Methods and compositions for treating aging-associated conditions
Inventors
Wyss-Coray, Anton • Castellano, Joseph M.
Assignees
US Department of Veterans Affairs
Publication Number
US-11141469-B2
Publication Date
2021-10-12
Expiration Date
2036-06-16
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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. These methods include enhancing a Tissue Inhibitor of Metalloproteinase (TIMP) activity, for example, TIMP2 activity, in the mammal in a manner sufficient to treat the adult mammal for the aging-associated condition. Compositions for practicing these methods are also provided. The treated aging-associated conditions include, but are not limited to, cognitive impairments.
The problem being solved addresses aging-associated structural and neurophysiological changes in the nervous system that impair cognitive function. Aging leads to synapse loss and neuronal function decline without significant neuronal death and is an early pathological event common to many neurodegenerative conditions such as Alzheimer's disease, which is the dominant risk factor for dementia. There are currently no effective treatments to counteract or prevent the decline in synaptic plasticity, learning, memory, and cognitive abilities associated with natural brain aging or neurodegeneration.
Claims Coverage
The patent contains two sets of independent claims focusing on methods of treating aging-associated conditions by enhancing TIMP activity, particularly focusing on TIMP polypeptides and nucleic acids encoding them, and the systemic administration thereof to mammals, especially elderly humans.
Enhancing TIMP activity to treat aging-associated conditions
A method of treating an adult mammal for an aging-associated condition by enhancing a TIMP activity in the mammal sufficiently to provide treatment. This includes activities of TIMP1, TIMP2, TIMP3, or TIMP4, with specific emphasis on systemic enhancement.
Administering TIMP active agents
The method involves increasing systemic levels of a TIMP active agent by administering TIMP polypeptides or nucleic acids encoding TIMP polypeptides to the mammal, including pegylated TIMP polypeptides and TIMP polypeptides fused to Fc regions to improve pharmacokinetics.
Use of specific TIMP polypeptides and nucleic acids
The TIMP polypeptides administered have sequences at least 60–90% identical to SEQ ID NOS: 1 to 4. The nucleic acids encoding these sequences can also be administered. The mammal treated is typically a primate, particularly a human elderly mammal (60 years or older).
Amelioration of symptoms of aging-associated cognitive impairment
The method ameliorates symptoms of aging-associated cognitive impairment or decline by enhancing TIMP activity through administration of TIMP polypeptides or nucleic acid encoding them, leading to improved cognitive and synaptic functions in the subject.
The claims fundamentally cover methods of treating aging-associated conditions by enhancing TIMP activity via administration of TIMP polypeptides or nucleic acids, focusing on systemic treatment to ameliorate cognitive impairments in elderly mammals, with detailed provision for various TIMP family members and modified forms.
Stated Advantages
TIMP2 administered systemically can reverse impairments in synaptic plasticity and age-related learning and memory deficits without needing direct delivery to the brain.
TIMP2 is not a growth factor or canonical immune signaling molecule, reducing risks such as tumorigenesis or proinflammatory side effects.
Using a naturally occurring blood protein like TIMP2 to limit cognitive dysfunction is less likely to produce harmful side effects compared to conventional small molecule drugs.
Systemic treatment with TIMP2 allows facile administration to elderly patients or individuals suffering cognitive impairment.
Documented Applications
Treating aging-associated conditions in adult mammals, including cognitive impairments such as mild cognitive impairment, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma, muscular dystrophy, vascular dementia, and other neurodegenerative and aging-related disorders affecting cognition.
Slowing, stabilizing, reducing, reversing, or abrogating aging-associated cognitive decline and impairments in synaptic plasticity, learning, and memory in elderly mammals, particularly humans aged 50 years or older.
Use in combination therapies with other drugs for cognitive impairment or aging-associated conditions, including cholinesterase inhibitors, memantine, and psychiatric symptom agents.
Use in animal models for experimental investigations of aging-associated cognitive dysfunction and treatment effects.
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