AAV mediated exendin-4 gene transfer to salivary glands to protect subjects from diabetes or obesity
Inventors
Chiorini, John A. • Di Pasquale, Giovanni • Mannucci, Edoardo
Assignees
US Department of Health and Human Services
Publication Number
US-9511103-B2
Publication Date
2016-12-06
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 an adeno-associated virus (AAV) virion comprising an AAV vector that encodes an exendin-4 protein to a salivary gland of the subject. The exendin-4 protein can be a fusion protein comprising a secretory segment, such as a nerve growth factor (NGF) secretory segment, joined to the amino terminus of the exendin-4 protein domain. This approach leads to sustained, site-specific expression and endocrine secretion of biologically active exendin-4 into the bloodstream, which improves weight profile, glucose homeostasis, and other metabolic effects.
The problem being solved arises from limitations in current diabetes and obesity treatments involving GLP-1 receptor agonists such as exenatide, which require repeated subcutaneous injections due to their short half-life and systemic administration. Existing gene therapy approaches using adenoviral or plasmid vectors have shown low or transient expression and safety concerns with systemic vector delivery. The disclosed method addresses the need for an effective and safe composition that delivers long-term stable expression of exendin-4 protein via gene transfer specifically targeting salivary glands, which function as an endocrine organ capable of secreting proteins into the bloodstream.
Claims Coverage
The patent contains one independent claim directed to a method for protecting a subject from Type II diabetes or obesity and its key inventive features.
Use of AAV virion encoding exendin-4 fusion protein for gene transfer to salivary gland
Administering to a salivary gland of a subject an adeno-associated virus virion comprising an AAV vector that encodes an exendin-4 fusion protein comprising a secretory segment joined to an exendin-4 protein.
NGF secretory segment as the secretory segment
The secretory segment of the exendin-4 fusion protein is a nerve growth factor (NGF) secretory segment effective for directing endocrine secretion when fused to exendin-4.
Furin protease cleavable NGF secretory segment
The NGF secretory segment is cleavable from the exendin-4 protein by a furin protease to facilitate secretion of the active exendin-4 domain.
Specific amino acid sequence of exendin-4 protein
The exendin-4 protein comprises the amino acid sequence of SEQ ID NO:8 corresponding to Gila monster exendin-4.
Specific nucleic acid sequences encoding exendin-4 proteins
The AAV vector comprises a nucleic acid sequence selected from SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, and SEQ ID NO:7 encoding the exendin-4 fusion protein.
Exendin-4 fusion protein comprising SEQ ID NO:2
The exendin-4 fusion protein comprises the amino acid sequence SEQ ID NO:2 representing the NGF secretory segment joined to the exendin-4 domain.
The claims cover a method of protecting a subject from Type II diabetes or obesity by administering to a salivary gland an AAV virion encoding a secretory-segment fused exendin-4 protein, particularly employing an NGF secretory segment cleavable by furin, and specifying particular amino acid and nucleic acid sequences of the exendin-4 fusion protein and encoding vectors.
Stated Advantages
Sustained, site-specific expression of exendin-4 protein with secretion into the bloodstream resulting in improved weight profile and glucose homeostasis.
AAV vectors provide long-term transgene expression and low immunogenicity, enhancing therapeutic effects for chronic diseases like diabetes and obesity.
Salivary gland targeting reduces systemic vector exposure, improving safety profile of gene therapy.
Fusion of NGF secretory segment to exendin-4 enhances endocrine secretion from salivary glands.
Documented Applications
Treatment and prevention of Type II diabetes by delivering exendin-4 encoding AAV virions to salivary glands.
Treatment and prevention of obesity by delivering exendin-4 encoding AAV virions to salivary glands.
Protection of subjects from incretin defects via administration of AAV virions encoding GLP-1 analog proteins including exendin-4.
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