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1. (WO2010078536) INHIBITION OF PCSK9 THROUGH RNAI
Latest bibliographic data on file with the International Bureau

Pub. No.: WO/2010/078536 International Application No.: PCT/US2010/000019
Publication Date: 08.07.2010 International Filing Date: 05.01.2010
IPC:
A61K 31/7115 (2006.01) ,A61K 31/712 (2006.01) ,A61K 31/7125 (2006.01)
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
70
Carbohydrates; Sugars; Derivatives thereof
7088
Compounds having three or more nucleosides or nucleotides
7115
Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
70
Carbohydrates; Sugars; Derivatives thereof
7088
Compounds having three or more nucleosides or nucleotides
712
Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
70
Carbohydrates; Sugars; Derivatives thereof
7088
Compounds having three or more nucleosides or nucleotides
7125
Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
Applicants:
RXI PHARMACEUTICALS CORPORATION [US/US]; 60 Prescott Street Worcester, MA 01605, US (AllExceptUS)
KAMENS, Joanne [US/US]; US (UsOnly)
KHVOROVA, Anastasia [US/US]; US (UsOnly)
Inventors:
KAMENS, Joanne; US
KHVOROVA, Anastasia; US
Agent:
LOCKHART, Helen, C.; Wolf, Greenfield & Sacks. P.C. 600 Atlantic Avenue Boston, MA 02210-2206, US
Priority Data:
61/204,34805.01.2009US
Title (EN) INHIBITION OF PCSK9 THROUGH RNAI
(FR) INHIBITION DE PCSK9 PAR ARNI
Abstract:
(EN) The invention relates to various PCSK9 RNAi constructs with gene silencing activities, and uses thereof The construct has a double- stranded region of 19-49 nucleotides, preferably 25, 26, or 27 nucleotides, and preferably blunt-ended The construct has selective minimal modifications to confer an optimal balance of biological activity, toxicity, stability, and target gene specificity The sense strand may be modified such that the construct is not cleaved by Dicer or other RNAse III, and the entire length of the antisense strand is loaded into RISC In addition, the antisense strand may also be modified by 2'-O-methyl groups at the 2nd 5'-end nucleotide to greatly reduce off-target silencing The constructs of the invention largely avoid the interferon response and sequence-independent apoptosis in mammalian cells, exhibits better serum stability, and enhanced target specificity.
(FR) L'invention porte sur divers produits de construction d'ARNi PCSK9 au moyen d'activités de silençage génique, et sur leurs utilisations. Le produit de construction comprend une région double brin de 19 à 49 nucléotides, de préférence 25, 26 ou 27 nucléotides, et de préférence à extrémité franche. Le produit de construction a subit des modifications sélectives minimales destinées à lui conférer un équilibre optimal d'activité biologique, de toxicité, de stabilité et de spécificité de gène cible. On peut modifier le brin sens de telle sorte que le produit de construction ne soit pas clivé par une l'enzyme Dicer ou autre ARNse III, et la longueur entière du brin antisens est chargée dans un système de traitement à jeu d'instructions réduit (RISC). De plus, on peut également modifier le brin antisens par des groupes 2'-O-méthyles au niveau du second nucléotide de l'extrémité 5' afin de beaucoup réduire le silençage hors cible. Les produits de construction de l'invention évitent largement la réponse d'interféron et l'apoptose indépendante de la séquence dans les cellules de mammifères, présentent une meilleure stabilité dans le sérum et une spécificité cible améliorée.
Designated States: AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW
African Regional Intellectual Property Organization (ARIPO) (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW)
Eurasian Patent Organization (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM)
European Patent Office (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, TR)
African Intellectual Property Organization (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG)
Publication Language: English (EN)
Filing Language: English (EN)
Also published as:
US20130197055