Transcription regulatory elements and uses thereof
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Assignees
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Publication Number
US-12296026-B2
Publication Date
2025-05-13
Expiration Date
Abstract
The invention provides regulatory elements, as well as vectors containing the same that may be used to stimulate transcription of a gene of interest in certain tissue types. The transcription regulatory elements described herein may be operably linked to a transgene, such as acid alpha-glucosidase (GAA), so as to promote expression of the GAA transgene in a cell, such as a muscle cell, liver cell, or neuron. The transcription regulatory elements described herein may be operably linked to a therapeutic transgene and used for the treatment of various disorders, such as lysosomal storage diseases, and particularly Pompe disease.
Core Innovation
The invention relates to transcription regulatory elements that include multiple operably linked promoter and regulatory segments arranged in a 5′-to-3′ direction. A first segment comprises a synapsin promoter having the nucleic acid sequence of SEQ ID NO: 8, a second segment comprises an apolipoprotein E hepatic control region (ApoE-HCR) having the nucleic acid sequence of SEQ ID NO: 1, and a third segment comprises a desmin promoter having the nucleic acid sequence of SEQ ID NO: 7. The components are operably linked in the order first segment-second segment-third segment.
The disclosed regulatory element is provided in a vector that includes the nucleic acid regulatory element operably linked to a transgene, where the vector is configured to induce transgene expression upon introduction into a cell. In particular embodiments, the transgene is acid alpha-glucosidase (GAA), and the target cell type includes a muscle cell, a neuron, or a hepatocyte. Viral vectors and AAV-based formats are described, including combinations with specific AAV serotypes.
The patent addresses the need for tissue-specific and multi-tissue expression for a therapeutic transgene in the context of lysosomal storage disease, including Pompe disease. The document describes hybrid promoter architectures, including combinations that incorporate ApoE-HCR with desmin and optionally a CNS-targeting promoter segment such as synapsin, to support expression in affected tissues while also enabling liver-directed expression. The disclosed constructs and vectors are described together with treatment of subjects using the therapeutic compositions.
Claims Coverage
The partial claim set provided includes one independent claim directed to a specific three-segment nucleic acid regulatory element architecture, plus dependent claims that define vector form, transgene/cell targeting, viral vector selection, allowable AAV serotypes, and non-viral composition formulations. The inventive features primarily center on the operably linked 5′-to-3′ arrangement of synapsin, ApoE-HCR, and desmin promoter segments.
Three-segment hybrid nucleic acid regulatory element in defined 5′-to-3′ order
A nucleic acid regulatory element comprising a first segment, a second segment, and a third segment operably linked to each other in a 5′-to-3′ direction as first segment-second segment-third segment, where the first segment comprises a synapsin promoter having SEQ ID NO: 8, the second segment comprises an apolipoprotein E hepatic control region (ApoE-HCR) having SEQ ID NO: 1, and the third segment comprises a desmin promoter having SEQ ID NO: 7.
Vector with hybrid regulatory element operably linked to a transgene
A vector comprising the nucleic acid regulatory element of the first claim operably linked to a transgene, where the vector is configured to induce transgene expression upon introduction into a cell.
Transgene as acid alpha-glucosidase (GAA) with specified target cells
The vector specifies that the transgene is acid alpha-glucosidase (GAA) and/or that the target cell is a muscle cell, a neuron, or a hepatocyte.
AAV vector format
The vector is an adeno-associated virus (AAV).
Selected AAV serotypes and AAVrh74
The AAV is selected from AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, or AAVrh74 serotypes.
Non-viral composition as formulated nucleic acid molecules
A composition includes a nucleic acid molecule comprising the nucleic acid regulatory element of the first claim, formulated as a liposome, vesicle, synthetic vesicle, exosome, synthetic exosome, dendrimer, or nanoparticle.
Across the provided claim set, coverage is anchored by a defined hybrid nucleic acid regulatory element that places synapsin promoter (SEQ ID NO: 8), ApoE-HCR (SEQ ID NO: 1), and desmin promoter (SEQ ID NO: 7) in a specified 5′-to-3′ operable order. The dependent claims extend this architecture into vectors configured to induce transgene expression, specify acid alpha-glucosidase (GAA) and target cell types, and define delivery/format options including AAV (with particular serotypes) and non-viral liposome/vesicle/exosome/dendrimer/nanoparticle formulations.
Stated Advantages
Hybrid promoter-driven expression in affected tissues while liver-directed expression promotes immune tolerance.
Reduced anti-GAA antibody reactivity with higher liver expression is described in the provided summary content.
Improved quadriceps pathology and glycogen recovery is described in the provided summary content.
CNS expression evidence for at least one hybrid construct is described in the provided summary content.
Documented Applications
Therapeutic transgene expression for lysosomal storage disease, including Pompe disease, using vectors and compositions that include the disclosed transcription regulatory elements and transgenes such as acid alpha-glucosidase (GAA).
In vivo mouse application described for hybrid promoter vectors driving hGAA activity/transcripts in liver, muscle, and spinal cord, including evidence for CNS expression for at least one hybrid construct.
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