[NEW โ€œ๐Ÿ’Š” ์‹ ์•ฝ ๊ฐœ๋ฐœ ํฌ๋Ÿผ] Adenoviral Gene Therapies -๋…ผ๋ฌธ ์ฒœ์‚ฌ ์•ˆ์ง„ํ˜•-

 

์•ˆ๋…•ํ•˜์„ธ์š”. ํ˜์‹ ์‹ ์•ฝ ๊ฐœ๋ฐœ์— ๊ด€๋ จ๋œ ๋…ผ๋ฌธ์„ ์†Œ๊ฐœํ•  K-BioX ๊ธฐ์ž๋‹จ ์•ˆ์ง„ํ˜•์ž…๋‹ˆ๋‹ค.

์ด ๋…ผ๋ฌธ์€ ์•„๋ฐ๋…ธ๋ฐ”์ด๋Ÿฌ์Šค ๋ฒกํ„ฐ๋ฅผ ์ด์šฉํ•œ ์œ ์ „์ž ์น˜๋ฃŒ์— ์ด์šฉ๋˜๋Š” ํ•ฉ์„ฑ์ƒ๋ฌผํ•™ ๊ธฐ๋ฒ•๋“ค์„ ์†Œ๊ฐœํ•œ ๋ฆฌ๋ทฐ ๋…ผ๋ฌธ์ž…๋‹ˆ๋‹ค.

https://pubs.acs.org/doi/10.1021/acsnano.1c04556

 

Synthetic Biology Approaches for Engineering

Next-Generation Adenoviral Gene Therapies

 

 

ํ•ฉ์„ฑ์ƒ๋ฌผํ•™์˜ ์ฒซ ๋ฒˆ์งธ ๊ณผ์ œ๋Š” ์•„๋ฐ๋…ธ๋ฐ”์ด๋Ÿฌ์Šค ๋ฒกํ„ฐ์˜ ๋ฉด์—ญ์›์„ฑ์„ ์ค„์ด๋Š” ๊ฒƒ์ž…๋‹ˆ๋‹ค. ๋ฉด์—ญ์›์„ฑ์€ ์œ ์ „์ž ์ „๋‹ฌ์„ ๋ง‰๊ณ  ๋…์„ฑ์„ ์œ ๋ฐœํ•  ์ˆ˜ ์žˆ์œผ๋ฉฐ,

์ด๋ฅผ ๊ทน๋ณตํ•˜๊ธฐ ์œ„ํ•ด ์—ฌ๋Ÿฌ ๊ธฐ๋ฒ•์ด ์ œ์‹œ๋˜์–ด ์™”์Šต๋‹ˆ๋‹ค.

ํ•˜๋‚˜์˜ ์„ฑ๊ณต์ ์ธ ์ „๋žต์€ ์•„๋ฐ๋…ธ๋ฐ”์ด๋Ÿฌ์Šค์˜ ์บก์‹œ๋“œ ๋‹จ๋ฐฑ์งˆ์„ ๋‹ค๋ฅธ ๊ฒƒ์œผ๋กœ ๋Œ€์ฒดํ•˜์—ฌ ์ค‘ํ™”ํ•ญ์ฒด์˜ ๊ณต๊ฒฉ์„ ํ”ผํ•˜๋Š” ๊ฒƒ์ž…๋‹ˆ๋‹ค.

 

๋งŒ์•ฝ ์•„๋ฌด๋Ÿฐ ์ฒ˜๋ฆฌ๋ฅผ ํ•˜์ง€ ์•Š์€ ์•„๋ฐ๋…ธ๋ฐ”์ด๋Ÿฌ์Šค ๋ฒกํ„ฐ๋ฅผ ์ธ์ฒด์— ์ฃผ์ž…ํ•œ๋‹ค๋ฉด ์ด๋Š” ์ €ํ˜ˆ์†ŒํŒ์ฆ๊ณผ ์‚ฌ์ดํ† ์นด์ธ ํญํ’ ๋“ฑ ์—ฌ๋Ÿฌ ๋ถ€์ž‘์šฉ์„ ๋‚˜ํƒ€๋‚ผ ์ˆ˜ ์žˆ๊ณ ,

ํ•ญ์› ์ œ์‹œ ์„ธํฌ๊ฐ€ MHC-II๋ฅผ ํ†ตํ•ด CD4+ cell์„ ํ™œ์„ฑํ™”ํ•˜๋ฉฐ, CD4+์— ์˜ํ•ด B์„ธํฌ๊ฐ€ ํ™œ์„ฑํ™”๋˜๊ณ  ์•„๋ฐ๋…ธ๋ฐ”์ด๋Ÿฌ์Šค์— ๋Œ€ํ•ญํ•˜๋Š” ์ค‘ํ™”ํ•ญ์ฒด์™€ ๊ธฐ์–ต์„ธํฌ

๋ฅผ ๋งŒ๋“ค์–ด์„œ ๋” ์ด์ƒ ์•„๋ฐ๋…ธ๋ฐ”์ด๋Ÿฌ์Šค๋ฅผ ์ด์šฉํ•œ ์œ ์ „์ž ์น˜๋ฃŒ๋Š” ๋ถˆ๊ฐ€๋Šฅํ•ด์ง‘๋‹ˆ๋‹ค.

 

 

์•„๋ฐ๋…ธ๋ฐ”์ด๋Ÿฌ์Šค(์ดํ•˜ Ad)์˜ ์บก์‹œ๋“œ๋Š” 7์ข…๋ฅ˜์˜ ๋‹จ๋ฐฑ์งˆ๋กœ ์ด๋ฃจ์–ด์ง€๋Š”๋ฐ, hexon, penton, fiber protein์ด ๋Œ€ํ‘œ์ ์ด๋ฉฐ, minorํ•œ ๋‹จ๋ฐฑ์งˆ๋กœ pIIIa, pVI, pVIII, pIX ์˜ 4์ข…๋ฅ˜๊ฐ€ ์กด์žฌํ•ฉ๋‹ˆ๋‹ค. Ad์˜ ์บก์‹œ๋“œ ๋‹จ๋ฐฑ์งˆ์„ minorํ•œ ์ข…๋ฅ˜๋กœ ๋ฐ”๊พธ๋ฉด ๋ฉด์—ญ์›์„ฑ์„ ์ค„์ผ ์ˆ˜ ์žˆ์Šต๋‹ˆ๋‹ค.

์ œ์•ฝํšŒ์‚ฌ ์•„์ŠคํŠธ๋ผ์ œ๋„ค์นด๋Š” ์ธ๊ฐ„ Ad26์„ ์‚ฌ์šฉํ•˜์—ฌ ์ฝ”๋กœ๋‚˜19 ๋ฐฑ์‹ ์„ ๊ฐœ๋ฐœํ•˜์˜€๋Š”๋ฐ,
Ad ๊ธฐ๋ฐ˜ ๋ฐฑ์‹ ์€ mRNA ๋ฐฑ์‹ ๊ณผ๋Š” ๋‹ฌ๋ฆฌ 4๋„์—์„œ๋„ ์•ˆ์ •ํ•˜๋‹ค๋Š” ์žฅ์ ์„ ๊ฐ€์ง€๊ณ  ์žˆ์Šต๋‹ˆ๋‹ค.

์ด ์™ธ์—๋„ albumin-binding-protein(ABD)๋ฅผ hexon์˜ ๊ฐ€์šด๋ฐ์— ์‚ฝ์ž…ํ•˜๊ณ  Ad๋ฅผ ์•Œ๋ถ€๋ฏผ์œผ๋กœ ๋‘˜๋Ÿฌ์‹ธ๋Š” ๋ฐฉ๋ฒ•๋„ ์žˆ๊ณ , CRISPER-Cas9์„ ์‚ฌ์šฉํ•˜์—ฌ ์ ํ˜ˆ๊ตฌ ๋ง‰์œผ๋กœ Ad๋ฅผ ๋‘˜๋Ÿฌ์‹ธ์„œ tumor cell์— ์˜ํ•ด uptake๋˜๊ธฐ ์‰ฝ๊ฒŒ ํ•˜๋Š” ์ „๋žต๋„ ์žˆ์Šต๋‹ˆ๋‹ค.

 

 

์ˆ˜์ •์ด ๋˜์ง€ ์•Š์€ Ad๋Š” coxsackievirus and Ad receptor (CAR) ์ด ์กด์žฌํ•˜์ง€ ์•Š๋Š” ์„ธํฌ์— ํ˜•์งˆ์„ ๋„์ž…ํ•  ์ˆ˜ ์—†์–ด์„œ ๊ฐ์—ผ์‹œํ‚ฌ ์ˆ˜ ์žˆ๋Š” ์„ธํฌ์˜ ์ข…๋ฅ˜๊ฐ€ ์ œํ•œ์ ์ž…๋‹ˆ๋‹ค. ๋”ฐ๋ผ์„œ ์ด ๋…ผ๋ฌธ์—์„œ๋Š” Fiber pseudotyping ํ˜น์€ xenotyping ์„ ํ•˜๊ฑฐ๋‚˜, tissue-specific tropism์„ ์ด‰์ง„์‹œํ‚ค๋Š” Bispecific scFv(single-chain variavle fragments) ๋ฅผ ๋ถ€์ฐฉํ•˜๊ธฐ๋„ ํ•˜๊ณ  , knob๋“ค์ด noncovalent associations์— ์˜ํ•ด ๋ฐฉํ•ด๋ฐ›์ง€ ์•Š๋„๋ก ํ•˜๊ธฐ ์œ„ํ•ด camelif nanobodies๋ฅผ ๋ถ€์ฐฉํ•˜๋Š” ๋ฐฉ๋ฒ•๋„ ๋‚˜์™€ ์žˆ์Šต๋‹ˆ๋‹ค. ์ด๋•Œ knob์˜ ์นด๋ณต์‹ค๊ธฐ๊ฐ€ Ad ์บก์‹œ๋“œ๋ฅผ ํ–ฅํ•˜๋Š” ๋Œ€์‹  ๋ฐ”๊นฅ์„ ํ–ฅํ•˜๋„๋ก ํ•˜๊ธฐ ์œ„ํ•ด T4 fibritin trimerization protein์„ ์ถ”๊ฐ€๋กœ ๋ถ€์ฐฉํ•˜์˜€์Šต๋‹ˆ๋‹ค.

 

์•„๋ฐ๋…ธ๋ฐ”์ด๋Ÿฌ์Šค์˜ E1A ์œ ์ „์ž๋Š” ์ข…์–‘์„ ์–ต์ œํ•˜๋Š” ๊ธฐ๋Šฅ์„ ๊ฐ€์ง€๊ณ  ์žˆ๋Š”๋ฐ, ์ด๋ฅผ ์ด์šฉํ•œ ์œ ์ „์  ๋…ผ๋ฆฌ ํšŒ๋กœ๋„ ์ด ๋…ผ๋ฌธ์— ์†Œ๊ฐœ๋˜์–ด ์žˆ์Šต๋‹ˆ๋‹ค.ย  ์ด ํšŒ๋กœ๋Š” miR-21์ด ๋งŽ์ด ๋ฐœํ˜„๋˜๊ณ  miR-199a-3p๊ฐ€ ์ ๊ฒŒ ๋ฐœํ˜„๋˜๋Š” ์ข…์–‘ ์„ธํฌ์˜ ํŠน์ง•์„ ์ด์šฉํ•˜๋ฉฐ, ์ข…์–‘ ์„ธํฌ์—์„œ๋งŒย  E1A ์œ ์ „์ž๋ฅผ ์ „์‚ฌ์‹œ์ผœ ์ข…์–‘์„ ์–ต์ œํ•  ์ˆ˜ ์žˆ์Šต๋‹ˆ๋‹ค.

 

CIBN domain๊ณผ fusion๋œ dCas9๋Š” gRNA๋ฅผ ํ†ตํ•ด ํƒ€๊ฒŸ ์œ ์ „์ž์™€ ๊ฒฐํ•ฉํ•˜๊ณ , VP64 ํ™œ์„ฑํ™” ๋„๋ฉ”์ธ์— ์ฒญ์ƒ‰๊ด‘์„ ๋น„์ถฐ ์ค„ ๋•Œ๋งŒ endogenous gene์„ ์ „์‚ฌ์‹œํ‚ค๋Š” ๊ฒƒ๋„ ๊ฐ€๋Šฅํ•ฉ๋‹ˆ๋‹ค.

 

์œ„ ๋…ผ๋ฌธ์€ โ€˜K-BioX Biomedical ์ €๋„ ๋””์Šค์ปค์…˜ ํฌ๋Ÿผโ€™ ์นดํ†ก ์˜คํ”ˆ์ฑ„ํŒ…๋ฐฉ์—์„œ ๋…ผ์˜๋˜๊ณ ย  ์žˆ์Šต๋‹ˆ๋‹ค.ย 

๋” ๋งŽ์€ ๋…ผ๋ฌธ ๋””์Šค์ปค์…˜์„ ์›ํ•˜์‹ ๋‹ค๋ฉด https://open.kakao.com/o/gBQ0CWTd

์œ„ ๋งํฌ๋ฅผ ํด๋ฆญํ•˜๊ณ  ํ˜„์žฌ 1000๋ช… ์ด์ƒ์ด ํ•จ๊ป˜ํ•˜๊ณ  ์žˆ๋Š” ์˜คํ”ˆ์ฑ„ํŒ…๋ฐฉ์— ์ฐธ์—ฌํ•˜์„ธ์š”!

 

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