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-8703921-B2
Publication Date
2014-04-22
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 compositions and methods that use complexes comprising one or more inhibitory nucleic acids and a targeting polypeptide, wherein the targeting polypeptide consists of a cell surface receptor ligand. These compositions can be used in methods of silencing gene expression in a cell, delivering agents to a target cell, and treating or preventing diseases or disorders in a subject. The complexes achieve targeted and efficient delivery of inhibitory oligonucleotides to cells expressing the corresponding cell surface receptors.
The problem addressed by the invention is the difficulty and impracticality of in vivo delivery of inhibitory nucleic acids, such as siRNA, which limits their therapeutic use. Existing viral vector-based siRNA delivery systems suffer from issues regarding specificity and safety. There is a need for improved treatments that enable high specificity of delivery to target cells, which current systems do not adequately provide.
The inventors developed novel complexes that couple a cell surface receptor targeting ligand, such as a chemokine, with a domain that binds an inhibitory oligonucleotide, such as protamine or viral antigens. This design allows efficient and targeted delivery of inhibitory nucleic acids, including various forms of siRNA, to cells expressing the receptor recognized by the ligand. The complexes can incorporate single or double stranded inhibitory nucleic acids, and can be used to deliver labeled or therapeutic agents. The invention also includes fusion molecules, vectors encoding these fusion molecules, and related pharmaceutical compositions and kits.
Claims Coverage
The patent contains independent claims covering a complex or fusion molecule comprising specific sequences, pharmaceutical compositions, and methods involving these complexes.
Complex comprising inhibitory nucleic acids and targeting polypeptide with specific amino acid sequence
A complex or fusion molecule comprising one or more inhibitory nucleic acids and a targeting polypeptide and nucleic acid binding moiety, wherein the targeting polypeptide and nucleic acid binding moiety comprise the amino acid sequence of SEQ ID NO: 2.
Inclusion of viral antigen in nucleic acid binding moiety
The nucleic acid binding moiety in the complex or fusion molecule further comprises a viral antigen, specifically a viral capsid antigen selected from gp120, gp160, and gp41.
Pharmaceutical composition comprising the complex with SEQ ID NO: 2
A pharmaceutical composition for treating or preventing a disease or disorder in a subject comprising one or more inhibitory nucleic acids and a targeting polypeptide and nucleic acid binding moiety, where the targeting polypeptide and nucleic acid binding moiety have the amino acid sequence of SEQ ID NO: 2.
Encoding nucleic acid sequences for complex or pharmaceutical composition
The targeting polypeptide and nucleic acid binding moiety are encoded by the nucleic acid sequence of SEQ ID NO: 1 in the complex, fusion molecule, or pharmaceutical composition.
Pharmaceutical composition for delivering agents to target cells
A pharmaceutical composition comprising one or more inhibitory nucleic acids coupled to an agent, and a targeting polypeptide and nucleic acid binding moiety having the amino acid sequence of SEQ ID NO: 2, enabling delivery of agents to target cells.
The independent claims cover complexes and fusion molecules comprising inhibitory nucleic acids and targeting polypeptides with defined sequences, pharmaceutical compositions including these complexes, and methods of delivery to target cells, emphasizing the incorporation of specific nucleic acid binding moieties and viral antigens for targeted and efficient delivery.
Stated Advantages
The compositions and methods provide highly efficient and targeted delivery of inhibitory oligonucleotides to cells expressing specific cell surface receptors.
The invention offers improved specificity in delivering siRNA and other inhibitory nucleic acids compared to existing viral vector-based delivery systems.
The technology allows for simple association of siRNA in saline without additional manipulations, facilitating flexible use of various siRNAs and labeled oligonucleotides for diagnostic and therapeutic purposes.
By targeting receptor-ligand interactions, the complexes enable targeted treatment of cancer, autoimmune diseases, and chronic infections with reduced off-target effects.
Documented Applications
Silencing or knocking down gene expression in cells via targeted delivery of inhibitory nucleic acids using complexes comprising cell surface receptor ligands.
Delivering inhibitory RNA molecules, including siRNA and antisense oligonucleotides, into cells expressing specific receptors.
Treating or preventing diseases or disorders in subjects, including various cancers such as leukemia, breast cancer, and other neoplasias, as well as immunological diseases and hyperproliferative disorders.
Delivering therapeutic agents or labels coupled to inhibitory nucleic acids to target cells for treatment or imaging purposes.
Diagnostic and prognostic imaging by delivering imaging agents into cells to determine prognosis or assess the course of treatment.
Ex vivo modulation of gene expression in tissue explants by introducing complexes into extracted cells prior to transplantation back into subjects.
Monitoring disease progression and treatment efficacy, including tumor progression in patients with neoplastic diseases.
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