Methods of facilitating cell survival using neurotrophin mimetics
Inventors
Longo, Frank M. • Massa, Stephen M.
Assignees
University of North Carolina at Chapel Hill • University of California • US Department of Veterans Affairs • University of California San Diego UCSD
Publication Number
US-7723328-B2
Publication Date
2010-05-25
Expiration Date
2026-04-03
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Abstract
Methods and compounds for treating neurodegenerative and other disorders. Included is the administering to a subject in need thereof an effective amount of a compound having binding specificity for a p75NTR receptor molecule. Enhanced survival of neural and other cells has been observed.
Core Innovation
The invention relates to methods and compounds for treating neurodegenerative and other disorders by administering to a subject an effective amount of a compound having binding specificity for a p75NTR receptor molecule. The compounds facilitate enhanced survival of neural and other cells expressing p75NTR and promote cell survival signaling, including inhibition of proNGF-induced cell death.
The problem addressed stems from the limitations of using neurotrophins therapeutically, such as poor pharmacological properties including low serum half lives, poor oral bioavailability, restricted central nervous system penetration, and potential adverse effects caused by the complex dual receptor signaling of neurotrophins. Furthermore, technical and ethical challenges exist in producing sufficient quantities of pure neurotrophins for therapeutic use. Thus, there is an unmet need for small molecule agents with favorable drug-like features, capable of targeting specific neurotrophin receptors, such as p75NTR, to treat neurodegenerative and other disorders.
Claims Coverage
The patent includes seven claims focusing on methods of treating Alzheimer's disease, facilitating neural cell survival, and activating p75NTR receptor molecules using specific compounds with defined structures.
Methods of treating Alzheimer's disease using specific compounds
Methods comprising administering to a subject an effective amount of a compound having a defined chemical structure that binds specifically to p75NTR to relieve or cause regression of Alzheimer's disease.
Methods of facilitating neural cell survival
Methods comprising treating neural cells with compounds having specific chemical structures that exhibit binding specificity for p75NTR to promote survival.
Methods for activating p75NTR receptor molecules
Methods comprising contacting cells containing p75NTR receptors (including neurons, oligodendrocytes, hair follicle cells) with compounds of specified chemical structures to activate the p75NTR receptor.
The claims cover methods for treating neurodegenerative disease, promoting neural survival, and activating p75NTR receptors through administration or contact with specific structurally defined compounds exhibiting binding specificity for p75NTR.
Stated Advantages
The compounds exhibit favorable drug-like features including oral bioavailability and blood-brain barrier penetration.
They promote survival signaling selectively through p75NTR without activating Trk receptors, reducing the likelihood of adverse effects associated with broad neurotrophin receptor activation.
The compounds inhibit proNGF-induced apoptosis in oligodendrocytes and block Aβ-induced neural degeneration, indicating neuroprotective benefits.
They can prevent hair loss by regulating p75NTR-mediated death of hair follicle cells.
Documented Applications
Treatment of neurodegenerative disorders including Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, epilepsy, Parkinson's disease, Pick's disease, multiple sclerosis, stroke, diabetic and peripheral neuropathies, spinal cord injury, brain injury, hypoxia, ischemia, nerve transplantation, peripheral nerve injury, and other conditions involving degeneration or dysfunction of cells expressing p75NTR.
Facilitation of survival of neural cells such as hippocampal neurons, cortical, sensory, sympathetic, motor neurons, oligodendrocytes, progenitor and stem cells, and hair follicle cells.
Prevention of proNGF-induced apoptotic cell death in mature oligodendrocytes.
Blocking amyloid-β (Aβ) induced neural degeneration relevant in Alzheimer's disease models.
Prevention of age-related or pathological hair loss by inhibiting p75NTR-regulated hair follicle cell death.
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