Compositions and methods for delivering inhibitory oligonucleotides
Inventors
Arya, Bira • Olkhanud, Purevdorj • Espinoza, Juan
Assignees
US Department of Health and Human Services
Publication Number
US-9415116-B2
Publication Date
2016-08-16
Expiration Date
2029-04-15
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Abstract
The present invention features compositions and methods that make use of complexes comprising one or more inhibitory nucleic acids and a targeting polypeptide, wherein the targeting polypeptide consists of a cell surface receptor ligand. The compositions can be used in methods of silencing gene expression in a cell, in delivering agents to a target cell, and in treating or preventing a disease or disorder in a subject.
Core Innovation
The invention features novel compositions and methods for delivering inhibitory oligonucleotides to cells in a targeted and efficient manner. These compositions utilize complexes comprising one or more inhibitory nucleic acids and a targeting polypeptide, wherein the targeting polypeptide consists of a cell surface receptor ligand. The ligand can be, for example, a chemokine, cytokine, antibody, or growth factor. This targeting enables delivery of the inhibitory nucleic acids specifically to cells expressing the corresponding cell surface receptor.
The problem addressed by the invention arises from limitations in in vivo delivery of inhibitory nucleic acids like siRNA, which suffer from difficulties such as poor specificity and safety concerns associated with viral vector delivery systems. Existing methods lack the high specificity of delivery needed for effective gene silencing without off-target effects. Therefore, there is a need for compositions and methods that enable efficient, cell-specific delivery of inhibitory nucleic acids to cells expressing particular target receptors, improving gene silencing and therapeutic efficacy.
The compositions use a targeting polypeptide that includes a receptor ligand linked to a nucleic acid binding moiety, such as protamine or viral antigens like capsid proteins gp120, gp160, or gp41, to facilitate the binding and delivery of inhibitory nucleic acids. The complexes may include fusion molecules where the targeting polypeptide and nucleic acid binding domain are linked via spacer peptides and can be encoded by specific nucleic acid sequences (e.g., SEQ ID NO: 1 or 3). These complexes can deliver various forms of inhibitory nucleic acids—including siRNA, shRNA, miRNA, single- or double-stranded RNA or DNA—to silence gene expression in the targeted cells.
Claims Coverage
The independent claims encompass compositions and methods involving complexes or fusion molecules comprising inhibitory nucleic acids, targeting polypeptides, and nucleic acid binding moieties, specifically those comprising or encoded by defined sequences.
Complex or fusion molecule comprising inhibitory nucleic acids and targeting polypeptide of specific sequence
The invention claims a complex or fusion molecule comprising one or more inhibitory nucleic acids, a targeting polypeptide, and a nucleic acid binding moiety, wherein the targeting polypeptide and nucleic acid binding moiety comprise the amino acid sequence of SEQ ID NO: 4.
Inclusion of viral antigen in nucleic acid binding moiety
The nucleic acid binding moiety further comprises a viral antigen, optionally a viral capsid antigen selected from gp120, gp160, and gp41.
Fusion molecules encoded by specific nucleic acid sequences
Fusion molecules comprising a targeting polypeptide and nucleic acid binding moiety encoded by the nucleic acid sequence SEQ ID NO: 3 or polypeptide comprising SEQ ID NO: 4.
Vectors and cells comprising fusion molecules
Vectors encoding the fusion molecule of SEQ ID NO: 3, and isolated cells comprising such vectors.
Pharmaceutical compositions comprising inhibitory nucleic acids, targeting polypeptide, and nucleic acid binding moiety
Pharmaceutical compositions for treating or preventing disease comprising inhibitory nucleic acids, a targeting polypeptide, and a nucleic acid binding moiety with the amino acid sequence of SEQ ID NO: 4, optionally encoded by SEQ ID NO: 3, and possibly further comprising an additional agent.
Pharmaceutical compositions delivering agents via inhibitory nucleic acids coupled to agents
Pharmaceutical compositions for delivering agents to target cells comprising inhibitory nucleic acids coupled to an agent, along with a targeting polypeptide and nucleic acid binding moiety comprising the amino acid sequence SEQ ID NO: 4.
The independent claims cover novel complexes and fusion molecules containing inhibitory nucleic acids and targeting polypeptides of defined sequences, including the use of viral antigen domains for nucleic acid binding, their encoding nucleic acids, vectors and cells comprising them, and pharmaceutical compositions for therapeutic delivery and treatment applications.
Stated Advantages
The invention provides highly efficient and targeted delivery of inhibitory oligonucleotides to cells expressing specific cell surface receptors, improving gene silencing efficacy.
The compositions enable specific targeting of cells, including tumor and immune cells, that express particular chemokine receptors or other surface receptors, reducing off-target effects.
The complexes are simple to prepare, stable under physiological conditions, and capable of delivering labeled or modified inhibitory nucleic acids for both therapeutic and diagnostic uses.
The approach allows for delivery of multiple inhibitory nucleic acids simultaneously and can be applied across various species and cell types.
Documented Applications
Silencing gene expression in cells by targeted delivery of inhibitory nucleic acids.
Delivering agents such as therapeutic molecules or imaging agents to target cells expressing the corresponding cell surface receptor ligand.
Treating or preventing diseases and disorders in subjects by decreasing expression of target genes using the complexes, including cancers such as leukemia and breast cancer, and immunological diseases.
Ex vivo modulation of gene expression in tissue explants or cells for therapeutic transplantation.
Diagnostic and prognostic uses including imaging to determine prognosis or course of treatment and diagnosis of metastasis.
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