Methods of treating cognitive symptoms of an aging-associated impairment by modulating C-C chemokine receptor type 3 (CCR3)
Inventors
Wyss-Coray, Anton • Rando, Thomas A. • Britschgi, Markus • Rufibach, Kaspar • Villeda, Saul A.
Assignees
US Department of Veterans Affairs • Leland Stanford Junior University
Publication Number
US-10626399-B2
Publication Date
2020-04-21
Expiration Date
2031-01-28
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Abstract
Methods of treating an adult mammal for an aging-associated impairment are provided. Aspects of the methods include modulating CCR3, e.g., by modulating eotaxin-1/CCR3 interaction, in the mammal in a manner sufficient to treat the mammal for the aging-associated impairment. A variety of aging-associated impairments may be treated by practice of the methods, which impairments include cognitive impairments.
Core Innovation
The invention provides methods for treating an adult mammal for aging-associated impairments by modulating C-C chemokine receptor type 3 (CCR3). This modulation includes, for example, adjusting eotaxin-1/CCR3 interaction in a manner that is sufficient to treat the aging-associated impairment, such as cognitive impairments. The methods may involve reducing active systemic eotaxin-1, modulating CCR3 activity, or administering agents that inhibit eotaxin-1 or CCR3 activity or expression.
The problem addressed by the invention is the decline in cognitive function and regenerative capacity that occurs in the aging adult brain. Aging is accompanied by changes that impair cognitive ability, including a decrease in adult neurogenesis, synaptic plasticity, and increased neuroinflammation, which contribute to cognitive impairments and susceptibility to neurodegenerative diseases such as Alzheimer's disease. Existing knowledge highlights cognitive decline driven by structural and neurophysiological changes, synapse loss, and neuronal vulnerability although significant neuronal death is not typically observed during natural aging.
Claims Coverage
The claims include one independent claim outlining a method to treat cognitive symptoms of aging-associated impairments by modulating CCR3, with dependent claims specifying various modes of modulating CCR3 activity or eotaxin-1/CCR3 interaction, types of agents used, subject species, and treatment outcomes.
Modulating CCR3 to treat cognitive symptoms of aging-associated impairment
A method of treating an adult mammal for a cognitive symptom of an aging-associated impairment by modulating CCR3 in the mammal to achieve treatment.
Modulating eotaxin-1/CCR3 interaction
Modulating CCR3 includes modulating eotaxin-1/CCR3 interaction to treat cognitive symptoms.
Reducing active systemic eotaxin-1
Modulating the interaction by reducing active systemic eotaxin-1 in the mammal, including administering effective amounts of active systemic eotaxin-1 reducing agents.
Using eotaxin-1 binding agents
Employing eotaxin-1 binding agents as reducing agents, such as antibodies or binding fragments thereof, or small molecules that inhibit eotaxin-1 activity.
Using eotaxin-1 expression inhibitory agents
Using agents that inhibit eotaxin-1 expression, which may include nucleic acid agents such as RNAi or antisense molecules.
Reducing CCR3 activity
Modulating eotaxin-1/CCR3 interaction by reducing CCR3 activity using effective CCR3 reducing agents.
Using CCR3 binding agents
Employing CCR3 binding agents including antibodies or binding fragments thereof, and small molecules that inhibit CCR3 activity.
Using CCR3 expression inhibitory agents
Using agents that inhibit CCR3 expression, including nucleic acid agents.
Subject species and age ranges
Methods are applicable to adult mammals, particularly primates and humans aged 60 years or older.
Treatment outcomes involving cognitive improvements
Treatment comprises increasing neurogenesis, increasing synaptic plasticity, and improving cognitive symptoms such as impaired learning and memory.
The claims collectively cover methods of treating cognitive symptoms of aging-associated impairments by modulating CCR3 or its interaction with eotaxin-1, using various agents to inhibit or reduce activity or expression, particularly focusing on effects on neurogenesis, synaptic plasticity, and cognitive improvements in adult mammals, especially humans.
Stated Advantages
The methods can ameliorate stem cell and cognitive impairments associated with aging.
Modulation of CCR3 and eotaxin-1/CCR3 interaction can restore or improve neurogenesis and synaptic plasticity in the aging brain.
Treatment can slow or reduce the progression of cognitive decline, stabilize cognitive ability, or improve cognitive function, including learning and memory.
Systemic manipulation of chemokine levels offers a therapeutic avenue to counteract aging-related cognitive impairments.
Documented Applications
Treatment of aging-associated cognitive impairments in adult mammals, particularly humans 60 years or older.
Treatment or prevention of cognitive impairments associated with natural aging processes such as mild cognitive impairment (MCI).
Treatment of cognitive symptoms in aging-associated neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma, myotonic dystrophy, vascular dementia, dementia with Lewy bodies, progressive supranuclear palsy, ataxia, multiple-system atrophy, and macular degeneration.
Treatment for improving neurogenesis, synaptic plasticity, learning, and memory in aging adults.
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