Boosting Treg cells for treating Alzheimer disease and related disorders
Inventors
DOROTHEE, Guillaume • Piaggio, Eliane • AIT AHMED, Dylla • AUCOUTURIER, Pierre
Assignees
Centre National de la Recherche Scientifique CNRS • Assistance Publique Hopitaux de Paris APHP • Institut National de la Sante et de la Recherche Medicale INSERM • Sorbonne Universite • Institut du Cerveau et de La Moelle Epiniere ICM
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Publication Number
US-10183061-B2
Publication Date
2019-01-22
Expiration Date
Abstract
The present invention relates to the boosting of Treg cells for the treatment of Alzheimer's disease and related disorders.
Core Innovation
The invention describes treating an Alzheimer's disorder in a subject in need thereof by administering a therapeutically effective amount of a booster of regulatory T (Treg) cells using a low dose of interleukin-2 (IL-2). The low dose of IL-2 is below 3.5 MIU/m2/day, and the subject is treated at an early stage of Alzheimer's disorder. The approach is positioned as selectively boosting Treg cells without substantial effector T-cell or B-cell expansion.
The invention addresses a background risk associated with Aβ vaccination and pro-inflammatory T-cell infiltration, where it is necessary to modulate Aβ-specific CD4+ T cells by boosting Treg cells. The disclosure further frames potential limitations associated with IL-2, including concern for neurologic side effects observed in cancer-related contexts, and positions the low-dose IL-2 booster approach to target Treg biology.
The invention provides timing and disease-stage positioning for administering IL-2, including early stage, pre-dementia/pro-dromal, mild cognitive impairment, and later stage windows such as mild and moderate dementia. The disclosure describes combinations and administration breadth, including multiple administration routes and a sustained-release option, and includes the detection of amyloid peptide, Tau protein, and/or phosphorylated Tau protein.
Claims Coverage
The independent claims cover three treatment outcomes for Alzheimer's disorder—treating at an early stage, delaying the onset of cognitive deficits, and delaying disease progression—by administering a therapeutically effective booster of Treg cells using a low dose of IL-2 below 3.5 MIU/m2/day. Across the independent claims, the key inventive framework is booster-of-Treg with low-dose IL-2, with timing tied to early stage, prior to cognitive deficits, or during mild cognitive impairment.
Early-stage booster of Treg cells with low-dose IL-2
A method for treating an Alzheimer's disorder in a subject in need thereof comprising administering a therapeutically effective amount of a booster of Treg cells, wherein the booster of Treg cells is a low dose of IL-2, wherein a low dose of IL-2 is below 3.5 MIU/m2/day, and wherein the subject is at an early stage of Alzheimer's disorder.
Delay of onset of cognitive deficits using low-dose IL-2 before deficits
A method for delaying an onset of cognitive deficits caused by Alzheimer's disorder in a subject in need thereof comprising administering a therapeutically effective amount of a booster of Treg cells, wherein the booster of Treg cells is a low dose of IL-2, wherein a low dose of IL-2 is below 3.5 MIU/m2/day, and wherein IL-2 is administered prior to cognitive deficits.
Delay progression using low-dose IL-2 at mild cognitive impairment stage
A method for delaying progression of an Alzheimer's disorder in a subject in need thereof comprising administering a therapeutically effective amount of a booster of Treg cells, wherein the booster of Treg cells is a low dose of IL-2, wherein a low dose of IL-2 is below 3.5 MIU/m2/day, and wherein IL-2 is administered at a stage of mild cognitive impairment.
Across the independent claims, the inventive concept is to boost Treg cells with low-dose IL-2 below 3.5 MIU/m2/day to treat, delay onset of cognitive deficits, or delay progression of an Alzheimer's disorder, with the IL-2 administration timed to an early stage, prior to cognitive deficits, or during mild cognitive impairment.
Stated Advantages
Selectively increases Treg frequency without Teff expansion, while using low-dose IL-2 below 3.5 MIU/m2/day.
Delays cognitive deficits and improves learning behavior in the described mouse model context.
Enhances plaque-associated microglia recruitment.
Reduces non-cognitive neurobehavioral disturbances.
Avoids acceleration of cognitive deficits that is associated with early Treg depletion and is associated with increased neuroinflammatory markers (TNFα, CCL2) when Tregs are depleted.
Documented Applications
Preventing, delaying onset, and/or delaying progression of Alzheimer's disease and related disorders by boosting Treg cells with low-dose IL-2 at defined stage windows, including early stage and mild cognitive impairment.
Monitoring/assessment context including detection of amyloid peptide, Tau protein, and/or phosphorylated Tau protein in the subject.
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