LSD1 enzyme inhibitor TAK-418 unlocks aberrant epigenetic machinery and improves autism symptoms in neurodevelopmental disorder models

Baba, Rina; Matsuda, Satoru; Arakawa, Yuuichi; Yamada, Ryuji; Suzuki, Noriko; Ando, Tatsuya; Oki, Hideyuki; Igaki, S.; Daini, Masaki; Hattori, Yasushi; Matsumoto, Shigemitsu; Ito, Mitsuhiro; Nakatani, Ayaka; Kimura, Haruhide

doi:10.1126/sciadv.aba1187

Cited by 17 publications

(29 citation statements)

References 40 publications

(47 reference statements)

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“… 7 In addition, TAK‐418 improved autism symptoms in two rodent models of neurodevelopmental disorder. 8 These results support the hypothesis that LSD1 inhibition may be an effective method for the treatment of Kabuki syndrome.…”

Section: Introductionsupporting

confidence: 78%

Safety, pharmacokinetics and pharmacodynamics of TAK‐418, a novel inhibitor of the epigenetic modulator lysine‐specific demethylase 1A

Yin

Arkilo

Khudyakov

et al. 2021

Brit J Clinical Pharma

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Funding informationThese studies were funded by Takeda Development Center Americas Aims: Dysregulation of histone methylation epigenetic marks may result in intellectual and developmental disability, as seen in Kabuki syndrome. Animal data suggest that increasing histone methylation by inhibiting lysine-specific demethylase 1A (LSD1) may improve cognitive outcomes in a model of Kabuki syndrome. TAK-418 is a novel LSD1 inhibitor, developed as a potential therapeutic agent for central nervous system disorders such as Kabuki syndrome. Here, we report safety, tolerability, pharmacokinetic and pharmacodynamic profiles of single and multiple doses of TAK-418 (ClinicalTrials.gov: NCT03228433, NCT03501069). Methods: Two randomized, double-blind, placebo-controlled, phase 1 studies of oral TAK-418 were performed, a first-in-human single-rising-dose (SRD) study (5-60 mg) in healthy adult male and female volunteers (placebo, n = 10; TAK-418, n = 30), and an SRD (120-160 mg) and multiple-rising-dose (MRD) study (20-160 mg once daily for 10 days) in healthy female volunteers (placebo, n = 2 [SRD] and n = 6 [MRD]; TAK-418, n = 6 [SRD] and n = 18 [MRD]).Results: TAK-418 was well tolerated. No clinically significant changes in laboratory test results or vital signs were observed and no serious adverse events were reported. TAK-418 had a nearly linear pharmacokinetic profile, with rapid absorption and short terminal half-life across the evaluated dose range. No obvious accumulation was observed after daily administration for 10 days. Administration with food delayed peak plasma concentrations but overall exposure was unaffected. TAK-418 rapidly crossed the blood-brain barrier and generally showed a dose-dependent response in the peripheral pharmacodynamic biomarker formyl-flavin adenine dinucleotide. Conclusion:The brain-penetrant LSD1 inhibitor TAK-418 was well tolerated, with pharmacokinetic and pharmacodynamic effects that support further investigation.

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Section: Introductionsupporting

confidence: 78%

Safety, pharmacokinetics and pharmacodynamics of TAK‐418, a novel inhibitor of the epigenetic modulator lysine‐specific demethylase 1A

Yin

Arkilo

Khudyakov

et al. 2021

Brit J Clinical Pharma

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“…In mouse models of neurodevelopmental disorders, TAK‐418 treatment mice normalized dysregulated mRNA expression by restoring homeostatic regulation of global gene expression. 297 These results suggest that neurodevelopmental disorders may be treated with TAK‐418 by inhibiting LSD1 enzymatic activity, thereby stabilizing aberrant gene expression through epigenetic regulation to restore global pathological gene expression. Kohanbash et al.…”

Section: Epigenetic‐targeted Therapy For Inflammation‐related Diseasesmentioning

confidence: 95%

Targeting epigenetic regulators for inflammation: Mechanisms and intervention therapy

Zhang

Meng

Zhou

et al. 2022

MedComm

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Emerging evidence indicates that resolution of inflammation is a critical and dynamic endogenous process for host tissues defending against external invasive pathogens or internal tissue injury. It has long been known that autoimmune diseases and chronic inflammatory disorders are characterized by dysregulated immune responses, leading to excessive and uncontrol tissue inflammation. The dysregulation of epigenetic alterations including DNA methylation, posttranslational modifications to histone proteins, and noncoding RNA expression has been implicated in a host of inflammatory disorders and the immune system. The inflammatory response is considered as a critical trigger of epigenetic alterations that in turn intercede inflammatory actions. Thus, understanding the molecular mechanism that dictates the outcome of targeting epigenetic regulators for inflammatory disease is required for inflammation resolution. In this article, we elucidate the critical role of the nuclear factor‐κB signaling pathway, JAK/STAT signaling pathway, and the NLRP3 inflammasome in chronic inflammatory diseases. And we formulate the relationship between inflammation, coronavirus disease 2019, and human cancers. Additionally, we review the mechanism of epigenetic modifications involved in inflammation and innate immune cells. All that matters is that we propose and discuss the rejuvenation potential of interventions that target epigenetic regulators and regulatory mechanisms for chronic inflammation‐associated diseases to improve therapeutic outcomes.

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“…To validate the LSD1 inhibition by T-448 in vivo, we measured the residual LSD1 enzyme activity in the tissues isolated from T-448-treated rats using an ex vivo enzyme assay. , T-448 at 1 and 3 mg/kg showed 50.2% and 85.5% inhibition of LSD1 enzyme activity in the hippocampus at 2 h after single oral administration, respectively (Figure C). At 8 h after the single administration, T-448 was almost completely eliminated from the plasma and hippocampus (Figure A, B).…”

Section: Resultsmentioning

confidence: 99%

Investigating the Therapeutic Potential of LSD1 Enzyme Activity-Specific Inhibition by TAK-418 for Social and Memory Deficits in Rodent Disease Models

Baba

Matsuda

Maeda

et al. 2022

ACS Chem. Neurosci.

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Inhibition of lysine-specific demethylase 1 (LSD1) enzyme activity is a promising approach to treat diseases associated with epigenetic dysregulation, such as neurodevelopmental disorders. However, this concept has not been fully validated because genetic LSD1 deletion causes embryonic lethality and conventional LSD1 inhibitors cause thrombocytopenia via the dissociation of LSD1-cofactor complex. To characterize the therapeutic potential of LSD1 enzyme inhibition, we used TAK-418 and T-448, the LSD1 enzyme activity-specific inhibitors with minimal impact on the LSD1-cofactor complex. TAK-418 and T-448, by inhibiting brain LSD1 enzyme activity, consistently improved social deficits in animal models of neurodevelopmental disorders without causing thrombocytopenia. Moreover, TAK-418 improved memory deficits caused by aging or amyloid precursor protein overexpression. In contrast, TAK-418 did not improve memory deficits caused by miR-137 overexpression. Thus, miR-137 modulation may be involved in memory improvement by LSD1 inhibition. TAK-418 warrants further investigation as a novel therapeutic agent for diseases with epigenetic dysregulation.

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LSD1 enzyme inhibitor TAK-418 unlocks aberrant epigenetic machinery and improves autism symptoms in neurodevelopmental disorder models

Cited by 17 publications

References 40 publications

Safety, pharmacokinetics and pharmacodynamics of TAK‐418, a novel inhibitor of the epigenetic modulator lysine‐specific demethylase 1A

Safety, pharmacokinetics and pharmacodynamics of TAK‐418, a novel inhibitor of the epigenetic modulator lysine‐specific demethylase 1A

Targeting epigenetic regulators for inflammation: Mechanisms and intervention therapy

Investigating the Therapeutic Potential of LSD1 Enzyme Activity-Specific Inhibition by TAK-418 for Social and Memory Deficits in Rodent Disease Models

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