Ligand-guided phagocytosis based therapy for treatment of Alzheimer's disease and other neurodegenerative diseases
Inventors
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Assignees
Member
University of Nevada, Las VegasThe University of Nevada, Las Vegas is a public research university offering comprehensive undergraduate, graduate, and professional programs. The institution is recognized for research initiatives, interdisciplinary curriculum, community partnerships, and diverse student support. UNLV provides resources spanning financial assistance, technology, career development, outreach, and research, advancing individual achievement and community engagement in a multicultural environment.
The University of Nevada, Las Vegas is a public research university offering comprehensive undergraduate, graduate, and professional programs. The institution is recognized for research initiatives, interdisciplinary curriculum, community partnerships, and diverse student support. UNLV provides resources spanning financial assistance, technology, career development, outreach, and research, advancing individual achievement and community engagement in a multicultural environment.
Publication Number
US-11034739-B2
Publication Date
2021-06-15
Expiration Date
Abstract
Disclosed are conjugates and compositions comprising an amyloid beta binding protein conjugated to a MerTK ligand. Disclosed are methods of clearing amyloid beta aggregates from a subject comprising administering a therapeutically effective amount of the conjugates and compositions comprising an amyloid beta binding protein conjugated to a MerTK ligand. Disclosed are methods of treating Alzheimer's Disease comprising administering to a subject in need thereof a therapeutically effective amount of conjugates and compositions comprising an amyloid beta binding protein conjugated to a MerTK ligand.
Core Innovation
The disclosure describes a ligand-guided MerTK phagocytosis therapy for neurodegenerative disease, especially Alzheimer’s disease. It centers on conjugates and compositions in which an amyloid beta (Aβ) binding protein is conjugated to a MerTK ligand, so that amyloid beta aggregates are cleared in a MerTK-dependent manner.
The compositions include Aβ binding proteins comprising specific amino acid sequences, including LDLSNEGLSGSLNGTLDKTLKQPL (SEQ ID NO:1) and related LDLSNEGLSGSLNGTLDKTLKQPL-family sequences. The MerTK ligand includes a MerTK ligand motif defined as K/R(X)1-2KKK, and the MerTK ligand can include Tubby/Tulp1 or fragments and/or short peptide sequences containing KRRKKK (SEQ ID NO:36) or KQKKK (SEQ ID NO:37).
The disclosure further describes redirecting Aβ clearance away from inflammatory RAGE-mediated phagocytosis toward MerTK-mediated, non-inflammatory clearance. It describes clearing Aβ aggregates and treating Alzheimer’s disease, including contexts where MerTK and Aβ are associated with microglia and where reduced inflammatory mediators are observed, together with a reduction of Aβ burden in mouse models.
Claims Coverage
The independent claim is directed to a conjugate composition comprising specific Aβ binding proteins conjugated to MerTK ligands, where the MerTK ligand contains a defined K/R(X)1-2KKK motif. The claim coverage centers on one independent composition claim and is further bounded by dependent claims that specify MerTK ligand identity, MerTK ligand sequence constraints, linker-conjugation structure, multiplicity of ligands, and methods of use for clearing Aβ aggregates or treating Alzheimer’s disease.
Amyloid beta binding protein–MerTK ligand conjugate composition
A composition comprising one or more amyloid beta binding proteins conjugated to one or more MerTK ligands, wherein the one or more amyloid beta binding proteins comprises the amino acid sequence of LDLSNEGLSGSLNGTLDKTLKQPL (SEQ ID NO:1), LDLSNRGSSGSLNGTSDKTLKQPL (SEQ ID NO:28), LDLSNRGSSGSSNGTLDKTLKQPL (SEQ ID NO:29), LDLSNEGSSGSSSGTLDKTLKQPL (SEQ ID NO:30), LDLSNEGRSGSSNGTSDKTLKQPL (SEQ ID NO:31), LDLSNESSSGSLSGTSDKTLKQPL (SEQ ID NO:32), or LDLSNEGLSGSSSGSSDKTLKQPL (SEQ ID NO:33), wherein the one or more MerTK ligands comprises the sequence K/R(X)1-2KKK.
MerTK ligand is Tubby, Tulp1, or a fragment thereof
The composition of the independent claim wherein the one or more MerTK ligands comprises Tubby, Tulp1, or a fragment thereof.
MerTK ligand includes KRRKKK or KQKKK
The composition of the independent claim wherein the one or more MerTK ligands comprises one of the amino acid sequences KRRKKK (SEQ ID NO:36) or KQKKK (SEQ ID NO:37).
Conjugation via a linker
The composition of the independent claim wherein the one or more amyloid beta binding proteins is conjugated to the one or more MerTK ligands via a linker.
Multiple MerTK ligands (two or more)
The composition of the independent claim wherein the composition comprises two or more MerTK ligands.
Therapeutic method for clearing amyloid beta aggregates
A method for clearing amyloid beta aggregates from a subject comprising administering a therapeutically effective amount of the composition of the independent claim.
Overall claim coverage is directed to conjugates that combine specified Aβ binding protein sequences with MerTK ligands defined by a K/R(X)1-2KKK motif. Dependent coverage narrows MerTK ligand identity and sequence, adds structural constraints such as linker-mediated conjugation and ligand multiplicity, and includes therapeutic use for clearing Aβ aggregates.
Stated Advantages
Reroutes Aβ clearance away from inflammatory RAGE-mediated phagocytosis toward MerTK-mediated, non-inflammatory clearance.
Reduces inflammatory mediators (including NO/ROS and cytokines) associated with the inflammatory pathway.
Reduces Aβ burden in mouse models.
Supports MerTK-associated clearance in contexts involving microglia and shows BBB-related association/co-localization described in the disclosure.
Documented Applications
Treating Alzheimer’s disease.
Clearing amyloid beta aggregates from a subject by administering a therapeutically effective amount of the claimed composition.
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