Ngaphaya kwe-gene: Ukujolisa kwi-neuroinflammation kwisifo sikaHuntington

UDkt. Rajeev Kumar: Kumnandi ukuba lapha. Enkosi

UGqr. Sarah Camargos: Nangona i-HD ibangelwa kukuguquka kwezakhi zofuzo okuchazwe kakuhle, kukho ukuqonda okukhulayo ukuba ukudumba kwemithambo-luvo kunokubangela ukuqhubela phambili kwesifo. [00:01:00] I-ANX005 yi-antibody ye-monoclonal ejolise kwi-C1q, inxalenye yendlela ehambelanayo. Ungachaza ngokufutshane ukuba kutheni inkqubo ehambelanayo ibalulekile kwisifo sikaHuntington?

UDkt. Rajeev Kumar: Enkosi ngombuzo. Inkqubo yokongeza yinto uninzi lwethu esifunde ngayo kwisikolo sezonyango, kwaye siyicinga njengenxalenye yempendulo yomzimba kwisifo. Iphawula iintsholongwane kunye neeseli ezonakeleyo ukuze isuswe. Kodwa engqondweni, iveliswa apha ekhaya, kwaye inendima eyahlukileyo.

Ngexesha lophuhliso oluqhelekileyo iiproteni ezincedisayo, ingakumbi i-C1q ephezulu kwi-cascade, zibeka uphawu lwee-synapses ezingaphezulu ukuze i-microglia ikwazi ukuzicheba, kwaye oko kusempilweni kwaye yinxalenye yendlela ingqondo ehlaziya ngayo imijikelezo yobuchopho eqhelekileyo. Nangona kunjalo, kwi-HD, inkqubo yokucheba ibonakala iphinda isebenze ngokwe-pathologically, kwaye kukho umsebenzi omhle kakhulu wangaphambi kweklinikhi, ngakumbi iphepha likaWilton kunye noogxa bakhe abavela kwi-Nature Medicine ukusuka ngo-2023, elibonisa ukuba kwiimodeli zikaHuntington, ii-C1q zibeka uphawu lwe-cortico-striatal [00:02:00] synapses.

Emva koko i-microglia iyayisusa, uze emva koko uphulukane nonxibelelwano kwangethuba, kwaye oku kulandelelana neempawu zokuqala kwi-HD. Oku kuqiniswa bubungqina bomntu emva kokufa kuba sibona ukuba kwiingqondo zikaHuntington, sibona izinto ezidityanisiweyo zeklasikhi kwi-synapse. Kwaye eneneni, ukuba sijonga izigulane, iimpawu zokuqalisa ze-CSF complement ezifana ne-C4a ziphakanyisiwe, kwaye ukuphakama kuhambelana nokuqhubela phambili kwesifo kunye nesigaba sesifo.

Ngoko ke kukho ubungqina bokwenyani bokuba i-complement ayisiyonto nje ebangela ukudumba kwemithambo-luvo, kodwa isenokuba ngumqhubi wokuthenwa kwe-synaptic ngendlela engaqhelekanga kwaye iqhubele phambili kwizifo kwizigulane ezininzi.

UGqr. Sarah Camargos: Kwabo bagqirha abangengabo oogqirha abaziingcali zempilo, kuthetha ukuthini ukuthintelwa kwe-C1q ngokwemigaqo esebenzayo? Kutheni i-C1q ikhethwe njengeyona nto iphambili yokunyanga?

UDkt. Rajeev Kumar: Ewe. Ngokwendlela esebenzayo, i-complement cascade yi-chain reaction, [00:03:00] kwaye i-C1q iphezulu kakhulu. Yimolekyuli yokuqaphela. Nje ukuba ibotshelelwe kwithagethi, yonke into yenzeka ngezantsi komsinga ngentshukumo. Kwaye i-ANX005 yi-antibody ye-monoclonal ebophelela i-C1q, ukuyithintela ekuqaliseni i-cascade. Ngoku, sifuna ukuqala phezulu endaweni yento esezantsi komsinga ngezizathu ezibini.

Okokuqala, ukuba uvala i-C1q, uthintela i-synaptic tagging kwimvelaphi yayo. Endaweni yokuzama ukucoca yonke into emva kokuba i-tagging sele yenzekile kwaye sele ufumana umonakalo, ungakuthintela oko kufakwa kwe-tagging. Kwaye okwesibini, ikhetha kakhulu. Inkqubo ye-complement ineengalo ezininzi. Inendlela ye-complement yakudala, kodwa ikwanazo neendlela ze-alternative kunye ne-lectin, kodwa ezi zidibana ngakumbi kwi-C3.

Ngoko ke, xa uvala kwi-C3, uvala yonke imisebenzi exhaswa yi-complement-mediated, enokukubeka emngciphekweni wokosuleleka. Ngokuvala nje ingalo ye-complement yakudala, sishiya ezo ndawo zingasebenzi, kwaye silandela inkqubo ye-pathologic esicinga ukuba yi-pathologic pruning, kwaye sishiya indlela eyahlukileyo kunye nomsebenzi wokujonga emva ungasebenzi.

Ngethemba, oko kucacile [00:04:00]. Sifuna ukufumana i-synaptic tagging kunye nokuthintela i-neuroinflammatory loop ebanzi.

UGqr. Sarah Camargos: Ngoko ke unciphisa iziphumo ezingajoliswanga, akunjalo? Ukwenza oku.

UDkt. Rajeev Kumar: Ewe. Kwaye eneneni, kuphando lwethu nakwizifundo ezinkulu ezilandelayo-- izifundo ezininzi ngoku ezenziwe ngale ANX-003, ngoku enegama elihlekisayo elibizwa ngokuba yiTanruprubart. Ewe, elo ligama kuba ngoku liphambi kwe-FDA kunye ne-European Medical Association ukuze kuvunywe i-Guillain-Barré syndrome.

Ngenxa yesi sizathu, asibonanga usulelo olukhulu olunxulumene nokuncitshiswa komsebenzi wokongeza ngokujolisa kwi-C1q. Ngoko ke luphawu oluhle lokhuseleko.

UGqr. Sarah Camargos: Ngoko ke uphando lwakho lubika imveliso yeminyaka ye-CAG okanye amanqaku e-CAP. Ungachaza ukuba kutheni le ndlela yokulinganisa imele xa kuphandwa abathathi-nxaxheba kunye nabathathi-nxaxheba abanesifo sikaHuntington ngaphambi konyango?

UDkt. Rajeev Kumar: Ewe. Kaloku, imveliso yobudala ye-CAP okanye ye-CAG, yindlela yokubamba ukuvezwa kobomi bonke kwimiphumo enobuthi ye-mutant huntingtin njengenani elinye [00:05:00]. Ngoko ke ingcamango kukuba umthwalo wesifo uxhomekeke kwinqanaba lokwanda kokuphindaphinda kwe-CAG. Ukuphindaphinda okude kuyingozi ngakumbi kwaye kubangela isifo sangaphambili, kunye nokuba umntu uphile ixesha elingakanani echaphazeleka kuloo nto.

Ngoko ke i-CAP iziphindaphinda ezi zinto kunye. Ubude bexesha, ubunzima bokukhula buphindaphinda iminyaka, kwaye ukuba kungaphezulu komda, umntu uhlala eba neempawu. Ngoko ke kufana neminyaka emininzi yokutshaya. Kulula kakhulu. Kwaye eneneni, le yindlela elungileyo yokutyebisa abantu bethu abagulayo ababonakala kwangethuba okanye abanesifo esingaphambi kokuba sibonakale emva kwexesha, kwaye ngokwenene ngaphakathi kwefestile apho sicinga ukuba singalinganisa inkqubela phambili kuphononongo olufutshane kwaye sityebise izigulane ezinokuxhamla kunyango.

UGqr. Sarah Camargos: Nceda usikhokele kwiziphumo kunye novavanyo lophando lwakho.

UDkt. Rajeev Kumar: Ewe. Olu luphononongo lwesigaba 1b oluneziko ezininzi, oluvulelekileyo, nolwengalo enye. Ngoko ke wonke umntu wafumana iyeza elisebenzayo. Akukho placebo. Sibhalise izigulane ezingamashumi amabini anesibhozo. [00:06:00] Kwakhona, amashumi alithoba ekhulwini abonakalisiwe, amashumi alithoba ekhulwini abonakalisiwe ngaphambi kokuba abonakale. Wonke umntu uqinisekisiwe ngokwemfuza, kwaye wayenemisebenzi egciniweyo. Ngoko ke amanqaku okuzimela ayengamashumi asibhozo kwikhulu.

Ekuqaleni, izigulane zafumana idosi yesibini ende yeeyure ezingamashumi amabini ananye, eyenziwe kancinci ukuze kuncitshiswe amathuba okuba nemiphumo emibi, nto leyo esinokuyithetha namhlanje. Isigulane safumana idosi yesibini, eyayinikwa ngokukhawuleza kwiintsuku ezintlanu okanye ezintandathu, saza saqala kwiiveki ezimbini emva kokuba singene kwingalo yokungenelela, safumana idosi rhoqo kwiiveki ezimbini ukuya kwiveki yamashumi amabini anesibini.

Emva koko izigulane zazisoloko zilandelelwa ukuze zikhangele iziphumo ezibi kunye nokusebenza kakuhle, kunye neempawu ze-pharmacokinetic kunye ne-pharmacodynamic kwiiveki ezingama-24, ezingama-28, kunye nezingama-36. Ngoko ke babenesithuba sonyango seeveki ezilishumi elinesibini, esingama-24, kwaye phakathi kweeveki ezingama-24 nezingama-36, babe nesithuba sonyango seeveki ezilishumi elinesibini ngaphandle konyango.

Kwaye oko kwakunomdla ngokwenene. Kwaye iinjongo eziphambili, ewe, yayikukhuseleko kunye nokunyamezeleka, i-pharmacokinetics yeyeza kwi-serum kunye ne-CSF. Kwaye ke [00:07:00] sifuna ukukhangela iimpawu ze-pharmacodynamic zokubandakanyeka okujoliswe kuko, amanqanaba e-C1q, iimpawu ze-complement ezisezantsi ezifana ne-C4a, i-C3, i-C3a, kunye ne-NfL njengophawu lokulimala kwe-neurofilament.

Ngoko ke besinomsebenzi wokuhlola weklinikhi, nto leyo eyayinomdla kakhulu. Ngoko ke sivavanye iComposite Unified Huntington's Rating Scale, okanye i-cUHDRS, kunye nezinto zayo. Ibandakanya amanqaku eTotal Functional Capacity, amanqaku eSymbol Digit Modality, ukufundwa kwamagama eStroop, kwaye, ewe, amanqaku eTotal Motor.

Ngoko ke i-CUHDRS yinqaku elidityanisiweyo elidibanisa zonke ezi ndlela zokusebenza kwe-motor kunye ne-cognitive measures ngomlinganiselo omnye, kwaye ihambelana kakuhle nokwehla kokusebenza kunye nokuwohloka kobuchopho. Ngoko ke asizange senze iindlela zokulinganisa imifanekiso kolu phononongo, kodwa yinto esicinga ngayo ngokuqinisekileyo kuphononongo olulandelayo.

UGqr. Sarah Camargos: Kwaye zeziphi iziphumo ezibalulekileyo malunga nokhuseleko kunye nokubandakanyeka ekujoliswe kuko?

UDkt. Rajeev Kumar: Ewe. Ngoko ke masithethe ngokubandakanyeka ekujoliswe kuko [00:08:00] kuqala. Ngoko ke sifikelela ekugcwalisweni okupheleleyo kwe-C1q kwi-serum kunye ne-CSF ngokwenene kwasekuqaleni, iimilinganiselo zexesha zokuqala, ezikwiiveki ezintandathu. Kwaye oku kubandakanyeka ekujoliswe kuko kwaqhubeka kulo lonke ixesha lonyango kwaye kwancipha kancinci kancinci ngexesha lokungasebenzi konyango. Ngoko ke amanqanaba amayeza e-CSF ayephantsi, kuphela yi-.2 - .25 ekhulwini.

Kwaye yiloo nto kanye ebesinokuyilindela nge-antibody ye-monoclonal enikwa yi-IV. Kodwa bekukho okwaneleyo okwadlula umqobo wegazi-ubuchopho kangangokuba sibone ukubandakanyeka kwe-pharmacodynamic. Kwaye okunomdla kakhulu kukuba xa ufumana ukugcwala okupheleleyo kwe-C1q, kubangela umlinganiselo wokubandakanyeka okujoliswe kuko, okuthetha ukuba ukugcwala kwe-C1q kubangela ukuqhekeka kwe-C4a kwinqanaba lolwelo oluzimeleyo.

Oku akukho kumphezulu wezicubu, ngoko ke akonakalisa. Ngoko ke luphawu. Kwaye oku mhlawumbi kunokubangela ezinye zeempendulo ezinxulumene nokufakwa, endiza kuthetha ngazo kwimizuzwana embalwa. Emva koko sibone nokuncipha okukhulu kwiimpawu ezisezantsi ze-[00:09:00] zokuqalisa ukusebenza kwe-complement, ezifana ne-CSF, i-C3, kunye ne-C3a.

Kwaye olu phuculo kwezi mpawu zokongeza luqhubeke ixesha elide de kwangexesha lokungasebenzi konyango. Ngoku, malunga nokhuseleko, kukho izinto ezimbini eziphambili. Enye kukuba xa unika iyeza, isigulane ngasinye siba nempendulo enxulumene nokufakwa, kwaye oko kunomdla kakhulu kwaye kuyamangalisa. Kwaye yiyo loo nto ukufakelwa kokuqala kuthatha iiyure ezingamashumi amabini ananye ukunika iyeza...

Ewe. Ngoko ke ngobusuku obunye. Akulula ukuyenza kuba ukuba uyeka kancinci, ufumana impendulo engamandla kangako, kwaye usela amayeza kwangaphambili ngee-H1 kunye nee-H2 blockers, i-acetaminophen, kunye ne-corticosteroids. Kwaye oku kunciphisa ubunzima bempendulo, ikakhulu i-maculopapular rash.

Kwaye kuyarhawuzelela, kuyarhawuzelela, kwaye abanye abantu baya kuhlambuluka. Ezi ziyalawuleka. Azinzima kangako. Uninzi lwezigulane lufumana iimpendulo zebanga lokuqala okanye lesibini, kwaye ziyaphela. Kwaye okunomdla kukuba, oku kubonakala ngathi yi-pseudoallergy [00:10:00] enxulumene nokuvuselelwa kwe-complement okwenzekayo. Khumbula ukuba i-fluid phase reaction endikhankanyileyo, i-C4 ukuya kwi-C4a, enye i-anaphylactoid iyakhutshwa, hayi i-IgE mediated.

Kwaye eneneni, wakuba ufumene i-C1q saturation epheleleyo, eyenzeka kuloo dosi yokuqala, awukuboni nakuphi na ukuthathwa okulandelayo. Yiyo loo nto ezinye iidosi zinokunikwa ngokukhawuleza kuba sele une-C1q activation epheleleyo. Awufumani ezi mpendulo zinxulumene nokufakwa. Ngoko ke loo nto inomdla kakhulu, kwaye ihambelana nendlela esebenza ngayo.

Omnye umba obalulekileyo wokhuseleko ziziganeko ezimbi ezibangelwa lunyango, ezinye zazo ezinokuba yingozi kakhulu. Ngoko ke sibone into eyenzekayo kwizigulane ezine-ANA ephezulu. Ngoko ke omnye umguli wafumana isifo esifana ne-lupus, omnye umntu wafumana i-ruminatus, kwaye omnye umntu wayenesifo se-hemolytic anemia.

Zonke ezi zinto zisonjululwe ngokuyeka unyango kunye/okanye ukunyanga — Umzekelo, isigulana esasinesifo esifana ne-lupus saphathwa ngee-steroids kunye ne-hydroxychloroquine [00:11:00]. Ngoku, oku akumangalisi kuba kukho ubungqina obubonisa ukuba izigulana eziswele izinto ezincedisayo zakuqala ezifana ne-C1q zinokufumana i-lupus.

Kubangela oku. Kwiizifundo ezizayo, kufuneka sibe nokuhlolwa okunamandla ngakumbi kwe-ANA kwaye mhlawumbi singabakhupheli ngaphandle abo baguli bane-ANA kwaye besoloko bejongwa ukuba bangaphi na izifo ezibangelwa kukuzikhusela komzimba. Kuba olu yayiluphononongo olufutshane; abaguli bebesebenzisa amayeza iiveki ezingamashumi amabini anesine kuphela. Kusenokwenzeka ukuba kusenokubakho ezinye izifo ezibangelwa kukuzimela komzimba ezinokucinezelwa okungapheliyo, kwaye loo nto yinto ekufuneka ihlolwe kwizifundo zesigaba sesithathu eside.

UGqr. Sarah Camargos: Ewe, kodwa ndiyakhumbula, ulinganise i-ANA antibody kuzo zonke ekuqaleni zazingaphantsi kwe-160.

UDkt. Rajeev Kumar: Ewe. Abantu abathathu abane-HIV, nokuba bane-titer ephantsi kakhulu banokubangela okanye banokubangela oku. Ngoko ke kukwabo bathathu kuphela. Ngoko ke oko kubonakala ngathi luphawu olucacileyo. Ngoko ke oku kufuneka kuthathelwe ingqalelo, ndicinga [00:12:00], njengoko ukusetyenziswa kwale chiza kusenokusasazeka ngakumbi, umzekelo, kwi-Guillain-Barré syndrome okanye kwezinye izifo ze-neurodegenerative apho i-neuroinflammation inokuba yimbangela.

UGqr. Sarah Camargos: Ngaba bekukho naziphi na ii-biomarkers ezibonakala zithembisa ngakumbi kwizilingo ezizayo? 

UDkt. Rajeev Kumar: Ewe, bekunomdla kakhulu kuba sifumanise ukuba inqanaba elisisiseko lokusebenza kwe-complement okanye umsebenzi we-complement olinganiswe ngumlinganiselo we-C4a ukuya kwi-C4 ratio libonakala lixela impendulo yonyango. Ngoko ke i-C4a luphawu lwendlela esebenzayo ngayo i-classical complement pathway a-, kwaye inyukile kwizigulane ezine-manifest Huntington.

Njengoko benditshilo ngaphambili, kubonakala ngathi inxulunyaniswa nokuqhubela phambili kwesifo kunye nenqanaba lesifo. Ngoko ke ukuba sihlukanisa izigulane ezine-C4a ephezulu ukuya kwi-C4 size siyithelekise ne-low ratio, singabona umahluko. Izigulane ezine-high ratio, ezibonakala ngathi zinokuvuvukala okukhulu kwemithambo-luvo okanye ukusebenza okuhambelanayo, [00:13:00] zibonakala zibonisa inzuzo yeklinikhi.

Kwaye singayisebenzisa loo nto ukwahlulahlula uvavanyo olulandelayo kwaye mhlawumbi sityebise uluntu lwethu kwiimvavanyo ezilandelayo. Kwaye iimpawu zokubandakanyeka ekujoliswe kuzo zokunyuka kwe-C4a kunye nokuthintela i-C3a, C kunye ne-C3 zazixabisekile. Baqinisekisile ukuba iyeza lenza oko sikufunayo. Likwinjongo, liyabandakanyeka, kwaye linefuthe elihlala lihleli ekuthinteleni ukusebenza kwe-complement.

Into enye esidanileyo kukukhanya kwe-neurofilament. Kwahlala kuzinzile ngokwenene. Ndingathi, ngokwenene, bekungathethi nto apha. Luphononongo olufutshane, luneeveki ezingamashumi amabini anesine kuphela. Siyazi ukuba kwi-HD, kukho umahluko omkhulu phakathi kwezigulane kumanqanaba e-NfL.

Uluhlu olutshintshayo lwe-NfL luphantsi kakhulu kwi-HD, lwahlukile kwi-ALS, apho inokuphawulwa khona. Kwaye, bekukho unyango oluthile, umzekelo, kwi-ALS, oluye lwabonisa ukuba amanqanaba e-NfL anokuncitshiswa. Asizange sibone oko apha. Yinto ekufuneka siyicinge ngayo kuphando olukhulu nolude [00:14:00], kwaye kundenza ndicinge ukuba kufuneka sithembele ngakumbi kumanyathelo okulinganisa i-MRI yevolumu njengophawu lwesibini lweziphumo xa senza uvavanyo lwe-Phase III olungaboni kabini, olulawulwa yi-placebo.

UGqr. Sarah Camargos: Kulungile. Nangona olu luphando lokhuseleko, ngaba kukho naziphi na iimpawu zeklinikhi ozifumene zikhuthaza, ingakumbi kolu luhlu lwezigulane ezine-ratio ye-C4/C4a? 

UDkt. Rajeev Kumar: Ewe, ngokuqinisekileyo. Lo msebenzi wokuncedisana osisiseko ophezulu, njengoko utshilo, kwabo bantu babenozinzo okanye uphuculo kwixesha leeveki ezingamashumi amabini anesine zonyango, kwaye oku kuqhubeke ixesha elide ngaphandle konyango, ngelixa iqela lemisebenzi ephantsi liye lehla kakhulu ngaxeshanye neqela lembali yendalo elithathwe, umzekelo, kuphando lwe-TRACK-HD.

Kwaye, ukuba ujonge abo baguli banomsebenzi ophezulu wokuncedisa, malunga ne-75% yabo bantu baphucukile, ngelixa kuphela i-36% yenqanaba eliphantsi lomsebenzi wokuncedisa eliphucukileyo. Kwaye oku bekufana kakhulu kuzo zonke iindlela zokusebenza, iindlela zokuqonda [00:15:00], kunye nemisebenzi yentshukumo.

Ngoko ke kulungile oko. Kwaye kubekho uphuculo kwiveki yesithandathu, nto leyo ebonisa ukuba oku akukokuncitshiswa kokuwohloka kwemithambo-luvo, kodwa bekukho ukusindiswa kwee-neurons kunye nee-synapses ezingasebenzi kakuhle kodwa ezingekafi ngokususa i-C1q kwezo synapses. Ezo synapses zigulayo, siza kuzibiza ngokuba, ngoku ziye zasebenza ngakumbi, kwaye bekukho ukuphucuka kweempawu.

Sifuna ukubona ukuba kwenzeka ntoni ngonyango lwexesha elide ngokubhekiselele ekucinezeleni ukonakala kwemithambo-luvo yesibini. Kodwa ndicinga ukuba kufuneka sicace kwaye sinyaniseke. Olu yayiluphononongo oluncinci, ilebheli evulekileyo, ingalo enye, akukho placebo, kwaye uhlalutyo lokuphendula endilubonisileyo phakathi komsebenzi ophezulu nophantsi wokongeza yayiluhlalutyo lwasemva kwexesha.

Nangona, abaphandi, izigulane, abaxhasi bonke babengaboni kakuhle kuba olo hlalutyo aluzange lwenziwe de kwagqitywa uphando. Ngoko ke kulungile kwaye kundinika ukuzithemba ngako. Kwaye iziphumo kuzo zonke ezo ndlela zonyango zahlukeneyo zazifana, kwaye oko kundinika ukuzithemba okungakumbi.

Kodwa, [00:16:00] luphononongo oluncinci. Izinto eziqwalaselwayo zezibalo kukuba, oku bekubalulekile ngokwezibalo. Senze uthelekiso oluninzi lwezibalo, kwaye bekungekho lungiso kwiithelekiso ezininzi. Ngoko ke kufuneka sinyaniseke kwaye siqaphele imida yesifundo sethu, kodwa kakhulu luphononongo olukhulu oluvelisa iingcamango.

Kusinika ukuzithemba kokuqhubeka nophando olukhulu. Oku kuncede ekungqineni ingcamango yebhayoloji, nangona kunjalo.

UGqr. Sarah Camargos: Kwaye ucinga ukuba ukuthintela okungezelelweyo kunokusebenza nakwizigaba zokugqibela zesifo, kungekuphela nje kweHuntington's yokuqala?

UDkt. Rajeev Kumar: Ewe, ndicinga ukuba kunokwenzeka ngokuqinisekileyo. Kodwa, indlela esebenza ngayo le ndlela ibonisa ukuba kufuneka sihambe kwangethuba. Enyanisweni, nakwinqanaba langaphambi kweempawu kuba siyazi ukuba kukho ukubekwa kwe-complement kwangoko. Sinee-synapses ezininzi kunye nee-neurons ezininzi ezinokugcinwa. Kwaye ukuphuculwa kweempawu kwangethuba kubonisa ukuba singasindisa ii-neurons eziphilileyo nezigulayo, kodwa ezingakafi [00:17:00]. Ngoko ke sifuna ukuzixela kwangaphambili ngaphambi kokulahleka kwee-synapses kunye nee-neurons. Ngoku, oko akuthethi ukuba asinakuba nentsebenziswano eluncedo kwisifo senqanaba lokugqibela, kodwa konke oku kuthetha ukuba mhlawumbi sifanele sihambe kwangethuba kunokuba sihambe kamva. Ndicinga ukuba sifuna ukusebenzisa i-ISS ngoku ukubhalisa izigulane kwizigaba ezahlukeneyo, njengoko olu nyango luphuhliswa. Kodwa ndicinga ukuba uvavanyo lokuqala olukhulu olulawulwa yi-placebo kufuneka lwenziwe kwizigulane ezineempawu zangethuba okanye isifo sangaphambi kwexesha. Uyazi, i-ISS kwinqanaba lesithathu, inqanaba lesibini, inqanaba lokuqala lokugqibela. 

UGqr. Sarah Camargos: Ingaba inkqubo yokongeza ngokuyintloko luphawu lokuwohloka kwemithambo-luvo okuqhubekayo, okanye ukholelwa ukuba iqhuba ngokukhutheleyo ukuqhubela phambili kwesifo? 

UDkt. Rajeev Kumar: Ndicinga ukuba kukho ubungqina obuninzi bokuba ngokwenene ngumqhubi kunokuba ngumntu obukeleyo, siza kubiza njalo. Ngoko ke ukuba sijonga ubungqina bangaphambi kweklinikhi, kwiimodeli zaseHuntington, ukuba sivimba i-C1q, igcina ii-synapses kwaye isindise iingxaki zokuqonda. Kwaye sinokubona ukuba ukusebenza okuphelelisayo kunye nokujoliswa kwe-synaptic [00:18:00] kwenzeka kwangoko, kwaye ukulahleka kwe-synapse kubonakala kwenzeka kwangoko, kungekuphela nje njengophawu olusemva kwexesha.

Ngaphezu koko, sibonile ukuba izigulane ezazine-activation esebenzayo ngakumbi yeyokuba yi-complement activation, yizo ezasabelayo. Oko kuthetha ukuba ngokwenene yinxalenye ye-causation kunokuba ibe yi-biomarker nje. Oku, uphando lwethu, kunika imeko ethembekileyo eyokuba i-complement iqhubela phambili, kodwa kufuneka sikuqinisekise oku kuphando olukhulu nolude ngokuqinisekileyo. 

UGqr. Sarah Camargos: Ngokuqinisekileyo. Yintoni eya kuba linyathelo elilandelayo lokwazi ukuba le ndlela iyayitshintsha ngokwenene na inkqubela yesifo? Uthetha nge-MRI neurofilament, ixesha elide...

UDkt. Rajeev Kumar: Ndicinga ukuba kufuneka senze zonke ezo zinto. Sifanele senze ubungakanani obulawulwa yi-placebo obungaboniyo kabini. Kufuneka bube bubude obaneleyo. Sifanele senze izinto ezininzi. Sifanele sijonge amanqanaba e-cUHGRS kunye nokulinganisa. Iyancipha malunga nenqaku elinye ngonyaka. Isiphumo esibalulekileyo ngokwezonyango mhlawumbi sincipha ngama-20, amashumi amathathu ekhulwini.[00:19:00] 

Ngoko ke ndingathi sidinga uphando lweenyanga ezilishumi elinesibhozo, ezingamashumi amabini anesine. Sifanele sicacise kwangaphambili kwaye sityebise izigulane ezinomsebenzi ophezulu wokongeza kwaye sizihlukanise ngaloo ndlela. Mhlawumbi amandla ngeli qela lincinci le-biomarker ephezulu. Kwaye, kufuneka singabandakanyi nje kuphela la manyathelo okongeza, i-NfL, kodwa ne-MRI yevolumu, ndicinga ukuba iyafuneka.

Ngoko ke olu luphononongo. Kuza kuba ngumsebenzi omninzi ukukwenza. Kuza kufuneka izixhobo ezininzi. Ndinethemba lokuba siza kukwenza. kwaye ndicinga ukuba i-Eneaxon, umxhasi, inomdla kakhulu ekwenzeni oko. Kakade ke, izixhobo ezifunekayo zininzi. I-Eneaxon yinkampani encinci. Ndinethemba lokuba isicelo sabo se-Guillain-Barré syndrome siza kuvunywa. Inkampani iza kuqala ukuba nemveliso evunyiweyo, eli yeza. Siza kuba nemali yokuyityala imali ukuze sifumane isalathiso eHuntington. Masithembe oko. 

UGqr. Sarah Camargos: Ngaba ukuthintela okongezelelweyo ekugqibeleni kungadityaniswa nonyango lokunciphisa i-huntingtin? 

UDkt. Rajeev Kumar: Ewe, ndicinga ukuba ngokwendlela yokusebenza, kuyavakala kakhulu. Kunengqondo ngokwenene. Ukwehla kweHuntingtin [00:20:00] kulandela umqhubi wemfuza onyukayo, akunjalo? Iproteni yokuzingela eguqulweyo ngokwayo, ukwanda kwe-somatic, imbangela eyintloko. Ukuthintela okuphelekayo kusebenza ngezantsi, kukhusela ii-synapses kwimiphumo eyonakalisayo yomqhubi wemfuza. Ekusebenzeni kwe-microglial, kufuneka sicinge ngayo. ukusebenza kwe-microglial kuqhutywa yi-mutant huntingtin. Oko kunokukhupha i-C1q, ephawula i-synapse, eqala le cascade yokuqina okuziqinisayo. Ukuba singayiwisa i-mutant huntingtin, kwaye ngezantsi sinokuchaphazela ukusebenza kwe-microglial kwaye sinciphise ukuthenwa kwe-synaptic okubangelwa yi-C1q.

Singahlasela amaqhuqhuva amabini ahlukeneyo ngaxeshanye size sibe nefuthe elikhulu. Kodwa, ukudibanisa iindlela zonyango ezimbini kunzima kakhulu. Ndicinga ukuba kufuneka sibonise ukusebenza kakuhle kwiindlela zonyango zokunciphisa i-hunttin. Sikwinqanaba elifanayo nedatha yakutshanje ye-uniQure. Masithembe ukuba siya kuvunywa apho. Kwaye, ndicinga ukuba kufuneka sibonise ngokwahlukeneyo ukusebenza kakuhle konyango lwe-anti-C1q, size emva koko sizidibanise. 

UGqr. Sarah Camargos: [00:21:00] Kuhle kakhulu. Ngaba ubona ukuba le ndlela yokunyanga iza kusetyenziswa kwezinye izifo ezibangela ukonakala kwemithambo-luvo, njengoko ukhankanyile, njengoko kwakunjalo kuGuillain-Barré? 

UDkt. Rajeev Kumar: Ewe, ndicinga ukuba kukho ithemba elikhulu elinokuba njalo kuba kukho ubungqina bokuba i-synaptic pruning eqhutywa yinkqubo eqhelekileyo inokubakho. Umzekelo, kwisifo sika-Alzheimer, kukho ubungqina obubonisa ukuba i-C1q ibeka ii-synapses kwanangaphambi kokuba kwenzeke ii-plaque.

Ukuba uvala loo ndlela, ungathintela ukulahleka kwe-synapse kwaye mhlawumbi izinto zemfuza ezifana ne-APOE, i-TREM2 ziyayiqinisa loo nto. I-Parkinson inezinye izinto ezidityaniswe emva kokufa kunye ne-biomarker. Kwi-ALS, kukho ukubekwa kwe-complement kwi-motor neurons, kodwa kukho obunye ubungqina kwi-ALS obusenokungabi luphawu olukhulu kangako, ingakumbi kwasekuqaleni, mhlawumbi kamva. Ukuvuselelwa kwe-complement kubalulekile.

Ngoko ke ndicinga ukuba, kuyakholelwa ukuba kukho izigulana ezithile okanye amaqela amancinci ezigulana kwizifo nganye ye-neurodegenerative ezincedisa ukusebenza kwayo ngumqhubi obalulekileyo. [00:22:00] Olu vavanyo olusisiseko lomsebenzi wokongeza lunokuba yindlela yokufumana ezo zigulana kwaye emva koko zenze uvavanyo kuloo maqela amancinci ngaphakathi kwezo zifo zahlukeneyo ze-neurodegenerative.

Ngoko ke ndinethemba. 

UGqr. Sarah Camargos: Nam. Kakade ke, olu luphando olusekwinqanaba lokuqala, ngoko ke imibuzo ekhawulezileyo yayikukhuseleko, ukubandakanyeka ekujoliswe kuko, ii-biomarkers, kunye nokuba ingaba iimvavanyo zolawulo ezinkulu zinokubonisa inzuzo ebalulekileyo yeklinikhi, akunjalo? 

UDkt. Rajeev Kumar: Ngokuqinisekile. 

UGqr. Sarah Camargos: Ngoko ke, Gqirha Rajeev, enkosi. Siyalixabisa ixesha lakho kunye nokuzimisela kwakho ukuthatha inxaxheba kwi-podcast, kwaye silangazelela ukubona indlela olu luhlu lophando oluya kutshintsha ngayo kwaye lunegalelo ngayo kunyango lwesifo sikaHuntington kwixesha elizayo. 

UDkt. Rajeev Kumar: Ndiyabulela ngeli thuba. 

UGqr. Sarah Camargos: Enkosi. [00:23:00]