Salivary gland regeneration
Inventors
Knox, Sarah • BAHNEY, Chelsea S. • ALSBERG, EBEN • Jeon, Oju
Assignees
Case Western Reserve University • University of California San Diego UCSD
Publication Number
US-12310954-B2
Publication Date
2025-05-27
Expiration Date
2039-12-10
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Abstract
A method is provided for promoting salivary gland regeneration in a subject in need thereof comprising administering to acinar progenitor cells of the salivary gland at least one of a cholinergic agonist or muscarinic agonist to promote acinar cell generation. In particular, formulations comprising a muscarinic agonist such as cevimeline encapsulated in an alginate hydrogel can be formulated for local administration to a salivary gland and used in treatment of xerostomia.
Core Innovation
The invention provides compositions and methods for salivary gland regeneration by promoting acinar cell replacement through targeted administration of muscarinic agonists. It was discovered that SOX2+ acinar progenitor cells are essential for replenishing acinar cells, with the ability to repopulate salivary tissue after radiation-induced damage. The regulation of these progenitors is significantly influenced by cholinergic signals, which can be mimicked by the administration of cholinergic or muscarinic agonists directly to the target tissue to restore secretory function.
The problem addressed by this invention is the lack of regenerative treatments for salivary gland dysfunction, particularly in conditions like xerostomia resulting from radiation therapy or autoimmune diseases such as Sjogren's syndrome. Existing therapies are largely palliative and include short-acting sialogogues or artificial saliva, which fail to provide long-term restoration of gland function and commonly cause undesirable side effects. There is a pressing need for approaches that restore the regenerative capacity of the glands and stimulate the replenishment of functional saliva-secreting acinar cells.
The core innovation specifically utilizes formulations comprising muscarinic agonists such as cevimeline, selectively for M1 and/or M3 muscarinic receptor subtypes, encapsulated in biodegradable, calcium cross-linked alginate hydrogels for localized, sustained delivery to the salivary gland. This local delivery exploits the findings that muscarinic receptor activation in acinar progenitor cells promotes their proliferation and differentiation, leading to regeneration of functional acini and improved salivary flow. The invention encompasses methods of administering these formulations directly to or adjacent to the salivary gland and provides for composition kits and controlled release technologies to optimize therapeutic outcomes.
Claims Coverage
The patent contains one independent claim covering a method for promoting regeneration in salivary glands involving the use of a muscarinic agonist encapsulated in a hydrogel for local administration.
Local administration of hydrogel-encapsulated muscarinic agonist to promote salivary gland regeneration
This inventive feature is a method that comprises: - Administering, in a local manner, a muscarinic agonist to the acinar progenitor cells and acinar cells of the salivary gland. - The muscarinic agonist is encapsulated in a hydrogel formulated for local administration into the salivary gland. - The method is intended to promote proliferation of acinar progenitor cells and acinar cells, resulting in increased saliva production. - The hydrogel may comprise ionically cross-linked alginate (including cross-linking by divalent calcium cations), with an alginate concentration ranging from 2% to 10% by weight and optionally being 2% to 10% oxidized. - The muscarinic agonist may be selective for the M1 and/or M3 muscarinic receptor subtype and may specifically be cevimeline or pilocarpine. - The hydrogel can sustain delivery of the muscarinic agonist for at least 1 to 4 weeks after administration. - The method is particularly described for treatment of the sublingual gland but is not limited thereto.
The independent claim broadly covers a method for promoting regeneration in salivary glands by local administration of a hydrogel-encapsulated muscarinic agonist, detailing the nature of the agonist, the hydrogel matrix, and the intended therapeutic effect.
Stated Advantages
The invention enables regeneration of functional salivary acini and restoration of saliva production by directly targeting progenitor cells, addressing the underlying cause of xerostomia rather than only offering symptomatic relief.
Local administration of muscarinic agonists through encapsulation in a hydrogel allows for sustained drug release, potentially reducing the frequency of administration and minimizing undesirable parasympathetomimetic side effects associated with systemic dosing.
The hydrogel formulation is biocompatible and biodegradable, enabling localized, sustained delivery of the therapeutic agent without causing toxic effects or eliciting a significant inflammatory response.
The approach offers the potential for permanent relief of xerostomia by regenerating the gland, rather than providing only temporary symptomatic improvement.
Documented Applications
Treatment of xerostomia caused by radiation-induced damage to the salivary glands.
Treatment of xerostomia associated with Sjogren's syndrome or other autoimmune diseases.
Regeneration of salivary gland acinar cells in patients with oral disorders affecting saliva production, including but not limited to: salivary gland tumors, cystic fibrosis, sialoadenitis, parotitis, sialoangitis, sialodochitis, sialolithiasis, sialodocholithiasis, mucocele, ranula, hyposecretion, ptyalism, sialorrhea, benign lymphoepithelial lesion of salivary gland, sialectasia, sialosis, stenosis of salivary duct, and stricture of salivary duct.
Veterinary treatment of xerostomia and other disorders affecting salivary glands in domestic animals and farm animals, including dogs, cats, sheep, goats, pigs, horses, and cattle.
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