Strategies for proprotein convertase subtilisin kexin 9 modulation: a perspective on recent patents.
BACKGROUND
Proprotein convertase subtilisin kexin 9 (PCSK9) is a new actor discovered in 2003 that is implicated in autosomal dominant hypercholesterolemia, cholesterol homeostasis and coronary heart disease. It has been shown to degrade the low-density lipoprotein (LDL) receptor independently of its catalytic activity. Several pharmacological strategies to reduce PCSK9 are being thoroughly investigated.


METHODS
This article reviews all different strategies that are presently pursued to modulate the functional activity of PCSK9 which is a prime target for controlling LDL-cholesterol. It also provides a briefing of all the patents up to July 2010 from various organizations including pharmaceutical companies and academic institutions that have been submitted and/or approved.


RESULTS
This review is addressed to researchers from academia and pharmaceutical companies who are engaged in PCSK9 research/cholesterol regulation and in the development of cholesterol lowering drugs. Readers will gain an up-to-date overview of the different strategies that have been investigated to reduce PCSK9 including antisense technology and specific antibodies.


CONCLUSIONS
Clinical trials have been launched using RNA interference approaches to reduce PCSK9 expression or specific antibodies targeting and inhibiting PCSK9 interaction with the LDL receptor. They constitute very promising approaches to reducing cholesterol levels and coronary heart disease.
Abifadel
Marianne
M
Institut National de la Santé et de la Recherche Médicale, Inserm UMR698, Hemostasis, Bio-Engineering and Cardiovascular Remodelling, Hôpital Bichat-Claude Bernard, 46 Rue Henri Huchard, 75877 Paris Cedex 18, France. marianne.abi-fadel@inserm.fr
Pakradouni
Jihane
J
Collin
Matthieu
M
Samson-Bouma
Marie-Elisabeth
ME
Varret
Mathilde
M
Rabès
Jean-Pierre
JP
Boileau
Catherine
C
D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D003327:Coronary Disease / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control / Q000628:therapy; D016503:Drug Delivery Systems; D015195:Drug Design; D005786:Gene Expression Regulation; D006801:Humans; D006937:Hypercholesterolemia / Q000503:physiopathology* / Q000628:therapy; D010330:Patents as Topic; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D034622:RNA Interference; D012697:Serine Endopeptidases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
D002784:Cholesterol; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases