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-11207361-B2
Publication Date
2021-12-28
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 relates to a gene transfer-based method to protect a subject from diabetes or obesity by administering to a salivary gland an adeno-associated virus (AAV) virion comprising an AAV vector that encodes an exendin-4 protein. This includes exendin-4 proteins that are fusion proteins comprising a secretory segment, such as an NGF secretory segment, joined to the amino terminus of an exendin-4 protein domain, AAV vectors encoding these proteins, and methods for their production and use.
Glucagon-like peptide 1 (GLP-1) receptor agonists like exendin-4 have therapeutic potential for type 2 diabetes mellitus (T2DM) and obesity due to their effects on insulin secretion and weight loss. However, native GLP-1 has a short half-life, and existing treatments like exenatide require frequent injections. Prior gene therapy approaches using adenoviral or plasmid vectors for GLP-1 receptor agonists have not achieved long-term effects due to transient or low expression levels, and systemic delivery carries risks.
The invention solves the problem of achieving stable, long-term, and site-specific expression of exendin-4 by using AAV vectors delivered to salivary glands, which can act as depot organs secreting proteins into the bloodstream. The approach uses AAV serotypes, such as AAV5, that efficiently transduce salivary gland cells, enabling sustained endocrine secretion of biologically active exendin-4. This overcomes unpredictability of protein sorting in salivary glands and enables protection from diabetes or obesity by continuous circulating exendin-4.
Claims Coverage
The patent presents multiple independent claims focusing on nucleic acid molecules, AAV vectors, and AAV virions encoding an exendin-4 fusion protein joined to a secretory segment with GLP-1 receptor agonist activity.
Nucleic acid molecule encoding exendin-4 fusion protein
A nucleic acid molecule encoding a fusion protein comprising an exendin-4 protein joined to a secretory segment, where the fusion protein is encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO:5, comprises an amino acid sequence at least 80% identical to SEQ ID NO:2 or SEQ ID NO:6, or comprises SEQ ID NO:2 or SEQ ID NO:6, and effects an agonist response at a GLP-1 receptor.
AAV vector encoding exendin-4 fusion protein
An adeno-associated virus (AAV) vector comprising a nucleic acid molecule encoding a fusion protein comprising an exendin-4 protein joined to a secretory segment, with the fusion protein defined as encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO:5, comprising an amino acid sequence at least 80% identical to SEQ ID NO:2 or SEQ ID NO:6, or comprising SEQ ID NO:2 or SEQ ID NO:6, and effecting an agonist response at a GLP-1 receptor.
AAV virion comprising the AAV vector
An AAV virion comprising an AAV vector as described above encoding an exendin-4 fusion protein joined to a secretory segment with GLP-1 receptor agonist activity.
The independent claims cover nucleic acid molecules encoding exendin-4 fusion proteins joined to secretory segments with activity at the GLP-1 receptor, AAV vectors comprising such nucleic acids, and AAV virions comprising those vectors, emphasizing sequences related to SEQ ID NO:2, SEQ ID NO:5, and SEQ ID NO:6, and their GLP-1 receptor agonist function.
Stated Advantages
Sustained, site-specific expression of exendin-4 in salivary glands leading to improved weight profile and glucose homeostasis.
Long-term protection from diabetes or obesity by continuous secretion of biologically active exendin-4 into the bloodstream.
Reduced need for frequent administration compared to current exendin-4 therapies requiring twice-daily injections.
Safe and well-tolerated delivery with low immunogenicity associated with AAV vectors and localized expression reducing systemic risks.
Documented Applications
Treatment and prevention of diabetes, including Type 1, Type 2, 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 causing diseases related to reduced incretin levels.
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