Aptamer-RNAi therapeutic compositions
Inventors
Assignees
Oregon Health and Science University • US Department of Veterans Affairs
Publication Number
US-9926565-B2
Publication Date
2018-03-27
Expiration Date
2035-09-22
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Abstract
A recombinant nucleic acid comprising an aptamer that binds CD4 and an RNAi sequence that silences the expression of RORγ2 is described herein. Pharmaceutical compositions comprising the recombinant nucleic acid, particularly topical compositions are also described. Methods of treating inflammatory disease using the pharmaceutical composition are also described.
Core Innovation
The invention discloses a recombinant polyribonucleotide comprising a first sequence that includes an aptamer that specifically binds CD4 and a second sequence that includes an RNAi that silences RORγt. This recombinant polyribonucleotide can be chemically synthesized or transcribed from a DNA template, including in vitro transcription. The polyribonucleotide may include 2′-fluororibonucleic acid modifications to enhance RNase resistance, exemplified by inclusion of 2′-fluoro cytosine and/or 2′-fluoro uracil. Pharmaceutical compositions including these recombinant polyribonucleotides, particularly for topical administration, are also disclosed.
The background identifies a problem in the treatment of autoimmune and inflammatory diseases mediated by Th17 cells, where current therapeutics typically target members of the IL-17 family or IL-17 receptors, which are widely distributed and also produced by innate immune cells. This can lead to deleterious effects such as increased risk of infection. The problem addressed is the need for therapeutics that specifically target Th17 cells to inhibit RORγt, a transcription factor required for Th17 differentiation, thereby selectively reducing Th17-mediated inflammation without affecting innate IL-17 production.
The core innovation addresses this by providing a CD4 aptamer-RNAi chimera that delivers RNAi specifically to CD4+ T cells, silencing RORγt expression, thereby suppressing Th17 cell function and IL-17 production. The aptamer enables cell-specific delivery to Th17 cells, sparing other immune cells that do not express CD4, such as γ/δ T cells. The compositions can be formulated for topical administration to treat Th17-mediated diseases including psoriasis.
Claims Coverage
The patent includes several independent claims covering nucleic acid compositions, expression vectors, pharmaceutical compositions, and methods of treating diseases mediated by Th17 cells employing the described recombinant polyribonucleotide.
Recombinant polyribonucleotide comprising CD4-binding aptamer and RORγt-silencing RNAi
A recombinant polyribonucleotide comprising the nucleic acid sequence of SEQ ID NO: 1, which includes an aptamer that specifically binds CD4 fused to an RNAi sequence that silences RORγt expression.
Expression vector encoding the recombinant polyribonucleotide with operably linked promoter
An expression vector comprising a nucleic acid sequence encoding SEQ ID NO: 1 operably linked to a promoter, capable of being stably transfected into a cell.
Pharmaceutical composition comprising an effective amount of the recombinant polyribonucleotide
Pharmaceutical compositions comprising an effective amount of the recombinant polyribonucleotide of SEQ ID NO: 1, including formulations for topical administration.
Method of treating diseases mediated by Th17 cells by administering the pharmaceutical composition
Methods of treating diseases mediated by Th17 cells in a subject comprising administering the pharmaceutical compositions containing the recombinant polyribonucleotide, wherein the diseases include rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis, inflammatory bowel disease, and type 1 diabetes mellitus.
The independent claims cover the nucleic acid chimera comprising the CD4-binding aptamer linked to RORγt RNAi, vectors encoding the chimera, pharmaceutical formulations including topical formulations, and therapeutic methods for treating a range of Th17-mediated inflammatory diseases by administering the compositions to subjects.
Stated Advantages
The aptamer-mediated delivery provides specific targeting of CD4+ T cells, enabling selective silencing of RORγt in Th17 cells while sparing other immune cells such as γ/δ T cells.
The inclusion of 2′-fluoro modifications enhances RNase resistance of the chimera, improving stability for therapeutic use.
Topical formulations enable treatment of diseases like psoriasis with potentially fewer systemic side effects.
The chimera can be chemically synthesized as a single RNA strand, facilitating high-yield and consistent production, advantageous for clinical application.
Documented Applications
Treatment of autoimmune and inflammatory diseases mediated by Th17 cells, including rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis, inflammatory bowel disease, and type 1 diabetes mellitus.
Topical administration of pharmaceutical compositions comprising the recombinant polyribonucleotide for treating psoriatic skin lesions.
Use in a psoriasis humanized SCID mouse xenograft model to evaluate therapeutic efficacy by topical application.
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