Involucrin-driven retroviral expression cassettes encoding human immunodeficiency virus envelope glycoproteins
Inventors
Gauduin, Marie-Claire • Blancou, Philippe
Assignees
Texas Biomedical Research Institute
Publication Number
US-10751406-B2
Publication Date
2020-08-25
Expiration Date
2033-10-24
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Abstract
The present invention provides for novel compositions and methods for delivering genes of interest to stem cells using vectors that contain differentiation-specific transcriptional regulatory elements. For example, stem cells in the internal epithelia could be transfected with a vaccine construct, which has an epithelial cell differentiation-specific promoter driving the expression of viral envelope proteins. When the promoter used is specific for terminally differentiated epithelial cells, then the viral envelope proteins will be expressed only in the upper part of the epithelia and therefore, stimulate the immune response. The infected epithelial stem cells in the basal layer will continue to produce new antigen-expressing cells, without being eliminated by the immune response. This invention will be useful in the development of vaccines against viral agents that target the internal mucosa like HIV.
Core Innovation
The invention provides novel nucleic acid compositions and methods for delivering genes of interest to stem cells using vectors that contain differentiation-specific transcriptional regulatory elements. In particular, it describes retroviral expression cassettes, such as those based on an involucrin promoter, which is specific for terminally differentiated epithelial cells, to drive the expression of immunogenic viral proteins including, but not limited to, HIV envelope glycoproteins.
The method allows for the expression of viral antigens solely in the upper layers of the epithelia, ensuring that only terminally differentiated cells express the antigen. This strategy ensures that epithelial stem cells within the basal layer remain intact and can continually give rise to new antigen-producing differentiated cells, which persistently expose the immune system to the antigens and thus sustain an immune response.
The background identifies the problem of insufficient long-term antigen presentation in existing HIV vaccine strategies, which leads to only weak and transient immune responses. The invention addresses this problem by enabling prolonged and localized expression of viral antigens at mucosal sites, thus potentially preventing infection at primary transmission sites, and supporting long-term immunity without the risk associated with replicating or attenuated live vaccines.
Claims Coverage
The patent has two independent claims, each defining an inventive feature centered on an involucrin-promoter-driven retroviral expression cassette for immunogenic viral proteins.
Involucrin promoter retrovirus-based expression cassette for immunogenic viral protein
A nucleic acid composition comprising: - A retrovirus-based expression cassette capable of expressing an immunogenic viral protein - An involucrin promoter - A 5′ retroviral long terminal repeat (LTR) lacking a U3 region - A nucleic acid sequence encoding the immunogenic viral protein - A 3′ retroviral LTR lacking a U3 region - The cassette does not contain a sequence encoding a functional Nef protein - The involucrin promoter controls expression of the immunogenic viral protein in a differentiated mucosal epithelial layer in a subject
Involucrin promoter retrovirus-based expression cassette for HIV envelope protein
A nucleic acid composition comprising: - A retrovirus-based expression cassette capable of expressing an immunogenic envelope protein of a human immunodeficiency virus - An involucrin promoter - A 5′ retroviral LTR lacking a U3 region - A nucleic acid sequence encoding the immunogenic envelope protein of the human immunodeficiency virus - A 3′ retroviral LTR lacking a U3 region - The cassette does not contain a functional Nef gene sequence - The involucrin promoter controls expression of the envelope protein in a differentiated mucosal epithelial layer in a subject
The inventive features focus on retroviral expression cassettes, driven by an involucrin promoter, specifically for controlled expression of immunogenic viral or HIV envelope proteins in differentiated mucosal epithelial layers, with removal of the functional Nef gene for safety.
Stated Advantages
Provides prolonged stimulation of the immune system with viral antigens, offering a strong barrier to viral replication.
Elicits a targeted immune response at the site of primary viral replication, such as mucosal entry points.
Achieves continuous antigen presentation in the epithelium, even through multiple cycles of epithelial renewal.
Allows permanent supply of antigen-producing cells without elimination of the source stem cells by the immune response.
Enables development of a single-dose, life-long lasting vaccine.
Documented Applications
Development of vaccines against viral agents that target the internal mucosa, such as HIV.
Use in immunogenic compositions for eliciting immune responses in subjects by targeting differentiated mucosal epithelial layers including vaginal, rectal, oral, and nasal epithelia.
Potential adaptation for vaccines against other pathogenic infections requiring cellular and humoral immunity.
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