Correction of LAMP3-associated salivary gland hypofunction by aquaporin gene therapy

Abstract

Sjögren’s disease (SjD) is a chronic autoimmune sialadenitis resulting in salivary gland hypofunction with dry mouth symptom. Previous studies showed that lysosome-associated membrane protein 3 (LAMP3) overexpression is involved in the development of salivary gland hypofunction associated with SjD. However, the molecular mechanisms are still unclear, and no effective treatment exists to reverse gland function in SjD. Analysis on salivary gland samples from SjD patients showed that salivary gland hypofunction was associated with decreased expression of sodium–potassium-chloride cotransporter-1 (NKCC1) and aquaporin 5 (AQP5), which are membrane proteins involved in salivation. Further studies revealed that LAMP3 overexpression decreased their expression levels by promoting endolysosomal degradation. Additionally, we found that LAMP3 overexpression enhanced gene transfer by increasing internalization of adeno-associated virus serotype 2 (AAV2) via the promoted endolysosomal pathway. Retrograde cannulation of AAV2 vectors encoding AQP1 gene (AAV2-AQP1) into salivary glands induced glandular AQP1 expression sufficient to restore salivary flow in LAMP3-overexpressing mice. LAMP3 could play a critical role in the development of salivary gland hypofunction in SjD by promoting endolysosomal degradation of NKCC1 and AQP5. But it also could enhance AAV2-mediated gene transfer to restore fluid movement through induction of AQP1 expression. These findings suggested that AAV2-AQP1 gene therapy is useful in reversing salivary gland function in SjD patients.

The Mayo Clinic Salivary Tissue-Organoid Biobanking: A Resource for Salivary Regeneration Research

“…Various therapeutic approaches are currently under assessment to address salivary flow restoration in xerostomia patients, with gene therapy being one of them. Ongoing clinical trials are exploring the use of AQP1 gene therapy, employing adeno-associated viruses (AAVs) known for their lower immunogenicity and longer-lasting gene expression compared to adenoviruses 57, 58 . However, it is worth noting that tissue damaged by radiation therapy may pose greater challenges for gene therapy, as the fundamental cause of SG dysfunction involves extensive disruption or destruction of the gland at both cellular and extracellular matrix (ECM) levels 59 .…”

State-of-the-art of the Bone Morphogenetic Protein research field: 13th International BMP Conference, Dubrovnik 2022

“…Sjögren's disease (SjD) is a chronic autoimmune sialadenitis resulting in salivary gland hypofunction with dry mouth symptom (31). Salivary gland hypofunction was associated with decreased expression of sodium-potassiumchloride cotransporter-1 (NKCC1) and aquaporin 5 (AQP5) (32). Upregulated BMP6 expression was found in SjD patients and correlated with low unstimulated saliva ow rate.…”

Bioengineered Salivary Gland Microtissues─A Review of 3D Cellular Models and their Applications

“…Efforts to address salivary gland hypofunction and xerostomia have led to the emergence of three interdisciplinary research focus areas: bioengineering of an artificial SG gland, − use of SG and non-SG stem cell therapy, − and delivery of gene therapy. − A substantial body of research has concentrated on the first two aspects, aiming to restore and regenerate the lost gland function. Various research groups have undertaken the challenge of optimizing the SG cell culture, facing inherent difficulties due to the slow proliferation potential and dynamic phenotypic characteristics in vitro. − To address challenges associated with two-dimensional (2D) culture systems, researchers have turned to the development and utilization of innovative biomaterials to mimic and serve as the native extracellular matrix (ECM). ,, A variety of natural, synthetic, and composite biomaterials have been employed to support SG cell growth in three-dimensional (3D) culture for extended periods and for use as transplantation scaffolds. ,, These advancements have also enhanced our understanding of the various SG cell types, including the diversity of stem/progenitor cell populations, which are crucial as treatment targets or for use in stem cell therapy. − Furthermore, efforts have been directed toward comprehending how ECM remodelling and the physicochemical properties of biomaterials influence the SG phenotype and secretory functions, which are paramount for successful clinical applications. ,, Clinical trials, on the other hand, have centered on delivering stem cells and their derivatives from different sources to alleviate xerostomia.…”