Hauv xyoo 2018, FDA tau pom zoo thawj cov tshuaj gene raws li cov tshuaj lipid nanoparticles (LNPs) - SiRNA Patiiran (ONPATTRO; Alnylam) - rau kev kho mob polyneuropathy tshwm sim los ntawm kev hloov pauv hloov pauv hloov pauv hloov pauv - kho amyloidosis. LNPs tau kawm ntau yam li cov cuab yeej xa khoom tau ntau xyoo, tab sis lawv tsis ntev los no tau txais kev saib xyuas tseem ceeb raws li lub platform uas muaj peev xwm xa mRNA.
LNPs feem ntau muaj plaub yam: cationic lossis ionized lipids, cholesterol, pab lipids, thiab polyethylene glycol lipids. Cov Cheebtsam no tso cai rau lub encapsulation ntawm ntau yam tshuaj, nrog rau cov molecules me me, peptides, thiab nucleic acids, tiv thaiv lawv los ntawm degradation los ntawm enzymes thiab pab txhawb lawv kev thauj mus los ntawm cell membranes. LNPs kuj txhawb kev rov ua haujlwm tam sim ntawd, thiab lawv txoj kev nyab xeeb tau raug lees paub los ntawm kev siv tshuaj tiv thaiv COVID-19 ntau. Ntxiv mus, cov tuam txhab tshuaj tau tsim muaj peev xwm tsim LNP txaus thaum muaj kev sib kis.
LNPs ua lub luag haujlwm tseem ceeb hauv kev nce qib tshuaj gene. Raws li lawv cov peev txheej ntawm kev ua, cov tshuaj noob tuaj yeem faib ua plaub hom: 1) gene ntxiv lossis hloov pauv, suav nrog kev siv LNPs xa cov kab mob kis uas muaj cov noob tshwj xeeb lossis mRNA encoding genes; 2) gene qhia tswj, uas suav nrog LNPs encapsulating siRNA lossis siRNA ua ke nrog hepatocyte phiaj ligand GalNac (N-acetylgalactosamine); 3) gene editing, uas ntiav cov kab mob vectors lossis LNPs xa cov khoom ntawm CRISPR-Cas9 gene editing system; thiab 4) cov tshuaj tiv thaiv DNA lossis RNA, xws li cov tshuaj tiv thaiv mRNA encapsulated hauv LNPs lossis polymer nanoparticles.
Txhawm rau nkag siab txog qhov tseem ceeb tam sim no thiab yav tom ntej ntawm LNPs hauv vivo txoj kev loj hlob ntawm cov tshuaj gene, ib qho kev tshuaj ntsuam xyuas tau ua rau pej xeem cov ntaub ntawv hais txog kev kho mob thiab pom zoo cov noob tshuaj kav thoob ntiaj teb. Qhov kev tshuaj ntsuam no suav nrog 538 cov cuab tam los ntawm 273 tuam txhab lag luam txij li lub Kaum Ob Hlis 2021, ntsuas qhov twg LNPs permeate tag nrho cov kav dej loj hlob thiab kev lag luam thoob ntiaj teb ntawm cov tshuaj noob raws li LNPs los ntawm 2021 txog 2036.
Ntawm plaub hom tshuaj gene, LNPs nthuav tawm qhov nruab nrab qhov nkag siab tshaj plaws (piv txwv li, feem pua ntawm cov cuab tam siv tus qauv no) hauv cov tshuaj nucleic acid hauv cov tshuaj tiv thaiv thiab kho cov noob, suav txog 7%. Qhov kev tshawb pom no qhia txog kev sib tw ntawm GalNAc coupling thaum xa cov nucleic acids loj dua hauv cov ntsiab lus no. Qhov permeability ntawm LNPs hauv cov noob ntxiv lossis hloov pauv yog qhov tsawg, raws li adeno-cov kab mob sib txuas (AAV)-raws li kev xa khoom muaj txiaj ntsig zoo dua. Tsis tas li ntawd, vim muaj kev sib tw los ntawm GalNAc coupling, gene qhia kev tswj pom qhov qis tshaj permeability. Feem ntau, cov noob tshuaj yeeb tshuaj tau pib los ntawm LNPs feem ntau tsom rau cov tshuaj tiv thaiv DNA thiab RNA, feem ntau hauv theem I kev sim tshuaj.
Kev lag luam loj tam sim no ntawm LNP-cov tshuaj gene txhawb tau kwv yees kwv yees li ntawm $ 51 nphom, feem ntau yog tsav los ntawm cov nyiaj tau los ntawm ob qhov tshuaj tiv thaiv COVID-19 mRNA, nrog Onpattro yog cov khoom lag luam ib sab ntawm lawv. Hauv lub sijhawm luv luv, kev lag luam loj yuav poob qis vim tias cov nyiaj tau los ntawm COVID-19 cov tshuaj tiv thaiv mRNA poob qis. Txawm li cas los xij, nws tau cia siab tias raws li cov tshuaj yeeb tshuaj noob loj hlob tuaj, cov tuam txhab yuav nqis peev ntxiv hauv LNP kev tsim kho tshiab, ua rau kev lag luam loj hlob. Los ntawm 2036, LNP gene tshuaj lag luam yog npaj yuav rov qab mus rau $ 48 billion.
Nyob rau kaum xyoo tom ntej, nws cia siab tias qhov muag ntawm mRNA tshuaj tiv thaiv thiab co- cov tshuaj tiv thaiv kab mob hauv cov ntsiab lus ntawm COVID-19 yuav ua rau muaj kev lag luam loj hauv LNP. Nrog kev pom zoo ntawm cov khoom lag luam los ntawm cov tuam txhab xws li Intellia Therapeutics thiab Beam Therapeutics, hauv vivo gene kho yog cia siab tias yuav tau txais qee qhov kev lag luam.
LNPs yuav txuas ntxiv los ua cov cuab yeej tseem ceeb rau cov tshuaj gene, tshwj xeeb yog cov tshuaj tiv thaiv mRNA. Kev siv dav dav ntawm LNPs tshaj li cov tshuaj tiv thaiv yuav nyob ntawm lub peev xwm ntawm cov tuam txhab los txiav cov lipids rau cov kab mob tshwj xeeb uas tsis yog lub siab. Lwm yam tseem ceeb uas tuaj yeem pab txhawb kev siv dav dav ntawm LNPs hauv kev tsim cov tshuaj gene suav nrog lub peev xwm los ntim cov noob loj, tshwj xeeb tshaj yog cov loj dua 5kB, uas yog qhov txwv ntim rau ntau AAV vectors.
Thaum lub sijhawm tam sim no ntawm LNPs tau dhau los kuaj xyuas thiab siv dav hauv cov tshuaj tiv thaiv mRNA, muaj cov kev txwv ntawm kev xa khoom, kev tiv thaiv kab mob, txee lub neej, thiab lwm yam nqi siv. Cov tiam tom ntej ntawm LNPs tuaj yeem siv cov khoom tshiab uas tsis yog- lipids (xws li fusion proteins thiab polymers) los daws cov kev txwv no. Hauv cov ntsiab lus, LNPs tuav lub peev xwm los hloov mus rau hauv lub sijhawm ntev - cov txheej txheem xa tshuaj, muab cov ntawv thov dav dav hauv thaj chaw tshuaj gene.
