Alpha B-crystallin as a therapy for ischemia or inflammation
Inventors
Steinman, Lawrence • Ousman, Shalina Sheryl • Robinson, William H.
Assignees
US Department of Veterans Affairs • Leland Stanford Junior University
Publication Number
US-8771689-B2
Publication Date
2014-07-08
Expiration Date
2027-12-11
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Abstract
The invention provides methods for treating inflammatory diseases by administering to the subject an effective amount of an agent that provides alpha B-crystallin activity, where the dose is effective to suppress or prevent initiation, progression, or relapses of disease, including the progression of established disease. In some embodiments, the methods of the invention comprise administering to a subject having a pre-existing inflammatory disease condition, an effective amount of alpha B-crystallin protein, to suppress or prevent relapses of the disease.
Core Innovation
The invention provides methods for treating inflammatory and ischemic diseases by administering an effective amount of an agent that provides alpha B-crystallin (αBC) activity to subjects. The dose is effective to suppress or prevent initiation, progression, or relapses of disease, including progression of an established disease condition. Specifically, it targets inflammatory and neurological inflammatory diseases such as multiple sclerosis, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy, rheumatoid arthritis, atherosclerosis, stroke, myocardial infarction, peripheral arterial vascular disease, Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis.
Alpha B-crystallin acts via modulating key inflammatory pathways, including the mitogen activated protein kinases p38 MapK and ERK pathways, which are implicated in the pathogenesis of various inflammatory and ischemic diseases. Administration of αBC affects immune cells such as T cells, macrophages, and CNS glial cells by suppressing pro-inflammatory cytokine production, diminishing severity of ischemic lesions, protecting CNS cells from further injury, and promoting repair of injured cells. Treatment includes systemic administration routes, typically other than oral, such as intravenous, intramuscular, intraperitoneal, and subcutaneous administration.
The problem being addressed is the lack of effective treatments that both suppress pathological immune responses and protect or repair CNS cells in inflammatory diseases like multiple sclerosis and related demyelinating autoimmune diseases. Current therapies may not prevent long-term progression or effectively induce repair. Additionally, in diseases such as ischemic myocardial infarction and stroke, inflammation contributes to tissue injury and progression, and there is a need for therapies that reduce this inflammation and tissue damage. The invention addresses limitations of current treatments, offering a therapeutic approach that engages molecular chaperone activity of αBC to modulate immune activity and cell survival pathways.
Claims Coverage
The patent contains one independent claim describing a method of inhibiting neuromyelitis optica, with further dependent claims specifying administration routes and monitoring methods. The key inventive features relate to the therapeutic use of alpha B-crystallin protein, routes of administration, patient diagnosis prior to treatment, immune monitoring, and polypeptide fusion formats.
Therapeutic administration of alpha B-crystallin protein for neuromyelitis optica
A method for inhibiting neuromyelitis optica in a patient by administering a therapeutically effective dose of alpha B-crystallin protein.
Systemic administration of alpha B-crystallin
Administration of the agent systemically, with specific routes including intraperitoneal, intravenous, intramuscular, and subcutaneous.
Intravenous administration preferred
Administration may be specifically intravenous, emphasizing this delivery route.
Treatment of diagnosed patients
The patient is diagnosed with neuromyelitis optica prior to administration of the therapeutic agent.
Monitoring T cell activation during therapy
Monitoring activation of T cells in tissues affected by neuromyelitis optica to assess treatment effect.
Use of fusion polypeptides comprising alpha B-crystallin and immunoglobulin Fc
The therapeutic agent may be a fusion polypeptide composed of alpha B-crystallin fused to an immunoglobulin Fc polypeptide to provide additional functional benefits such as increased stability or half-life.
The independent claims focus on the therapeutic use of alpha B-crystallin protein to inhibit neuromyelitis optica, emphasizing systemic administration, patient diagnosis, immune monitoring, and fusion polypeptides for enhanced therapeutic effects.
Stated Advantages
Administration of alpha B-crystallin suppresses pro-inflammatory cytokine production and T cell and macrophage proliferation.
Alpha B-crystallin protects central nervous system cells from injury and apoptosis, particularly glial cells, via inhibition of caspase-3 activation and modulation of ERK and NF-κB pathways.
Treatment with alpha B-crystallin diminishes the extent and severity of ischemic lesions such as myocardial infarction, stroke, and arterial occlusion.
Alpha B-crystallin therapy can reduce inflammatory infiltrates and cell death in experimental models of autoimmune diseases.
Therapeutic administration of alpha B-crystallin to animals with ongoing inflammatory disease reverses clinical symptoms and reduces immune cell activation.
Documented Applications
Treatment of inflammatory diseases including neurological inflammatory conditions such as multiple sclerosis, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy.
Treatment of inflammatory conditions including rheumatoid arthritis, demonstrated in a collagen-induced arthritis rodent model.
Treatment of ischemic diseases including myocardial infarction, stroke, peripheral arterial vascular disease.
Treatment of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis.
Treatment of anterior ischemic optic neuropathy demonstrated through experimental models with functional visual evoked potential improvements.
Use in stroke treatment, including administration up to 12 hours after stroke onset to improve lesion size and neurological outcomes.
Improvement of myocardial function and reduction of apoptosis following ischemia-reperfusion injury demonstrated in murine in vivo and endothelial cell in vitro models.
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