Glucan-encapsulated siRNA for treating type 2 diabetes mellitus
Inventors
Kunos, George • JOURDAN, Tony • CZECH, Michael Paul • AOUADI, MYRIAM
Assignees
University of Massachusetts Amherst • US Department of Health and Human Services
Publication Number
US-10077446-B2
Publication Date
2018-09-18
Expiration Date
2034-06-24
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Abstract
Compositions comprising glucan-encapsulated siRNA directed against a region of the gene encoding the human CB1 receptor for use in the treatment of type 2 diabetes mellitus in a human subject. Additionally, methods for treating type 2 diabetes mellitus in a subject, comprising administering to the subject a composition comprising glucan-encapsulated siRNA directed against the CB1 receptor.
Core Innovation
This invention provides compositions comprising glucan-encapsulated small interfering RNA (siRNA) directed against a region of the human gene encoding the cannabinoid receptor 1 (CB1R), and methods of treating type 2 diabetes mellitus (T2DM) by administering such compositions to human subjects. The siRNA targets selective regions of the CNR1 gene to knock down CB1 receptor expression primarily in macrophages, particularly phagocytic macrophages, upon glucan-mediated uptake, resulting in selective gene suppression.
The background highlights that T2DM is characterized by insulin resistance progressing to beta-cell failure, with inflammation playing a pathogenic role via proinflammatory cytokines and inflammasome activation in pancreatic islets. The endocannabinoid system, specifically CB1 receptor activation, promotes metabolic disturbances including insulin resistance and dyslipidemia. Prior attempts to block CB1R therapeutically were limited by psychiatric adverse effects.
The innovation overcomes these challenges by employing sequence-specific siRNA encapsulated in a β-1,3-D-glucan shell, optionally complexed with an amphipathic peptide Endoporter (EP) to facilitate cellular uptake and endosomal escape, to selectively silence CB1R expression on macrophages involved in pancreatic islet inflammation. This leads to improvements in glycemic control and preservation of pancreatic beta-cell function, thus offering a novel approach for treating or preventing T2DM with peripheral specificity and reduced side effects.
Claims Coverage
The patent contains independent claims covering a siRNA compound encapsulated in glucan for targeting cannabinoid receptor 1 gene regions and methods of treating T2DM using such compositions. Main inventive features are extracted from these independent claims.
Glucan-encapsulated siRNA targeting specific CNR1 gene regions
A siRNA compound consisting of 15 to 40 nucleotides that is at least 90% complementary to contiguous portions of the CNR1 open reading frame (specifically SEQ ID NOs:14-18 and 20-22) encapsulated within a glucan particle, particularly β-1,3-D-glucan.
siRNA complexed with α-helical amphipathic peptide Endoporter (EP)
The siRNA is complexed with EP prior to glucan encapsulation to facilitate membrane interaction and endosomal escape, enhancing delivery efficacy to target macrophages.
Pharmaceutical compositions comprising glucan-encapsulated siRNA
Pharmaceutical compositions include therapeutically effective amounts of the glucan-encapsulated siRNA compound with pharmaceutically acceptable carriers, diluents, penetration enhancers, and excipients.
Methods of treating or preventing type 2 diabetes mellitus via macrophage CB1R knockdown
Administering an effective amount of glucan-encapsulated siRNA directed against CNR1 to a subject in need results in selective uptake by phagocytic macrophages and knockdown of macrophage CB1 receptors by at least about 70%, leading to treatment or prevention of T2DM.
The claims collectively cover glucan-encapsulated siRNA compounds targeting defined CNR1 gene regions, their pharmaceutical formulations, and methods for treatment or prevention of type 2 diabetes mellitus by selective knockdown of CB1 receptors in macrophages, utilizing glucan encapsulation and optionally complexation with Endoporter peptide to enhance delivery and efficacy.
Stated Advantages
The compositions enable selective knockdown of CB1 receptors in macrophages, improving glycemic control without affecting body weight or causing central nervous system effects.
Peripheral CB1 receptor antagonism via siRNA prevents beta-cell loss and inflammatory cell infiltration in pancreatic islets, effectively reversing or delaying T2DM progression.
Use of glucan encapsulation facilitates targeted delivery to macrophages, thereby reducing off-target effects and increasing therapeutic specificity.
Documented Applications
Treatment or prevention of type 2 diabetes mellitus in human subjects by administering glucan-encapsulated siRNA directed against CB1 receptor gene (CNR1) to knock down CB1 receptor expression in macrophages.
Pharmaceutical compositions comprising glucan-encapsulated siRNA for therapeutic uses involving beta-cell preservation and improvement of insulin secretion in T2DM.
Use of glucan-encapsulated siRNA for in vivo knockdown of macrophage CB1 receptor to mitigate inflammatory signaling and improve glycemic control in diabetic subjects.
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