AAV mediated aquaporin gene transfer to treat Sjogren's syndrome
Inventors
Assignees
National Institutes of Health NIH • US Department of Health and Human Services
Publication Number
US-10166299-B2
Publication Date
2019-01-01
Expiration Date
2033-08-30
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Abstract
The invention relates to a gene transfer-based method to protect a subject from Sjogren's syndrome. The method comprises administering to the subject an AAV virion comprising an AAV vector that encodes aquaporin-1 (AQP-1) protein. Also provided are AQP-1 proteins and nucleic acid molecules that encode such proteins. Also provided are AAV vectors and AAV virions that encode an AQP-1 protein.
Core Innovation
The invention provides a gene transfer-based method to protect a subject from Sjögren's syndrome-related xerostomia by administering to the subject an AAV vector or virion that encodes an aquaporin (AQP) protein, specifically AQP-1. The method is applicable for treatment, prevention, and maintenance of salivary gland function impaired by Sjögren's syndrome. The invention also includes isolated AQP-1 proteins, nucleic acid molecules encoding such proteins, and vectors and virions that encode AQP-1.
Sjögren's syndrome is a systemic autoimmune disease characterized by immune-mediated destruction of exocrine glands producing saliva and tears, causing xerostomia (dry mouth) and xerophthalmia (dry eyes). The syndrome involves immune cell infiltration, production of autoantibodies, and proinflammatory cytokines leading to loss of gland function. Existing treatments effective for other autoimmune diseases have proven ineffective in Sjögren's syndrome. There remains a need for effective compositions to protect from and treat xerostomia associated with Sjögren's syndrome.
The invention addresses this need by introducing an AAV-mediated gene therapy encoding AQP-1. AQP-1 is a plasma membrane channel protein that facilitates water passage across cell membranes, thus potentially restoring fluid secretion impaired in Sjögren's syndrome. Administration of AAV virions encoding AQP-1 unexpectedly restores salivary function and reduces glandular inflammation despite ongoing autoimmune mechanisms. This approach provides a novel therapeutic avenue by enabling increased water transport in damaged or dysfunctional salivary gland cells, thereby treating and preventing xerostomia related to Sjögren's syndrome.
Claims Coverage
The patent includes one independent claim which covers a method of treatment using AAV vectors encoding AQP-1 administered to specific glands. The claim recites inventive features related to protein selection, vector composition, and therapeutic outcomes.
Method of treating Sjögren's syndrome-associated xerostomia or xerophthalmia by administering an AAV vector encoding AQP-1 directly to salivary or lachrymal glands
A method comprising administration of an adeno-associated virus vector encoding an aquaporin-1 protein to the subject's salivary gland or lachrymal gland for treating xerostomia or xerophthalmia associated with Sjögren's syndrome.
Selection of aquaporin-1 proteins capable of forming water channels
The aquaporin-1 protein encoded is selected from those comprising at least a portion of sequences SEQ ID NO:2, SEQ ID NO:5, SEQ ID NO:8, SEQ ID NO:11, or SEQ ID NO:14, or proteins having at least 80% sequence identity to these, and retain the ability to form water channels.
Use of specific nucleic acid vector sequences encoding AQP-1
The AAV vector comprises a nucleic acid sequence at least 90% identical to SEQ ID NO:16 or SEQ ID NO:18 which encodes the AQP-1 protein for therapeutic use.
Maintenance or improvement of salivary or lachrymal gland function upon administration
Administration of the vector maintains or improves the level of salivary gland function or lachrymal gland function relative to pre-administration levels.
Administration of the AAV vector in virion form
The vector is administered as a virion, specifically as an AAV virion encapsidating the vector encoding AQP-1.
The claims cover a therapeutic method administering AAV vectors encoding specific AQP-1 proteins to salivary or lachrymal glands, employing defined sequences and formulations, resulting in maintenance or improvement of gland function in Sjögren's syndrome-associated conditions.
Stated Advantages
Administration of an AAV virion encoding AQP-1 protects a subject from Sjögren's syndrome-related xerostomia.
Expression of AQP-1 in salivary gland cells improves secretory activity and produces a systemic effect, also improving lachrymal gland function.
Administration of AQP-1 reduces proinflammatory cytokine production and immune cell infiltration in affected glands.
Documented Applications
Treatment of Sjögren's syndrome-associated xerostomia by administering an AAV vector or virion encoding AQP-1 to the salivary gland.
Treatment of Sjögren's syndrome-associated xerophthalmia by administering an AAV vector or virion encoding AQP-1 to the lachrymal gland.
Use of AAV encoding AQP-1 for preventing or ameliorating symptoms related to Sjögren's syndrome including reduced salivary and lachrymal gland function.
Ex vivo transfection of salivary gland cells with AAV vectors encoding AQP-1 for subsequent transplantation or treatment.
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