Target for diabetes treatment and prevention
Inventors
Marion, Vincent • Petrovsky, Nikolai
Assignees
VAXINE Pty Ltd • Institut National de la Sante et de la Recherche Medicale INSERM • Universite de Strasbourg
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11826403-B2
Publication Date
2023-11-28
Expiration Date
Abstract
The present invention relates to the identification of ALMS1 as the missing player involved in the regulation of the insulin-mediated glucose uptake through GLUT4 sorting vesicles, and to the down-regulation of ALMS1 by αPKC. Accordingly, the present invention relates to a molecule capable of preventing the binding of αPKC on ALMS1 for use for treating or preventing diabetes, in particular type 2 diabetes. In addition, the present invention relates to a method for identifying molecule capable of preventing the binding of αPKC on ALMS1.
Core Innovation
The invention identifies ALMS1 (Alstrom syndrome protein 1) as a key insulin-dependent regulator of GLUT4-mediated glucose uptake via an ALMSome protein complex in adipocytes. It describes a mechanism in which insulin-stimulated GLUT4 trafficking and glucose absorption depend on ALMS1 and associated components, including the interaction of ALMS1 with αPKC (Protein Kinase C alpha type). The invention links this pathway to insulin resistance, hyperglycemia, obesity, and hyperinsulinaemia as conditions relevant to diabetes progression and onset.
The invention proposes diabetes therapeutic strategies that target the interaction between αPKC and ALMS1. One strategy is administering a molecule inhibiting αPKC binding to ALMS1, with the stated preference that such inhibition promotes or restores GLUT4 trafficking and glucose absorption without interfering with TBC1D4 binding to ALMS1. Another strategy is enhancing TBC1D4 binding to ALMS1 or upregulating ALMS1 expression as alternative approaches.
The invention further describes interaction modulators as molecule types including peptides, stapled peptides, peptide mimetics, antibodies and aptamers. It describes methods for identifying and screening modulators using insulin-responsive cellular systems and binding and interaction analyses, and it provides mechanistic support in adipocytes and mouse models for the role of ALMS1 in GLUT4 localization and related vesicle acidification processes involving the ALMSome complex and a v-ATPase proton pump.
Claims Coverage
The provided independent claim covers a method for treating or delaying diabetes-related conditions by administering an αPKC-to-ALMS1 binding-inhibiting peptide with specific SEQ ID NO: 14 fragment and residue-span constraints. Dependent claims further narrow the treated indication and constrain the peptide and its compatibility with TBC1D4 binding, including stapled peptide and specific peptide length windows.
αPKC binding inhibition to ALMS1 using a SEQ ID NO: 14 peptide fragment
Administering a molecule inhibiting binding of αPKC (Protein Kinase C alpha type) to ALMS1 (Alstrom syndrome protein 1) to a subject in need of treatment, wherein the molecule is a peptide comprising a fragment of SEQ ID NO: 14, between 5 and 50 amino acids in length, spanning one or more specified amino acid residues (S227, S232, F262, D266, W267, K269, E271, G285, T296, V329, and I332 of SEQ ID NO: 14).
Treatment or delay of type 2 diabetes mellitus
The method includes further treating or delaying the progression or onset of type 2 diabetes mellitus.
Peptide does not interfere with TBC1D4 binding to ALMS1
The method includes using a molecule that does not interfere with TBC1D4 binding to ALMS1.
Peptide length constrained to 5–20 amino acids
The peptide is between 5 and 20 amino acids in length.
Stapled peptide format
The peptide is a stapled peptide.
Peptide length constrained to 5–30 amino acids
The peptide length is between 5 and 30 amino acids in length.
Overall claim coverage is centered on administering a peptide fragment of SEQ ID NO: 14 that inhibits αPKC binding to ALMS1 while optionally maintaining TBC1D4 binding compatibility, with dependent claims narrowing the diabetes subtype to type 2 diabetes mellitus and specifying peptide format and length ranges, including a stapled peptide option.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
Interested in licensing this patent?