Compositions and methods for treating age-related diseases
Inventors
Wyss-Coray, Anton • Pluvinage, John Vincent • Bassik, Michael C. • Haney, Michael • Smith, Benjamin • Bertozzi, Carolyn
Assignees
US Department of Veterans Affairs • Leland Stanford Junior University
Publication Number
US-11891442-B2
Publication Date
2024-02-06
Expiration Date
2038-12-21
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Abstract
Provided herein are compositions, methods, kits and systems for treating cells, tissues and subjects to alter age-related biology (e.g., to study or to treat age-related diseases and conditions). In particular, provided herein are compositions, methods, and uses for inhibition or modification of sialic acid or its cognate receptor to restore phagocytosis in aged cells.
Core Innovation
Provided herein are compositions, methods, kits and systems for treating cells, tissues and subjects to alter age-related biology (e.g., to study or to treat age-related diseases and conditions). In particular, the invention provides compositions, methods, and uses for inhibition or modification of sialic acid or its cognate receptor to restore phagocytosis in aged cells.
The invention addresses the problem that brain-resident microglia, peripheral macrophages and other cell types maintain homeostasis through phagocytic clearance of pathogens, apoptotic cells, and debris, but this process deteriorates with normal aging and age-related disease. Aberrant phagocytosis contributes to the pathogenesis of various age-related diseases including frontotemporal dementia, age-related macular degeneration, atherosclerosis, cancer and Alzheimer's disease.
Existing strategies like heterochronic parabiosis or transfusion of young serum restore aged phagocytic function but have many disadvantages including donor acquisition, complications, risk of infection, cost, and lack of specific effects on phagocyte rejuvenation. Accordingly, compositions and methods are needed to restore phagocytosis specifically in aged macrophages, microglia and other phagocytic cells.
Claims Coverage
The patent includes one independent claim directed to a method of treating a neurodegenerative disease using a specific anti-CD22 antibody.
Use of an anti-CD22 antibody for treating Niemann-Pick disease Type C
A method comprising exposing one or more of a subject's microglia, macrophage and/or other phagocytic cells to an anti-CD22 antibody to treat the neurodegenerative disease Niemann-Pick disease Type C (NPC).
Methods for administering the anti-CD22 antibody to achieve CNS exposure
Administration methods that bypass or promote transfer across the blood brain barrier, including direct application to the surface, parenchyma, ventricles, or cerebrospinal fluid of the central nervous system. These methods include intrathecal and epidural administration, using single shots, multiple doses, or continuous administration via programmable external or implantable pumps.
Assaying for CD22 expression to guide therapy
Methods comprising assaying microglia, macrophage or other phagocytic cell samples from the subject for CD22 expression to inform treatment.
The claims cover methods of treating NPC via CNS-targeted delivery of anti-CD22 antibody to inhibit CD22 on phagocytic cells, employing various administration routes and assessing CD22 expression to guide treatment.
Stated Advantages
The compositions and methods promote restoration of phagocytosis in aged macrophages, microglia, and other cells.
Targeting the CD22-sialic acid axis selectively rejuvenates phagocytes without inducing a pro-inflammatory hyperphagic state.
Long-term CNS delivery of a CD22 blocking antibody reprograms microglia to a homeostatic state and improves cognitive function in aged mammals.
Anti-CD22 antibody treatment improves clinical measures and reduces pro-inflammatory microglial activation in a disease model of Niemann-Pick disease Type C.
Documented Applications
Treatment of age-related diseases and conditions involving impaired phagocytosis, including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Niemann-Pick disease Type C.
Restoration of phagocytosis in aged microglia, macrophages and other phagocytic cells to remove pathological material like myelin debris, amyloid beta oligomers, and alpha-synuclein fibrils.
Combination therapies with agents that interfere with β-amyloid or tau accumulation, or cancer-related conditions.
Use of anti-CD22 antibodies and agents modifying sialic acid for studying and treating neurodegenerative and age-related diseases.
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