►mRNA-kev kho raws li- yav tom ntej thiab kev nyuaj
Tsis muaj qhov tsis ntseeg tias qhov kev vam meej tas mus li ntawm mRNA thev naus laus zis yav tom ntej yuav ua rau nws tau siv dav hauv ntau thaj chaw, tshwj xeeb tshaj yog kev kho mob qog noj ntshav thiab tshuaj tiv thaiv kab mob sib kis. Piv txwv li, mRNA-raws li pluripotent stem cell induction, mRNA nuclease- pab tsim, thiab cov txheej txheem xa protein tau pib siv hauv kev tsim tshuaj. Hauv ob peb xyoos tom ntej no, cov kev kho mob uas tshwm sim los ntawm mRNA thev naus laus zis yuav ua tiav txoj kev loj hlob sai, xws li (1) kev ua xua rau kev kho mob, uas siv cov plasmid DNA thiab mRNA edited los tswj kev tsis haum tshuaj los ntawm T pab thiab Treg hlwb; (2) Kev tiv thaiv kab mob qog noj ntshav: txhim kho lossis hloov lub cev tsis muaj zog tiv thaiv kab mob, ua kom pom zoo dua thiab tua cov qog nqaij hlav cancer, lossis siv microRNA thiab mRNA los tswj kev tiv thaiv kab mob -cov noob caj noob ces, yog li ua kom lub cev tsis muaj zog tiv thaiv kab mob qog noj ntshav; (3) genome engineering therapy lossis gene therapy, suav nrog kev hloov cov noob ib txwm lossis kho cov nucleic acid genome sequences tau zoo thiab raug los hloov cov noob uas ploj lawm lossis tsis zoo, yog li kho cov kab mob caj ces lossis txhawb cov txheej txheem tsis muaj txiaj ntsig lossis txoj hauv kev, muab lawv lub peev xwm los kho cov kab mob caj ces; (4) Kev kho cov protein hloov: cov tshuaj mRNA raug txiav txim siab los muab lwm txoj hauv kev zoo rau kev kho noob, tshwj xeeb tshaj yog cov hloov pauv protein, vim lawv tsis txhob muaj kev pheej hmoo ntawm kev sib koom ua ke ntawm genome thiab muab cov lus qhia muaj zog.
Nws yog ib qho tsim nyog hais tias qhov kev hloov kho noob caj ces tsis ntev los no -CRISPR/Cas genome kho yog siv. CRISPR/Cas gene editing yog dav siv nyob rau hauv kev tshawb fawb ntawm txoj kev loj hlob thiab evolution. Txawm li cas los xij, nyob rau xyoo tas los no, cov kws tshawb fawb tau siv Cas cov proteins los ntawm prokaryotes los kho cov kab mob sib kis raws li cov cuab yeej cuab tam thiab kev tiv thaiv kab mob ntawm CRISPR hauv nws cov lus qhia prokaryotic. Cov proteins no muaj teeb meem, tab sis thaum lawv nkag mus rau tib neeg lub cev, lawv yuav ua rau lub cev tiv thaiv kab mob thiab tsim cov tshuaj tiv thaiv tshwj xeeb [4]. Tsis tas li ntawd, CRISPR/Cas thev naus laus zis kuj tau koom ua ke rau hauv cov qog cell molecular biology tshawb fawb, siv los kho cov genome sai thiab raug, tsim cov noob hloov mus kawm qog-cov noob caj noob ces, lossis tshem tawm cov noob rau kev tshawb fawb kho qog.
Tsis tas li ntawd, mRNA-raws li kev kho mob ua ke tau maj mam dhau los ua ib txoj hauv kev kho cov qog nqaij hlav malignant. Raws li tau hais ua ntej, cov tshuaj tiv thaiv ib txwm tsis zoo li qhov zoo tshaj plaws los tiv thaiv kev hloov pauv sai sai ntawm kev kis tus kab mob. Kev siv cov tshuaj tiv thaiv mRNA los tsim cov tshuaj tiv thaiv lossis kev kho mob yog txoj hauv kev zoo tshaj plaws kom muaj cov kab mob tshiab COVID-19 sib kis. Cov tshuaj tiv thaiv tau tsim los siv mRNA thev naus laus zis qhia txog lawv qhov zoo hauv kev tsim khoom nrog rau lawv txoj kev nyab xeeb thiab kev tiv thaiv lossis kho cov teebmeem hauv kev sim tshuaj. Hauv kaum xyoo tom ntej no, tus kheej- nthuav tawm lossis rov ua cov tshuaj tiv thaiv RNA thiab cov tshuaj tiv thaiv mRNA uas tsis yog rov ua dua yuav raug siv ntau dua.
Ntxiv nrog rau kev tshawb nrhiav cov tshuaj tiv thaiv mRNA rau cov kab mob sib kis, kev siv mRNA hauv kev kho mob qog noj ntshav kuj tseem yuav ua tiav txoj kev loj hlob tseem ceeb hauv kaum xyoo tom ntej. Nws yog ib qho tsim nyog hais tias kev txhim kho hauv vitro transcription mRNA kev kho mob tseem nyob rau theem pib. Yuav ua li cas kom tau txais ib qho loj ntawm cov hluavtaws mRNA uas tuaj yeem siv rau kev kho mob tseem yog qhov nyuaj. Cov teeb meem cuam tshuam nrog cov tshuaj tiv thaiv extracellular kuj yuav tsum tau daws. Txoj kev xa khoom zoo yuav tsum tau txhim kho tsis tu ncua. Cov tshuaj tiv thaiv yog tiv thaiv los ntawm ntau yam enzyme cuam tshuam los yog zam cov tshuaj degradation thaum hla lub cell barrier.
Txhawm rau kov yeej cov teeb meem no, suav nrog kev siv hauv vitro mRNA thev naus laus zis los rov- kho thiab hloov kho autologous T cells lossis dendritic hlwb los ntawm cov neeg mob, thaum txuas ntxiv txhim kho txoj hauv kev xa cov tshuaj tiv thaiv mRNA. Tam sim no, biopharmaceuticals thiab thev naus laus zis kev lag luam tab tom nqis peev peev los sim daws cov teeb meem hauv qab no:
Kev ruaj ntseg- cov teeb meem ntsig txog
Raws li tau hais ua ntej, mRNA molecules muaj qhov nruab nrab ntawm 1,000-6,000 lub hauv paus khub thiab qhov hnyav molecular (4-5 × 105 Dalton), vim tias mRNA yog synthesized siv enzymes. Piv nrog cov sRNAs me me, mRNAs kuj loj, ua rau lawv tsis ruaj khov thiab nyuaj rau kev tsim khoom. Cov txheej txheem siv los hloov oligonucleotides xws li xauv nucleic acid (LNA) thiab xauv nucleic acid (UNA) chemistry yog txwv rau cov khoom siv mRNA. Yog li ntawd, muaj kev xav tau ceev ceev rau cov cuab yeej siv tshuaj uas tuaj yeem txhaj cov tshuaj molecules rau hauv tib neeg lub cev thaum tswj kev ruaj ntseg ntawm cov tshuaj molecules thiab txhawb nqa cell uptake.
Txoj kev xa khoom zoo
Txawm hais tias muaj ntau txoj kev xa khoom tam sim no muaj
1.Lipid-raws li kev xa khoom: siv lipids lossis lawv cov derivatives/zoo sib xws los tsim cov khoom (LNP), uas tuaj yeem siv rau hauv vivo xa ntawm mRNA kho thiab tshuaj tiv thaiv. LNPs yog cov khoom nanoscale uas tsim los ntawm cov khoom siv hluavtaws lossis cov khoom siv physiological lipid. Qhov zoo dua yog tias RNA encapsulated hauv LNP tsis tshua muaj peev xwm degraded enzymatically, thiab encapsulation efficiency yog qhov siab thiab yooj yim los tsim. Tsis tas li ntawd, cov hlwb xa cov mRNA molecules zoo rau hauv cytoplasmic sol los ntawm phagocytizing LNP;
2.Peptide-raws li kev xa khoom: ntau yam peptides, tshwj xeeb tshaj yog cov uas muaj cationic amino acids (xws li lysine thiab arginine), tuaj yeem ua tus xa khoom xa tuaj thiab tsim cov complexes zoo dua ntawm cov cab kuj thiab mRNA los ntawm kev sib cuam tshuam electrostatic. Kev tsim cov complexes txo qhov muaj peev xwm ntawm enzymatic degradation;
3. Polymer-raws li kev xa khoom: Cov khoom siv polymer (xws li polyamines, dendrimers thiab copolymer) tuaj yeem siv los xa cov neeg sib tw mRNA zoo. Cov cab kuj tseem muaj qhov zoo ntawm kev tiv thaiv cov enzyme degradation thiab txhawb kev xa khoom hauv lub cev. Qhov teeb meem yog tias lawv feem ntau tsis ruaj khov. Yog li ntawd, cov qauv ntawm cov ntaub ntawv polymer yuav tsum tau hloov kho kom ruaj khov thiab kev nyab xeeb ntawm cov neeg sib tw tshuaj. Piv txwv li, ntxiv lipid chains, hyperbranched pawg thiab biodegradable subunits, uas yuav ua rau kom cov txheej txheem ntws;
4. Tus kab mob-zoo li relicon particles (VRP): Encapsulate me me activating RNA (saRNA) thiab tus kab mob relicon particles, thiab xa cov encoding mus rau cytoplasm. Thaum nyob rau hauv lub cell, saRNA yuav tus kheej -replicate thiab nthuav qhia cov antigen teev. Qhov zoo ntawm VRP xa khoom yog kev ua haujlwm siab. Txawm li cas los xij, nws ntsib ob qhov teeb meem loj. Ua ntej, yuav tsum muaj cov txheej txheem tsim khoom tshwj xeeb rau - nplai ntau lawm ntawm VRPs. Thib ob, tib neeg lub cev tuaj yeem tsim cov tshuaj tiv thaiv kab mob tiv thaiv kab mob vector;
5. Cationic nanoemulsion: Cationic lipids muaj li ntawm nanoemulsions kuj siv rau RNA xa. Cov tebchaw no siv lawv cov khoom siv hydrophobic thiab hydrophilic kom stabilize cov lipid yam ntxwv ntawm cov tshuaj los yog tshuaj tiv thaiv, vim hais tias cov tshuaj sib cuam tshuam ntawm cov molecules tuaj yeem tiv thaiv mRNA los ntawm enzyme degradation, yog li ua tiav kev xa khoom ruaj khov ntawm cov molecules. Thiab nanoemulsions tuaj yeem tsim los ntawm qee cov tswv yim yooj yim, xws li kev sib zog sib zog, ultrasound lossis microfluidics;
6. Nyob rau hauv lub neej yav tom ntej, cov txheej txheem sab hauv ntawm cov tiam tom ntej ntawm LNP yuav tsum tau ua kom muaj zog, thiab nws lub cev ruaj khov yuav tsum tau txhim kho ntxiv, xws li cov khoom lipid nanoparticles, nanostructured lipid carriers thiab cationic lipid nucleic acid complexes. Los ntawm kev siv tshuaj, kev muaj peev xwm tswj tau qhov chaw thiab lub sijhawm ntawm kev xa tshuaj thiab tso tawm hauv lub cev tuaj yeem txhim kho ntxiv, muab kev kho mob zoo dua lossis / thiab kev nyab xeeb dua rau ntau yam kab mob.
Teeb meem kev nyab xeeb
Qhov teeb meem ntawm cov tshuaj tiv thaiv mRNA tuaj yeem ua rau cov lus teb interferon zoo li tsis meej, uas tej zaum yuav yog lub hauv paus ua rau muaj kev phiv cuam tshuam txog kev mob thiab autoimmunity? Lwm qhov teeb meem kev nyab xeeb tej zaum yuav yog los ntawm cov tshuaj tiv thaiv kab mob.
Tam sim no, European thiab Asmeskas kev tswj hwm tshuaj tsis tau tshaj tawm cov cai tshwj xeeb ntawm cov tshuaj mRNA
Tej zaum nws yuav yog raws li kev kho mRNA uas yog los ntawm ntau hom tshuaj tiv thaiv kab mob los yog tshuaj tiv thaiv, yog li mRNA tshuaj tshawb fawb thiab kev txhim kho tau muab cais ua cov tshuaj kho mob siab heev (ATMP) lossis cov tshuaj kho noob tshuaj (GTMP) los ntawm European Medicines Agency (EMA). Txawm li cas los xij, raws li cov khoom lag luam mRNA tseem tuaj yeem tshwm sim hauv kev kho mob, nws yog qhov tsim nyog los tsim cov kev cai tshwj xeeb ntxiv kom lawv cov kev tshawb fawb thiab kev txhim kho smoother, yam tsawg kawg hauv kev nyab xeeb thiab kev ua tau zoo ntawm kev sim tshuaj cuam tshuam txog hom tshuaj tshawb fawb thiab kev loj hlob xav tau cov kev cai meej, Los yog raws li qhov tshwj xeeb ntawm mRNA, hloov kho cov kev qhia tshwj xeeb uas tsim los ntawm DNA tshuaj tiv thaiv kab mob tshiab thiab kev loj hlob ntawm cov tshuaj tiv thaiv kab mob thiab kev tshawb fawb. mRNA?
Nws tuaj yeem lees paub tias txoj kev kho RNA tau ua kom muaj kev vam meej hauv ntau qhov chaw, thiab ntau txoj kev kho mob yog nyob ntawm ntau theem ntawm kev kho mob (ua ntej) kev loj hlob. Nrog rau kev nce qib ntawm molecular biology thiab ntau ntawm tib neeg thiab cov khoom siv tau nqis peev, kev kho mRNA tau dhau los ua qhov tseeb. Nrog rau kev nqis peev ntau hauv daim teb no, kev kho mRNA yuav raug thawb mus rau qhov siab tshiab thiab dhau los ua qhov kev cia siab tshiab rau kev kho mob qog noj ntshav, kab mob thiab kab mob caj ces.
