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Isku-dhafka hyperlipidemia waxaa lagu gartaa heerarka sare ee plasma ee lipoproteins cufnaanta hoose (LDL) iyo lipoproteins-ka hodanka ah ee triglyceride, taasoo keenta khatarta sii kordheysa ee cudurada wadnaha atherosclerotic ee bukaankan.
ANGPTL3 waxay joojisaa lipoprotein lipase iyo endosepiase, iyo sidoo kale qaadashada beerka ee lipoprotein-ka hodanka ah ee triglyceride. Sidayaal ANGPTL3 kala duwanaanshiyaha aan dhaq-dhaqaaqin waxay lahaayeen heerar hoose oo ah triglycerides, kolestaroolka LDL, kolestaroolka cufnaanta sare ee lipoprotein (HDL), iyo kolestaroolka aan HDL ahayn, iyo sidoo kale khatarta hoose ee cudurada wadnaha atherosclerotic. zodasiran waa daawo yar oo faragalinaysa RNA (RNAi) taas oo beegsata muujinta ANGPTL3 ee beerka.

Isku-dhafka hyperlipidemia waxaa loola jeedaa heerarka sare ee kolestaroolka lipoprotein-cufnaanta hoose (LDL-C) iyo lipoprotein-ka hodanka ah ee triglyceride. Lipoproteins-ka hodanka ku ah triglyceride (oo ay ku jiraan chylomicrons, lipoproteins cufnaanta aad u hooseeya (VLDL), iyo kolestaroolka hadhaaga ah) ayaa door muhiim ah ka ciyaara horumarinta cudurka atherosclerotic. Ma jirto daaweyn wax ku ool ah oo loogu talagalay hyperlipidemia isku dhafan.
Bates waxaa loo yaqaanaa inay hoos u dhigto heerarka triglyceride (TG), laakiin dhimista ayaa xaddidan. Isla mar ahaantaana, daawooyinka hoos u dhigaya TG oo ay ku jiraan Bates (sida eicosapentaenoic acetic acid, iwm.) wax saameyn ah kuma laha khatarta cudurka atherosclerotic ee uu keeno heerarka kolestaroolka haraaga ah oo sarreeya. Intaa waxaa dheer, daraasadihii hore ee bukaannada horeyba u qaatay statins waxay muujiyeen in isku-darka daawooyinka TG-hoos u dhigaya aysan hoos u dhigin khatarta dhacdooyinka wadnaha. Arrimahan ayaa ka dhigaya daaweynta isku-dhafka hyperlipidemia mid aad u adag.
ANGPTL3 (angiopoietin-sida borotiinka 3) waxay nidaamisaa lipids iyo dheef-shiid kiimikaadka lipoprotein, oo ay ku jiraan TG iyo kolestaroolka lipoprotein-ka aan cufan ahayn (HDL-C), iyadoo dib u celinaysa xannibaadda lipoprotein lipase, endosepiase, iyo lipoprotein cufnaanta hoose (LDL) ee hepaprotein-ku-tiirsan. Waxaa la ogaaday in kala duwanaanshaha kala-baxa ee Angptl3 ee kor u kacaya liproprotein lipasse iyo firfircoonaanta endosepiase, oo ay ku jiraan chylotoron zasmain-ka hooseeya xaaladaha badan, ee verlyerotol, verlycepoteins liproprotein [IDL], LDL, cufnaanta sare, ldl. Lipoprotein (HDL), lipoprotein (a), iyo qaybahooda kolestaroolka. Dadka heterozygous-ka ah ee sidda kala duwanaanshahan waxay leeyihiin qiyaastii 40% hoos u dhac ku yimid khatarta cudurka atherosclerotic, mana jiro nooc caafimaad oo xun oo la helay. ANGPTL3 waxa lagu muujiyaa beerka, iyo daawaynta aamusinta hidda-wadaha ee lagu beegsanayo mRNA-keeda, oo loo yaqaanno dawooyinka RNA (siRNA) ee faragelinta yar, ayaa ah daawaynta isku-dhafka ah ee ballan-qaadka ah ee hyperlipidemia.
Sebtembar 12, 2024, New England Journal of Medicine (NEJM) ayaa daabacday daraasad ARCHES 2 ah oo xaqiijinaysa in dawada siRNA ee zodasiran ay si weyn hoos ugu dhigtay heerarka TG ee bukaannada qaba hyperlipidemia isku dhafan [1]. ARCHES-2 waa laba-indho-indho la'aan, placebo-control, qiyaasta qiyaasta sahaminta wajiga 2b. Wadarta 204 bukaan oo qaba hyperlipidemia isku-dhafan (soonka heerarka TG 150-499 mg/dL, heerarka LDL-C ³70 mg/dL ama heerarka aan HDL-C ³100 mg/dL) ayaa la diiwaan galiyay. Waxaa loo qaybiyay zodasiran 50 mg, kooxda 100 mg, kooxda 200 mg iyo kooxda xakamaynta placebo. Bukaan-socodka ayaa la siiyay irbado subcutaneous usbuuca 1 iyo 12, waxaana la siiyay ka hortag ilaa toddobaadka 36.
Meesha ugu dambeysa waxay ahayd boqolkiiba isbeddelka TG ee asaasiga ah ilaa toddobaadka 24. Daraasadu waxay ogaatay in usbuuca 24, heerarka TG ee kooxda zodasiran ay si weyn hoos ugu dhacday habka qiyaasta qiyaasta (Heerka TG ee koox kasta oo qiyaas ah ayaa hoos loo dhigay 51, 57 iyo 63 boqolkiiba, siday u kala horreeyaan, marka la barbardhigo kuwa ku jira kooxda placebo) (P<0.001) ANGPTL3 ayaa sidoo kale hoos u dhacay 54 dhibcood, 70 dhibcood iyo 74 dhibcood, siday u kala horreeyaan. Heerarka non-hdl-c ayaa hoos u dhacay boqolkiiba 29 dhibcood, 29 boqolkiiba dhibcood, iyo 36 boqolkiiba dhibcood, apolipoprotein B heerarka hoos u 19 dhibcood boqolkiiba, 15 dhibcood, iyo 22 dhibcood boqolkiiba, iyo LDL-C heerarka hoos 16 boqolkiiba dhibcood, 14 boqolkiiba dhibcood, iyo 20 boqolkiiba 6 natiijooyinka, kuwaas oo 3. Todobaadka 24-aad, zodasiran
88% bukaanada ku jira kooxda 200 mg, soonka TG ayaa ku dhacay heerka caadiga ah.

Fallaadhaha cas ee maalmaha 1 iyo 12 waxay muujinayaan zodasiran ama maamulka placebo.

Heerarka TG ee soonka ayaa caadi hoos ugu dhacay usbuuca 24 (150
mg/dL ama ka yar)
Tiir kastaa wuxuu u taagan yahay hal bukaan.

Daraasadu waxay sidoo kale ogaatay in zotasiran ay nabdoon tahay dhammaan kooxaha qiyaasta, iyada oo bukaanada 2 kaliya ay joojiyeen daraasadda sababtoo ah dhacdooyinka xun (1 ee kooxda placebo iyo 1 ee kooxda 100 mg zotasiran). Dhammaan dhacdooyinka xun xun ee kooxda zotasiran ayaa soo kabsaday dhammaadka daraasadda, waxaana jiray hal dhimasho oo ka mid ah kooxda placebo. Dhacdada kaliya ee xun ee walaaca ayaa ahayd kororka HBA1c ee kooxda 200 mg zotasiran marka la barbar dhigo placebo (macnaha isbeddelka aasaasiga ah ilaa toddobaadka 24 [± SD], 0.38 ± 0.66% vs. -0.03 ± 0.88% bukaannada qaba cudurka macaanka ee hore u jiray). Bukaannada aan lahayn sonkorowgu waxay ahaayeen 0.12± 0.19% vs. -0.03±0.19%).
Gaar ahaan, ku dhawaad ​​​​dhammaan bukaannada daraasadda ku jira (96%) ayaa lagu daweeyay statins (37% kuwaas oo ahaa statins-dose sare), 1% waxaa lagu daweeyay borotiinka beddela enzyme subtilysin 9 inhibitor (PCSK9i), iyo 21% waxaa lagu daweeyay fibrates. Sidaa darteed, ku-darka zodasiran ee ku salaysan habka daaweynta caadiga ah ee hadda jira ayaa weli lagu gaadhay saameyno hoos u dhigista dufanka, taas oo bixisa nidaam cusub oo loogu talagalay daaweynta hyperlipidemia isku dhafan mustaqbalka.
Toddobaadka 24, qiyaasta ugu badan ee 200 mg ee zotasiran ee daraasadda ayaa hoos u dhigtay heerarka kolestaroolka hadhaaga 34.4 mg/dL marka la barbardhigo placebo. Iyada oo ku saleysan moodooyinka hadda jira, dhimistan ayaa la filayaa inay hoos u dhigto dhacdooyinka xun xun ee wadnaha boqolkiiba 20. zodasiran waxay awood u leedahay in loo isticmaalo monotherapy dhammaan qaybaha lipoprotein si loo yareeyo khatarta dhacdooyinka wadnaha iyo xididdada bukaanka. Cilmi baaris dheeraad ah ayaa sidaas darteed lagama maarmaan u ah in la go'aamiyo awoodda daawadan si loo yareeyo khatarta cudurka atherosclerotic.
Wajiga 2b, laba-indhoole, randomized, placebo-control MUIR, oo isku mar lagu daabacay NEJM, waxay isticmaashay daroogo kale siRNA, plozasiran, si loogu daaweeyo hyperlipidemia isku dhafan [2]. plozasiran waxaa loogu talagalay in lagu yareeyo muujinta APOC3, hiddo-wadaha ku dhejinaya apolipoprotein C3 (APOC3), nidaamiyaha dheef-shiid kiimikaadka TG, ee beerka, taas oo yaraynaysa TG iyo heerarka kolestaroolka hadhaaga ah. Hoos u dhigista TG iyo heerarka kolestaroolka hadha ee lagu arkay daraasadda waxay la mid yihiin kuwa laga helay daraasadda ARCHES-2. Sidaa darteed, waxaa la qiyaasayaa in bukaanada qaba hyperlipidemia isku dhafan, labada daawo ay leeyihiin saameyn isku mid ah si loo yareeyo heerka lipoprotein-ka hodanka ah ee triglyceride iyo kolestaroolka hadhaaga ah.
Natiijooyinka labada daraasadood ee siRNA waxay muujinayaan in tani ay tahay koox aad u rajo leh oo dawooyin ah oo keeni doona doorashooyin cusub oo loogu talagalay daaweynta hyperlipidemia isku dhafan iyo hagaajinta natiijooyinka wadnaha ee bukaanka.