Dual targeting for cell-specific delivery to the central nervous system
Inventors
Brown, Kathlynn C. • Venugopal, Indu • McGuire, Michael • Xu, Weiliang • Powell, Amanda • LI, Yitong • Marafino, John
Assignees
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Publication Number
US-12516086-B2
Publication Date
2026-01-06
Expiration Date
Abstract
Disclosed are MGS peptides, MTS peptides, linkers and combinations combining any combination thereof. Disclosed are MGS peptides comprising the amino acid sequence of any of the sequences set forth in SEQ ID NOs: 1-8 Disclosed are MTS peptides comprising the amino acid sequence of any of the sequences set forth in SEQ ID NOS: 9-14. Disclosed are compositions comprising at least one MGS peptide conjugated to at least one MTS peptide, wherein the MGS peptide comprises the amino acid sequence of GFHNVYPYTWGGFSDIDLMADEI (SEQ ID NO: 1); EQRWVQMLHILQTRYAGEWPG (SEQ ID NO: 2); FQHINPFPYTYSMEDTDVEIK (SEQ ID NO: 3); or YAAWPASGAWT (SEQ ID NO: 4). In some aspects, the disclosed compositions can further comprise one or more linkers.
Core Innovation
The disclosure describes multifunctional peptide compositions comprising a Molecular Guide System (MGS) peptide and a Molecular Transport System (MTS) peptide. The MGS peptide is conjugated to the MTS peptide via a linker or reaction-group moiety, and representative chemical structures for MGS-MTS conjugates are provided. The compositions include dimeric and tetrameric MGS cores, multi-MGS to multi-MTS configurations, and chimeric conjugates.
The MGS peptides are defined by SEQ ID NOs 1-8 and the MTS peptides are defined by SEQ ID NOs 9-14. The conjugates include reaction-group moieties described for conjugation to a moiety such as cargo, with optional lipid modification and pharmaceutical compositions including a pharmaceutically acceptable carrier. The compositions are presented in the context of transporting a moiety across the blood-brain barrier (BBB) and/or through choroid plexus and cerebrospinal fluid (CSF) routes.
The disclosure further specifies targeting and cargo applications for CNS disorder therapeutics and other payload types including imaging agents and siRNA. Receptor-mediated MGS/MTS dual targeting is described for improved CSF/brain transport, and stability in human serum is also described in connection with the conjugate approach. Example embodiments include intravenous administration and intrathecal administration.
Claims Coverage
The provided independent claims are clm-00001 and clm-00007. They cover two inventive features: sequence-defined peptides that target CNS cells, and CNS compositions that conjugate defined MGS and MTS peptides through a multi-linker architecture.
Cns-targeting MGS peptide sequence set
A peptide comprising the amino acid sequence consisting of GFHNVYPYTWGGFSDIDLMADEI (SEQ ID NO: 1) or EQRWVQMLHLQTRYAGEWPG (SEQ ID NO: 2) or FQHNPFPYTYSMEDTDVEIK (SEQ ID NO: 3), wherein the peptide targets central nervous system (CNS) cells.
Conjugated MGS-MTS composition with three linkers
A composition comprising a Molecular Guide System (MGS) peptide comprising the amino acid sequence of GFHNVYPYTWGGFSDIDLMADEI (SEQ ID NO: 1) or EQRWVQMLHLQTRYAGEWPG (SEQ ID NO: 2) or FQHNPFPYTYSMEDTDVEIK (SEQ ID NO: 3); a first linker comprising at least one reactive group capable of binding a C-terminus of the MGS peptide and at least one additional reactive group capable of chemically reacting with a moiety; a second linker; a third linker comprising at least one reactive group capable of binding a C-terminus of a Molecular Transport System (MTS) peptide and at least one additional reactive group capable of chemically reacting with a moiety; and the MTS peptide comprising the amino acid sequence of DAYKLQTSLDWQMWNP (SEQ ID NO: 9) or FPSWTSKNQQWTNQRQ (SEQ ID NO: 11) or SKETYSMNAQRQHERS (SEQ ID NO: 13).
The claim set provides coverage for sequence-defined CNS-targeting peptides and for compositions that conjugate defined MGS and MTS peptides through a multi-linker construct using reactive groups capable of binding peptide C-termini and reacting with a moiety.
Stated Advantages
Improved CSF/brain transport via MTS lipidation and receptor-mediated MGS/MTS dual targeting for microglial and neuronal targeting.
Stability in human serum for the disclosed conjugates.
Documented Applications
CNS disorder therapeutics for diseases/injury including Parkinson's disease, Alzheimer's disease, glioblastoma, amyotrophic lateral sclerosis, multiple sclerosis, and traumatic brain injury.
Imaging agents for CNS imaging applications.
siRNA delivery, including microglial and neuronal targeting using dimeric and tetrameric MGS cores.
Delivery/administration for transporting cargo to the CNS via BBB/choroid plexus/CSF routes, including intravenous administration and intrathecal administration.
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