Methods of treating or preventing pruritis by blocking natriuretic polypeptide B
Inventors
Hoon, Mark A. • MISHRA, Santosh K.
Assignees
US Department of Health and Human Services
Publication Number
US-9987330-B2
Publication Date
2018-06-05
Expiration Date
2034-12-04
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Abstract
Disclosed is a method of treating, reducing, or preventing pruritis in a mammal, the method comprising administering at least one natriuretic polypeptide b (Nppb) blocking agent to a mammal in an amount effective to treat or prevent pruritis in the mammal. An in vitro method of identifying a compound that inhibits Nppb activity is also disclosed.
Core Innovation
The invention provides a method of treating, reducing, or preventing pruritis in a mammal by administering at least one natriuretic polypeptide b (Nppb) blocking agent in an amount effective to treat or prevent pruritis. The method includes administering Nppb blocking agents that are not Nppb-saporin conjugates. Additionally, an in vitro method to identify compounds that inhibit Nppb activity is disclosed, involving reporter gene expression assays in cells transduced with natriuretic polypeptide receptor A (Npra).
Pruritis may be transient or chronic and can be caused by or associated with skin conditions such as psoriasis, atopic dermatitis, or skin infections, systemic conditions including renal failure, liver disease, AIDS, diabetes, cancer, or treatments like chemotherapy and kidney dialysis. The Nppb blocking agents act by inhibiting or reducing Nppb biological activity through various mechanisms, including inhibition of Nppb or Npra expression, blocking binding of Nppb to Npra, or inhibiting Nppb signaling. Such agents include antibodies, antisense nucleic acids, RNA interference agents, chemical inhibitors, or receptor/Fc fusion proteins.
The invention recognizes that Nppb is required for pruriception and that blocking Nppb or its receptor Npra can treat pruritis. The disclosed in vitro method facilitates identification of compounds that inhibit Nppb activity by measuring reduction in reporter gene expression in cells expressing Npra with a nucleotide cyclase domain and a reporter controlled by cAMP. The method offers a real-time assay to discover Nppb inhibitors that may be useful as pruritis treatments.
Claims Coverage
There are two independent claims defining inventive features related to methods of treating or reducing pruritis by administering specific Nppb blocking agents.
Use of specific chemical inhibitors to treat pruritis
The method comprises administering HS-142-1 or [Asu7,23′]b-ANA-(7-28)] in an amount effective to treat or reduce pruritis in a mammal in need thereof.
Treatment of pruritis by administering [Asu7,23′]b-ANA-(7-28)] specifically
The method comprises administering [Asu7,23′]b-ANA-(7-28)] to the mammal in an amount effective to treat or reduce pruritis.
The claims cover methods for treating or reducing pruritis by administering specific Nppb blocking agents, focusing on two chemical inhibitors, HS-142-1 and [Asu7,23′]b-ANA-(7-28)]. The claims define treatment applicability to various forms and causes of pruritis in mammals, including humans.
Stated Advantages
The invention provides improved compositions and methods for treating pruritis, which can significantly reduce chronic itch that adversely affects quality of life.
The method offers a treatment approach that targets a key neuropeptide, Nppb, which is necessary for itch transmission, enabling broad effectiveness across varied causes of pruritis.
The in vitro assay described can efficiently identify compounds that inhibit Nppb activity, facilitating discovery of new therapeutic agents for pruritis.
Documented Applications
Treatment or prevention of pruritis associated with skin conditions such as psoriasis, atopic dermatitis (eczema), and fungal or Trichomonas skin infections.
Treatment or prevention of pruritis related to systemic conditions including renal failure, liver disease (such as cirrhosis), acquired immune deficiency syndrome (AIDS), polycythemia vera, diabetes, hyperthyroidism, cancer (including Hodgkin's lymphoma, non-Hodgkin's lymphoma, and Kaposi's sarcoma), and conditions induced by chemotherapy or kidney dialysis.
Treatment of pruritis mediated or induced by pruritogens including histamine, chloroquine, endothelin (ET-1), 2-methyl serotonin (5HT), SLIGRL-NH2 (PAR2), and compound 48/80 (48/80).
Treatment of pruritis mediated by interleukin (IL)-31, a cytokine associated with chronic itch in some skin disorders.
Use in mammals generally, including humans, to treat or reduce pruritis by blocking Nppb signaling.
An in vitro screening method for identifying compounds that inhibit Nppb activity, useful for discovering anti-pruritic agents.
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