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Mixed hyperlipidemia inoratidzwa nepamusoro-soro yeplasma mazinga e-low-density lipoproteins (LDL) uye triglyceride-rich lipoproteins, zvichiita kuti kuwedzera kwengozi yeatherosclerotic cardiovascular disease muhuwandu hwevarwere.
ANGPTL3 inhibits lipoprotein lipase uye endosepiase, pamwe nekutora chiropa che triglyceride-rich lipoproteins. Vatakuri ve ANGPTL3 inactivated variant vaiva nemazinga akaderera e triglycerides, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, uye isiri HDL cholesterol, pamwe chete nengozi yakaderera yeatherosclerotic cardiovascular disease. zodasiran idiki rinokanganisa RNA (RNAi) mushonga unonangana ANGPTL3 kutaura muchiropa.

Mixed hyperlipidemia inoreva mazinga akakwirira e low-density lipoprotein cholesterol (LDL-C) uye triglyceride-rich lipoprotein. Triglyceride-rich lipoprotein (kusanganisira chylomicrons, yakaderera kwazvo density lipoproteins (VLDL), uye yakasara cholesterol) inoita basa rakakosha mukukura kwechirwere che atherosclerotic. Iko hakuna kurapa kunoshanda kune yakasanganiswa hyperlipidemia.
Bates vanozivikanwa kuderedza triglyceride (TG) mazinga, asi kuderedza kunogumira. Panguva imwecheteyo, TG inoderedza zvinodhaka zvinosanganisira Bates (zvakadai se eicosapentaenoic acetic acid, nezvimwewo) hazvina simba guru panjodzi yechirwere che atherosclerotic chinokonzerwa nekukwirira kweholesterol yakasara. Uye zvakare, zvidzidzo zvekare kune varwere vatotora statins zvakaratidza kuti kusanganiswa kweTG-kudzikisa zvinodhaka hakuderedze njodzi yezviitiko zvemoyo. Zvinhu izvi zvinoita kuti kurapwa kwemusanganiswa hyperlipidemia kuve kwakaoma.
ANGPTL3 (angiopoietin-like protein 3) inodzora lipids uye lipoprotein metabolism, kusanganisira TG uye isiri-yakakwirira-density lipoprotein cholesterol (HDL-C), ne reversibly inhibiting lipoprotein lipase, endosepiase, uye yakaderera-density lipoprotein (LDL) receptor uptapopotic. Zvakaonekwa kuti ANGPTL3 inactivation yakasiyana-siyana inotungamirira kukuwedzera lipoprotein lipase uye endosepiase basa, izvo zvinotungamirira kune yakaderera plasma lipoprotein mazinga muzviitiko zvakawanda, Izvi zvinosanganisira triglyceride-rich lipoproteins (kureva Chylomicrons, residual cholesterol, VLDL, medium density lipoprotein), LDLLHD lipoprotein [IHD Lpoprotein], high density lipoprotein. lipoprotein (a), uye cholesterol yavo zvikamu. Heterozygous vanhu vanotakura musiyano uyu vane inenge 40% yakaderedzwa njodzi yeatherosclerotic chirwere, uye hapana yakaipa kiriniki phenotype yakawanikwa. ANGPTL3 inoratidzwa muchiropa, uye marapirwo ekunyararidza majini akanangana nemRNA yayo, inozivikanwa sediki inopindira RNA (siRNA) mishonga, inovimbisa kurapwa kwakasanganiswa kwehyperlipidemia.
Musi waGunyana 12, 2024, iyo New England Journal of Medicine (NEJM) yakaburitsa ARCHES 2 chidzidzo ichisimbisa kuti siRNA mushonga zodasiran yakaderedza zvakanyanya TG mazinga muvarwere vane musanganiswa hyperlipidemia [1]. ARCHES-2 iri kaviri-mapofu, placebo-inodzorwa, dose-range yekuongorora chikamu 2b kuyedza. Huwandu hwevarwere ve204 vane hyperlipidemia yakasanganiswa (kutsanya TG mazinga 150-499 mg / dL, LDL-C mazinga ³70 mg / dL kana asiri-HDL-C mazinga ³100 mg / dL) akanyoreswa. Vakakamurwa kuva zodasiran 50 mg boka, 100 mg boka, 200 mg boka uye placebo control boka. Varwere vakagamuchira majekiseni e-subcutaneous pavhiki 1 uye 12, uye vakagamuchira kutevera-prophylaxis kusvika vhiki 36.
Mhedziso yekutanga yaiva yehuwandu hwekuchinja muTG kubva kune imwe yekutanga kusvika kuvhiki 24. Chidzidzo chacho chakawana kuti nevhiki 24, mazinga eTG muboka rezodasiran akanyanya kuderedzwa nenzira inotarisana nedosi (TG mazinga muboka rega rega rega akaderedzwa ne51, 57 uye 63 muzana, zvichienderana, zvichienzaniswa nevaya vari muboka re placebo) (P <0.0). ANGPTL3 zvakare yakadzikira ne54 muzana mapoinzi, 70 muzana mapoinzi uye 74 muzana mapoinzi, zvichiteerana. Non-hdl-c mazinga akadzikira ne29 percentage points, 29 percentage points, and 36 percentage points, apolipoprotein B mazinga akadzikira ne19 percent, 15 percentage points, and 22 percent percent, uye LDL-C mazinga akadzikira ne16 percent, 14 percent point, and 20 percentage per svondo, 20 percent and the respected percentage. Muvhiki 24, zodasiran
Mune 88% yevarwere muboka re 200 mg, kutsanya TG yakanga yawira kune yakajairika.

Miseve mitsvuku pamazuva 1 uye 12 inoratidza zodasiran kana placebo kutonga.

Kutsanya TG mazinga akadzikira kusvika akajairika pavhiki 24 (150
mg/dL kana zvishoma)
Mbiru imwe neimwe inomiririra murwere mumwe chete.

Chidzidzo chacho chakacherechedzawo kuti zotasiran yakanga yakachengeteka mumapoka ose emushonga, nevarwere ve2 chete vakarega kudzidza nekuda kwezviitiko zvakashata (1 muboka re placebo uye 1 muboka re 100 mg zotasiran). Zvese zviitiko zvakakomba zvakakomba muboka rezotasiran zvakapora pakupera kwechidzidzo, uye pakave nerufu rumwe muboka replacebo. Chiitiko chakashata chekunetseka chaiva kuwedzera kweHBA1c muboka re 200 mg zotasiran kana ichienzaniswa ne placebo (kureva kushanduka kubva pakutanga kusvika kuvhiki 24 [± SD], 0.38 ± 0.66% vs. -0.03 ± 0.88% kune varwere vane preexisting diabetes). Varwere vasina chirwere cheshuga vaiva 0.12±0.19% vs. -0.03±0.19%).
Kunyanya, vanenge varwere vose vari muchidzidzo (96%) vakanga vachirapwa nemishonga (37% iyo yaiva yakakwirira-dose statins), 1% vakanga vachirapwa neproprotein-inoshandura enzyme subtilysin 9 inhibitor (PCSK9i), uye 21% vakanga vachibatwa nefibrate. Nokudaro, kuwedzerwa kwezodasiran pamusana pechirongwa chemazuva ano chekurapa chichiri kubudirira zvakanyanya kuderedza lipid-kuderedza migumisiro, iyo inopa chirongwa chitsva chekurapa kwe hyperlipidemia yakasanganiswa mune ramangwana.
Pavhiki 24, chiyero chepamusoro che 200 mg ye zotasiran muchidzidzo chakaderedza kusara kwecholesterol mazinga ne 34.4 mg / dL kana ichienzaniswa ne placebo. Kubva pamienzaniso yemazuva ano, kuderedzwa uku kunotarisirwa kuderedza zviitiko zvakakomba zvemwoyo ne20 muzana. zodasiran ine mukana wekushandiswa se monotherapy kune ese lipoprotein zvikamu kuderedza njodzi yemoyo zviitiko muvarwere. Kumwe kutsvagisa saka kwakakosha kuona kugona kwemushonga uyu mukuderedza njodzi yechirwere che atherosclerotic.
The Phase 2b, kaviri-mapofu, randomized, placebo-inodzorwa MUIR kudzidza, yakabudiswa panguva imwe chete muNEJM, yakashandisa imwe siRNA mushonga, plozasiran, kurapa yakasanganiswa hyperlipidemia [2]. plozasiran yakagadzirirwa kuderedza kutaura kweAPOC3, iyo gene encoding apolipoprotein C3 (APOC3), mutongi weTG metabolism, muchiropa, nokudaro kuderedza TG uye yakasara cholesterol mazinga. Kudzikiswa kweTG uye kusara kwecholesterol mazinga akaonekwa muchidzidzo aive akafanana neaya anowanikwa mune ARCHES-2 kudzidza. Nokudaro, zvinofungidzirwa kuti kune varwere vane hyperlipidemia yakasanganiswa, mishonga miviri iyi ine migumisiro yakafanana mukuderedza chiyero che triglyceride-rich lipoprotein uye yakasara cholesterol.
Mhedzisiro yezvidzidzo zviviri zveSiRNA zvinoratidza kuti iyi ikirasi inovimbisa yemishonga iyo ichaunza sarudzo nyowani dzekurapa hyperlipidemia yakasanganiswa uye kuvandudza mhedzisiro yemoyo muvarwere.