nkhani

Kuphatikizika kwa hyperlipidemia kumadziwika ndi kuchuluka kwa plasma kwa otsika kachulukidwe lipoproteins (LDL) ndi triglyceride-rich lipoproteins, zomwe zimapangitsa kuti chiwopsezo chowonjezeka cha matenda a mtima a atherosclerotic mwa odwalawa.
ANGPTL3 imalepheretsa lipoprotein lipase ndi endosepiase, komanso chiwindi cha triglyceride-rich lipoproteins. Onyamulira a ANGPTL3 osagwiritsidwa ntchito mosiyanasiyana anali ndi milingo yotsika ya triglycerides, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, ndi cholesterol yosakhala ya HDL, komanso chiwopsezo chochepa cha atherosclerotic cardiovascular disease. zodasiran ndi mankhwala ang'onoang'ono osokoneza a RNA (RNAi) omwe amalunjika ku ANGPTL3 m'chiwindi.

Kuphatikizika kwa hyperlipidemia kumatanthawuza kuchuluka kwa mafuta otsika kwambiri a lipoprotein cholesterol (LDL-C) ndi triglyceride-rich lipoproteins. Ma lipoprotein olemera a triglyceride (kuphatikiza ma chylomicrons, low density lipoproteins (VLDL), ndi cholesterol yotsalira) amagwira ntchito yofunika kwambiri pakukula kwa atherosulinosis. Palibe chithandizo chamankhwala chosakanikirana cha hyperlipidemia.
Bates amadziwika kuti amachepetsa milingo ya triglyceride (TG), koma kuchepetsako kumakhala kochepa. Nthawi yomweyo, TG kutsitsa mankhwala kuphatikizapo Bates (monga eicosapentaenoic acetic acid, etc.) alibe kwambiri chiwopsezo cha atherosclerotic matenda chifukwa cha okwera otsalira mafuta m`thupi milingo. Kuphatikiza apo, kafukufuku wam'mbuyomu mwa odwala omwe atenga kale ma statins awonetsa kuti kuphatikiza mankhwala ochepetsa TG sikuchepetsa chiopsezo cha matenda amtima. Zinthu izi zimapangitsa kuti chithandizo cha hyperlipidemia chikhale chovuta kwambiri.
ANGPTL3 (angiopoietin-like protein 3) imayang'anira lipids ndi lipoprotein metabolism, kuphatikizapo TG ndi non-high-density lipoprotein cholesterol (HDL-C), mwa kulepheretsa mosinthika lipoprotein lipase, endosepiase, ndi low-density lipoprotein (LDL) receptor-dependent. Zapezeka kuti kusinthika kwa ANGPTL3 kumayambitsa kuchulukira kwa lipoprotein lipase ndi endosepiase ntchito, zomwe zimabweretsa kutsika kwa plasma lipoprotein nthawi zambiri, Izi zimaphatikizapo triglyceride-rich lipoproteins (ie Chylomicrons, cholesterol yotsalira, VLDL, medium density lipoprotein), LDL-HD lipoprotein [I] HDL, lipoprotein (a), ndi zigawo zake za cholesterol. Anthu a heterozygous omwe amanyamula izi amakhala ndi chiopsezo chochepa cha 40% cha matenda a atherosclerotic, ndipo palibe choyipa chachipatala chomwe chapezeka. ANGPTL3 imawonetsedwa m'chiwindi, ndipo njira zochizira jini zomwe zimayang'ana mRNA yake, yomwe imadziwika kuti mankhwala ang'onoang'ono osokoneza a RNA (siRNA), ndi njira yosakanizidwa yosakanizidwa yothandizira hyperlipidemia.
Pa Seputembara 12, 2024, New England Journal of Medicine (NEJM) idasindikiza kafukufuku wa ARCHES 2 wotsimikizira kuti mankhwala a siRNA zodasiran amachepetsa kwambiri ma TG mwa odwala omwe ali ndi hyperlipidemia yosakanikirana [1]. ARCHES-2 ndi kuyesa kwapawiri, koyendetsedwa ndi placebo, kufufuza kwa mlingo wa 2b. Odwala a 204 omwe ali ndi hyperlipidemia yosakanikirana (kusala kudya kwa TG 150-499 mg / dL, LDL-C milingo ³70 mg/dL kapena non-HDL-C milingo ³100 mg/dL) analembetsa. Anagawidwa mu gulu la zodasiran 50 mg, 100 mg gulu, 200 mg gulu ndi gulu lolamulira la placebo. Odwala adalandira jakisoni wa subcutaneous pa sabata 1 ndi 12, ndipo adalandira kutsatira-prophylaxis mpaka sabata 36.
Chomaliza chachikulu chinali kusintha kwa chiwerengero cha TG kuyambira pachiyambi mpaka sabata la 24. Kafukufukuyu anapeza kuti pa sabata la 24, magulu a TG mu gulu la zodasiran adachepetsedwa kwambiri m'njira yodalira mlingo (magawo a TG mu gulu lililonse la mlingo adachepetsedwa ndi 51, 57 ndi 63 peresenti, motsatira, poyerekeza ndi omwe ali mu gulu la placebo) (P <0.0). ANGPTL3 idatsikanso ndi 54 peresenti, 70 peresenti ndi 74 peresenti, motsatira. Milingo ya Non-hdl-c idatsika ndi 29 peresenti, 29 peresenti, ndi 36 peresenti, misinkhu ya apolipoprotein B inatsika ndi 19 peresenti, 15 peresenti, ndi 22 peresenti, ndipo milingo ya LDL-C idatsika ndi 16 peresenti, 14 peresenti, ndi 20 peresenti, 6 mpaka 20 peresenti, sabata ndi 6. Mu sabata 24, zodasiran
Mu 88% ya odwala omwe ali mu gulu la 200 mg, kusala TG kudagwera pamlingo wabwinobwino.

Mivi yofiira pamasiku 1 ndi 12 imawonetsa zodasiran kapena placebo management.

Kusala kudya kwa TG kunatsika mpaka pa sabata 24 (150
mg/dL kapena kuchepera)
Mzati uliwonse umaimira wodwala mmodzi.

Kafukufukuyu adawonanso kuti zotasiran inali yotetezeka m'magulu onse a mlingo, ndi odwala 2 okha omwe amasiya phunzirolo chifukwa cha zochitika zoyipa (1 m'gulu la placebo ndi 1 mu gulu la 100 mg zotasiran). Zochitika zoyipa zonse mu gulu la zotasira zidachira pakutha kwa kafukufukuyu, ndipo panali imfa imodzi pagulu la placebo. Choyipa chokhacho chodetsa nkhawa chinali kuwonjezeka kwa HBA1c mu gulu la 200 mg zotasiran poyerekeza ndi placebo (kusintha kwakutanthawuza kuchokera pa chiyambi mpaka sabata 24 [± SD], 0.38 ± 0.66% vs. -0.03 ± 0.88% mwa odwala omwe ali ndi matenda a shuga). Odwala opanda shuga anali 0.12 ± 0.19% vs. -0.03 ± 0.19%).
Makamaka, pafupifupi odwala onse omwe anali mu phunziroli (96%) anali kuthandizidwa ndi statins (37% omwe anali otsika kwambiri), 1% anali kuchiritsidwa ndi proprotein-converting enzyme subtilysin 9 inhibitor (PCSK9i), ndipo 21% anali kuchiritsidwa ndi ma fibrate. Choncho, Kuwonjezera zodasiran pamaziko a panopa ochiritsira regimen akadali akwaniritsa ndithu zamadzimadzi-kutsitsa zotsatira, amene amapereka dongosolo latsopano zochizira hyperlipidemia wosanganiza m`tsogolo.
Pa sabata la 24, mlingo waukulu wa 200 mg wa zotasiran mu phunziroli umachepetsa cholesterol yotsalira ndi 34.4 mg/dL poyerekeza ndi placebo. Malingana ndi zitsanzo zamakono, kuchepetsa uku kukuyembekezeka kuchepetsa zochitika zazikulu za mtima ndi 20 peresenti. zodasiran amatha kugwiritsidwa ntchito ngati monotherapy kwa zigawo zonse za lipoprotein kuti achepetse chiopsezo cha zochitika zamtima mwa odwala. Kufufuza kwina kotero ndikofunikira kuti mudziwe kuthekera kwa mankhwalawa pochepetsa chiopsezo cha atherosulinosis.
Phase 2b, kafukufuku wapawiri-wakhungu, wosasinthika, woyendetsedwa ndi placebo, wofalitsidwa nthawi imodzi ku NEJM, adagwiritsa ntchito mankhwala ena a siRNA, plozasiran, pochiza hyperlipidemia yosakanikirana [2]. plozasiran idapangidwa kuti ichepetse mawu a APOC3, jini encoding apolipoprotein C3 (APOC3), wowongolera TG metabolism, m'chiwindi, potero amachepetsa TG ndi ma cholesterol otsalira. Kuchepetsa kwa TG ndi ma cholesterol otsalira omwe adawonedwa mu kafukufukuyu anali ofanana ndi omwe amapezeka mu kafukufuku wa ARCHES-2. Chifukwa chake, akuti kwa odwala omwe ali ndi hyperlipidemia yosakanikirana, mankhwalawa amakhala ndi zotsatira zofanana pakuchepetsa kuchuluka kwa triglyceride-rich lipoprotein ndi cholesterol yotsalira.
Zotsatira za maphunziro awiri a siRNA zikuwonetsa kuti ili ndi gulu lodalirika kwambiri la mankhwala omwe adzabweretse njira zatsopano zothandizira mankhwala osakanikirana a hyperlipidemia ndikuwongolera zotsatira za mtima kwa odwala.