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

Genç, Barış; Gautam, Mukesh; Helmold, Benjamin; Koçak, Nuran; Gunay, Aksu; Goshu, Gashaw M.; Silverman, Richard B.; Özdinler, P. Hande

doi:10.1038/s41598-022-09332-4

Cited by 8 publications

(9 citation statements)

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“…They also displayed significantly less branching and arborization. We, therefore, utilized average axon length and the extent of branching and arborization as two quantitative outcome measure to assess the cellular responses of diseased CSMN to compound treatment (Al-Ali et al, 2016; Gautam et al, 2022; Genc et al, 2022a; Nguyen et al, 2012; Ozdinler and Macklis, 2006; Ristanovic et al, 2006; Sholl, 1953; Whitlon, 2017).…”

Section: Resultsmentioning

confidence: 99%

“…P3 motor cortices were isolated from prp-hTDP-43 A315T -UeGFP mice, dissected, dissociated, and digested with 100 U/ml papain enzyme (Worthington) and 100U/ml DNase enzyme (NEB) at 37°C for 20 minutes. After digestion, tissue was gently triturated and a single cell suspension was prepared, as described (Gautam et al, 2022; Genc et al, 2022a). Cells were cultured on poly-L-lysine (10mg/mL, Sigma) coated 100-mm plastic dishes (Fisherbrand).…”

Section: Methodsmentioning

confidence: 99%

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SBT-272 improves TDP-43 pathology in the ALS motor cortex by modulating mitochondrial integrity, motility, and function

Gautam¹,

Genç²,

Helmold³

et al. 2022

Preprint

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Mitochondrial defects are one of the common underlying causes of neuronal vulnerability in motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), and TDP-43 pathology is the most common proteinopathy in ALS. Disrupted inner mitochondrial membrane (IMM) reported in the upper motor neurons (UMNs) of ALS patients with TDP-43 pathology is recapitulated in the UMNs of well-characterized mutant hTDP-43 mouse models of ALS. The construct validity, such as common cellular pathology in mice and human, offers a unique opportunity to test treatment strategies that may translate. SBT-272 is a well-tolerated brain-penetrant small molecule that stabilizes cardiolipin, a phospholipid found in IMM, thereby restoring mitochondrial structure and respiratory function. We investigated whether SBT-272 can improve IMM structure and health in UMNs diseased with TDP-43 pathology in our well-characterized UMN reporter line for ALS. We found that SBT-272 significantly improved mitochondrial structural integrity and restored mitochondrial motility and function. This led to improved health of diseased UMNs in vitro. In comparison to edaravone and AMX0035, SBT-272 appeared more effective in restoring health of diseased UMNs. Chronic treatment of SBT-272 for sixty days starting at an early symptomatic stage of the disease in vivo led to a reduction in astrogliosis, microgliosis, and retention of UMN degeneration in the ALS motor cortex. Our results underscore the therapeutic potential of SBT-272, especially within the context of TDP-43 pathology and mitochondrial dysfunction.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

SBT-272 improves TDP-43 pathology in the ALS motor cortex by modulating mitochondrial integrity, motility, and function

Gautam¹,

Genç²,

Helmold³

et al. 2022

Preprint

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“…Improved therapeutic efficacy in end-stage is important for increasing late-stage quality of life and survival. Previous preclinical and clinical literature demonstrated combination treatments have a synergistic effect: rasagiline and riluzole ( Waibel et al, 2004 ); minocycline and creatine ( Klivenyi et al, 2004 ); Lithium and Neu2000 ( Shin et al, 2007 ); minocycline + riluzole + nimodipine ( Kriz et al, 2003 ); minocycline-creatine and celoxicob-creatine ( Gordon et al, 2008 ); and most recently, riluzole, edaravone, and Nu-9 ( Genc et al, 2022 ). A previous computational study also illustrated that combination therapies may be able to re-stabilize ALS and halt progression by returning the pathophysiology to homeostasis ( Mitchell and Lee, 2012a ; Irvin et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

“…A previous computational study also illustrated that combination therapies may be able to re-stabilize ALS and halt progression by returning the pathophysiology to homeostasis ( Mitchell and Lee, 2012a ; Irvin et al, 2015 ). While polypharmacy is an interesting concept moving forward, care must be taken to consider possible drug interactions ( Genc et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Comparing therapeutic modulators of the SOD1 G93A Amyotrophic Lateral Sclerosis mouse pathophysiology

et al. 2023

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IntroductionAmyotrophic Lateral Sclerosis (ALS) is a paralyzing, multifactorial neurodegenerative disease with limited therapeutics and no known cure. The study goal was to determine which pathophysiological treatment targets appear most beneficial.MethodsA big data approach was used to analyze high copy SOD1 G93A experimental data. The secondary data set comprised 227 published studies and 4,296 data points. Treatments were classified by pathophysiological target: apoptosis, axonal transport, cellular chemistry, energetics, neuron excitability, inflammation, oxidative stress, proteomics, or systemic function. Outcome assessment modalities included onset delay, health status (rotarod performance, body weight, grip strength), and survival duration. Pairwise statistical analysis (two-tailed t-test with Bonferroni correction) of normalized fold change (treatment/control) assessed significant differences in treatment efficacy. Cohen’s d quantified pathophysiological treatment category effect size compared to “all” (e.g., all pathophysiological treatment categories combined).ResultsInflammation treatments were best at delaying onset (d = 0.42, p > 0.05). Oxidative stress treatments were significantly better for prolonging survival duration (d = 0.18, p < 0.05). Excitability treatments were significantly better for prolonging overall health status (d = 0.22, p < 0.05). However, the absolute best pathophysiological treatment category for prolonging health status varied with disease progression: oxidative stress was best for pre-onset health (d = 0.18, p > 0.05); excitability was best for prolonging function near onset (d = 0.34, p < 0.05); inflammation was best for prolonging post-onset function (d = 0.24, p > 0.05); and apoptosis was best for prolonging end-stage function (d = 0.49, p > 0.05). Finally, combination treatments simultaneously targeting multiple pathophysiological categories (e.g., polytherapy) performed significantly (p < 0.05) better than monotherapies at end-stage.DiscussionIn summary, the most effective pathophysiological treatments change as function of assessment modality and disease progression. Shifting pathophysiological treatment category efficacy with disease progression supports the homeostatic instability theory of ALS disease progression.

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“…111 NU-9 also enhanced axon outgrowth more than riluzole and edaravone, and this enhancement was additive when used in combination with either of these ALS drugs. 112 The straightforward synthesis of (+)-78 starts by attaching the linker to the starting aldehyde (Scheme 5). A Mitsunobu reaction of commercially available (R)-ethyl lactate (+)-( 80) with 3,5-ditrifluoromethylphenol (79) provided ether (81) followed by DIBAL reduction to give aldehyde 82.…”

Section: S C H E M Ementioning

confidence: 99%

Small molecules targeting different cellular pathologies for the treatment of amyotrophic lateral sclerosis

Elmansy

Reidl

Rahaman

et al. 2023

Medicinal Research Reviews

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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease in which the motor neuron circuitry displays progressive degeneration, affecting mostly the motor neurons in the brain and in the spinal cord. There are no effective cures, albeit three drugs, riluzole, edaravone, and AMX0035 (a combination of sodium phenylbutyrate and taurursodiol), have been approved by the Food and Drug Administration, with limited improvement in patients. There is an urgent need to build better and more effective treatment strategies for ALS. Since the disease is very heterogenous, numerous approaches have been explored, such as targeting genetic mutations, decreasing oxidative stress and excitotoxicity, enhancing mitochondrial function and protein degradation mechanisms, and inhibiting neuroinflammation. In addition, various chemical libraries or previously identified drugs have been screened for potential repurposing in the treatment of ALS. Here, we review previous drug discovery efforts targeting a variety of cellular pathologies that occur from genetic mutations that cause ALS, such as mutations in SOD1, C9orf72, FUS, and TARDP‐43 genes. These mutations result in protein aggregation, which causes neuronal degeneration. Compounds used to target cellular pathologies that stem from these mutations are discussed and comparisons among different preclinical models are presented. Because the drug discovery landscape for ALS and other motor neuron diseases is changing rapidly, we also offer recommendations for a novel, more effective, direction in ALS drug discovery that could accelerate translation of effective compounds from animals to patients.

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

Cited by 8 publications

References 60 publications

SBT-272 improves TDP-43 pathology in the ALS motor cortex by modulating mitochondrial integrity, motility, and function

SBT-272 improves TDP-43 pathology in the ALS motor cortex by modulating mitochondrial integrity, motility, and function

Comparing therapeutic modulators of the SOD1 G93A Amyotrophic Lateral Sclerosis mouse pathophysiology

Small molecules targeting different cellular pathologies for the treatment of amyotrophic lateral sclerosis

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