Methods and compositions for treating aging-associated conditions
Inventors
Wyss-Coray, Anton • Castellano, Joseph M.
Assignees
US Department of Veterans Affairs
Publication Number
US-10617744-B2
Publication Date
2020-04-14
Expiration Date
2036-06-06
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Abstract
Methods of treating an adult mammal for an aging-associated condition are provided. Aspects of the methods include enhancing a TIMP activity, e.g., a TIMP2 activity, in the mammal in a manner sufficient to treat the adult mammal for the aging-associated condition. Also provided are compositions for use in practicing methods of the invention. A variety of aging-associated conditions may be treated by practice of the methods, which conditions include cognitive impairments.
Core Innovation
Methods of treating an adult mammal for an aging-associated condition are provided, where the methods include enhancing a TIMP (tissue inhibitor of metalloproteinase) activity, such as a TIMP2 activity, in the mammal in a manner sufficient to treat the adult mammal for the aging-associated condition. The invention includes the use of compositions for practicing these methods, capable of treating a variety of aging-associated conditions including cognitive impairments.
The problem being solved is the significant decline in synaptic plasticity, learning, memory, and other cognitive abilities associated with normal brain aging and neurodegenerative diseases. Synapse loss and neuronal function impairment contribute to age-related cognitive decline and susceptibility to neurodegenerative conditions such as Alzheimer's disease. There are currently no effective treatments for these age-associated declines in cognitive function and synaptic plasticity.
Claims Coverage
The patent claims cover several inventive features related to enhancing TIMP activity to treat aging-associated conditions, primarily focusing on the use of TIMP polypeptides and nucleic acids encoding them, methods to enhance systemic TIMP activity, and treatment of aging-associated cognitive impairments in adult mammals, particularly primates.
Enhancing TIMP activity to treat aging-associated conditions
A method to treat an adult mammal for an aging-associated condition by enhancing a TIMP activity in the mammal in a manner sufficient for treatment.
Use of TIMP1 to TIMP4 activities
Utilization of specific TIMP activities, including TIMP1, TIMP2, TIMP3, or TIMP4, with emphasis on enhancing TIMP2 activity.
Enhancement of systemic TIMP activity
The method involves increasing a systemic TIMP activity, including increasing systemic levels of a TIMP active agent in the mammal.
Administration of TIMP active agents
Treatment includes administering TIMP active agents such as TIMP polypeptides or mimetics to increase systemic TIMP levels.
Use of TIMP polypeptides with specific sequence identity
Employing TIMP polypeptides having sequences at least 60% identical to known human TIMP sequences (SEQ ID NOS:1 to 4).
Enhancing endogenous TIMP expression and potentiating TIMP activity
Methods including enhancing expression of endogenous TIMP coding sequences and potentiating TIMP activity in the subject.
Treatment of elderly primates with aging-associated cognitive impairments
Application of the method to elderly mammals, particularly primates such as humans, suffering from cognitive impairments or aging-associated diseases.
Administration of TIMP2 polypeptide or nucleic acid to ameliorate aging-associated cognitive decline
Administering a TIMP2 polypeptide or nucleic acid encoding it to enhance TIMP2 activity and ameliorate symptoms of aging-associated cognitive impairment or decline.
The claims collectively cover methods of enhancing TIMP, particularly TIMP2, activity through administration of polypeptides, nucleic acids, or other agents to treat aging-associated conditions with focus on cognitive impairments in adult mammals, especially elderly primates including humans.
Stated Advantages
TIMP2 treatment enhances synaptic plasticity and restores learning and memory deficits in aged subjects.
TIMP2 is naturally produced and found in blood, reducing the likelihood of harmful side effects compared to small molecule drugs.
Systemic administration of TIMP2 confers cognitive benefits without the need for direct brain delivery.
TIMP2 is not a growth factor or canonical immune signaling molecule, thus avoiding potential tumorigenic or proinflammatory effects.
The invention provides a novel effective therapeutic agent for treating cognitive decline associated with aging or neurodegenerative diseases.
Documented Applications
Treating aging-associated cognitive impairments and decline including natural aging-related mild cognitive impairment.
Treating cognitive impairments associated with aging-related neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma, muscular dystrophy, vascular dementia, dementia with Lewy bodies, progressive supranuclear palsy, ataxias, and multiple-system atrophy.
Slowing, stabilizing, reducing, or reversing cognitive decline and synaptic plasticity loss in elderly or adult mammals including humans.
Enhancing hippocampal-dependent learning and memory in aged subjects.
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