

3. Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Center for Developmental Therapeutics, Northwestern University, Evanston, Illinois, USA.

4. Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

5. Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, 60208.

6. Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Northwestern University, Feinberg School of Medicine, Chicago, IL, 60611.

7. Les Turner ALS Center, Northwestern University, Feinberg School of Medicine, Chicago, IL, 60611.

SOURCE: Medical Express Neuroscience, February 23, 2021

ALS neuron damage reversed with new compound

by Northwestern University


    1. Editor’s Note: No, it cannot. The compound has been given a codename for various reasons, probably including because it is experimental; unproven in humans; has intellectual property and potential commercial value and perhaps other reasons. We will be closely following progress and that is all anyone can do for now.

  1. Dear editor
    In spg 6 nipa1 I have read about bmp signaling. So my question: is bmpr 2
    Activating or inhibiting can restore function in spg 6?
    How important is bmpr 2 activation? In spg I have found the drug fk506 that is tacrolimus.
    Low dose that can restore the function of axonal transport and axonal loss by inhibition of calcineurin.
    Please help me out.

    1. Editor’s Note: If anyone can answer your questions, it may be Evan Reid of Cambridge University, who has investigated BMP signalling in HSP for many years. Suggest that you contact him for his thoughts.

    1. Editor’s Note: It is possible, but it is a long way to go from the promising results that have been achieved so far and a drug being approved for use. We will follow progress closely and report on this website.

    1. Editor’s Note: Fluoxetine (Prozac) is known to affect several genes and the pathways and proteins that they regulate, including BMP which several studies have implicated in the mechanism behind some forms of HSP. However, it is hard to imagine a drug in the SSRI class used to treat psychiatric disorders being suitable for treating HSP if for no other reason than it would need to be taken long-term and there are known significant, common, adverse side-effects.

  2. I have had HSP since 2008, HEREDITARY SPASTIC PARAPARESIA, progressive degenerative, I am much worse, now I barely walk with two canes, muscle stiffness in my legs. ALS-like symptoms.
    I want to test the NU-9. Participate in rehearsals. HOW LONG DO WE HAVE TO WAIT WHILE WE ARE DYING WITH ELA. THANK YOU

    1. Editor’s Note: The article talks about doing more detailed toxicology studies before a phase I clinical trial, so it may not be too long. Some safety studies have already been done as well as animal experiments with promising results. We are closely watching developments and will report them on the website.

  3. I have studied regarding ambroxol hydrochloride research. is it like the nu 9 compound? It restores misfolded protein of motor neurons. Nipa1 mutation.
    It works as a chaperon and removes cell toxins, waste products and misfolded protein.
    Can it improve upper motor neuron health?
    Plz let me know as per my assumptions if it can work for hsp.

    1. Editor’s Note: This compound is approved for use in respiratory conditions to thin mucus and make it easier to cough up. It has recently received attention for its neuroprotective property as it crosses the blood-brain barrier and enters the central nervous system. It was the subject of a clinical trial last year in people with Parkinson’s disease to gauge its potential as a neuroprotective compound. We have no information to help answer your questions about how similar this compound might be to NU-9; and whether or not it might be effective in improving upper motor neuron health in HSP generally or in SPG6 (NIPA1) specifically.

  4. I have had PLS for a little over 15 years now. It has not only affected my walking and moving, but my speech also. I would love to be a candidate when the trials begin, but it would be difficult to travel to Chicago to do so. Would it be possible to do the trial from the St. Louis Missouri area, and do virtual contact, or have doctor here monitor any progression? Thank you!

    1. Editor’s Note: This compound is still in the pre-clinical investigation phase. When clinical trials are planned in the future, decisions will be made about which forms of which diseases will be included; eligibility and exclusion criteria for participants defined; when, where and how data collection and monitoring will take place etc etc. None of these things would be decided as yet. If and when clinical trials become reality for this compound, there will be broad communications coverage to attract potential participants.

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