Method and compositions comprising small RNA agonist and antagonists to modulate inflammation
Inventors
Gallo, Richard L. • Bernard, Jamie
Assignees
Office of General Counsel of VA • University of California San Diego UCSD
Publication Number
US-9303258-B2
Publication Date
2016-04-05
Expiration Date
2032-04-05
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Abstract
The disclosure provides methods and compositions for modulating inflammation.
Core Innovation
The invention provides methods and compositions for modulating inflammation, particularly related to inflammation in the skin caused by ultraviolet (UV) light exposure. It offers a mechanism by which UV exposure causes inflammation, especially involving U1 small nuclear RNA (snRNA) fragments that induce inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). The compositions include isolated photo-fragmented U1 snRNA oligonucleotides, including specific nucleotide fragments of U1 snRNA that can stimulate TNF-α and IL-6 production.
The problem being solved relates to the need for a better understanding and control of the sunburn response and the inflammatory reaction caused by excessive solar exposure. This excessive UV exposure can result in acute and long-term skin damage, and inflammation plays a critical role in repairing damage and resisting infection. Prior to this invention, the molecular mechanism initiating cytokine response after UV damage was unknown. The disclosure identifies UV-damaged U1 snRNA as a key endogenous signal detected by Toll-like receptor 3 (TLR3), triggering inflammation through cytokine production.
The disclosure also provides methods of identifying agonists and antagonists of inflammation by measuring production of UVB-U1 snRNA products or TNF-α and IL-6 expression following UV exposure. Agonists promote UVB-U1 snRNA and cytokine production to stimulate inflammation, useful for treating infections and cancer. Conversely, antagonists inhibit these processes to reduce inflammation and tissue damage caused by UV irradiation and other necrosis, useful to treat inflammatory diseases such as psoriasis, acne, and autoimmune disorders. Pharmaceutical compositions are provided, including topical formulations for skin application, comprising U1 snRNA or its fragments.
Claims Coverage
The patent includes seven claims, with claim 1 as an independent claim directed to a composition, and claims 2 to 5 directed to methods using this composition. The main inventive features revolve around specific nucleotide sequences derived from U1 snRNA fragments and their use in modulating inflammation.
Composition comprising specific U1 snRNA loop fragments chemically linked to a charge neutralizing agent
The composition includes nucleotide sequences selected from loops “a”, “b”, or “c” of U1 snRNA (SEQ ID NOs: 2, 3, and 4), their variants where uracil (U) is replaced by thymine (T), complements, sequences with non-natural nucleotides, or oligonucleotides with 99% identity to these sequences that stimulate IL-6 and/or TNF-α production in mammalian cells. These nucleotide sequences are chemically linked to a charge neutralizing agent and incorporated into a pharmaceutically acceptable carrier.
Method of inducing inflammation by contacting tissue with the composition
A method for inducing inflammation comprising contacting a tissue with the composition comprising the defined U1 snRNA nucleotide sequences described in claim 1, wherein the composition induces production of TNF-α and/or IL-6.
Method of treating an infection by administering the composition
A method of treating an infection in a subject comprising contacting tissue with the composition described in claim 1, wherein the composition induces TNF-α and/or IL-6 production.
Method of treating a skin infection with the composition
A method specifically treating a skin infection by contacting tissue with the composition of claim 1, inducing TNF-α and/or IL-6 production.
Method of treating a skin wound with the composition
A method of treating a skin wound by contacting tissue with the composition of claim 1, where the composition induces TNF-α and/or IL-6 production.
The claims cover compositions of photo-fragmented U1 snRNA nucleotide sequences chemically linked to charge neutralizing agents formulated for pharmaceutical use and methods for inducing inflammation or treating infections or wounds by administering these compositions to tissues.
Stated Advantages
Provides a mechanism to modulate inflammation caused by UV exposure via U1 snRNA fragments, allowing stimulation or inhibition of inflammatory responses.
Offers therapeutic strategies to treat infections and cancer by promoting beneficial inflammation at targeted sites.
Allows treatment of inflammatory diseases and reduction of skin damage from UV irradiation and tissue necrosis by antagonizing UVB U1 snRNA activity.
Documented Applications
Treatment of inflammatory skin diseases including psoriasis and itch by administering U1 snRNA agonists.
Treatment of bacterial and fungal infections by promoting inflammatory responses through UVB U1 snRNA agonists.
Treatment of skin wounds and skin cancer using UVB U1 snRNA to induce inflammatory cytokines.
Reduction of UV-induced skin damage, solar aging, and inflammation from sunburn or necrosis using antagonists of UVB U1 snRNA activity, including antibodies against TLR3 or U1 snRNA, or siRNA targeting UVB U1 snRNA.
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