AAV mediated exendin-4 gene transfer to salivary glands to protect subjects from diabetes or obesity
Inventors
Chiorini, John A. • DiPasquale, Giovanni • Mannucci, Edoardo
Assignees
US Department of Health and Human Services
Publication Number
US-10300095-B2
Publication Date
2019-05-28
Expiration Date
2032-04-19
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Abstract
The invention relates to a gene transfer-based method to protect a subject from diabetes or obesity. The method comprises administering to a salivary gland of the subject an AAV virion comprising an AAV vector that encodes an exendin-4 protein. Also provided are exendin-4 proteins and nucleic acid molecules that encode such exendin-4 proteins. Also provided are AAV vectors and AAV virions that encode an exendin-4 protein. One embodiment is an exendin-4 protein that is a fusion protein comprising an NGF secretory segment joined to the amino terminus of an exendin-4 protein domain.
Core Innovation
The invention provides a gene transfer-based method to protect a subject from diabetes or obesity by administering to a salivary gland of the subject an adeno-associated virus (AAV) virion comprising an AAV vector that encodes an exendin-4 protein. This method results in sustained, site-specific expression of exendin-4 from the salivary glands, with the secreted protein entering the bloodstream to produce therapeutic effects on glucose homeostasis and weight profile.
Exendin-4 proteins described include fusion proteins comprising a secretory segment, such as a nerve growth factor (NGF) secretory segment, joined to the amino terminus of an exendin-4 protein domain. The secretory segment is key to directing endocrine secretion from the salivary glands. The disclosure also provides nucleic acid molecules that encode these exendin-4 proteins, AAV vectors encoding such proteins, and AAV virions comprising said vectors.
The background identifies the problem that while GLP-1 receptor agonists like native GLP-1 and exendin-4 are effective in treating diabetes and obesity, their short half-life (due to rapid degradation) and need for frequent injections limit their usability. Prior gene therapy methods using adenoviral or plasmid vectors for GLP-1 analogs suffered from low or transient expression and safety concerns with systemic delivery. AAV vectors, especially AAV5, have potential to provide long-term expression with low immunogenicity but delivering GLP-1 receptor agonists safely and effectively, particularly via gene transfer to salivary glands, remained unmet. Protein sorting in salivary glands is unpredictable, making it uncertain whether therapeutic proteins would be secreted systemically.
Claims Coverage
The independent claim focuses on a method of preventing weight gain by administering an AAV virion encoding a GLP-1 protein fused to a secretory segment to the salivary gland. Four main inventive features are extracted.
Use of AAV virion encoding GLP-1 protein joined to a secretory segment
A method of preventing weight gain in a subject comprising administering to a salivary gland an AAV virion comprising an AAV vector encoding a glucagon-like peptide-1 (GLP-1) protein joined to a secretory segment.
Energy expenditure increase via salivary gland administration
Administration of the AAV virion to the salivary gland increases energy expenditure in the subject.
Maintenance of normal BMI by salivary gland administration
Administration of the AAV virion to the salivary gland allows the subject to maintain a normal body mass index (BMI).
Secretory segment characteristics
The secretory segment joined to the GLP-1 protein is cleavable by a furin protease and specifically can be a nerve growth factor (NGF) secretory segment comprising SEQ ID NO:10.
The claims cover a method of preventing weight gain by using AAV vectors encoding GLP-1 proteins fused to secretory segments, administered to salivary glands, with specific emphasis on energy expenditure increase, BMI maintenance, and use of a furin-cleavable NGF secretory segment.
Stated Advantages
Provides sustained, site-specific expression of exendin-4 leading to an improved weight profile and improved glucose homeostasis.
Enables long-term expression of therapeutic proteins with low immunogenicity and safety due to AAV vector use.
Avoids the need for frequent subcutaneous administration of exendin-4 or GLP-1 receptor agonists.
Demonstrates reduction in weight gain, improved insulin sensitivity, improved adipokine profiles, and reduced glycemia in animal models of obesity and diabetes.
Documented Applications
Treatment and prevention of diabetes, including Type 1 diabetes, Type 2 diabetes, gestational diabetes, and maturity onset diabetes of the young (MODY).
Treatment and prevention of obesity, including monogenic and polygenic forms of obesity.
Protection of subjects from incretin defects, which underlie certain forms of diabetes.
Gene therapy based delivery of exendin-4 or GLP-1 analog proteins via administration of AAV virions to salivary glands of subjects in need.
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