amakuru

Hyperlipidemiya ivanze irangwa no kwiyongera kwa plasma ya lipoproteine ​​nkeya (LDL) hamwe na lipoproteine ​​ikungahaye kuri triglyceride, bigatuma ibyago byiyongera by’indwara zifata umutima-mitsi-mitsi muri aba baturage barwayi.
ANGPTL3 ibuza lipoprotein lipase na endosepiase, hamwe no gufata umwijima wa lipoproteine ​​ikungahaye kuri triglyceride. Abatwara ANGPTL3 idakora yari ifite urugero rwo hasi rwa triglyceride, cholesterol ya LDL, cholesterol ya lipoprotein nyinshi (HDL), hamwe na cholesterol itari HDL, ndetse n’ibyago bike byo kwandura indwara zifata umutima na Atherosclerotique. zodasiran numuti muto wivanga RNA (RNAi) yibasira imvugo ya ANGPTL3 mumwijima.

Hyperlipidemiya ivanze bivuga urwego rwo hejuru rwa cholesterol ya lipoprotein nkeya (LDL-C) na lipoproteine ​​ikungahaye kuri triglyceride. Lipoproteine ​​ikungahaye kuri Triglyceride (harimo chylomicrons, lipoproteine ​​nkeya cyane (VLDL), na cholesterol isigaye) igira uruhare runini mu iterambere ry’indwara ya ateriyose. Nta buryo bwiza bwo kuvura hyperlipidemiya ivanze.
Bates izwiho kugabanya triglyceride (TG), ariko kugabanuka ni bike. Muri icyo gihe, TG igabanya imiti irimo Bates (nka acide eicosapentaenoic acetike, nibindi) nta ngaruka nini igira ku byago by’indwara ya aterosklerotike iterwa na cholesterol isigaye. Byongeye kandi, ubushakashatsi bwibanze ku barwayi bamaze gufata statin bwerekanye ko imiti igabanya TG igabanya ibyago byo kwandura umutima. Izi ngingo zituma kuvura hyperlipidemiya ivanze bigorana cyane.
ANGPTL3 (angiopoietin isa na poroteyine 3) igenga lipide na lipoprotein metabolism, harimo TG hamwe na cholesterol ya lipoprotein idafite ubukana bwinshi (HDL-C), ikabuza lipoprotein lipase, endosepiase, na lipoprotein (LDL) reseptor iterwa na hepatike ya lipoproteine. Byagaragaye ko variant ya ANGPTL3 itera lipoprotein lipase hamwe nigikorwa cya endosepiase, ari nako biganisha kuri plasma lipoproteine ​​nkeya mu bihe byinshi, Muri byo harimo lipoproteine ​​ikungahaye kuri triglyceride (ni ukuvuga Chylomicrons, cholesterol isigaye, LLL, Lipoproteine, LDL) lipoproteine ​​(a), hamwe na cholesterol. Abantu ba Heterozygous batwara iyi variant bafite hafi 40% ibyago byo kugabanuka kwindwara ya ateriyose, kandi nta fenotipiki mbi yubuvuzi yabonetse. ANGPTL3 igaragarira mu mwijima, kandi imiti yo gucecekesha gene yibasira mRNA yayo, izwi ku izina ry’imiti mito ya RNA (siRNA), ni imiti itanga imiti ivura hyperlipidemiya.
Ku ya 12 Nzeri 2024, Ikinyamakuru cy’ubuvuzi cya New England (NEJM) cyasohoye ubushakashatsi bwa ARCHES 2 bwemeza ko ibiyobyabwenge bya siRNA zodasiran byagabanije cyane urugero rwa TG ku barwayi bafite hyperlipidemiya ivanze [1]. ARCHES-2 ni impumyi-ebyiri, igenzurwa na platbo, icyiciro cya kabiri cyubushakashatsi icyiciro cya 2b. Abarwayi 204 bafite hyperlipidemiya ivanze (kwiyiriza ubusa kwa TG 150-499 mg / dL, LDL-C urwego 70 mg / dL cyangwa urwego rutari HDL-C ³100 mg / dL) bariyandikishije. Bagabanijwemo itsinda rya zodasiran 50 mg, itsinda rya mg 100, itsinda rya 200 mg hamwe nitsinda rishinzwe kugenzura imyanya. Abarwayi bahawe inshinge zo munsi yicyumweru cya 1 nicya 12, bahabwa gukurikiranwa kugeza icyumweru cya 36.
Iherezo ryambere ni ihinduka ryijanisha muri TG kuva kumurongo kugeza kucyumweru 24. Ubushakashatsi bwerekanye ko mugihe cyicyumweru cya 24, urwego rwa TG mumatsinda ya zodasiran rwagabanutse cyane muburyo buterwa na dose (urwego rwa TG muri buri tsinda rya dose rwagabanutseho amanota 51, 57 na 63%, ugereranije nu bari mu itsinda rya placebo) (P <0.001 kubigereranya byose). ANGPTL3 nayo yagabanutseho amanota 54 ku ijana, amanota 70 ku ijana na 74 ku ijana. Urwego rutari hdl-c rwaragabanutseho amanota 29 ku ijana, amanota 29 ku ijana, n’amanota 36 ku ijana, urwego rwa apolipoproteine ​​B rwaragabanutseho amanota 19 ku ijana, amanota 15 ku ijana, n’amanota 22 ku ijana, naho LDL-C yagabanutseho amanota 16 ku ijana, amanota 14 ku ijana, n’amanota 20 ku ijana, kandi ibisubizo byakomeje kugeza ku cyumweru cya 36. Mu cyumweru cya 24, zodasiran
Muri 88% by'abarwayi bo mu itsinda rya mg 200, kwiyiriza ubusa TG byari byagabanutse ku buryo busanzwe.

Imyambi itukura kumunsi wa 1 na 12 yerekana zodasiran cyangwa ubuyobozi bwa placebo.

Kwiyiriza ubusa kwa TG byagabanutse mubisanzwe icyumweru 24 (150
mg / dL cyangwa munsi)
Buri nkingi igereranya umurwayi umwe.

Ubushakashatsi bwagaragaje kandi ko zotasiran yari ifite umutekano mu matsinda yose y’imiti, abarwayi 2 gusa ni bo bahagaritse ubushakashatsi kubera ibintu bibi (1 mu itsinda rya placebo na 1 mu itsinda rya 100 mg zotasiran). Ibintu byose bikomeye byabaye mumatsinda ya zotasiran byakize nyuma yubushakashatsi, kandi hapfuye umuntu umwe mumatsinda yabobo. Gusa ikintu kibi cyateye impungenge ni kwiyongera kwa HBA1c mumatsinda 200 mg zotasiran ugereranije na placebo (bivuze guhinduka kuva kumurongo kugeza ku cyumweru cya 24 [± SD], 0.38 ± 0,66% na -0.03 ± 0,88% kubarwayi barwaye diyabete mbere). Abarwayi badafite diyabete bari 0,12 ± 0.19% na -0.03 ± 0.19%).
By'umwihariko, abarwayi hafi ya bose bari mu bushakashatsi (96%) bavurwaga na statine (37% muri bo bakaba bari bafite statin nyinshi), 1% bavurwaga na poroteyine ihindura enzyme subtilysin 9 inhibitor (PCSK9i), naho 21% bakavurwa na fibre. Kubwibyo, kongeramo zodasiran hashingiwe kuri gahunda isanzwe yo kuvura isanzwe iracyafite ingaruka zitari nke zo kugabanya lipide, zitanga uburyo bushya bwo kuvura hyperlipidemiya ivanze mugihe kizaza.
Ku cyumweru cya 24, igipimo ntarengwa cya mg 200 za zotasiran mu bushakashatsi cyagabanije urugero rwa cholesterol zisigaye kuri 34.4 mg / dL ugereranije na placebo. Ukurikije ibyitegererezo bigezweho, uku kugabanuka guteganijwe kugabanya ibintu bikomeye byumutima mubi 20%. zodasiran ifite ubushobozi bwo gukoreshwa nka monotherapy kubintu byose bya lipoproteine ​​kugirango bigabanye ibyago byindwara zifata umutima nimiyoboro. Ubundi bushakashatsi rero burakenewe kugirango hamenyekane ubushobozi bwibi biyobyabwenge mukugabanya ibyago byindwara ya ateriyose.
Icyiciro cya 2b, impumyi ebyiri, zitabishaka, zigenzurwa na MUIR ubushakashatsi bwa MUIR, bwasohotse icyarimwe muri NEJM, bwakoresheje undi muti wa siRNA, plozasiran, mu kuvura hyperlipidemiya ivanze [2]. plozasiran yagenewe kugabanya imvugo ya APOC3, gene ikubiyemo apolipoprotein C3 (APOC3), igenga metabolism ya TG, mu mwijima, bityo bikagabanya TG hamwe na cholesterol isigaye. Kugabanuka kwa TG hamwe na cholesterol isigaye byagaragaye mubushakashatsi byari bisa nibiboneka mubushakashatsi bwa ARCHES-2. Kubwibyo rero, biravugwa ko ku barwayi bafite hyperlipidemiya ivanze, imiti yombi igira ingaruka zimwe mu kugabanya urugero rwa lipoproteine ​​ikungahaye kuri triglyceride na cholesterol isigaye.
Ibyavuye mu bushakashatsi bubiri bwa siRNA byerekana ko iki ari icyiciro cy’imiti itanga ikizere kizazana uburyo bushya bwo kuvura hyperlipidemiya ivanze no kuzamura umusaruro w’umutima n’imitsi ku barwayi.