Treatment of neurodevelopmental disorders
Inventors
Hammock, Bruce D. • Hwang, Sung Hee • Yang, Jun • Hashimoto, Kenji
Assignees
Chiba University NUC • University of California San Diego UCSD
Publication Number
US-12357598-B2
Publication Date
2025-07-15
Expiration Date
2039-12-20
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Abstract
Provided herein are methods of preventing, reducing, ameliorating, mitigating, inhibiting, treating and/or reversing a neurodevelopmental disorder related to prenatal maternal immune activation in an individual in need thereof comprising administering to said individual an agent that increases the level of epoxy-fatty acids wherein said individual experienced maternal immune activation one or more times during gestation. Also provided herein are methods of preventing, reducing, ameliorating, mitigating, inhibiting treating and/or reversing schizophrenia or autism spectrum disorder an individual comprising administering to said individual an agent that increases the level of epoxy-fatty acids.
Core Innovation
The invention provides methods of preventing, reducing, ameliorating, mitigating, inhibiting, treating and/or reversing neurodevelopmental disorders related to prenatal maternal immune activation (MIA) by administering an agent that increases the level of epoxy-fatty acids (EpFAs) to an individual who experienced maternal immune activation during gestation. The methods include administration of agents that increase EpFAs alone or in combination with a second agent.
The invention particularly addresses neurodevelopmental disorders such as schizophrenia and autism spectrum disorder (ASD). These disorders are associated with prenatal environmental factors, including maternal immune activation caused by infections, inflammatory biomarkers, or exposure to toxins such as pesticides or herbicides including glyphosate.
The problem being solved is the lack of known the mechanisms and treatments for neurodevelopmental disorders related to prenatal MIA, where increased activity of soluble epoxide hydrolase (sEH), which breaks down EpFAs, is implicated. The invention is based on discovery that increased sEH plays a key role in the onset of such neurodevelopmental disorders and that administration of agents that increase EpFA levels, such as sEH inhibitors, can prevent or mitigate these disorders.
Claims Coverage
The patent contains independent claims focused on methods of treating autism spectrum disorder (ASD) related to prenatal maternal immune activation using specific agents that increase epoxy-fatty acids.
Use of agents that increase epoxy-fatty acids in treating ASD related to maternal immune activation
A method of reducing, ameliorating, and/or mitigating ASD related to prenatal maternal immune activation in an individual by administering an agent that increases the level of epoxy-fatty acids, where the individual experienced maternal immune activation one or more times during gestation, and the agent is a compound of Formula (II).
Use of specific sEH inhibitors as agents increasing epoxy-fatty acids
The agent that increases epoxy-fatty acids is an inhibitor of soluble epoxide hydrolase (sEH), selected from compounds including 1-(1-methylsulfonyl-piperidin-4-yl)-3-(4-trifluoromethoxy-phenyl)-urea (TUPS), 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), 1-(1-ethylsulfonyl-piperidin-4-yl)-3-(4-trifluoromethoxy-phenyl)-urea (TUPSE), and 1-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea (CPTU).
Administration specifics for individuals already diagnosed or at risk
Methods include treating individuals diagnosed as having experienced maternal immune activation during gestation or exposure to toxins during gestation. The individual may be a child, juvenile, or adult, and may have been diagnosed as having ASD prior to administration.
The claims principally cover methods of treating ASD related to prenatal maternal immune activation by administering agents that increase epoxy-fatty acid levels, particularly with specific sEH inhibitors, addressing individuals across various age groups and conditions experienced during gestation.
Stated Advantages
Agents that increase epoxy-fatty acids, including soluble epoxide hydrolase (sEH) inhibitors, can prevent cognitive and social deficits associated with neurodevelopmental disorders such as schizophrenia and autism spectrum disorder.
Administration of sEH inhibitors prevents loss of parvalbumin (PV) and glutamic acid decarboxylase (GAD67) immunoreactivity in the medial prefrontal cortex, which are associated with cognitive function.
Treatment reduces endoplasmic reticulum (ER) stress markers elevated in offspring following maternal immune activation.
Early intervention during juvenile and adolescent stages with sEH inhibitors has prophylactic and therapeutic potential against abnormal behaviors related to neurodevelopmental disorders.
Use of sEH inhibitors during pregnancy can prevent ASD-like behaviors caused by maternal exposure to toxins such as glyphosate in offspring.
Documented Applications
Treatment and prevention of neurodevelopmental disorders related to prenatal maternal immune activation, specifically schizophrenia and autism spectrum disorder.
Use in individuals diagnosed with or at risk of developing ASD or schizophrenia due to maternal immune activation or exposure to toxins during gestation.
Therapeutic use of agents increasing epoxy-fatty acid levels to maintain parvalbumin and GAD67 expression in the medial prefrontal cortex.
Prophylactic administration of sEH inhibitors to pregnant mothers to prevent onset of neurodevelopmental disorders in offspring.
Use of sEH inhibitors to prevent ASD-like behaviors in juvenile offspring following maternal glyphosate exposure.
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