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IONIS-PKK(Rx) a Novel Antisense Inhibitor of Prekallikrein and Bradykinin Production

Kallikrein is the key contact system mediator responsible for the conversion of high-molecular-weight kininogen into the inflammatory vasodilator peptide bradykinin, a process regulated by C1-esterase inhibitor (C1-INH). In hereditary angioedema (HAE), genetic mutations result in deficient or dysfun...

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Detalles Bibliográficos
Autores principales: Ferrone, Jason D., Bhattacharjee, Gourab, Revenko, Alexey S., Zanardi, Thomas A., Warren, Marshelle S., Derosier, Frederick J., Viney, Nicholas J., Pham, Nguyen C., Kaeser, Gwendolyn E., Baker, Brenda F., Schneider, Eugene, Hughes, Steven G., Monia, Brett P., MacLeod, A. Robert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Mary Ann Liebert, Inc., publishers 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461157/
https://www.ncbi.nlm.nih.gov/pubmed/30817230
http://dx.doi.org/10.1089/nat.2018.0754
Descripción
Sumario:Kallikrein is the key contact system mediator responsible for the conversion of high-molecular-weight kininogen into the inflammatory vasodilator peptide bradykinin, a process regulated by C1-esterase inhibitor (C1-INH). In hereditary angioedema (HAE), genetic mutations result in deficient or dysfunctional C1-INH and dysregulation of the contact system leading to recurrent, sometimes fatal, angioedema attacks. IONIS-PKK(Rx) is a second-generation 2′-O-(2-methoxyethyl)-modified chimeric antisense oligonucleotide, designed to bind and selectively reduce prekallikrein (PKK) mRNA in the liver. IONIS-PKK(Rx) demonstrated dose-dependent reduction of human prekallikrein hepatic mRNA and plasma protein in transgenic mice and dose- and time-dependent reductions of plasma PKK in Cynomolgus monkeys. Similar dose-dependent reductions of plasma PKK levels were observed in healthy human volunteers accompanied by decreases in bradykinin generation capacity with an acceptable safety and tolerability profile. These results highlight a novel and specific approach to target PKK for the treatment of HAE and other diseases involving contact system activation and overproduction of bradykinin.