Method of reducing the effects of aging-associated impairment of neurogenesis comprising 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-11236340-B2
Publication Date
2022-02-01
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
Methods of treating an adult mammal for an aging-associated impairment are provided. Aspects of the methods include modulating CCR3, for example via modulation of eotaxin-1/CCR3 interaction, in the mammal in a manner sufficient to treat the mammal for the aging-associated impairment, which includes cognitive impairments.
Aging in the nervous system is accompanied by structural and neurophysiological changes that lead to cognitive decline and susceptibility to degenerative disorders. Despite significant neuronal death not typically observed during natural aging, neurons become vulnerable to sub-lethal age-related alterations in structure, synaptic integrity, and molecular processing, impairing cognitive function. Synapse loss is an early pathological event common to many neurodegenerative conditions and the best correlate to neuronal and cognitive impairments associated with these conditions. Aging is the dominant risk factor for dementia-related neurodegenerative diseases such as Alzheimer's disease.
A greater fraction of the population suffers from aging-associated cognitive impairments as lifespans increase, making it crucial to elucidate means to maintain cognitive integrity by protecting against or counteracting effects of aging. The invention addresses this problem by providing methods of modulating CCR3 activity such that effects of aging-associated impairments, including reductions in neurogenesis and cognitive decline, can be treated or ameliorated in adult mammals.
Claims Coverage
The patent includes one independent claim claiming methods of reducing effects of aging-associated impairment of neurogenesis by modulating CCR3 in adult mammals. The main inventive features relate to modulation of the CCR3 receptor and its interaction with eotaxin-1, including means to reduce active systemic eotaxin-1 and CCR3 activity.
Modulating CCR3 to treat aging-associated impairment of neurogenesis
A method of reducing the effects of aging-associated impairment of neurogenesis in an adult mammal by modulating C-C chemokine receptor type 3 (CCR3) in the adult mammal in a manner sufficient to reduce the effects.
Modulating eotaxin-1/CCR3 interaction
The method comprises modulating the interaction between eotaxin-1 and CCR3 as part of the modulation of CCR3.
Reducing active systemic eotaxin-1
Modulation of eotaxin-1/CCR3 interaction is performed by reducing active systemic eotaxin-1 in the mammal, for example by administering an effective amount of an agent that reduces systemic eotaxin-1.
Using eotaxin-1 binding agents to reduce eotaxin-1
The active systemic eotaxin-1 reducing agent may include eotaxin-1 binding agents such as antibodies or binding fragments thereof, or small molecules that bind to and inhibit eotaxin-1.
Reducing eotaxin-1 expression
The agent may reduce eotaxin-1 expression, including nucleic acid-based expression inhibitory agents like RNAi or antisense molecules.
Reducing CCR3 activity
Eotaxin-1/CCR3 interaction may also be modulated by reducing CCR3 activity through administration of an active CCR3 reducing agent.
Using CCR3 binding agents to reduce CCR3 activity
The CCR3 reducing agent may include CCR3 binding agents such as antibodies or binding fragments thereof, or small molecule antagonists that inhibit CCR3 activity.
Reducing CCR3 expression
CCR3 expression can be reduced by expression inhibitory agents such as nucleic acids including RNAi or antisense molecules.
Application to primates and humans
The method is applicable to primates including humans, particularly adult humans age 60 years or older suffering from aging-associated neurogenesis impairment or cognitive impairments.
The claims cover methods of reducing aging-associated neurogenesis impairment by modulating CCR3, specifically targeting eotaxin-1/CCR3 interaction, through reducing systemic eotaxin-1 levels or CCR3 activity or expression, using binding agents such as antibodies or small molecules, and are applicable particularly in humans suffering aging-associated cognitive decline.
Stated Advantages
The methods can slow or reduce progression of aging-associated cognitive decline.
They can stabilize cognitive abilities in individuals experiencing or at risk for cognitive decline.
They can reduce, reverse, or abrogate cognitive impairments associated with aging.
The methods increase neurogenesis, synaptic plasticity, and improve learning and memory.
Documented Applications
Treatment and prevention of aging-associated impairments, particularly aging-associated cognitive impairment including mild cognitive impairment and cognitive impairment associated with natural aging process.
Treatment of cognitive impairments associated with aging-related diseases e.g., 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.
Reducing cognitive impairment due to systemic inflammation, radiation, chemotherapy, frailty, and kidney dysfunction.
Slowing progression, stabilizing, reducing, or reversing cognitive decline in aging individuals or individuals with aging-associated cognitive disorders.
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