iindaba

I-hyperlipidemia edibeneyo ibonakaliswe ngamanqanaba e-plasma aphakamileyo e-low-density lipoproteins (LDL) kunye ne-triglyceride-rich lipoproteins, ekhokelela ekunyuseni komngcipheko we-atherosclerotic cardiovascular disease kwesi sigulana sabantu.
I-ANGPTL3 inqanda i-lipoprotein lipase kunye ne-endosepiase, kunye nokunyuka kwesibindi se-triglyceride-rich lipoproteins. Abathwali be-ANGPTL3 engasebenziyo eyahlukileyo babenamanqanaba aphantsi e-triglycerides, i-cholesterol ye-LDL, i-cholesterol ephezulu ye-lipoprotein (i-HDL), kunye ne-non-HDL ye-cholesterol, kunye nomngcipheko ophantsi we-atherosclerotic cardiovascular disease. I-zodasiran lichiza elincinci eliphazamisayo le-RNA (RNAi) elijolise kwi-ANGPTL3 ibonakaliso esibindini.

I-hyperlipidemia edibeneyo ibhekisela kumanqanaba aphezulu e-low-density lipoprotein cholesterol (LDL-C) kunye ne-triglyceride-rich lipoproteins. I-triglyceride-rich lipoproteins (kuquka i-chylomicrons, i-lipoproteins ephantsi kakhulu (i-VLDL), kunye ne-cholesterol eseleyo) idlala indima ebalulekileyo ekuphuhliseni isifo se-atherosclerosis. Akukho unyango olusebenzayo lwe-hyperlipidemia edibeneyo.
I-Bates iyaziwa ukunciphisa amanqanaba e-triglyceride (TG), kodwa ukunciphisa kulinganiselwe. Kwangaxeshanye, TG ukwehlisa amachiza kuquka Bates (ezifana eicosapentaenoic acetic acid, njl) akukho mpembelelo ibalulekileyo kumngcipheko wesifo atherosclerotic okubangelwa amanqanaba aphezulu entsalela cholesterol. Ukongeza, izifundo zangaphambili kwizigulane esele zithatha i-statins zibonise ukuba indibaniselwano ye-TG-ehlisa amayeza ayinciphisi umngcipheko weziganeko ze-cardiovascular. Ezi zinto zenza ukuba unyango lwe-hyperlipidemia edibeneyo lunzima kakhulu.
I-ANGPTL3 (i-angiopoietin-like protein 3) ilawula i-lipids kunye ne-lipoprotein metabolism, kubandakanywa i-TG kunye ne-non-high-density lipoprotein cholesterol (i-HDL-C), ngokuthintela ngokuphindaphindiweyo i-lipoprotein lipase, i-endosepiase, kunye ne-low-density lipoprotein (LDL) i-hepatic receptor-dependence. Kuye kwafunyaniswa ukuba i-ANGPTL3 eyahlukayo yokungasebenzi ikhokelela ekunyuseni kwe-lipoprotein lipase kunye nomsebenzi we-endosepiase, nto leyo ekhokelela kumanqanaba aphantsi e-plasma lipoprotein kwiimeko ezininzi, Ezi ziquka i-triglyceride-rich lipoproteins (okt Chylomicrons, i-cholesterol eseleyo, i-VLDL, i-medium density lipoprotein), i-lipoprotein ephakathi, i-LDLLpoprotein ephezulu i-lipoprotein (a), kunye neenxalenye zabo ze-cholesterol. Abantu be-Heterozygous abaphethe olu tshintsho banomngcipheko ophantsi we-40% wesifo se-atherosclerotic, kwaye akukho phenotype yeklinikhi embi efunyenweyo. I-ANGPTL3 ibonakaliswe esibindini, kwaye unyango lokuthulisa ufuzo lujolise kwi-mRNA yayo, eyaziwa ngokuba yi-RNA encinci ephazamisayo (siRNA) iziyobisi, lunyango oluthembisayo lwe-hypolipidemia.
NgoSeptemba 12, 2024, iNew England Journal of Medicine (NEJM) yapapasha uphando lwe-ARCHES 2 oluqinisekisa ukuba i-siRNA ichiza i-zodasiran yanciphisa kakhulu amanqanaba e-TG kwizigulane ezine-hyperlipidemia edibeneyo [1]. I-ARCHES-2 yi-double-blind blind, i-placebo-controlled, i-dose-range yokuhlola ulingo lwesigaba se-2b. I-totali yezigulane ze-204 ezine-hyperlipidemia edibeneyo (amanqanaba e-TG yokuzila i-150-499 mg / dL, amanqanaba e-LDL-C ³70 mg / dL okanye amanqanaba angekho e-HDL-C ³100 mg / dL) abhalisiwe. Zahlulwe zaba zodasiran 50 mg iqela, 100 mg iqela, 200 mg iqela kunye neqela lolawulo placebo. Izigulane zafumana ii-injection ezingaphantsi kwe-subcutaneous kwiveki ye-1 kunye ne-12, kwaye zifumana i-prophylaxis yokulandela kude kube yiveki ye-36.
Isiphelo esiphambili sasiyipesenti yokuguqulwa kwepesenti kwi-TG ukusuka kwisiseko ukuya kwiveki ye-24. Uphononongo lufumene ukuba ngeveki ye-24, amanqanaba e-TG kwiqela le-zodasiran ancitshiswe kakhulu ngendlela exhomekeke kwi-dose (amanqanaba e-TG kwiqela ngalinye le-dose ancitshiswe nge-51, i-57 kunye ne-63 yeepesenti, ngokulandelanayo, xa kuthelekiswa nalawo akwiqela le-placebo) (P <0.0). I-ANGPTL3 iphinde yehla ngeepesenti ze-54, iipesenti ze-70 kunye neepesenti ze-74, ngokulandelanayo. Amanqanaba e-non-hdl-c anciphile ngamanqaku epesenti angama-29, ipesenti ze-29, kunye neepesenti ze-36, amanqanaba e-apolipoprotein B ancipha ngeepesenti ze-19, iipesenti ze-15, kunye neepesenti ze-22, kunye namanqanaba e-LDL-C ancipha ngeepesenti ze-16, iipesenti ze-14, kunye ne-20 yepesenti, kunye ne-20 yeepesenti, ipesenti ze-20 ngokulandelanayo. Kwiveki ye-24, zodasiran
Kwi-88% yezigulane kwiqela le-200 mg, ukuzila ukutya kwe-TG kuye kwawa kumgangatho oqhelekileyo.

Iintolo ezibomvu ngeentsuku ze-1 kunye ne-12 zibonisa i-zodasiran okanye ulawulo lwe-placebo.

Amanqanaba e-TG yokuzila ukutya anciphile ukuya kwisiqhelo ngeveki ye-24 (150
mg/dL okanye ngaphantsi)
Ntsika nganye imela isigulane esinye.

Uphononongo luphinde lwaqaphela ukuba i-zotasiran yayikhuselekile kuwo onke amaqela e-dose, kunye nezigulane ze-2 kuphela eziyekisa ukufunda ngenxa yeziganeko ezimbi (i-1 kwiqela le-placebo kunye ne-1 kwi-100 mg yeqela le-zotasiran). Zonke iziganeko ezimandundu kwiqela le-zotasiran zachacha ekupheleni kophononongo, kwaye kwabakho ukufa omnye kwiqela le-placebo. Isiganeko esibi kuphela sokukhathazeka kukunyuka kwe-HBA1c kwi-200 mg yeqela le-zotasiran xa kuthelekiswa ne-placebo (utshintsho oluthetha ukusuka kwisiseko ukuya kwiveki ye-24 [± SD], 0.38 ± 0.66% vs. -0.03 ± 0.88% kwizigulane ezine-preexisting diabetes). Izigulane ezingenaso isifo seswekile zaziyi-0.12±0.19% vs. -0.03±0.19%).
Ngokukodwa, phantse zonke izigulane kwisifundo (96%) ziphathwa nge-statins (i-37% yazo yayiyi-statins ephezulu), i-1% yayiphathwa nge-proprotein-converting enzyme subtilysin 9 inhibitor (PCSK9i), kwaye i-21% yayiphathwa nge-fibrate. Ke ngoko, ukongezwa kwe-zodasiran ngokwesiseko sonyango lwangoku lonyango oluqhelekileyo luseneziphumo ezininzi zokunciphisa i-lipid, ebonelela ngerejimeni entsha yonyango lwe-hyperlipidemia edibeneyo kwixesha elizayo.
Ngeveki ye-24, i-dose ephezulu ye-200 mg ye-zotasiran kwisifundo yanciphisa amanqanaba e-cholesterol aseleyo nge-34.4 mg / dL xa kuthelekiswa ne-placebo. Ngokusekelwe kwiimodeli zangoku, oku kuncitshiswa kulindeleke ukuba kunciphise iziganeko eziphambili zenhliziyo nge-20 ekhulwini. I-zodasiran inamandla okusetyenziswa njenge-monotherapy kuwo onke amacandelo e-lipoprotein ukunciphisa umngcipheko weziganeko zentliziyo kwizigulane. Uphando olongezelelweyo ke ngoko luyimfuneko ukufumanisa amandla ale chiza ekunciphiseni umngcipheko wesifo se-atherosclerotic.
Isigaba se-2b, i-double-blind blind, i-randomized, isifundo se-MUIR esilawulwa yi-placebo, epapashwe ngaxeshanye kwi-NEJM, yasebenzisa enye i-siRNA ichiza, i-plozasiran, ukunyanga i-hyperlipidemia edibeneyo [2]. I-plozasiran yenzelwe ukunciphisa ukubonakaliswa kwe-APOC3, i-gene encoding apolipoprotein C3 (APOC3), umlawuli we-TG metabolism, kwisibindi, ngaloo ndlela ukunciphisa i-TG kunye ne-cholesterol eseleyo. Ukuncipha kwi-TG kunye namanqanaba e-cholesterol aseleyo aqatshelwe kuphononongo ayefana nalawo afunyenwe kwi-ARCHES-2 yophononongo. Ngoko ke, kucingelwa ukuba kwizigulane ezine-hyperlipidemia edibeneyo, amachiza amabini aneempembelelo ezifanayo ekunciphiseni inqanaba le-triglyceride-rich lipoprotein kunye ne-cholesterol eseleyo.
Iziphumo zezifundo ezimbini ze-siRNA zibonisa ukuba le yiklasi ethembisayo kakhulu yamachiza eya kuzisa iinketho ezintsha zonyango lwe-hyperlipidemia edibeneyo kunye nokuphucula iziphumo zentliziyo kwizigulane.