Compositions and methods for oligodendrocyte development
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Publication Number
US-12358959-B2
Publication Date
2025-07-15
Expiration Date
Abstract
The present invention provides compositions and methods for increasing myelination in the nervous system or a subject, including for the treatment of a disease or disorder characterized by a deficiency or loss of myelination (e.g., a demyelinating disease).
Core Innovation
The disclosed invention relates to increasing myelination of a neuron and/or increasing oligodendrocyte or precursor thereof proliferation in a subject by activating GPR56 on oligodendrocyte lineage cells. The patent identifies microglia-derived transglutaminase 2 (TG2; Tgm2) as a GPR56 ligand during white matter development and repair, acting through the GPR56 N-terminal region to expose a tethered agonist on the GPR56 stalk domain and enable downstream signaling.
Activation of GPR56 engages downstream RhoA signaling, which promotes oligodendrocyte precursor cell proliferation and differentiation. The disclosed embodiments state that this pathway increases mature oligodendrocytes and myelinated axons, linking the TG2-GPR56 interaction to improved myelination outcomes. The patent further provides gene and construct embodiments that include nucleotide sequences encoding GPR56-binding amino acid sequences.
The document describes ligand and construct formats that include GPR56-binding peptide sequences, including SEQ ID NO: 1 (TYFAVLMVS) and SEQ ID NO: 2 (TYFAVLMVSSVEVDAVHKHYLS), with the sequences stated to bind GPR56. It also describes covalently lipid/transmembrane-linked polypeptides and BBB-targeted TG2/GPR56-ligand constructs, including tethered agonist-related formats. Disease-context embodiments include BFPP and demyelinating diseases, and include demyelination and repair settings involving GPR56-dependent effects.
Claims Coverage
The independent claims cover two related methods for increasing myelination and/or oligodendrocyte or precursor thereof proliferation by delivering a vector encoding a GPR56-binding amino acid sequence that is contacted with GPR56+ oligodendrocytes or precursors. The inventive features across the independent claims consist of vector delivery and encoding a specific GPR56-binding peptide (SEQ ID NO: 1 or SEQ ID NO: 2).
Vector-encoded GPR56-binding peptide for increased myelination
A method of increasing myelination of a neuron and/or increasing oligodendrocyte or precursor thereof proliferation by injecting an effective amount of a vector contacting an oligodendrocyte or precursor comprising GPR56, where the vector comprises a nucleotide sequence encoding an amino acid sequence TYFAVLMVS (SEQ ID NO: 1) that binds GPR56.
Vector-encoded GPR56-binding peptide for increased myelination
A method of increasing myelination and/or oligodendrocyte or precursor thereof proliferation by injecting an effective amount of a vector contacting an oligodendrocyte or precursor comprising GPR56, where the vector comprises a nucleotide sequence encoding an amino acid sequence TYFAVLMVSSVEVDAVHKHYLS (SEQ ID NO: 2) that binds GPR56.
Across the independent claims, the core coverage is the use of an injected vector encoding a defined GPR56-binding amino acid sequence (SEQ ID NO: 1 or SEQ ID NO: 2) to contact GPR56+ oligodendrocyte lineage cells, with the intended outcome of increasing myelination and/or oligodendrocyte or precursor proliferation.
Stated Advantages
Increases myelination of a neuron.
Increases oligodendrocyte or precursor thereof proliferation.
Promotes OPC proliferation and differentiation, leading to increased mature oligodendrocytes and myelinated axons.
TG2-mediated rescue of remyelination deficits in a GPR56-dependent manner.
Documented Applications
Treatment or application to subjects with demyelinating diseases including multiple sclerosis, periventricular leukodystrophy, periventricular leukomalacia, optic neuritis, neuromyelitis optica, acute disseminated encephalomyelitis, idiopathic inflammatory demyelinating disease, central pontine myelolysis, and progressive multifocal leukoencephalopathy.
Application to subjects with bilateral frontoparietal polymicrogyria (BFPP).
Remyelination in demyelinated cerebellar slice cultures, described as GPR56-dependent rescue by TG2.
OPC proliferation activation in the presence of laminin-111, described as GPR56-dependent and associated with reduced active RhoA when Tgm2 is deleted.
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