KR20230043123A - Glut1 발현을 위한 아데노-연관 바이러스 벡터 및 이의 사용 - Google Patents
Glut1 발현을 위한 아데노-연관 바이러스 벡터 및 이의 사용 Download PDFInfo
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Abstract
GLUT1 단백질 또는 이의 기능적 변이체를 발현하는 벡터로서 재조합 아데노-연관 바이러스(rAAV) 비리온을 사용하는 GLUT1 결핍 증후군 및 관련 장애에 대한 유전자 요법이 본원에 제공된다. rAAV 비리온은 내피-특이적 프로모터, 예를 들어, FLT-1 또는 Tie-1 프로모터를 사용할 수 있다. 캡시드는 AAV6, AA8, AAV9, AAVrh.74, 또는 AAVrh.10 캡시드 또는 이의 기능적 변이체일 수 있다. 다른 프로모터 또는 캡시드가 사용될 수 있다. 또한, 예컨대 rAAV 비리온의 뇌내 및/또는 정맥내에 의한, 치료 방법, 및 기타 조성물 및 방법이 제공된다.
Description
관련 출원에 대한 상호 참조
본 출원은 2021년 8월 5일 출원된, 미국 특허 출원 제63/061,726호에 대한 우선권을 주장하며, 그 내용은 그 전체가 참조로서 본원에 통합된다.
서열 목록에 관한 진술
본 출원과 연관된 서열 목록은 종이 사본 대신에 텍스트 형식으로 제공되며, 본 출원에 참고로 원용된다. 서열 목록을 담은 텍스트 파일의 명칭은 ROPA_018_01WO_ST25.txt이다. 텍스트 파일은 약 190 KB이며, 2021년 8월 3일 생성되고, EFS-Web을 통해 전자적으로 제출되고 있다.
포도당 수송자 1(glucose transporter 1, GLUT1)을 암호화하는 SLC2A1 유전자에서의 돌연변이는 GLUT1 결핍 증후군(GLUT1 Deficiency Syndrome, GLUT1 DS)이라고 불리는 신경발달 장애와 연관된다. GLUT1 DS는 상 염색체 우성 장애로, 종종 반수체부족성(haploinsufficiency)을 생성하고 증후성 이형접합성(symptomatic heterozygosity)을 부여하는 드노보 돌연변이를 갖는 산발성 질환으로 존재한다.
GLUT1은 인슐린-독립적 포도당 수송자다. 드 비보 질환(De Vivo disease)으로도 알려진, 고전적인 GLUT1 DS를 앓고 있는 환자는 뇌 포도당 수치가 낮고 조기 발병 발작(12개월 중앙값), 발달 지연, 후천성 소두증(머리 성장 감속), 복합 운동 장애(경직, 운동실조, 근긴장이상); 발작성 안구-두 운동; 및 저혈당증, 또는 뇌척수액(CSF) 내 저 포도당 농도를 특징으로 하는 표현형을 나타낸다. 질환의 임상 경과는 조기 치료의 중요성을 보여준다. Alter 등의 J. Child Neurol. 30(2):160-169 (2015). GLUT1은 혈관신생 및 혈액-뇌 장벽(BBB)의 유지를 포함하는, 내피 세포의 기능에 관여하였다. 그러나, 반수체부족성 마우스 모델에서의 연구는 BBB의 물리적 무결성을 유지하는 데 있어서 GLUT1의 역할에 관한 상충되는 증거를 제공하였다. GLUT1의 내피 세포 계통 특이적 녹아웃은 이동에 영향을 미치지 않으면서 내피 에너지 가용성을 감소시키고 증식을 감소시켜, 발달 혈관신생을 지연시킴에도 불구하고(Veys 등의 Circ. Res. 2020; 127:466-482), 특이적으로 내피 세포에서 GLUT1 발현을 회복시키는 효과는 시험되지 않았다.
이 질환에 대한 치료 전략은 Tang 등의 Ann. Clin. Trans. Neurol. 2019; 6(9):1923-1932에서 검토하고 있다. 현재의 표준 치료는 케톤 생성 식이요법으로, 포도당을 대체하는 케톤의 수준을 높여, 혈액에서 뇌에서 사용할 수 있게 한다. 중성지방 트리헵타노인(Triheptanoin) 치료가 케톤 생성 식이요법의 대안으로 제안되었다. 아데노-연관 바이러스(AAV) 벡터를 사용하는 유전자 요법도 시도하였다. 뉴런에서 GLUT1 결핍을 표적화하면서, 뉴런-특이적 프로모터(예를 들어, 시냅신)의 조절 하에 GLUT1을 암호화하는 AAV9 벡터를 출생 후 어린 마우스 모델에서 시험하였다. 다른 연구는 구성적 프로모터(예를 들어, CMV 프로모터) 또는 내인성 GLUT1 유전자의 프로모터를 사용하였다. 항경련성 탄산 탈수효소 억제제인 아세타졸아마이드 등을 포함하는 다양한 소분자도 시험하였다.
GLUT1의 반수체부족성은 뇌 혈관신생을 정지시켜, 내피 팁 세포의 포도당 의존성과 관련이 있을 수 있는 상대적으로 작은 대뇌 미세혈관구조를 초래하는 반면, Tang 등은 내피 세포 내 낮은 GLUT1이 이러한 병리를 유발하는지 여부는 아직 조사되지 않은 것으로 관찰하였다. GLUT1 단백질은 희소돌기아교세포, 미세아교세포 및 뇌실막 세포를 포함하는 추가 뇌 세포에서 발현된다.
유전자 요법에 의해 GLUT1 DS를 해결하는 데에는 여러 가지 어려움이 존재한다. 임상적으로 의미 있는 효과를 달성하기 위해 필요한 벡터를 이용한 CNS 적용 정도 및 어떤 GLUT1의 치료 수준이 요구되는지 둘 다 매우 예측불가능하다.
GLUT1 결핍 증후군에 대한 요법에 대한 충족되지 않은 수요가 존재한다. 본원에 제공된 유전자 요법은 이러한 요구를 해결한다.
본 발명은 일반적으로 GLUT1 또는 이의 기능적 변이체를 암호화하는 폴리뉴클레오티드의 아데노-연관 바이러스(AAV)-기반 전달을 사용하는 신경 질환 또는 장애에 대한 유전자 요법에 관한 것이다.
GLUT1 결핍 증후군(DS)은 적절한 신경 기능 결여에 뿌리를 둔 임상적 발현을 갖는 신경발달 장애이지만, 본 유전자 요법은, 이론에 구속되지 않고, 혈관신생 및 중추 신경계(CNS)에서 혈관계의 발달을 가이드하는 역할을 하는 내피 세포를 표적으로 할 수 있다. 발생중인 중추 신경계 CNS 혈관계로 AAV를 직접 전달하고, 내피 팁 세포에서 GLUT1 단백질 발현이 후속하게 되면, 혈관신생 및 신경발달의 중요한 시기 동안 CNS 전체에 걸쳐 혈관 성장 및 형성을 촉진할 수도 있다.
일 측면에서, 본 개시는 프로모터에 작동 가능하게 연결된, GLUT1 또는 이의 기능성 변이체를 암호화하는 폴리뉴클레오티드 서열을 포함하는, 발현 카세트를 제공한다.
일부 실시예에서, 프로모터는 내피 프로모터, 선택적으로 Tie-1 프로모터, Tie-2(TEK) 프로모터, FLT-1 프로모터, FLK-1(KDR) 프로모터, ICAM-2 프로모터, VE-카드헤린(CDH5) 프로모터, VWF 프로모터, ENG 프로모터, PDGFB 프로모터, ESM1 프로모터, APLN 프로모터, 또는 Claudin-5(Ple261) 프로모터이며, 단 내피 프로모터는 Glut1 프로모터가 아니다.
일부 실시예에서, 프로모터는 FLT-1 프로모터이다.
일부 실시예에서, FLT-1 프로모터는 인간 FLT-1(hFLT-1) 프로모터이다.
일부 실시예에서, hFLT-1 프로모터는 서열번호 1과 적어도 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 또는 100% 동일성을 공유한다.
일부 실시예에서, 프로모터는 Tie-1 프로모터이다.
일부 실시예에서, Tie-1 프로모터는 인간 Tie-1(hTie-1) 프로모터이다.
일부 실시예에서, hTie-1 프로모터는 서열번호 2과 적어도 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 또는 100% 동일성을 공유한다.
일부 실시예에서, 프로모터는 혈관 내피-카드헤린(VE-카드헤린) 프로모터이다.
일부 실시예에서, VE-카드헤린 프로모터는 인간 VE-카드헤린 (hVE-카드헤린) 프로모터이다.
일부 실시예에서, hVE-카드헤린 프로모터는 서열번호 3과 적어도 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 또는 100% 동일성을 공유한다.
일부 실시예에서, 프로모터는 유비쿼터스 프로모터이다.
일부 실시예에서, 프로모터는 CMV 프로모터이다.
일부 실시예에서, 프로모터는 CAG 프로모터이다.
일부 실시예에서, 발현 카세트는 폴리A 신호, 선택적으로 인간 성장 호르몬(hGH) 폴리A를 포함한다.
일부 실시예에서, 발현 카세트는 마멋(Woodchuck) 간염 바이러스 전사후 조절 요소(WPRE), 선택적으로 WPRE(x)를 포함한다.
일부 실시예에서, 발현 카세트는 서열번호 4과 적어도 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 또는 100% 동일성을 공유하는 서열을 포함하는 3' 미번역 영역(3' UTR)을 포함한다.
일부 실시예에서, GLUT1을 암호화하는 폴리뉴클레오티드 서열은 SLC2A1 폴리뉴클레오티드이다.
일부 실시예에서, SLC2A1 폴리뉴클레오티드는 인간 SLC2A1 폴리뉴클레오티드이다.
일부 실시예에서, GLUT1을 암호화하는 폴리뉴클레오티드 서열은 서열번호 5과 적어도 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 또는 100% 동일성을 공유한다.
일부 실시예에서, 발현 카세트는 5' 및 3' 역위 말단 반복(ITR), 임의로 AAV2 ITR이 측면에 위치한다.
일부 실시예에서, 발현 카세트는 서열번호 8-16, 서열번호 97, 서열번호 99, 및 서열번호 101 중 어느 하나와 적어도 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 또는 100% 동일성을 공유한다,
또 다른 측면에서, 본 개시는 본 개시의 발현 카세트 중 어느 하나를 포함하는, 유전자 요법 벡터를 제공한다.
일부 실시예에서, 유전자 요법 벡터는 재조합 아데노-연관 바이러스(rAAV) 벡터이다.
일부 실시예에서, rAAV 벡터는 AAV6, AAV8, AAV9, 또는 AAVrh.74, AAVrh.10 벡터, 또는 이의 기능적 변이체이다.
일부 실시예에서, rAAV 벡터는 AAV2 벡터가 아니다.
일부 실시예에서, rAAV 벡터는 서열번호 76-82 중 어느 하나와 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 또는 100% 동일성을 공유하는 캡시드 단백질을 포함한다.
또 다른 측면에서, 본 개시는 이를 필요로 하는 대상체에서 질환 또는 장애를 치료 및/또는 예방하는 방법을 제공하며, 상기 방법은 본 개시의 벡터 중 어느 하나를 대상체에게 투여하는 단계를 포함한다.
일부 실시예에서, 질환 또는 장애는 신경 장애이다.
일부 실시예에서, 질환 또는 장애는 포도당 수송자 1 결핍 증후군(GLUT1 DS) 또는 드 비보 질환이다.
일부 실시예에서, 벡터는 뇌실내(ICV) 주사에 의해 투여된다.
일부 실시예에서, 투여는, 선택적으로 기준 rAAV 벡터와 비교하여 증가된 수준으로, 뇌에서 GLUT1을 암호화하는 폴리뉴클레오티드 서열의 발현의 증가 및/또는 CSF에서 포도당 수준 또는 젖산 수준의 증가를 초래하며, 여기서 선택적으로 상기 증가는 적어도 약 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% 또는 그 이상의 증가이다.
일부 실시예에서, 투여는, 선택적으로 기준 rAAV 벡터와 비교하여 증가된 수준으로, 뇌에서 GLUT1 단백질의 발현을 초래한다.
일부 실시예에서, 벡터는 1E11 벡터 게놈(vg), 1E12 vg, 1E13, 1E14, 2E14 또는 3E14의 투여량으로 투여된다.
또 다른 측면에서, 본 개시는 세포에서 GLUT1을 발현하는 방법을 제공하며, 상기 방법은 본 개시의 벡터 중 어느 하나와 세포를 접촉시키는 단계를 포함한다.
일부 실시예에서, 세포는 내피 세포이다.
일부 실시예에서, 내피 세포는 생체 내 내피 세포이다.
일부 실시예에서, 세포는 뉴런이다.
일부 실시예에서, 뉴런은 생체 내 뉴런이다.
일부 실시예에서, 상기 방법은 대상체에게 벡터를 생체 내 투여하는 단계를 포함한다.
추가 측면에서, 본 개시는 폴리뉴클레오티드(예를 들어, 벡터 게놈), 약학적 조성물, 키트, 및 기타 조성물 및 방법을 제공한다.
다양한 다른 측면 및 실시예가 다음의 상세한 설명에 개시된다. 본 발명은 첨부된 청구범위에 의해서만 제한된다.
도 1은 벡터 게놈의 다양한 비제한적인 예에 대한 벡터 다이어그램을 보여준다.
도 2는 벡터 게놈의 비제한적인 예의 벡터 다이어그램을 도시한다. 벡터 게놈의 전체 폴리뉴클레오티드 서열은 서열번호 17이다. 대문자 부분은 발현 카세트(서열번호 8)이다.
도 3은 벡터 게놈의 비제한적인 예의 벡터 다이어그램을 도시한다. 벡터 게놈의 전체 폴리뉴클레오티드 서열은 서열번호 19이다. 대문자 부분은 발현 카세트(서열번호 10)이다.
도 4는 벡터 게놈의 비제한적인 예의 벡터 다이어그램을 도시한다. 벡터 게놈의 전체 폴리뉴클레오티드 서열은 서열번호 21이다. 대문자 부분은 발현 카세트(서열번호 12)이다.
도 5는 벡터 게놈의 비제한적인 예의 벡터 다이어그램을 도시한다. 벡터 게놈의 전체 폴리뉴클레오티드 서열은 서열번호 96이다. 대문자 부분은 발현 카세트(서열번호 97)이다. 벡터 게놈의 전체 폴리뉴클레오티드 서열의 대안은 서열번호 23이다. 발현 카세트의 대안은 서열번호 14이다.
도 6은 벡터 게놈의 비제한적인 예의 벡터 다이어그램을 도시한다. 벡터 게놈의 전체 폴리뉴클레오티드 서열은 서열번호 25이다. 대문자 부분은 발현 카세트(서열번호 16)이다.
도 7은 벡터 게놈의 비제한적인 예의 벡터 다이어그램을 도시한다. 벡터 게놈의 전체 폴리뉴클레오티드 서열은 서열번호 98이다. 대문자 부분은 발현 카세트(서열번호 99)이다.
도 8은 벡터 게놈의 비제한적인 예의 벡터 다이어그램을 도시한다. 벡터 게놈의 전체 폴리뉴클레오티드 서열은 서열번호 100이다. 대문자 부분은 발현 카세트(서열번호 101)이다.
도 9. hGlut1 단백질 CHO-Lec2 세포의 AAV9-매개 발현. CHO-Lec2 세포를 여러 내피-특이적 프로모터 중 하나 (즉, hFLT1, mTie1 또는 hGlut1) 또는 유비쿼터스 CMV 프로모터에 의해 지시되는 hGlut1 이식유전자 단백질을 발현하는 AAV9 벡터로 형질도입하였다. [SLC2A1 = GLUT1 유전자].
도 10a-10c. 인간 대뇌 미세혈관 내피 세포(hCMEC/d3s)의 형질감염 후 이식유전자 단백질(Glut1-GFP)의 발현.
도 10a. Glut1-GFP 이식유전자의 발현을 지시하는 여러 내피 세포 프로모터 중 하나를 함유하는 작제물로 형질감염 후 72시간차 GFP 형광.
도 10b. 2개의 유비쿼터스 프로모터(CMV 또는 CAG) 중 하나를 함유하는 작제물로 형질감염 후, Glut1이 없는 대조군 벡터(CMV-GFP)로 형질감염 후 또는 형질감염이 없는 대조군 벡터(NFX 없음)의 72시간차 GFP 형광. Operetta CLS™ (PerkinElmer®)를 사용하여 획득한 이미지.
도 10c. 관심 프로모터(hFLT1, mTie, hTie 또는 hGlut1) 및 GLUT1(SLC2A1) 유전자(T2A 연결-GFP) 및 AAV2 역위 말단 반복(ITR)이 측면에 위치한 조절 요소를 함유하는 발현 카세트의 다이어그램.
도 11a-11c. 인간 GLUT1(SLC2A1)의 발현 후 hCMEC/d3 세포에서의 2-디옥시-D-글루코오스(포도당) 흡수. 인간 대뇌 미세혈관 내피 세포(hCMEC/d3s)를 CAG-GFP(음성 대조군) 또는 여러 내피-특이적 프로모터 중 하나(즉, hFLT1, mTie1 또는 hGlut1)에 의해 또는 유비쿼터스 CMV 프로모터에 의해 지시되는 hGLUT1-t2A-eGFP 이식유전자를 발현하는 플라스미드로 형질감염시켰다. 포도당 흡수는 배양 배지에서 0.5 mM 2-디옥시-D-글루코오스(2-DG)를 갖는 발광 기반 키트(Promega®)를 사용하여 측정하였다. 포도당 흡수는 위상차 영상화를 사용하여 총 세포에 의해 정규화하였다 [오차 막대는 S.E.M을 나타냄; 병태 당 n=6 복제물].
도 11a. 제1 실험에서 형질감염 후 72시간차에 포도당(2-DG) 흡수를 측정하였다.
도 11b. 제2 실험에서 형질감염 후 72시간차에 포도당(2-DG) 흡수를 측정하였다.
도 11c. 형질감염 후 96시간차에 포도당(2-DG) 흡수를 측정하였다.
도 12a-12b. 인간 GLUT1(SLC2A1)의 발현 후 hCMEC/d3 세포에서의 2-디옥시-D-글루코오스(포도당) 흡수. 인간 대뇌 미세혈관 내피 세포(hCMEC/d3s)를 여러 내피-특이적 프로모터 중 하나(즉, hFLT1, mTie1 또는 hGlut1)에 의해 또는 유비쿼터스 CMV 프로모터에 의해 지시되는 hGLUT1-t2A-eGFP 이식유전자를 발현하는 플라스미드로 형질감염시켰다. 형질감염되지 않은 hCMEC/d3을 대조군(CON)으로 사용하였다. 포도당 흡수는 배양 배지에서 다양한 농도(0 mM, 0.1 mM, 0.5 mM 또는 1.0 mM)의 2-디옥시-D-글루코오스를 갖는 발광 기반 키트(Promega®)를 사용하여 측정하였다. 제조사의 권장사항에 따라 수행된, 실시간-Glo MT 세포 생존력 검정(Promega®)을 이용한 멀티플렉싱을 통해 세포당 기준으로 포도당 흡수를 정규화하였다.
도 12a는 72시간 시점에서 인간 Glut1(SLC2A1)의 발현 후 hCMEC/d3 세포에서의 포도당 흡수를 보여준다.
도 12b는 96시간 시점에서 인간 Glut1(SLC2A1)의 발현 후 hCMEC/d3 세포에서의 포도당 흡수를 보여준다.
도 13. hCMEC/d3 세포에서 hGLUT1(SLC2A1)의 AAV9-매개 발현 후 2-디옥시-D-글루코오스(포도당) 흡수. 인간 대뇌 미세혈관 내피 세포(hCMEC/d3s)를 CAG-GFP(음성 대조군) 또는 여러 내피-특이적 프로모터 중 하나(즉, hFLT1, mTie1 또는 hGlut1)에 의해 또는 유비쿼터스 CMV 프로모터에 의해 지시되는 hGLUT1 이식유전자를 발현하는 AAV9 벡터(3 x 105 벡터 게놈/세포)로 형질도입하였다. 포도당(2-DG) 흡수는 발광-기반 포도당 흡수-Glo 키트(Promega®)를 사용하여 형질도입 후 72시간차에 측정하였으며, 실시간-Glo MT 세포 생존력 검정(Promega®)을 사용하여 세포당 정규화하였다 [오차 막대는 S.E.M을 나타냄; 병태 당 n=4 복제물].
도 2는 벡터 게놈의 비제한적인 예의 벡터 다이어그램을 도시한다. 벡터 게놈의 전체 폴리뉴클레오티드 서열은 서열번호 17이다. 대문자 부분은 발현 카세트(서열번호 8)이다.
도 3은 벡터 게놈의 비제한적인 예의 벡터 다이어그램을 도시한다. 벡터 게놈의 전체 폴리뉴클레오티드 서열은 서열번호 19이다. 대문자 부분은 발현 카세트(서열번호 10)이다.
도 4는 벡터 게놈의 비제한적인 예의 벡터 다이어그램을 도시한다. 벡터 게놈의 전체 폴리뉴클레오티드 서열은 서열번호 21이다. 대문자 부분은 발현 카세트(서열번호 12)이다.
도 5는 벡터 게놈의 비제한적인 예의 벡터 다이어그램을 도시한다. 벡터 게놈의 전체 폴리뉴클레오티드 서열은 서열번호 96이다. 대문자 부분은 발현 카세트(서열번호 97)이다. 벡터 게놈의 전체 폴리뉴클레오티드 서열의 대안은 서열번호 23이다. 발현 카세트의 대안은 서열번호 14이다.
도 6은 벡터 게놈의 비제한적인 예의 벡터 다이어그램을 도시한다. 벡터 게놈의 전체 폴리뉴클레오티드 서열은 서열번호 25이다. 대문자 부분은 발현 카세트(서열번호 16)이다.
도 7은 벡터 게놈의 비제한적인 예의 벡터 다이어그램을 도시한다. 벡터 게놈의 전체 폴리뉴클레오티드 서열은 서열번호 98이다. 대문자 부분은 발현 카세트(서열번호 99)이다.
도 8은 벡터 게놈의 비제한적인 예의 벡터 다이어그램을 도시한다. 벡터 게놈의 전체 폴리뉴클레오티드 서열은 서열번호 100이다. 대문자 부분은 발현 카세트(서열번호 101)이다.
도 9. hGlut1 단백질 CHO-Lec2 세포의 AAV9-매개 발현. CHO-Lec2 세포를 여러 내피-특이적 프로모터 중 하나 (즉, hFLT1, mTie1 또는 hGlut1) 또는 유비쿼터스 CMV 프로모터에 의해 지시되는 hGlut1 이식유전자 단백질을 발현하는 AAV9 벡터로 형질도입하였다. [SLC2A1 = GLUT1 유전자].
도 10a-10c. 인간 대뇌 미세혈관 내피 세포(hCMEC/d3s)의 형질감염 후 이식유전자 단백질(Glut1-GFP)의 발현.
도 10a. Glut1-GFP 이식유전자의 발현을 지시하는 여러 내피 세포 프로모터 중 하나를 함유하는 작제물로 형질감염 후 72시간차 GFP 형광.
도 10b. 2개의 유비쿼터스 프로모터(CMV 또는 CAG) 중 하나를 함유하는 작제물로 형질감염 후, Glut1이 없는 대조군 벡터(CMV-GFP)로 형질감염 후 또는 형질감염이 없는 대조군 벡터(NFX 없음)의 72시간차 GFP 형광. Operetta CLS™ (PerkinElmer®)를 사용하여 획득한 이미지.
도 10c. 관심 프로모터(hFLT1, mTie, hTie 또는 hGlut1) 및 GLUT1(SLC2A1) 유전자(T2A 연결-GFP) 및 AAV2 역위 말단 반복(ITR)이 측면에 위치한 조절 요소를 함유하는 발현 카세트의 다이어그램.
도 11a-11c. 인간 GLUT1(SLC2A1)의 발현 후 hCMEC/d3 세포에서의 2-디옥시-D-글루코오스(포도당) 흡수. 인간 대뇌 미세혈관 내피 세포(hCMEC/d3s)를 CAG-GFP(음성 대조군) 또는 여러 내피-특이적 프로모터 중 하나(즉, hFLT1, mTie1 또는 hGlut1)에 의해 또는 유비쿼터스 CMV 프로모터에 의해 지시되는 hGLUT1-t2A-eGFP 이식유전자를 발현하는 플라스미드로 형질감염시켰다. 포도당 흡수는 배양 배지에서 0.5 mM 2-디옥시-D-글루코오스(2-DG)를 갖는 발광 기반 키트(Promega®)를 사용하여 측정하였다. 포도당 흡수는 위상차 영상화를 사용하여 총 세포에 의해 정규화하였다 [오차 막대는 S.E.M을 나타냄; 병태 당 n=6 복제물].
도 11a. 제1 실험에서 형질감염 후 72시간차에 포도당(2-DG) 흡수를 측정하였다.
도 11b. 제2 실험에서 형질감염 후 72시간차에 포도당(2-DG) 흡수를 측정하였다.
도 11c. 형질감염 후 96시간차에 포도당(2-DG) 흡수를 측정하였다.
도 12a-12b. 인간 GLUT1(SLC2A1)의 발현 후 hCMEC/d3 세포에서의 2-디옥시-D-글루코오스(포도당) 흡수. 인간 대뇌 미세혈관 내피 세포(hCMEC/d3s)를 여러 내피-특이적 프로모터 중 하나(즉, hFLT1, mTie1 또는 hGlut1)에 의해 또는 유비쿼터스 CMV 프로모터에 의해 지시되는 hGLUT1-t2A-eGFP 이식유전자를 발현하는 플라스미드로 형질감염시켰다. 형질감염되지 않은 hCMEC/d3을 대조군(CON)으로 사용하였다. 포도당 흡수는 배양 배지에서 다양한 농도(0 mM, 0.1 mM, 0.5 mM 또는 1.0 mM)의 2-디옥시-D-글루코오스를 갖는 발광 기반 키트(Promega®)를 사용하여 측정하였다. 제조사의 권장사항에 따라 수행된, 실시간-Glo MT 세포 생존력 검정(Promega®)을 이용한 멀티플렉싱을 통해 세포당 기준으로 포도당 흡수를 정규화하였다.
도 12a는 72시간 시점에서 인간 Glut1(SLC2A1)의 발현 후 hCMEC/d3 세포에서의 포도당 흡수를 보여준다.
도 12b는 96시간 시점에서 인간 Glut1(SLC2A1)의 발현 후 hCMEC/d3 세포에서의 포도당 흡수를 보여준다.
도 13. hCMEC/d3 세포에서 hGLUT1(SLC2A1)의 AAV9-매개 발현 후 2-디옥시-D-글루코오스(포도당) 흡수. 인간 대뇌 미세혈관 내피 세포(hCMEC/d3s)를 CAG-GFP(음성 대조군) 또는 여러 내피-특이적 프로모터 중 하나(즉, hFLT1, mTie1 또는 hGlut1)에 의해 또는 유비쿼터스 CMV 프로모터에 의해 지시되는 hGLUT1 이식유전자를 발현하는 AAV9 벡터(3 x 105 벡터 게놈/세포)로 형질도입하였다. 포도당(2-DG) 흡수는 발광-기반 포도당 흡수-Glo 키트(Promega®)를 사용하여 형질도입 후 72시간차에 측정하였으며, 실시간-Glo MT 세포 생존력 검정(Promega®)을 사용하여 세포당 정규화하였다 [오차 막대는 S.E.M을 나타냄; 병태 당 n=4 복제물].
정의
섹션 제목은 조직화를 목적으로만 제공되며, 특정 측면 또는 실시예로 기술된 주제를 제한하는 것으로 해석되어서는 안 된다.
달리 정의되지 않는 한, 본원에 사용된 모든 기술 및 과학 용어는 본 발명이 속하는 기술 분야의 통상의 기술을 가진 자에 의해 일반적으로 이해되는 것과 동일한 의미를 갖는다. 본원에서 설명되는 것과 유사하거나 등가인 방법 및 재료가 본 발명의 실시에 사용될 수 있지만, 적절한 방법 및 재료가 아래에 기술된다. 본원에 언급된 모든 간행물, 특허 출원, 특허 및 기타 참고 문헌은 그 전체가 참조로서 명시적으로 포함된다. 상충하는 경우, 정의를 포함하는 본 명세서가 우선할 것이다. 또한, 본원에 설명된 재료, 방법 및 예는 단지 예시일 뿐이며 한정하려는 의도가 아니다.
본원에 언급된 모든 간행물 및 특허는 각각의 개별 간행물 또는 특허가 구체적으로 그리고 개별적으로 참조로서 통합되도록 표시된 것처럼 그 전체가 참조로서 본원에 통합된다. 상충하는 경우, 본원의 임의의 정의를 포함하여 본 출원이 우선할 것이다. 그러나, 본원에 인용된 임의의 참고 문헌, 논문, 간행물, 특허, 특허 공개, 및 특허 출원에 대한 언급은, 이들이 유효한 선행기술을 구성하거나 세계 어느 국가에서도 통상적인 일반 지식의 일부를 구성한다는 것을 인정하거나 임의의 형태의 제안으로서 취해져선 안 된다.
본 설명에서, 달리 명시되지 않는 한, 임의의 농도 범위, 백분율 범위, 비율 범위, 또는 정수 범위는 인용된 범위 내의 임의의 정수의 값과, 적절한 경우, 이의 분수(예를 들어, 정수의 1/10 및 1/100)을 포함하는 것으로 이해되어야 한다. 숫자 또는 숫자 바로 앞에 있는 "약"이라는 용어는 숫자 또는 숫자 범위 ±10%임을 의미한다. 본원에서 사용된 용어 "a" 및 "an"은 달리 명시되지 않는 한 열거된 구성요소 중 "하나 이상"을 지칭함을 이해해야 한다. 선택 접속사(예를 들어, "또는")의 사용은 그 선택사항 중 하나, 둘 다, 또는 이들의 임의의 조합을 의미하는 것으로 이해되어야 한다. 용어 "및/또는"은 선택사항 중 하나 또는 둘 다를 의미하는 것으로 이해되어야 한다. 본원에서 사용되는 바와 같이, 용어 "포함하다" 및 "포함한다"는 동의어로 사용된다.
본원에서 사용되는 바와 같이, 용어 "동일성" 및 "동일한"은 폴리펩티드 또는 폴리뉴클레오티드 서열에 대해, "쿼리" 서열과 "대상" 서열의 정렬, 예컨대 BLAST 알고리즘에 의해 생성된 정렬에서 정확히 일치하는 잔기의 백분율을 지칭한다. 동일성은, 달리 명시되지 않는 한, 대상 서열의 전체 길이에 걸쳐 계산된다. 따라서, 쿼리 서열이 대상 서열에 정렬될 때, 대상 서열 내의 잔기의 적어도 x%(반내림됨)가 쿼리 서열 내의 상응하는 잔기와 정확히 일치하는 것으로 정렬되는 경우, 쿼리 서열은 대상 서열과 "적어도 x%의 동일성을 공유한다". 대상 서열이 가변 위치(예를 들어, X로 표시된 잔기)를 갖는 경우, 쿼리 서열 내의 임의의 잔기에 대한 정렬은 일치로 간주된다.
본원에서 사용되는 바와 같이, "AAV 벡터" 또는 "rAAV 벡터"는 AAV 말단 반복 서열(ITR)이 측면에 위치하는 하나 이상의 관심 폴리뉴클레오티드(또는 이식유전자)를 포함하는 재조합 벡터를 지칭한다. 이러한 AAV 벡터는 rep 및 cap 유전자 산물을 암호화하고 발현하는 플라스미드로 형질감염된 숙주 세포에 존재할 때 감염성 바이러스 입자로 복제 및 패키징될 수 있다. 대안적으로, AAV 벡터는 rep 및 cap 유전자를 발현하도록 안정적으로 조작된 숙주 세포를 사용하여 감염성 입자로 패키징될 수 있다.
본원에서 사용되는 바와 같이, "AAV 비리온" 또는 "AAV 바이러스 입자" 또는 "AAV 벡터 입자"는 적어도 하나의 AAV 캡시드 단백질 및 캡슐화된 폴리뉴클레오티드 AAV 벡터로 이루어진 바이러스 입자를 지칭한다. 본원에서 사용되는 바와 같이, 입자가 이종 폴리뉴클레오티드(즉, 포유류 세포에 전달될 이식유전자와 같은 야생형 AAV 게놈 이외의 폴리뉴클레오티드)를 포함하는 경우, 이는 일반적으로 "AAV 벡터 입자" 또는 단순히 "AAV 벡터"로서 지칭된다. 따라서, AAV 벡터 입자의 생산은 AAV 벡터의 생산을 반드시 포함하는데, 이러한 벡터가 AAV 벡터 입자 내에 포함되기 때문이다.
본원에서 사용되는 바와 같이, "프로모터"는 진핵 세포에서 폴리뉴클레오티드로부터 RNA 전사의 개시를 촉진할 수 있는 폴리뉴클레오티드 서열을 지칭한다.
본원에서 사용되는 바와 같이, "벡터 게놈"은 측부 서열(AAV에서, 역위 말단 반복)을 포함하여, 벡터(예를 들어, rAAV 비리온)에 의해 패키징된 폴리뉴클레오티드 서열을 지칭한다. 용어 "발현 카세트" 및 "폴리뉴클레오티드 카세트"는 측부 ITR 서열 사이의 벡터 게놈의 부분을 지칭한다. "발현 카세트"는 벡터 게놈이 발현을 유도하는 요소(예: 프로모터)에 작동가능하게 연결된 유전자 산물을 암호화하는 적어도 하나의 유전자를 포함한다는 것을 의미한다.
본원에서 사용되는 바와 같이, 용어 "필요로 하는 환자" 또는 "필요로 하는 대상체"는 본원에 개시된 재조합 유전자 요법 벡터 또는 유전자 편집 시스템으로 치료 또는 개선될 수 있는 질환, 장애 또는 병태의 위험이 있거나 이를 앓고 있는 환자 또는 대상체를 지칭한다. 예를 들어, 필요로 하는 환자 또는 대상체는 중추 신경계와 관련된 장애로 진단된 환자 또는 대상체일 수 있다. 대상체는 SLC2A1 유전자의 돌연변이 또는 SLC2A1 유전자의 전부 또는 일부의 결실, 또는 GLUT1 단백질의 비정상적인 발현을 유발하는, 유전자 조절 서열의 결실을 가질 수 있다. "대상체" 및 "환자"는 본원에서 상호 교환적으로 사용된다. 본원에서 설명되는 방법에 의해 치료되는 대상체는 신생아, 유아, 청소년 또는 성인일 수 있다.
본원에서 사용되는 바와 같이, 용어 "변이체" 또는 "기능적 변이체"는 부모 단백질의 하나 이상의 원하는 활성을 보유하는 부모 단백질과 비교하여 하나 이상의 아미노산 치환, 삽입 또는 결실을 갖는 단백질을 상호 교환적으로 지칭한다.
본원에서 사용되는 바와 같이, "유전자 파괴"는 유전자에서 기능의 부분적 또는 완전한 상실 또는 비정상적인 활성을 지칭한다. 예를 들어, 대상체는 대상체의 적어도 일부 세포(예를 들어, 내피 세포 및/또는 뉴런)에서 GLUT1 단백질의 발현을 감소시키거나 상실 또는 비정상적인 기능을 초래하는 SLC2A1 유전자의 발현 또는 기능의 유전자 파괴를 겪을 수 있다.
본원에서 사용되는 바와 같이, "치료하는"은 질환 또는 장애의 하나 이상의 증상을 개선하는 것을 지칭한다. 용어 "예방하는"은 질환 또는 장애의 하나 이상의 증상의 개시를 지연 또는 방해하거나 SLC2A1-관련 신경 질환 또는 장애, 예를 들어 GLUT1 결핍 증후군(GLUT1 DS)의 진행을 늦추는 것을 지칭한다.
GLUT1 단백질 또는 폴리뉴클레오티드
본 개시는 포도당 수송자 1(glucose transporter 1, GLUT1) 단백질과 관련된 조성물 및 사용 방법을 고려한다. SLC2A1에서의 다양한 돌연변이는 GLUT1 DS와 연관된 것으로 알려져 있다. 유전된 돌연변이와 드노보 돌연변이가 모두 관찰되었다. 일부 경우에, 이형접합성 미스센스 돌연변이는 질환을 유발하기에 충분하다.
GLUT1의 폴리펩티드 서열은 다음과 같다:
MEPSSKKLTGRLMLAVGGAVLGSLQFGYNTGVINAPQKVIEEFYNQTWVHRYGESILPTTLTTLWSLSVAIFSVGGMIGSFSVGLFVNRFGRRNSMLMMNLLAFVSAVLMGFSKLGKSFEMLILGRFIIGVYCGLTTGFVPMYVGEVSPTALRGALGTLHQLGIVVGILIAQVFGLDSIMGNKDLWPLLLSIIFIPALLQCIVLPFCPESPRFLLINRNEENRAKSVLKKLRGTADVTHDLQEMKEESRQMMREKKVTILELFRSPAYRQPILIAVVLQLSQQLSGINAVFYYSTSIFEKAGVQQPVYATIGSGIVNTAFTVVSLFVVERAGRRTLHLIGLAGMAGCAILMTIALALLEQLPWMSYLSIVAIFGFVAFFEVGPGPIPWFIVAELFSQGPRPAAIAVAGFSNWTSNFIVGMCFQYVEQLCGPYVFIIFTVLLVLFFIFTYFKVPETKGRTFDEIASGFRQGGASQSDKTPEELFHPLGADSQV
(서열번호 26).
일부 실시예에서, GLUT1 단백질은 서열번호 26)과 적어도 75%, 80%, 85%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 또는 100% 동일한 폴리펩티드 서열을 포함한다.
일부 실시예에서, 본 개시는 캡시드 및 벡터 게놈을 포함하는, 재조합 아데노-연관 바이러스(rAAV) 비리온을 제공하며, 벡터 게놈은 프로모터에 작동 가능하게 연결된, GLUT1 단백질 또는 이의 기능적 변이체를 암호화하는 폴리뉴클레오티드 서열을 포함한다. 일부 실시예에서, 본 개시는 캡시드 및 벡터 게놈을 포함하는, 재조합 아데노-연관 바이러스(rAAV) 비리온을 제공하며, 벡터 게놈은 프로모터에 작동 가능하게 연결된, GLUT1 단백질을 암호화하는 폴리뉴클레오티드 서열을 포함한다. GLUT1 단백질을 암호화하는 폴리뉴클레오티드는 다음과 적어도 75%, 80%, 85%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 또는 100% 동일한 폴리뉴클레오티드 서열을 포함할 수 있다:
ATGGAGCCCAGCAGCAAGAAGCTGACGGGTCGCCTCATGCTGGCCGTGGGAGGAGCAGTGCTTGGCTCCCTGCAGTTTGGCTACAACACTGGAGTCATCAATGCCCCCCAGAAGGTGATCGAGGAGTTCTACAACCAGACATGGGTCCACCGCTATGGGGAGAGCATCCTGCCCACCACGCTCACCACGCTCTGGTCCCTCTCAGTGGCCATCTTTTCTGTTGGGGGCATGATTGGCTCCTTCTCTGTGGGCCTTTTCGTTAACCGCTTTGGCCGGCGGAATTCAATGCTGATGATGAACCTGCTGGCCTTCGTGTCCGCCGTGCTCATGGGCTTCTCGAAACTGGGCAAGTCCTTTGAGATGCTGATCCTGGGCCGCTTCATCATCGGTGTGTACTGCGGCCTGACCACAGGCTTCGTGCCCATGTATGTGGGTGAAGTGTCACCCACAGCCCTTCGTGGGGCCCTGGGCACCCTGCACCAGCTGGGCATCGTCGTCGGCATCCTCATCGCCCAGGTGTTCGGCCTGGACTCCATCATGGGCAACAAGGACCTGTGGCCCCTGCTGCTGAGCATCATCTTCATCCCGGCCCTGCTGCAGTGCATCGTGCTGCCCTTCTGCCCCGAGAGTCCCCGCTTCCTGCTCATCAACCGCAACGAGGAGAACCGGGCCAAGAGTGTGCTAAAGAAGCTGCGCGGGACAGCTGACGTGACCCATGACCTGCAGGAGATGAAGGAAGAGAGTCGGCAGATGATGCGGGAGAAGAAGGTCACCATCCTGGAGCTGTTCCGCTCCCCCGCCTACCGCCAGCCCATCCTCATCGCTGTGGTGCTGCAGCTGTCCCAGCAGCTGTCTGGCATCAACGCTGTCTTCTATTACTCCACGAGCATCTTCGAGAAGGCGGGGGTGCAGCAGCCTGTGTATGCCACCATTGGCTCCGGTATCGTCAACACGGCCTTCACTGTCGTGTCGCTGTTTGTGGTGGAGCGAGCAGGCCGGCGGACCCTGCACCTCATAGGCCTCGCTGGCATGGCGGGTTGTGCCATACTCATGACCATCGCGCTAGCACTGCTGGAGCAGCTACCCTGGATGTCCTATCTGAGCATCGTGGCCATCTTTGGCTTTGTGGCCTTCTTTGAAGTGGGTCCTGGCCCCATCCCATGGTTCATCGTGGCTGAACTCTTCAGCCAGGGTCCACGTCCAGCTGCCATTGCCGTTGCAGGCTTCTCCAACTGGACCTCAAATTTCATTGTGGGCATGTGCTTCCAGTATGTGGAGCAACTGTGTGGTCCCTACGTCTTCATCATCTTCACTGTGCTCCTGGTTCTGTTCTTCATCTTCACCTACTTCAAAGTTCCTGAGACTAAAGGCCGGACCTTCGATGAGATCGCTTCCGGCTTCCGGCAGGGGGGAGCCAGCCAAAGTGACAAGACACCCGAGGAGCTGTTCCATCCCCTGGGGGCTGATTCCCAAGTG
(서열번호 5).
일부 실시예에서, GLUT1 단백질을 암호화하는 폴리뉴클레오티드 서열은 코돈 최적화된 서열이다. GLUT1 단백질을 암호화하는 폴리뉴클레오티드는 다음과 적어도 75%, 80%, 85%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 또는 100% 동일한 폴리뉴클레오티드 서열을 포함할 수 있다:
ATGGAACCATCATCCAAAAAGCTGACCGGACGACTGATGCTTGCAGTTGGCGGTGCGGTCTTGGGGAGCCTGCAGTTTGGGTACAATACTGGCGTAATCAATGCCCCGCAGAAGGTTATTGAAGAATTTTACAATCAAACGTGGGTACATCGCTACGGTGAATCCATTCTTCCTACAACTCTGACCACACTCTGGAGCCTTTCTGTAGCGATTTTTTCCGTCGGGGGCATGATAGGATCATTTTCCGTCGGTCTTTTTGTGAACCGCTTTGGCCGGAGAAATTCCATGCTGATGATGAATCTTCTCGCTTTCGTGAGTGCCGTCCTCATGGGATTTAGTAAACTGGGTAAATCTTTCGAGATGTTGATACTGGGGAGATTTATTATCGGCGTGTATTGTGGTTTGACCACGGGCTTTGTACCAATGTATGTTGGCGAGGTTTCTCCGACAGCATTGAGAGGTGCACTCGGGACCTTGCACCAGTTGGGCATCGTAGTAGGAATCCTTATAGCGCAAGTTTTCGGGCTCGATTCCATCATGGGGAACAAAGATCTCTGGCCATTGCTCCTCTCAATAATTTTTATACCGGCATTGCTTCAGTGTATTGTTCTTCCTTTTTGCCCAGAGTCCCCTAGGTTCCTGCTCATAAACAGGAATGAGGAGAATCGCGCTAAGTCCGTGTTGAAAAAACTTAGGGGAACTGCAGACGTTACTCACGATTTGCAAGAGATGAAGGAGGAATCTAGGCAAATGATGCGCGAGAAGAAGGTTACCATACTCGAACTCTTCCGCTCCCCCGCGTACAGGCAGCCCATTCTTATCGCGGTCGTCTTGCAGTTGTCACAACAGTTGAGTGGGATTAATGCAGTTTTCTATTATAGCACGTCCATATTTGAAAAAGCAGGCGTCCAACAACCTGTCTATGCAACTATAGGCTCAGGCATTGTAAACACAGCGTTTACTGTAGTATCACTGTTTGTCGTTGAGCGGGCTGGTCGAAGGACCTTGCACCTCATAGGACTGGCGGGCATGGCGGGCTGTGCGATTCTTATGACAATTGCGCTCGCGCTGTTGGAACAGCTTCCGTGGATGTCCTATCTCTCTATAGTAGCAATATTTGGATTTGTTGCATTTTTTGAAGTTGGGCCCGGACCTATCCCCTGGTTCATCGTCGCGGAGCTCTTTTCCCAAGGCCCAAGACCGGCTGCCATTGCTGTTGCAGGCTTCTCAAACTGGACGAGTAATTTCATAGTAGGTATGTGTTTCCAGTATGTTGAACAGCTCTGTGGGCCCTATGTCTTTATCATCTTTACTGTGTTGCTCGTGTTGTTCTTTATCTTCACTTATTTCAAAGTACCCGAGACAAAGGGCAGGACGTTTGACGAGATTGCATCTGGTTTTAGACAAGGAGGTGCCTCACAGAGTGATAAAACCCCGGAGGAATTGTTTCATCCGCTGGGAGCCGACTCACAGGTC
(서열번호 27)
선택적으로, 벡터 게놈을 암호화하는 폴리뉴클레오티드 서열은 GCCACCATGG(서열번호 28)를 포함하지만 이에 한정되지 않는, Kozak 서열을 포함할 수 있다. Kozak 서열은 GLUT1 단백질 또는 이의 기능적 변이체를 암호화하는 폴리뉴클레오티드 서열과 중첩될 수 있다. 예를 들어, 벡터 게놈은 다음과 적어도 75%, 80%, 85%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 또는 100% 동일한 폴리뉴클레오티드 서열(Kozak은 밑줄이 그어져 있음)을 포함할 수 있다:
gccaccATGGAGCCCAGCAGCAAGAAGCTGACGGGTCGCCTCATGCTGGCCGTGGGAGGAGCAGTGCTTGGCTCCCTGCAGTTTGGCTACAACACTGGAGTCATCAATGCCCCCCAGAAGGTGATCGAGGAGTTCTACAACCAGACATGGGTCCACCGCTATGGGGAGAGCATCCTGCCCACCACGCTCACCACGCTCTGGTCCCTCTCAGTGGCCATCTTTTCTGTTGGGGGCATGATTGGCTCCTTCTCTGTGGGCCTTTTCGTTAACCGCTTTGGCCGGCGGAATTCAATGCTGATGATGAACCTGCTGGCCTTCGTGTCCGCCGTGCTCATGGGCTTCTCGAAACTGGGCAAGTCCTTTGAGATGCTGATCCTGGGCCGCTTCATCATCGGTGTGTACTGCGGCCTGACCACAGGCTTCGTGCCCATGTATGTGGGTGAAGTGTCACCCACAGCCCTTCGTGGGGCCCTGGGCACCCTGCACCAGCTGGGCATCGTCGTCGGCATCCTCATCGCCCAGGTGTTCGGCCTGGACTCCATCATGGGCAACAAGGACCTGTGGCCCCTGCTGCTGAGCATCATCTTCATCCCGGCCCTGCTGCAGTGCATCGTGCTGCCCTTCTGCCCCGAGAGTCCCCGCTTCCTGCTCATCAACCGCAACGAGGAGAACCGGGCCAAGAGTGTGCTAAAGAAGCTGCGCGGGACAGCTGACGTGACCCATGACCTGCAGGAGATGAAGGAAGAGAGTCGGCAGATGATGCGGGAGAAGAAGGTCACCATCCTGGAGCTGTTCCGCTCCCCCGCCTACCGCCAGCCCATCCTCATCGCTGTGGTGCTGCAGCTGTCCCAGCAGCTGTCTGGCATCAACGCTGTCTTCTATTACTCCACGAGCATCTTCGAGAAGGCGGGGGTGCAGCAGCCTGTGTATGCCACCATTGGCTCCGGTATCGTCAACACGGCCTTCACTGTCGTGTCGCTGTTTGTGGTGGAGCGAGCAGGCCGGCGGACCCTGCACCTCATAGGCCTCGCTGGCATGGCGGGTTGTGCCATACTCATGACCATCGCGCTAGCACTGCTGGAGCAGCTACCCTGGATGTCCTATCTGAGCATCGTGGCCATCTTTGGCTTTGTGGCCTTCTTTGAAGTGGGTCCTGGCCCCATCCCATGGTTCATCGTGGCTGAACTCTTCAGCCAGGGTCCACGTCCAGCTGCCATTGCCGTTGCAGGCTTCTCCAACTGGACCTCAAATTTCATTGTGGGCATGTGCTTCCAGTATGTGGAGCAACTGTGTGGTCCCTACGTCTTCATCATCTTCACTGTGCTCCTGGTTCTGTTCTTCATCTTCACCTACTTCAAAGTTCCTGAGACTAAAGGCCGGACCTTCGATGAGATCGCTTCCGGCTTCCGGCAGGGGGGAGCCAGCCAAAGTGACAAGACACCCGAGGAGCTGTTCCATCCCCTGGGGGCTGATTCCCAAGTG
(서열번호 29).
일부 실시예에서, Kozak 서열은 다음 중 어느 하나를 포함하거나 이로 구성되는 대안적인 Kozak 서열이다:
(gcc)gccRccAUGG (서열번호 30);
AGNNAUGN;
ANNAUGG;
ACCAUGG; 및
GACACCAUGG (서열번호 31).
일부 실시예에서, 벡터 게놈은 Kozak 서열을 포함하지 않는다.
벡터 게놈
본 개시의 AAV 비리온은 벡터 게놈을 포함한다. 벡터 게놈은 발현 카세트(또는 폴리뉴클레오티드 서열의 발현을 필요로 하지 않는 유전자-편집 용도를 위한 폴리뉴클레오티드 카세트)를 포함할 수 있다. 임의의 적절한 역위 말단 반복(ITR)이 사용될 수 있다. ITR은 캡시드와 동일한 혈청형 또는 상이한 혈청형(예를 들어, AAV2 ITR이 사용될 수 있음)으로부터 유래될 수 있다.
일부 실시예에서, 5' ITR은 다음과 적어도 75%, 80%, 85%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 또는 100% 동일한 폴리뉴클레오티드 서열을 포함한다:
CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCT
(서열번호 32)
일부 실시예에서, 5' ITR은 다음과 적어도 75%, 80%, 85%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 또는 100% 동일한 폴리뉴클레오티드 서열을 포함한다:
GCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTTGTAGTTAATGATTAACCCGCCATGCTACTTATCTACGTA
(서열번호 6)
일부 실시예에서, 5' ITR은 다음과 적어도 75%, 80%, 85%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 또는 100% 동일한 폴리뉴클레오티드 서열을 포함한다:
CTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTTGTAGTTAATGATTAACCCGCCATGCTACTTATCTACGTA
(서열번호 33)
일부 실시예에서, 3' ITR은 다음과 적어도 75%, 80%, 85%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 또는 100% 동일한 폴리뉴클레오티드 서열을 포함한다:
AGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG
(서열번호 34)
일부 실시예에서, 3' ITR은 다음과 적어도 75%, 80%, 85%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 또는 100% 동일한 폴리뉴클레오티드 서열을 포함한다:
TACGTAGATAAGTAGCATGGCGGGTTAATCATTAACTACAAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGC
(서열번호 7)
일부 실시예에서, 벡터 게놈은 하나 이상의 필러 서열을 포함하며, 예를 들어, 다음과 적어도 75%, 80%, 85%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 또는 100% 동일한 서열을 포함한다:
GCGGCAATTCAGTCGATAACTATAACGGTCCTAAGGTAGCGATTTAAATACGCGCTCTCTTAAGGTAGCCCCGGGACGCGTCAATTGACTACAAACCGAGTATCTGCAGAGGGCCCTGCGTATG (서열번호 35);
CTTCTGAGGCGGAAAGAACCAGATCCTCTCTTAAGGTAGCATCGAGATTTAAATTAGGGATAACAGGGTAATGGCGCGGGCCGC (서열번호 36); 또는
GTTACCCAGGCTGGAGTGCAGTGGCACATTTCTGCTCACTGCAACCTCCTCCTCCCTGGGTTC (서열번호 37).
프로모터
일부 실시예에서, GLUT1 단백질 또는 이의 기능성 변이체를 암호화하는 폴리뉴클레오티드 서열은 프로모터에 작동 가능하게 연결된다.
본 개시는 다양한 프로모터의 사용을 고려한다. 본 개시의 실시예에 유용한 프로모터는, 제한 없이, 거대세포바이러스(CMV) 프로모터, 포스포글리세레이트 키나아제(PGK) 프로모터, 또는 CMV 인핸서 및 닭 베타-액틴 프로모터 및 토끼 베타-글로빈 유전자(CAG)의 일부분으로 이루어진 프로모터 서열을 포함한다. 일부 경우에, 프로모터는 합성 프로모터일 수 있다. 예시적인 합성 프로모터는 Schlabach 등의 PNAS USA. 107(6):2538-43 (2010)에 의해 제공된다. 일부 실시예에서, 프로모터는 다음과 적어도 75%, 80%, 85%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 또는 100% 동일한 폴리뉴클레오티드 서열을 포함한다:
ACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCATCTCCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCGATGGGGGCGGGGGGGGGGGGGGCGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGGGCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTCCGAAAGTTTCCTTTTATGGCGAGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAGCGCGCGGCGGGCGG
(서열번호 38)
일부 실시예에서, GLUT1 단백질 또는 이의 기능성 변이체를 암호화하는 폴리뉴클레오티드 서열은 유도성 프로모터에 작동 가능하게 연결된다. 유도성 프로모터는 제제의 첨가 또는 축적에 반응하여 또는 제제의 제거, 분해 또는 희석에 반응하여 폴리뉴클레오티드 서열이 전사적으로 발현되게 하거나 전사적으로 발현되지 않게 하도록 구성될 수 있다. 제제는 약물일 수 있다. 제제는 테트라사이클린, 또는 독시사이클린을 포함하지만 이에 한정되지 않는, 이의 유도체 중 하나일 수 있다. 일부 경우에, 유도성 프로모터는 tet-on 프로모터, tet-off 프로모터, 화학적으로 조절된 프로모터, 물리적으로 조절된 프로모터(즉, 광의 존재 또는 부재 또는 저온 또는 고온에 반응하는 프로모터)이다. 유도성 프로모터는 중금속 이온 유도성 프로모터(예컨대 마우스 유방 종양 바이러스(mMTV) 프로모터 또는 다양한 성장 호르몬 프로모터), 및 T7 RNA 중합효소의 존재 시 활성인 T7 파지 유래의 프로모터를 포함한다. 유도성 프로모터의 이러한 목록은 비제한적이다.
일부 경우에, 프로모터는 비-신경 세포에서보다 훨씬 더 큰 정도로 뉴런에서 발현을 유도할 수 있는 프로모터와 같은, 조직-특이적 프로모터이다. 일부 실시예에서, 조직-특이적 프로모터는 뉴런-특이적 프로모터이다. 일부 실시예에서, 조직-특이적 프로모터는 hSYN1(인간 시냅신), INA(알파-인터넥신), NES(네스틴), TH(티로신 히드록실라제), FOXA2(Forkhead box A2), CaMKII(칼모듈린-의존성 단백질 키나아제 II), 및 NSE(뉴런-특이적 엔올라제)를 포함하지만 이에 한정되지 않는 임의의 다양한 뉴런-특이적 프로모터로부터 선택된다. 일부 경우에, 프로모터는 유비쿼터스 프로모터이다. "유비쿼터스 프로모터(ubiquitous promoter)"는 실험 또는 임상 조건 하에서 조직-특이적이지 않은 프로모터를 지칭한다. 일부 경우에, 유비쿼터스 프로모터는 CMV, CAG, UBC, PGK, EF1-알파, GAPDH, SV40, HBV, 닭 베타-액틴, 및 인간 베타-액틴 프로모터 중 어느 하나이다.
일부 실시예에서, 프로모터 서열은 표 3으로부터 선택된다. 일부 실시예에서, 프로모터는 서열번호 1-3 및 39-51 중 어느 하나와 적어도 75%, 80%, 85%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 또는 100% 동일한 폴리뉴클레오티드 서열을 포함한다.
프로모터 | 서열 | 서열번호 |
인간 FLT-1 (hFLT-1) | TTTGCTTCTAGGAAGCAGAAGACTGAGGAAATGACTTGGGCGGGTGCATCAATGCGGCCAAAAAAGACACGGACACGCTCCCCTGGGACCTGAGCTGGTTCGCAGTCTTCCCAAAGGTGCCAAGCAAGCGTCAGTTCCCCTCAGGCGCTCCAGGTTCAGTGCCTTGTGCCGAGGGTCTCCGGTGCCTTCCTAGACTTCTCGGGACAGTCTGAAGGGGTCAGGAGCGGCGGGACAGCGCGGGAAGAGCAGGCAAGGGGAGACAGCCGGACTGCGCCTCAGTCCTCCGTGCCAAGAACACCGTCGCGGAGGCGCGGCCAGCTTCCCTTGGATCGGACTTTCCGCCCCTAGGGCCAGGCGGCGGAGCTTCAGCCTTGTCCCTTCCCCAGTTTCGGGCGGCCCCCAGAGCTGAGTAAGCCGGGTGGAGGGAGTCTGCAAGGATTTCCTGAGCGCGATGGGCAGGAGGAGGGGCAAGGGCAAGAGGGCGCGGAGCAAAGACCCTGAACCTGCCGGGGCCGCGCTCCCGGGCCCGCGTCGCCAGCACCTCCCCACGCGCGCTCGGCCCCGGGCCACCCGCCCTCGTCGGCCCCCGCCCCTCTCCGTAGCCGCAGGGAAGCGAGCCTGGGAGGAAGAAGAGGGTAGGTGGGGAGGCGGATGAGGGGTGGGGGACCCCTTGACGTCACCAGAAGGAGGTGCCGGGGTAGGAAGTGGGCTGGGGAAAGGTTATAAATCGCCCCCGCCCTCGGCTGCTCTTCATCGAGGTCCGCGGGAGGCTCGGAGCGCGCCAGGCGGACACTCCTCTCGGCTCCTCCCCGGCAGCGGCGGCGGCTCGGAGCGGGCTCCGGGGCTCGGGTGCAGCGGCCAGCGGGCGCCTGGCGGCGAGGATTACCCGGGGAAGTGGTTGTCTCCTGGCTGGAGCCGCGAGACGGGCGCTCAGGGCGCGGGGCCGGCGGCGGCGAACAAGAGGACGGACTCTGGCGGCCGGGTCGTTGGCCGCGGGGAGCGCGGGCACCGGGCGAGCAGGCCGCGTCGCGCTCACC | 1 |
인간 FLK-1 (hFLK-1) | TGGAGCCGCCAAATATTTTGGGAAATAGCGGGAATGTTGGCGAACTGGGCAAGTGCGTTTTCTGATTAAGAGCAACCAGATTCAGCTTTTTAAACTACAATTATACTGGCCAAACAAAATACCCTTATACAAAAACCAAAACTACTGGCAGGAGTCGCTGCCAGCTTGCGACCCGGCATACTTGGCTGAGTATCCGCTTCTCCCTTGTGGCTCCAAACTGCTGCAGATTCTCGGCCACTTCAGACGCGCGCGATGGCGAAGAGGGTCCTGCACTTTGACGCGCCTGGTGAGGGAGCGCTGCTCTTCGCAGCGCTCCTGGTGATGCTCCCCAAATTTCGGGGACCGGCAAGCGATTAAATCTTGGAGTTGCTCAGCGCCCGTTACCGAGTACTTTTTATTTACACCAGAAACAAAGTTGTTGCTCTGGGATGTTCTCTCCTGGGCGACTTGGGGCCCAGCGCAGTCCAGTTGTGTGGGGAAATGGGGAGATGTAAATGGGCTTGGGGAGCTGGAGATCGCCGCCGGGTACCCGGGTGAGGGGCGGGGCTGGCCGCACGGGAGAGCCCCTCCTCCGCTCCGGCCCCGCCCCGCATGGCCCCGCCTCCGCGCTCTAGAGTTTCGGCACCAGCTCCCACCCTGCACTGAGTCCCGGGACCCCGGGAGAGCGGTCAATGTGTGGTCGCTGCGTTTCCTCTGCCTGCGCCGGGCATCACTTGCGCGCCGCAGAAAGTCCGTCTGGCAGCCTGGATATCCTCTCCTACCGGCACCCGCAGACGCCCCTGCAGCCGCGGTCGGCGCCCGGGCTCCCTAGCCCTGTGCGCTCAACTGTCCTGCGCTGCGGGGTGCCGCGAGTTCCACCTCCGCGCCTCCTTCTCTAGACAGGCGCTGGGAGAAAGAACCGGCTCCCGAGTTCTGGGCATTTCGCCCGGCTCGAGGTGCA | 85 |
인간 Tie-1 (hTIE-1) | AGCTCCTCCCAGCCTCAGGCCCAGGAATGGGAATCTCTGTGGGTCACACATCAGTAGGGAGGTCTTTCCCGATCCTTTTCTATGCTACTCCAGGAGTCAAAGCGTCTCCTGGGACTTTTCAGGGCGCTTCAGAAGAGCCCTGGGCCTAAACCAGCTCAACCAAGCTGCAGGGACCCAGCCTCCTGAGAAAAGTGAATGTGAGCCCGGTGCATTCAGAGGAGAATGAAGCCTTCACCCAGAACACACTCTGGGAAGATGTCCCAGGCCCAGGGGGAGGGTTTGTACTACCAGACCTAAGTCACCTAAACTGACACCAAGTCTCATCCATCCCAACCATTCCATTCCGGGTCAGAGGGGTCATCGATTTAACCAGCAAGGCTGCCCATCCAACGGTTGCTCCCTCTGCTCCCTGGAAGGGCCTCCTCGTGGGCGTTCTGTACCTACAGGTCTTGTTCCGTTCTGGGAACTGCCAGTGGTGGCAAGAGGTGGAGCAACGGGTGCCAGGGCAGGGAGAGGTGAGTCTGGGAGGGAAGCAGAGGCAAGATCCATGGGGCTTTAGAGACTTTGCCAAAGCAGTGCGACTGCTCCCAGGTTGTTGTCAGCCGTCAAGAGTGAGTGCACCTCCCTGGGCAGACTTCTGCTGCCCCAGTGCCCAGGAATAGGCAGGGGTTTGCCGCAAAATGAATGACACCTGGCAGACAATAAGCTGAAGCTTTCATTAGCAGCTTAAGCTGAGGACTATCTATGCAACCGATACTCCCTGTGTGCTCCCCGGGACTGCTTAATGTGAGCCCTTGTGGAGCGATTGGCACCAAGAAAGCAAGGACTAAGTCAGAAGTTCAAGTCCCAGCCTTGCCACAGCCTCAGGGTGCCCTCGAGCACAGCAAGCCTCAGTTTTCCCATCTGTACAATGAGAGAGGTACACAAGGTAGACTCGAAGGCTCTTTGTTGCCAGGGCCCTGTGTTCCTTTGAGTGTATGTGCTTCTCAGGCCCACAGAGGTCCTTTGTGTTTCGTATGTGAACTGCTCTCTAGGAAACCCATGTAACTGTCTGTGTCCTGGGGCACATACATGAGGACTCATGTGGGCCGTATTGTGTGTTTGTGCCGGGGGGAGGGGAGACCCCAGAACAATGTCCCCCACCCCACCCCCCTCCTCAATAGGCGGAAGCCACTGGCTTCCTCCCTTTCCTGCCTCCTGCCTCCTTTGTGCCAGCAAGACTGAGTACTGGAGAGAGACAGGGGATGGGAAAAATCAGTCCAGCTGTCCCCAGGTCTGCCCTTACCATAACCTTCCCCCCACCTCAAGTGACTCCTCCCAGGCCACACCCATCCCCAGCCTTGTGGGGGCCAGATTGGGGGGCCTAGAGGCTCAAAGGCAGAATGAGTCCTCCCACCCCCTACCCTGCCACCCCTCCCACCCAAGCCACCTCATTTCCTCTTCCTCCCCAGCACCGACCCACACTGACCAACACAGGCTGAGCAGTCAGGCCCACAGCATCTGACCCCAGGCCCAGCTCGTCCTGGCTGGCCTGGGTCGGCCTCTGGAGTATGGTCTGGCGGGTGCCCCCTTTCTTGCTCCCCATCCTCTTCTTGGCTTCTCATGTGG | 2 |
마우스 Tie-1 (mTIE-1) | AAGCTTCCGACCGTTAGTCAGAGAACTGTAAGTGCTCAGAGCCTGGCTGACAATGATCTGGAATGAACCAGATAACAACATAATAAAATCTCAGTAAAATAATTTAACAGTTAGCTTGGAAGCTGGTCAGCTCTGGGGAAATCAGGGTAAATTGTGCTGTCATGAACTGTCCCACACTGACATCGGCCAAAGTGAATATGAACTTTGGTAGATCCAATGCCTGTTCTATTTATTTTTCCAGTGAAAAGTATTTTGATAGAGCTTTTCATTTTGTAAATACACTGAGTTAACCAAAATATCATGGATTTCCGTTTGTTCTTAAGACATGCAACTCGTCTACGGCTATACCACTCTGAACGCGCCCGATCTCGGAAGACATGCAACTCAAATGTAAATACAGTAGAATATTACTTAGGTAGAAACTCCTGGTGATTTTAAAAGATTGGAAAAGAATATGAGGAAGAGTTGAATAATGCAAATTCTAGTGTGTGTGCTACCGAAGTGAACACTTAATGCACAGTCTACAGACTAGGACATTTTATCGTGTGTTGTAAAATTGGGTAGAAACTTGTGTTTGTGAAAACTGAGCATTAAAACCTTACAGAGACCGTTTCTTGTTTACTTTTGAAAAAAAAAAGAGTCACGTGAGCCTCATTTTGTATTTGTGTGTGTGTGTGTGTGTGTGTCTCCCCTCCTCCCAGCGTGTGTGTGCTGGGAGGAGGGGAGACCCCAGAACAATGTCCTGCCTCCAAACCTTCTCAATAGGCGGAAGCCACTGGCTTCCTCCCTTTCCTGTCTCCCGTGCTCCAGCAATGCAGATGGAAGGGACCGAAGGGATGGGAGAGAGAGCCCAACCATCCCCAGATCTGTCCTTGTCACAACCTGCCTCCCACCTCTAATGCCCCCCCTTCCAGAGACTTCCAGGCCACACCCATCCCGGGCTTGTGGGGGCTGGACACGGGAGGACTACAGGCGACAACTCTTCCCACCCTCTCTCCCTGCCACCCCTCCTACCCTAACCATCATTTCCTCTTCCTCCCCAGCACCGAGGTGCACTGAGCTGGACAGGCTGAACACTCAGACCCACAGCAACTGACCCCGGGCCCAGCTGGCCTTGGCTGGCCCAGGGCAGCTTCCAGAGT | 86 |
인간 Tie-2 (hTIE-2) | GCTGGAGTGCAGTGGCACGATCTCGGCTCACTGCAACCTCTGCCTCCCAGGTTCAAACAATTCTCCTGCCTCAGCCTCCAGAGTAGCTGGGGTTACAGGTGCACGCCAGCAAGCACAGCTAAATTTTGTATTTTTAGTAGAGATGGGGTTTTGCCATGTTGGCCAGGCTGGTCTCAAACTCCTGACCTCAGGTGATCCACTCCCAAAGTGCTGGGATTATAGGCGTGAGCCACTGTGCCAGGCCCACTGTTTTTGTTTTTTTTTTTCGTGATGACAAATTTAAAGTCATCTCATAGGAATAGAAAATAGCTTTTTAGTAGAAGCTCTTGGAATTTAAATTGAGACTGAATGGAAAGATGAAAGAAAATAAACTTATTAACATTTAATGAGAACCTTCAAAGAACTAGGCATAGTACCAAATGGTTTTATATTTTTAAACCTCATTTATTCCTCTCAAAACACCTGGGAAGGAGATATTTTTGCCATTTCACAGCTGTTGAAACTGAGGCTCAAAAAGACTAAGTAACTTTTCTCAGCTACACATGTGGCTGAGCCAGTATTTGAACCCAGTTCTGTTTGCAGACAGAACCTGGGCTTTTTCACACCTGCAAACTGGAAACATTAATTGGTTCTTAAGATCATCATCGATGTGATAAAACCTGGGACAGAAATTAGTCAAGACTAGCTGCATCTGCCTTTTCCTCTGGTGGGTAGGAAAAGGAGGAGTATAATGATTTCCTCAGGCATGAAGGTCGATGATGAGCAAAGTGTATACTCTCTAATCTAATGTCATAATTCATATTGTGGAGTAATTATCTGGATAAGTGTAGGGTCTCTGACCTCATTCTAGATATTGTACATTCCATGGCTATTTTCATTTTGGTCCATGAACTCTCTTTGCTCTCATGAGCACCATTTTTATCCCAATCTAATCCTGTATGTTTGTGTTTTTACACAGATTAGTTTTTAAATGTTATATATAATTTGCTTCTGAAACACCATTGCTCAATGACTACCAAATCTTTCTCATTACCAAAATCCTTCTATGCCAACTTCTTCAAGAAATTTGATCACCTTTAGATGAATTGTTAATGAAAATTAAAGCTATAGCCGGCAACATGGGTATCTTTGGGCTAATGGCCAACCAACAGGCCATCTGTGTGAAAGAAAACAGGCTAACAATTTTGGACTCTGGTCTCTTGGGGCTACATTGAGCATTGACCTCACCGGTGCTCACTGAAATTAATTGCTTTTCAGGTTGTATTTTCTCATCACGGAAACCTTCTTCTCCCAATTCAAACCATGTGGGTTAAAATGAGAAAACAAAAGCCAAAACGGCTTCCCACACCCAAAAGCTCCTTCTGTCAGAGATCCCAGTAGCCCCGGGAGAGCTGTTAGAAGTCTGAGAAGGATTGGTCATCATCGCATACCATACATAGGTGGAGGGCTTGTTATTCTCAGTTTCCCGCCTATGAGAGGATACCCCTATTGTTTCTGAAAATGCTGACCGGGACCCACACTTCCAACAAAAATTCCTCTGCCCCTACAGCAGCAGCAAAAGCAGCAGCAGAAGCAACAGCAACAGATAAGTGTTTTGATGAATTGCGAGATGGATAGGGCTTGAGTGCCCCCAGCCCTGCTGATACCAAATGCCTTTAAGATACAGCCTTTCCCATCCTAATCTACAAAGGAAACAGGAAAAAGGAACTTAAAACTCCCTGTGCTCAGACAGAAATGAGACTGTTACAGCCTGCTTCTGTGCTGTTCCTTCTTGCCTCTAACTTGTAAACAAGACGTAGTAGGACGATGCTAATGGAAAGTCACAAACCGCTGGGTTTTTGAAAGGATCCTTGGGACCTCATGCACATTTGTGGAAACTGGATGGAGAGATTTGGGGAAGCATGGACTCTTTAGCCAGCTTAGTTCTCTGTGGAGTCAGCTTGCTCCTTTCTGGTAAGGTTTGGCTTTATTTTTTTTAATTTAGTATTTTAAAAAACAGAGTTAGTGATTTCTGGGTGCTCTCCCCAAATCTCATCAGTGCTGATGAACAAGGGGTGGCTGTAGCAAAGGCACCATTTC | |
인간 VE- 카드헤린 (hVE-카드헤린) |
CTAGTAGCAGAAACAAGGTCCTCTGGAAGAGCAACTGATGCTCTTAGGTACTGAAGCATCATCCTGCCCCAGAGACCACTCGCATATGAAGCACACATATTCAGTCTGCCTTACTTGTGTTAATGATTGCCAGTGTCCCTCTGACCTCCTAGCCCTGAAAAGTGTGGCCTGAAGGTCATTTCAGAGACGGGGAGAGCTGCTCAGAGAAGCCAATCGGCGAGTCTAGGACACACAGACAGGATCTAGTCCCAGAGTTCGCTAGCCTAGGTGAGCGTCCCCTGGCCCCTTATACCACTTCCTTCTCCAGCTTGCATCTAATCTGCTCTGGCAGACCATCGTGTTTCCTGTCTTCCTGGCAGCCTCCAGCACGCTCAGTGCTACTCCCTGCGCATGCGCCCTCCTCCCAGTACCTTCTCTGACTCCAGTGGGCTTGGAGTGCGAGGAGGAAGGGTGAGGAAGGGGTGAAATCAGGTATTGGATCCACAGGGGGTCTGAAGAGCACTAGCCTGGCCTTTTGGGACTGAACTTCTGCTATGAAGACCTCCACTGCCATCCCTGGAGTCCGGGGCACATCCAAGGCTTGCTGTCCATCGTTTACTGTTTACAGATGACAACAATGACTGTGTTCGGGGCAGAAATATCCACCAGGGCTAGAGTACAAAAGGAGTTTGCATTGATGGCCGGACAGGCCCTGTCCCTGGCAGCCTGCCAGCGCTGAGTATGAGACCCAGCGGGAAGTGCTACCCTGGCAGACGTGTCCACTGAGTACACAGACCACCAAGGCAGGCAGCTCTCGGGGAAGCTGTCTATGCTGGGCCAGCCCACCTTGAGGGCAGGGAACAGAACAGATTGTGGCAGAGAGGAAAATGTGGAGCTTCTGTTTGTTCACAGACACACGCACTCGCCCACGCACGCACGCACGCACGCACGCACGCACGAATGCACGCACGCAGTAGTTGAATGCTATGGATTCCGCTCAGAGCTGAGAACAGCCCCAGCGACAGTTCCCTGGCCTCTCTCCTTACTCTGATGTCCTCATCTGTCTTCACATGGTCTCAGGACGCTAATACTCCATCCTAATGTACACTCCTTTCCCTGGGCCTCCGTTCCAGTTCAGTTCTCAGAGGACCTGGAGGGAGTGATTGGCTACACCAACTTTGCTTTCGTTCACCAAGCCCATGTCTCTACTTGGGTGTCTAATGGGCATCTCCAACATTACCTACCCCAAACAGAAAACCCTTTCTTCCCCCCAACCACACCCCACCCTACCCCCACAGTATTTTCTCCATGCCCGGAAAGATCTGCTCTCTTATGGTCCCTCTTTGCCTCACTGAAAAGCAGGACAAGTTGGGGACTTCCCAAACTTTTATGCATGAAGAAACCCAGGCAATTTGCCAAAAGGTACACTCTGGGGGTCTGTCATTTACTCTGAGCCAGAACCCTGAAATTTTTACTAACCCATCACATAATGAATGAAGAGAATCTTTTTCTTTTTTTTTTTTTTTCTTTTTTTTTGGTTTTTCGAGACAGGGTTTCTCTGTATAGCCCTGGCTATCCTGGAACACACTCTGTAGACCAGGCTGGCCTCGAACTCAGAAATCCACCTGCCTCTGCCTCCCGAGTGCTGGGATTAAAGGCGTGCGCCACCACGCCTGGCTGAATGAAGAGAATCTTGACCTCATCTCCCCAGCCTCTTGGTCCTGAGGGACCCTGGTCTACCTACTGCTTTGCTGTCTTCTTAGCTCTTCTTACTTTTTTGCTGACTCAGACCTATGGCTATCTCCATTATACAGATGAGGAGACTGAGGCATGGATCCCTGGTTGGTCCATGGTCACGTGAAGCCCATCACCCAGTATTTGTAAAGTGAGATGGGCCAGGCTGGTACCTTGGAACTGAAACTCACACTGCCCTACCTGGAAGAATCTGACAGGCAAAATCTGCTGCTGAAAGTGATTGTCTGTCACGTTTCTCAGCTGCCCGACTCTGAGAACTCCACAGCCCCCTTTCGTTCCACCATACTACAGAGTCGCCACGGAAAGCCGGCTCTGTGGAGAAGCTGAGGTAGCTGGGTTTCTGTCTGGGTTACTCTGTCCAGCGAGGAAACAAGTACCTTAGACCCACTAAGCCTCTGCTTTCTGAACTGTAAAGTGGGGGATATGACACCTGCCTCCCAGGGATGGCTGAATGCTCTGGCAGAAGCTTAGAGCCCCCACAGCTACCCCTAGGCTCACAGCTCCTCCGATGAGACCTAGAATTGAGGTATGAGTTGAATACCCCAGGCAGGTCCAAGGCTTCCACGGGCCCAGGCTGACCAAGCTGAGGCCGCCCACCGTAGGGCTTGCCTATCTGCAGGCAGCTCACAAAGGAACAATAACAGGAAACCATCCCGAGGGGAAGTGGGCCAGGGCCAGTTGGAAAACCTGCCTCCCTCCCAGCCTGGGTGTGGCTCCCCTCTCCCCTCCTGAGGCAATCAACTGTGCTCTCCACAAAGCTCGGCCCTGGACAGACT | 3 |
인간 VE- 카드헤린 (hVE-카드헤린) (짧은 버전) |
CATCCATGCCCATGGCCTCAGATGCCAGCCATAAGCTGTTGGGTTCCAAACCTCGACTCCAGGCTGGACTCACCCCTGTCTCCCCCACCAGCCTGACACCTCCACCTGGGTATCTAACGAGCATCTCAAACTCAACCTGCCTGAGACAGAGGAATCACTATCCCCTCCTCCTCCAAAAATATCCTTCCATCACACTCCCCATCTTGTGCTCTGATTTACTAAACGGCCCTGGGCCCTCTCTTTCTCAGGGTCTCTGCTTGCCCAGCTATATAATAAAACAAGTTTGGGACTTCCCAACCATTCACCCATGGAAAAACAGAAGCAACTCTTCAAAGGACAGATTCCCAGGATCTGCCCTGGGAGATTCCAAATCAGTTGATCTGGGGTGAGCCCAGTCCTCTGTAGTTTTTAGAAGCTCCTCCTATGTCTCTCCTGGTCAGCAGAATCTTGGCCCCTCCCTTCCCCCCAGCCTCTTGGTTCTTCTGGGCTCTGATCCAGCCTCAGCGTCACTGTCTTCCACGCCCCTCTTTGATTCTCGTTTATGTCAAAAGCCTTGTGAGGATGAGGCTGTGATTATCCCCATTTTACAGATGAGGAAACTGTGGCTCCAGGATGACACAACTGGCCAGAGGTCACATCAGAAGCAGAGCTGGGTCACTTGACTCCACCCAATATCCCTAAATGCAAACATCCCCTACAGACCGAGGCTGGCACCTTAGAGCTGGAGTCCATGCCCGCTCTGACCAGGAGAAGCCAACCTGGTCCTCCAGAGCCAAGAGCTTCTGTCCCTTTCCCATCTCCTGAAGCCTCCCTGTCACCTTTAAAGTCCATTCCCACAAAGACATCATGGGATCACCACAGAAAATCAAGCTCTGGGGCTAGGCTGACCCCAGCTAGATTTTTGGCTCTTTTATACCCCAGCTGGGTGGACAAGCACCTTAAACCCGCTGAGCCTCAGCTTCCCGGGCTATAAAATGGGGGTGATGACACCTGCCTGTAGCATTCCAAGGAGGGTTAAATGTGATGCTGCAGCCAAGGGTCCCCACAGCCAGGCTCTTTGCAGGTGCTGGGTTCAGAGTCCCAGAGCTGAGGCCGGGAGTAGGGGTTCAAGTGGGGTGCCCCAGGCAGGGTCCAGTGCCAGCCCTCTGTGGAGACAGCCATCCGGGGCCGAGGCAGCCGCCCACCGCAGGGCCTGCCTATCTGCAGCCAGCCCAGCCCTCACAAAGGAACAATAACAGGAAACCATCCCAGGGGGAAGTGGGCCAGGGCCAGCTGGAAAACCTGAAGGGGAGGCAGCCAGGCCTCCCTCGCCAGCGGGGTGTGGCTCCCCTCCAAAGACGGTCGGCTGACAGGCTCCACAGAGCTCCACTCACGCTCAGCCCTGGACGGACAGGCAGTCCAACGGAACAGAAACATCCCTCAGCCCACAGGCACGGTGAGTGGGGGCTCCCACACTCCCCTCCACCCCAAACCCGCCACCCTGCGCCCAAGATGGGAGGGTCCTCAGCTTCCCCATCTGTAGAATGGGCATCGTCCCACTCCCATGACAGAGAGGCTCC | 88 |
인간 세포간 부착 분자 2 (hICAM-2) |
GTCTCCCAGGCATGACTCCAACAATGCATCCCATGGGATTTGGGGTTCCCCAGATCTGGGGCTTGTAGGCCTGACTCTCCCCTGTGCACACGTCTCATACACGCATGCGTGCACCCATTGCCTGCCCCGCCCCTTGCACAGGGAGTCAGCAGGGAGGACTGGGTTATGCCCTGCTTATCAGCAGCTTCCCAGCTTCCTCTGCCTGGATTCTTAGAGGCCTGGGGTCCTAGAACGAGCTGGTGCACGTGGCTTCCCAAAGATCTCTCAGATAATGAGAGGAAATGCAGTCATCAGTTTGCAGAAGGCTAGGGATTCTGGGCCATAGCTCAGACCTGCGCCCACCATCTCCCTCCAGGCAGCCCTTGGCTGGTCCCTGCGAGCCCGTGGAGACTGCCAGTC | 89 |
인간 폰 빌레브란트 인자 (hVWF) |
ATCTTTAGCCGATCCATTCAACCCTGGCCAGGATCCAAATGGACTGTTTTTGTCAGGGCCAGGACCGGATCCTTCATACCTGGGGTGCATAGGAAGTGTTAGTACTCCCCTTCCTCCAAACACAGCAGCAAAATTGGCTCAGGTTGAGGTGTTTTTCTCAACTTCCCTGGAGTCCAGCCCTGGAAGCTGGATCAGGAAGCTGTGTTGTTCTACTGTGATTCCCCCTGGCCTGTATCAGCTTGCCCTGAAACAACCAGCATTCCTGGTTATCCCACACAGGTGGGGCACTCTAGGAAGACCAGGGATCAAGTGTGGGGGTGTAGGGATAGGGGGTGTTTGGGGAGGGCAAGGCAGTTAATTAAGGCAGCTGCCAGGAGGTCTCCCTCCAAACTCTACAAAGCTTTATCAGCTTGGAGGTACTTCTAATACCATTTCCTTTCATTGTTTCCTTTTGGTAATTAAAAGGAGGCCAATCCCCTGTTGTGGCAGCTCACAGCTATTGTGGTGGGAAAGGGAGGGTGGTTGGTGGATGTCACAGCTTGGGCTTTATCTCCCCCAGCAGTGGGGACTCCACAGCCCCTGGGCTACATAACAGCAAGACAGTCCGGAGCTGTAGCAGACCTGATTGAGCCTTTGCAGCAGCTGAGAGCATGGCCTAGGGTGGGCGGCACCATTGTCCAGCAGCTGAGTTTCCCAGGGACCTTGGAGATAGCCGCAGCCCTCATTTGCAGGGGA | 90 |
Ple261 (인간 Claudin5) | TGGCTTCCGGAGGGTGGCCTGGGGGCTGGGGTGCCAGGGACACCATCGCCACTGGTGGGAGGGCAGGGCACAGCCCCTCCGTGTCCCTTTGTCTCTCCTGTCTGAAGGCCAGAGCAGGCTGCTAGGCCTGGGGCCACCACTGCCCCTGGGTGCTACACCCAGTGTGCTGGGTCACTGGGAACTTCCTGAAGTGGTGTCACCTGAACTGGGCCCCCAAGGATGGGGTGCGGGCAGTACCGCAGGAAGAGGAGCAGCCCCTGTGAAGATTGAGAGGTCTGGGAAGCCCCTGCGGCTTGGGAGAGTGGGGGTCGCCAGGCAGGGGGAAAGCCCCTGTGCCACCGCTTTTTGCCAGAGACTCAGGCTCCAGAGAGGCAGTGAGTGGCATGGGGGGTGAGGCTGGGGCCCTGGGCCTGACCTCCACACGCCTGCCTGGCCTCTCTGTTTGCCATGGGATGAGAGAGACAGTGCTGGGACTCAGAGCGGGGCTGGAGAGTGAGAGTGCGAGAAAGGGCCTGGGTGGGGCTTGGACCCCGGGGCGGGCTTTCTGGAGAGCCCCCCTACGAGGGCCTCTACGGCGGTGACGGGGTGGGGGGCTTCTGCAAACCTTGGTCAGGGAAGTGGAGCTGGCTCGAGTGGAAGAGACCACCCGGCTCAGTCGGGGATGTGGGAGTGGACTGGGTGGTGCAGACTGGGGGTCGAGCGCCTTCTGAAGTGACGGGGCCGGGACGCGCAGGGAGGCGGCCCAAGAAGCGCGCCCTAGGCCAGCCCAGAATGCGCTCGGCCGCGACTAGGACAACGGCGGGTGGGGCTGGGGGCGGCTGCCGGGCGGGGAGCGGTCCCGCGCCCTCAGCTACCCCTCAAGAGCCGTTGTTTCCCTAACTTCAGCTGCCAGAGGCTCTGTGATTGGCTGCGGCACGATGACCCGCGCACGGATTGGCTGCTTCGGGCCGGGGGGCCGGGCCCGGGGGACAGAATCCGCCCCCGAACCTTCAAAGAGGGTACCCCCCGGCAGGAGCTGGCAGACCCAGGAGGTGCGACAGACCCGCGGGGCAAACGGACTGGGGCCAAGAGCCGGGAGCGCGGGCGCAAAGGCACCAGGGCCCGCCCAGGGCGCCGCGCAGCACGGCCTTGG | 91 |
인간 엔도글린 (hENG) | CGCCTTGCTGTGCCACTTTGGGACTTCCCTCCCTAGCCTGAGCTTCAGTTTTCCTGCCTGTTAGGCAGCCCCATGTCAACTGCACTTAGTAGGCCGGGTTTGATGCCCGACAAGACGTGAAGTGGTGGAGGTGGGCAGGATCCCAGCGCTACCATCTTCTTGAACCAGTGATCTCAACACATCGGATTTCTGTTTCCTCATCTGCAAAATGGGATCAGTGAGCTCAGGTGGGTCACAAATTCTACAGGAACTACTTTAGCCAAGCCCGGCCCCCTGAAAGTTCCCCTCGGTGGGCTGTTAGGGTGATTGTTTTCATCTGTGGGGCTCCCTGATGCGTCCCACCCACCAGCCTTGGAGAGGGTGGGATGGGAGGGTGGGGTGCTTGGGGAGACAAGCCTAGAGCCTGGGCCCTCCCACCCCACTGCCTCCCCCCATCCCAGGGCCCCCCACCCAGTGACAAAGCCCGTGGCACTTCCTCTACCCGGTTGGCAGGCGGCCTGGCCCAGCCCCTTCTCTAAGGAAGCGCATTTCCTGCCTCCCTGGGCCGGCCGGGCTGGATGAGCCGGGAGCTCCCTGCTGCCGGTCATACCACAGCCTTCATCTGCGCCCTGGGGCCAGGACTGCTGCTGTCACTGCCATCCATTGGAGCCCAGCACCCCCTCCCCGCCCATCCTTCGGACAGCAACTCCAGCCCAGCCCCGCGTCCCTGTGTCCACTTCTCCTGACCCCTCGGCCGCCACCCCAGAAGGCTGGAGCAGGGACGCCGTCGCTCCGGCCGCCTGCTCCCCTCGGGTCCCCGTGCGAGCCCACGCCGGCCCCGGTGCCCGCCCGCAGCCCTGCCACTGGACACAGGATAAGGCCCAGCGCACAGGCCCCCACGTGGACACC | 92 |
인간 혈소판 유래 성장 인자 서브유닛 B (hPDGFB |
GCCCAGGCTGGAGTGCAGTGGCACAGTCACAACTCACTGCAGCCTCAAACTCCTGGGCTCAAAACGATCCACAGTCTCCTGAGTAGCTGGGACTACAGGAGCTTGTTACCACACCCAGCTCCAGTTTATAAATTCATCTCCAGTTTATAAAGGAGGAAACCGAGGTACTGAGAGGTTAAAAAACCTTCCTGCAGACACTTGTCCAGCAAGTGGCCACTCCAGGATTTGGACCAAGGTGATGTGTCTTCAGGCTGTGTCTCTGCCACTGTGCCACGCTGCTGGGTGGTAGGCAGCAGTGGGTGGGTGCCTGCAGTGGTCTGTAAAGACCACCTGAGATGTCCTTCCTCCTCTGTTCCACCCTGTCCAGGTCCAAGAAGACAGTCTATGAAGAGAGAGCAGGTGTGACTCTCTCAGTGTGCTCCTCTGTGAGAAGCAGGCTGACATCCCAAAGGGAAGGGCGGATAACAGAGACAGTGCAAGCGGAGGAGATGAGGGTGCCTCAAAGCCGGGAGGCTGGGTGATGCAGGAGCCTGCGTGTCCCGAGGGGGGTGCTGGGCCCAGTGTGAGTACGTGTGACTGTGACTGAGACAGTGTGACTGCTGAAGGCAGGGACACAGCAGCTCCCTGACTGGGGGCAGAAGGCGTTAACTGTGTGAAGGCTGGTTGTGGGTGGGTGGGCTCTGGGCCTCGAACCCGGGGGCTGAGGGAGATAGTAAACAGCAGGGTGACTGACGGGAAGATCATGTTGGTAGCCCTGCGAAGATGCTGCAGGGCTGTGGGGGTTTGTGTGACTTTGCAGTTCAACAAATTCAAATTCAGCCAACGCTGGCAGGGCCTGTTGTGCCAGGCAACCAGCTAGGAGGAGGAGACTCGGACCCAGCTTGCAGCTGAAGGGCGCTGGCTGCCGGGTTCTGTGGGTTCACCTTGCGGTGTCTTCCCTTGCTAACACTGAGTCCTTACAATAGCCCCATCTCCAGGTTGAGGCTAGATGGAGGGGACAGAGGGAAGTGACTTGCCCAAGGTGACCCAAGCTCCCGAGTGCCAGGGCAGGATCTGAATTCAGGCTCTCAGACTGCAGAGCCTGAGTCCCTCCCTGCCATGCCTGTGCCAGGGTGGAAATGTCTGGTCCTGGAGGGGAGCGTGGACTCCTGGCCTTGGCTCTGGAGACATCCCCCTAGACCACGTGGGCTCCTAACCTGTCCATGGTCACTGTGCTGAGGGGCGGGACGGTGGGTCACCCCTAGTTCTTTTTTCCCCAGGGCCAGATTCATGGACTGAAGGGTTGCTCGGCTCTCAGAGACCCCCTAAGCGCCCCGCCCTGGCCCCAAGCCCTCCCCCAGCTCCCGCGTCCCCCCCCTCCTGGCGCTGACTCCGGGCCAGAAGAGGAAAGGCTGTCTCCACCCACCTCTCGCACTCTCCCTTCTCCTTTATAAAGGCCGGAACAGCTGAAAGGGTGGCAACTTCTCCTCCTGCAGCCGGGAGCGGCCTGCCTGCCTCCCTGCGCACCCGCAGCCTCCCCCGCTGCCTCCCTAGGGCTCCCCTCCGGCCGCCAGCGCCCATTTTTCATTCCCTAGATAGAGATACTTTGCGCGCACACACATACATACGCGCGCAAAAAGGAAAAAAAAAAAAAAAAGCCCACCCTCCAGCCTCGCTGC | 93 |
인간 내피 세포 특이적 분자 1 (hESM1) |
ACATCCAATGCCCGCTCTGCCTCATCTTCTATGGGAAACAAGAATTTTAGAGGTCAGGTAGCCTAACACCATCAATTCTCAAAAGAGGAAGCTGAGGCCAAGAGAAGTCCTGTGAATTTCTTACAGCTCATTTGTGACAGACCAAGAATTACCCACTTTACTGGGTTGTTATTTACTAAGTGACAGTGAGTCTATATCTCTTTTGACAAGTGAGGTGGGGGCATGGAATTCGGCATGTGGTTGGTGTAAGAACTCCCCTCTCTCCTCTTTAACCTTACTTAATAAGACCCTGGCACAGTTGATATTTTAAGAGGGCTACTCTGTTTTCCCAGAGGGACCTAGGCACGGTAACCCTCTTAGCATGCAGACCTTGTTTCCTGAGGGGTAATGTTTCCCTTCCCTGTGACTTGTTTCTTGGGGGCTGTGTTCTGATTTTCCTGCTGAGCCACTTGTTGCCTTGGGCTGGCTGCCGCGCTTGGCAGTTTTTAGTGAGGGCTCTGATAGATGCCAGGAGGTGAGGGGAAGGGCTCTGGGTGGACTCCGTCATTGGACAAGCAGACTTAGTGATGGATGAGCCTTCCCCTGAGGAAGTTTTGGATCAGAAGTCCAACTGATAAGTTTTTCCAGAATTGAGTAACCCAGAAGCAGTGCCGAAAGGATCTTACCTCTCTTGTGGCTTTTTGTATTGATTTTAAAAGAAATTCTCAGAGGCAGTTCCACATTGTACTGGAAGCACAGCTATATCCACAATAGGCTTAGATATATGTAACATGAATTGCTTTAGAAATAACATTTGAGGAGAGGGGTGAGAGGAAGGAAGAGAGGGTCTTAAAAAATAGCCCTATCAAAATATTTTCTTTCTTCTAAGTATTGAAAAGACACAATATAACCCTTTCTTCTTTCAAATGATCTCATAGCTATTTGTTGAGGGGAAATACCAAATGTTTATTATTTTTTTTGAAGAAGCTTCTTCGGTCCTGATGATTCATGTTGATATCATTTTCCTCCTGACTACAGAGGCTCTGAGACAAAGCTACACCTCAAGTGATATGCCAGGGTCAGAACAATTCCCGTCCTGAAGGAGGGTGTGCAACCTTCTTTATCCCTCCTTCACAGACGTCCTTGAGCCCTTGAGACGGATGTGAGTGAGTTTTTCAGTCCTCATGCAAAACAACCATCTAAACATAACAGATGACATCAGCTTGGGCTTTTCAATTCCTGGATGGCAGCAGCGTGTTAATCCAGCCTTCATCCTGGATTTCATAAACCAAAACAAGAGAGCCTGGCAGGAGGACAGCGCTGCTGCTGGGTTGAGGAAATTGATGACGGGAAAGCATGCGGGCAACCCAGTGTATAAAACTCATAAACGTGTAGGCAGAGGCTCAGCTACCAGTTTGGACGGCTGCTTCCCACCAGCAAAGACCACGACTGGAGAGCCGAGCCGGAGGCAGCTGG | 94 |
인간 아펠린 (hAPLN) | TGGCACACACGCACCCTGTCCAATGTATCTTTTGTGTAAATCTGGACTTAACACTTCAAGCAAACTGCCTGGCTTGCTGAAAGGTGGAGACACCTTTCGATTCAGTCTTTTAATATGTGTTGAGTGCCACCTATGTGCAGAGCAAGATATTGGGGACTTTGGAGAGATCCAGAAGAGTGAGAAGACAGTATCCTACCTTAGGGGGTTCCCAGTCCAATGAGGGAAGCAGCCCCATGCCTTGGGAGCTCCCAAGCTATAGAAGCAGCTAACAATCGAGTCTGGAAAGGCAAACAACTTCAGGACCCGCTTCTAAAGCGGAATCGCAAGTACACGCAAAATGAATCCAGCCTTGACTGTGTGGAGTTGGGTAAACCACCTGCCTCTTACGTTGATGGGGAACTAGAATGAGGACAGCTCCAGGGAACAAGAAAGGGTAGACCATAGGAGCTGTCCCATGTCCCAACAGTGGGGAGGAGCTGATGGGCGGCCCCTGCTGGATTAGTGTTATCCTGAGAAGGCTTCTGGATGCGATGGGATTTGAGGTGCTGCTGCAAAGAATGAATTGCTCACGGAAGGGTGGGGTGGGGGCATTCCAGGTAGAGGGTGCCTCCTGGGGGATGCAGGGAACATGAGGGGCCTGGGCAATTAATCAAGCCTTGGGCACAAGCCTAGGCAGTCACCCCCAATTCAAAGCCAGTTGAAAATGCAGAGGAGAGAGGAGGGCCAGTGTTTGGTTGTCTTGACCAAACCCTTGAAGCTGGCCAGCGGCAAGGGCAAGGACCAGGGTCAGAGGTAGAGGGCGTGAGTGAAGGCAACCCAGACTGAGTCCTTCCCTAAGCGCCCAGGTTTCCTGACAGCTGTTAAGGAAGCAAGGTGAGAAAGGGTTAAGTGTGCCCCTCCACCGCCCCAAATGCTTCCTGTGTTTGAAATCCTTCAGGTCTCTGCAAACCCTCTGGCCCCCGGCCAGGCGGGCATTGTCCGGGGAGCGGTTGTAGGTTGTCAGAGAGGCCGCGCAGCCTTTGTTGTGGGGCCACCTCGGGGTTCCCTCTCGCGCTCACGCTCGGGCTGGGGCTGCAGAGTGCGTGCCTGGAGGGGGGCGGTGCGGGAGGCTCGCTCCCTCTCCCTCTTCCTGCCCCCCCTCTAGCCCTCCCGATGACCACATGACCAAGTGGGCTCGCGGCCAAGCCACAAGCTACAAAATGCAGCCCCTGGAGTGAGCGGGGAGCATTCTCTCTGGCAGCCGGGGTCACGGGCAGTTGCAGCCGCGGCCGAGCAGCCAGCCGCTAAGAAAGAGCTCGCCGCTGCCGCTCCCGGAGCCGCCGAGGCCAGCTTCGCGGCGCTGCCCCGCGGCGGGAGAGGAGGCTGCAGAAGAGCGGAGGCGGCCAGCGG | 95 |
인간 베타-액틴 (HuBa) | GCCCAGCACCCCAAGGCGGCCAACGCCAAAACTCTCCCTCCTCCTCTTCCTCAATCTCGCTCTCGCTCTTTTTTTTTTTCGCAAAAGGAGGGGAGAGGGGGTAAAAAAATGCTGCACTGTGCGGCGAAGCCGGTGAGTGAGCGGCGCGGGGCCAATCAGCGTGCGCCGTTCCGAAAGTTGCCTTTTATGGCTCGAGCGGCCGCGGCGGCGCCCTATAAAACCCAGCGGCGCGACGCGCCACCACCGCCGAGTC | 39 |
닭 베타-액틴 (CBA) | GGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCATCTCCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCGATGGGGGCGGGGGGGGGGGGGGCGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGGGCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTCCGAAAGTTTCCTTTTATGGCGAGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAGCGCGCGGCGGGCGGGA | 40 |
거대세포바이러스 (CMV) | TGGTGATGCGGTTTTGGCAGTACACCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAATAACCCCGCCCCGTTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCGTTTAGTGAACCG | 41 |
거대세포바이러스 (CMV) (제2 버전) | TAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACCGT | 42 |
거대세포바이러스 (CMV) (제3 버전) | CGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCT | 43 |
CAG 프로모터 (제1 버전) |
ACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCATCTCCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCGATGGGGGCGGGGGGGGGGGGGGCGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGGGCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTCCGAAAGTTTCCTTTTATGGCGAGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAGCGCGCGGCGGGCGG | 44 |
CAG 프로모터 (제2 버전) |
CGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCATCTCCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCGATGGGGGCGGGGGGGGGGGGGGCGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGGGCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTCCGAAAGTTTCCTTTTATGGCGAGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAGCGCGCGGCGGGCG | 45 |
인간 EF1-알파 (EF1-α) | CAACCTTTGGAGCTAAGCCAGCAATGGTAGAGGGAAGATTCTGCACGTCCCTTCCAGGCGGCCTCCCCGTCACCACCCCCCCCAACCCGCCCCGACCGGAGCTGAGAGTAATTCATACAAAAGGACTCGCCCCTGCCTTGGGGAATCCCAGGGACCGTCGTTAAACTCCCACTAACGTAGAACCCAGAGATCGCTGCGTTCCCGCCCCCTCACCCGCCCGCTCTCGTCATCACTGAGGTGGAGAATAGCATGCGTGAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACGGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTT | 46 |
인간 Synapsin1 (Syn), 짧은 버전 | AGTGCAAGTGGGTTTTAGGACCAGGATGAGGCGGGGTGGGGGTGCCTACCTGACGACCGACCCCGACCCACTGGACAAGCACCCAACCCCCATTCCCCAAATTGCGCATCCCCTATCAGAGAGGGGGAGGGGAAACAGGATGCGGCGAGGCGCGTGCGCACTGCCAGCTTCAGCACCGCGGACAGTGCCTTCGCCCCCGCCTGGCGGCGCGCGCCACCGCCGCCTCAGCACTGAAGGCGCGCTGACGTCACTCGCCGGTCCCCCGCAAACTCCCCTTCCCGGCCACCTTGGTCGCGTCCGCGCCGCCGCCGGCCCAGCCGGACCGCACCACGCGAGGCGCGAGATAGGGGGGCACGGGCGCGACCATCTGCGCTGCGGCGCCGGCGACTCAGCGCTGCCTC | 47 |
3' 연장부를 갖는 인간 Synapsin1 (Syn) | AGTGCAAGTGGGTTTTAGGACCAGGATGAGGCGGGGTGGGGGTGCCTACCTGACGACCGACCCCGACCCACTGGACAAGCACCCAACCCCCATTCCCCAAATTGCGCATCCCCTATCAGAGAGGGGGAGGGGAAACAGGATGCGGCGAGGCGCGTGCGCACTGCCAGCTTCAGCACCGCGGACAGTGCCTTCGCCCCCGCCTGGCGGCGCGCGCCACCGCCGCCTCAGCACTGAAGGCGCGCTGACGTCACTCGCCGGTCCCCCGCAAACTCCCCTTCCCGGCCACCTTGGTCGCGTCCGCGCCGCCGCCGGCCCAGCCGGACCGCACCACGCGAGGCGCGAGATAGGGGGGCACGGGCGCGACCATCTGCGCTGCGGCGCCGGCGACTCAGCGCTGCCTCAGTCTGCGGTGGGCAGCGGAGGAGTCGTGTCGTGCCTGAGAGCGCAG | 48 |
5' 연장부를 갖는 인간 Synapsin1 (Syn) | CTGCAGAGGGCCCTGCGTATGAGTGCAAGTGGGTTTTAGGACCAGGATGAGGCGGGGTGGGGGTGCCTACCTGACGACCGACCCCGACCCACTGGACAAGCACCCAACCCCCATTCCCCAAATTGCGCATCCCCTATCAGAGAGGGGGAGGGGAAACAGGATGCGGCGAGGCGCGTGCGCACTGCCAGCTTCAGCACCGCGGACAGTGCCTTCGCCCCCGCCTGGCGGCGCGCGCCACCGCCGCCTCAGCACTGAAGGCGCGCTGACGTCACTCGCCGGTCCCCCGCAAACTCCCCTTCCCGGCCACCTTGGTCGCGTCCGCGCCGCCGCCGGCCCAGCCGGACCGCACCACGCGAGGCGCGAGATAGGGGGGCACGGGCGCGACCATCTGCGCTGCGGCGCCGGCGACTCAGCGCTGCCTC | 49 |
인간 CamKIIa (CaMKIIa) | ACTTGTGGACAAAGTTTGCTCTATTCCACCTCCTCCAGGCCCTCCTTGGGTCCATCACCCCAGGGGTGCTGGGTCCATCCCACCCCCAGGCCCACACAGGCTTGCAGTATTGTGTGCGGTATGGTCAGGGCGTCCGAGAGCAGGTTTCGCAGTGGAAGGCAGGCAGGTGTTGGGGAGGCAGTTACCGGGGCAACGGGAACAGGGCGTTTTGGAGGTGGTTGCCATGGGGACCTGGATGCTGACGAAGGCTCGCGAGGCTGTGAGCAGCCACAGTGCCCTGC | 50 |
eSYN 프로모터 | GACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGACTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGCTGCAGAGGGCCCTGCGTATGAGTGCAAGTGGGTTTTAGGACCAGGATGAGGCGGGGTGGGGGTGCCTACCTGACGACCGACCCCGACCCACTGGACAAGCACCCAACCCCCATTCCCCAAATTGCGCATCCCCTATCAGAGAGGGGGAGGGGAAACAGGATGCGGCGAGGCGCGTCGCGACTGCCAGCTTCAGCACCGCGGACAGTGCCTTCGCCCCCGCCTGGCGGCGCGCGCCACCGCCGCCTCAGCACTGAAGGCGCGCTGACGTCACTCGCCGGTCCCCCGCAAACTCCCCTTCCCGGCCACCTTGGTCGCGTCCGCGCCGCCGCCGGCCCAGCCGGACCGCACCACGCGAGGCGCGAGATAGGGGGGCACGGGCGCGACCATCTGCGCTGCGGCGCCGGCGACTCAGCGCTGCCTCAGTCTGCGGTGGGCAGCGGAGGAGTCGTGTCGTGCCTGAGAGCGCAGG | 51 |
hGLUT1 프로모터 |
ACCATTTTGCTAGAGAAGGCCGCGGAGGCTCAGAGAGGTGCGCACACTTGCCCTGAGTCACACAGCGAATGCCCTCCGCGGTCCCAACGCAGAGAGAACGAGCCGATCGGCAGCCTGAGCGAGGCAGTGGTTAGGGGGGGCCCCGGCCCCGGCCACTCCCCTCACCCCCTCCCCGCAGAGCGCCGCCCAGGACAGGCTGGGCCCCAGGCCCCGCCCCGAGGTCCTGCCCACACACCCCTGACACACCGGCGTCGCCAGCCAATGGCCGGGGTCCTATAAACGCTACGGTCCGCGCGCTCTCT | 102 |
바람직한 실시예에서, 벡터 게놈은 서열번호 1과 적어도 75%, 80%, 85%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 또는 100% 동일한 폴리뉴클레오티드 서열을 포함한다. 바람직한 실시예에서, 벡터 게놈은 서열번호 2과 적어도 75%, 80%, 85%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 또는 100% 동일한 폴리뉴클레오티드 서열을 포함한다. 바람직한 실시예에서, 벡터 게놈은 서열번호 3과 적어도 75%, 80%, 85%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 또는 100% 동일한 폴리뉴클레오티드 서열을 포함한다.
프로모터의 추가 예시적인 예는 시미안 바이러스 40 유래 SV40 후기 프로모터, 바큘로바이러스 폴리헤드론 인핸서/프로모터 요소, 단순 포진 바이러스 티미딘 키나아제(HSV tk), 거대세포바이러스(CMV) 유래 즉시 초기 프로모터, 및 LTR 요소를 포함하는 다양한 레트로바이러스 프로모터이다. 다양한 다른 프로모터가 당 기술분야에 공지되어 있고 일반적으로 이용 가능하며, 많은 이러한 프로모터의 서열은 GenBank 데이터베이스와 같은 서열 데이터베이스에서 이용 가능하다.
기타 조절 요소
일부 경우에, 본 개시의 벡터는 인핸서, 인트론, 폴리-A 신호, 2A 펩티드 암호화 서열, WPRE(마멋 간염 바이러스 전사후 조절 요소), 및 HPRE(B형 간염 전사후 조절 요소)로 이루어진 군으로부터 선택된 하나 이상의 조절 요소를 추가로 포함한다.
일부 실시예에서, 벡터는 CMV 인핸서를 포함한다.
특정 실시예에서, 벡터는 하나 이상의 인핸서를 포함한다. 특정 실시예에서, 인핸서는 CMV 인핸서 서열, GAPDH 인핸서 서열, β-액틴 인핸서 서열, 또는 EF1-α 인핸서 서열이다. 전술한 서열들은 당 기술분야에 공지되어 있다. 예를 들어, CMV 초기(IE) 인핸서의 서열은 다음과 같다:
CGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATG
(서열번호 52)
소정의 실시예에서, 벡터는 하나 이상의 인트론을 포함한다. 특정 실시예에서, 인트론은 토끼 글로빈 인트론 서열, 닭 β-액틴 인트론 서열, 합성 인트론 서열, 또는 EF1-α 인트론 서열이다.
소정의 실시예에서, 벡터는 폴리A 서열을 포함한다. 특정 실시예에서, 폴리A 서열은 토끼 글로빈 폴리A 서열, 인간 성장 호르몬 폴리A 서열, 소 성장 호르몬 폴리A 서열, PGK 폴리A 서열, SV40 폴리A 서열, 또는 TK 폴리A 서열이다. 일부 실시예에서, 폴리-A 신호는 소 성장 호르몬 폴리아데닐화 신호(bGHpA)일 수 있다.
소정의 실시예에서, 벡터는 하나 이상의 전사물 안정화 요소를 포함한다. 특정 실시예에서, 전사물 안정화 요소는 WPRE 서열, HPRE 서열, 스캐폴드-부착 영역, 3' UTR, 또는 5' UTR이다. 특정 실시예에서, 벡터는 5' UTR 및 3' UTR 둘 다를 포함한다.
일부 실시예에서, 벡터는 표 4로부터 선택된 5' 미번역 영역(UTR)을 포함한다. 일부 실시예에서, 벡터 게놈은 서열번호 53-61 중 어느 하나와 적어도 75%, 80%, 85%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 또는 100% 동일한 폴리뉴클레오티드 서열을 포함한다.
5' 미번역 영역 | 서열 | 서열번호 |
인간 베타-액틴 엑손/인트론 | CGCGTCCGCCCGCGAGCACAGAGCCTCGCCTTTGCCGATCCGCCGCCCGTCCACACCCGCCGCCAGGTAAGCCCGGCCAGCCGACCGGGGCATGCGGCCGCGGCCCTTCGCCCGTGCAGAGCCGCCGTCTGGGCCGCAGCGGGGGGCGCATGGGGCGGAACCGGACCGCCGTGGGGGGCGCGGGAGAAGCCCCTGGGCCTCCGGAGATGGGGGACACCCCACGCCAGTTCGCAGGCGCGAGGCCGCGCTCGGGCGGGCGCGCTCCGGGGGTGCCGCTCTCGGGGCGGGGGCAACCGGCGGGGTCTTTGTCTGAGCCGGGCTCTTGCCAATGGGGATCGCACGGTGGGCGCGGCGTAGCCCCCGTCAGGCCCGGTGGGGGCTGGGGCGCCATGCGCGTGCGCGCTGGTCCTTTGGGCGCTAACTGCGTGCGCGCTGGGAATTGGCGCTAATTGCGCGTGCGCGCTGGGACTCAATGGCGCTAATCGCGCGTGCGTTCTGGGGCCCGGGCGCTTGCGCCACTTCCTGCCCGAGCCGCTGGCGCCCGAGGGTGTGGCCGCTGCGTGCGCGCGCGCGACCCGGTCGCTGTTTGAACCGGGCGGAGGCGGGGCTGGCGCCCGGTTGGGAGGGGGTTGGGGCCTGGCTTCCTGCCGCGCGCCGCGGGGACGCCTCCGACCAGTGTTTGCCTTTTATGGTAATAACGCGGCCGGCCCGGCTTCCTTTGTCCCCAATCTGGGCGCGCGCCGGCGCCCCCTGGCGGCCTAAGGACTCGGCGCGCCGGAAGTGGCCAGGGCGGCAGCGGCTGCTCTTGGCGGCCCCGAGGTGACTATAGCCTTCTTTTGTGTCTTGATAGTTCGCCAGCCTCTGCTAACCATGTTCATGCCTTCTTCTTTTTCCTACAGCTCCTGGGCAACGTGCTGGTTATTGTGCTGTCTCATCATTTTGGCAAAGAATTC | 53 |
닭 베타-액틴 엑손/인트론 + 토끼 글로빈 인트론 |
GTCGCTGCGCGCTGCCTTCGCCCCGTGCCCCGCTCCGCCGCCGCCTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCGGGACGGCCCTTCTCCTCCGGGCTGTAATTAGCGCTTGGTTTAATGACGGCTTGTTTCTTTTCTGTGGCTGCGTGAAAGCCTTGAGGGGCTCCGGGAGGGCCCTTTGTGCGGGGGGAGCGGCTCGGGGGGTGCGTGCGTGTGTGTGTGCGTGGGGAGCGCCGCGTGCGGCTCCGCGCTGCCCGGCGGCTGTGAGCGCTGCGGGCGCGGCGCGGGGCTTTGTGCGCTCCGCAGTGTGCGCGAGGGGAGCGCGGCCGGGGGCGGTGCCCCGCGGTGCGGGGGGGGCTGCGAGGGGAACAAAGGCTGCGTGCGGGGTGTGTGCGTGGGGGGGTGAGCAGGGGGTGTGGGCGCGTCGGTCGGGCTGCAACCCCCCCTGCACCCCCCTCCCCGAGTTGCTGAGCACGGCCCGGCTTCGGGTGCGGGGCTCCGTACGGGGCGTGGCGCGGGGCTCGCCGTGCCGGGCGGGGGGTGGCGGCAGGTGGGGGTGCCGGGCGGGGCGGGGCCGCCTCGGGCCGGGGAGGGCTCGGGGGAGGGGCGCGGCGGCCCCCGGAGCGCCGGCGGCTGTCGAGGCGCGGCGAGCCGCAGCCATTGCCTTTTATGGTAATCGTGCGAGAGGGCGCAGGGACTTCCTTTGTCCCAAATCTGTGCGGAGCCGAAATCTGGGAGGCGCCGCCGCACCCCCTCTAGCGGGCGCGGGGCGAAGCGGTGCGGCGCCGGCAGGAAGGAAATGGGCGGGGAGGGCCTTCGTGCGTCGCCGCGCCGCCGTCCCCTTCTCCCTCTCCAGCCTCGGGGCTGTCCGCGGGGGGACGGCTGCCTTCGGGGGGGACGGGGCAGGGCGGGGTTCGGCTTCTGGCGTGTGACCGGCGGCTCTAGAGCCTCTGCTAACCATGTTCATGCCTTCTTCTTTTTCCTACAGCTCCTGGGCAACGTGCTGGTTATTGTGCTGTCTCATCATTTTGGCAAAGAATTC | 54 |
5' UTR-Syn1 Hs | AGTCTGCGGTGGGCAGCGGAGGAGTCGTGTCGTGCCTGAGAGCGCAGCTGTGCTCCTGGGCACCGCGCAGTCCGCCCCCGCGGCTCCTGGCCAGACCACCCCTAGGACCCCCTGCCCCAAGTCGCA | 55 |
CMV IE 엑손 | TCAGATCGCCTGGAGAGGCCATCCACGCTGTTTTGACCTCCATAGTGGACACCGGGACCGATCCAGCCTCCGCGGCCGGGAACGGTGCATTGGAACGCGGATTCCCCGTGCCAAGAGTGAC | 56 |
TPL-eMLP (아데노바이러스 유래 인핸서 요소) |
CTCACTCTCTTCCGCATCGCTGTCTGCGAGGGCCAGCTGTTGGGCTCGCGGTTGAGGACAAACTCTTCGCGGTCTTTCCAGTACTCTTGGATCGGAAACCCGTCGGCCTCCGAACGGTACTCCGCCACCGAGGGACCTGAGCGAGTCCGCATCGACCGGATCGGAAAACCTCTCGAGAAAGGCGTCTAACCAGTCACAGTCGCAAGGTAGGCTGAGCACCGTGGCGGGCGGCAGCGGGTGGCGGTCGGGGTTGTTTCTGGCGGAGGTGCTGCTGATGATGTAATTAAAGTAGGCGGTCTTGAGACGGCGGATGGTCGAGGTGAGGTGTGGCAGGCTTGAGATCCAGCTGTTGGGGTGAGTACTCCCTCTCAAAAGCGGGCATTACTTCTGCGCTAAGATTGTCAGTTTCCAAAAACGAGGAGGATTTGATATTCACCTGGCCCGATCTGGCCATACACTTGAGTGACAATGACATCCACTTTGCCTTTCTCTCCACAGGTGTCCACTCCCAG | 57 |
인간 EF1-α 인트론/엑손 |
CTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACCTGGCTCCAGTACGTGATTCTTGATCCCGAGCTGGAGCCAGGGGCGGGCCTTGCGCTTTAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACGTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAGGATCTGCACACTGGTATTTCGGTTTTTGGGCCCGCGGCCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTCCAGGGGGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTGGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGGCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAG | 58 |
인간 EF1-α, 인트론 A | GTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACCTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAG | 59 |
5' UTR 인간 CamKIIa |
TCAGAAGCCCCGGGCTCGTCAGTCAAACCGGTTCTCTGTTTGCACTCGGCAGCACGGGCAGGCAAGTGGTCCCTAGGTTCGGG | 60 |
β-글로빈 인트론 | GTGAGTCTATGGGACCCTTGATGTTTTCTTTCCCCTTCTTTTCTATGGTTAAGTTCATGTCATAGGAAGGGGAGAAGTAACAGGGTACACATATTGACCAAATCAGGGTAATTTTGCATTTGTAATTTTAAAAAATGCTTTCTTCTTTTAATATACTTTTTTGTTTATCTTATTTCTAATACTTTCCCTAATCTCTTTCTTTCAGGGCAATAATGATACAATGTATCATGCCTCTTTGCACCATTCTAAAGAATAACAGTGATAATTTCTGGGTTAAGGCAATAGCAATATTTCTGCATATAAATATTTCTGCATATAAATTGTAACTGATGTAAGAGGTTTCATATTGCTAATAGCAGCTACAATCCAGCTACCATTCTGCTTTTATTTTATGGTTGGGATAAGGCTGGATTATTCTGAGTCCAAGCTAGGCCCTTTTGCTAATCATGTTCATACCTCTTATCTTCCTCCCACAG | 61 |
일부 실시예에서, 벡터는 표 5로부터 선택된 3' 미번역 영역을 포함한다. 일부 실시예에서, 벡터 게놈은 서열번호 62-70 중 어느 하나와 적어도 75%, 80%, 85%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 또는 100% 동일한 폴리뉴클레오티드 서열을 포함한다.
3' 미번역 영역 | 서열 | 서열번호 |
WPRE(x) (돌연변이된 마멋 간염 조절 요소 - 버전 1) | AATCAACCTCTGGATTACAAAATTTGTGAAAGATTGACTGGTATTCTTAACTATGTTGCTCCTTTTACGCTATGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATTGCTTCCCGTATGGCTTTCATTTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGAGTTGTGGCCCGTTGTCAGGCAACGTGGCGTGGTGTGCACTGTGTTTGCTGACGCAACCCCCACTGGTTGGGGCATTGCCACCACCTGTCAGCTCCTTTCCGGGACTTTCGCTTTCCCCCTCCCTATTGCCACGGCGGAACTCATCGCCGCCTGCCTTGCCCGCTGCTGGACAGGGGCTCGGCTGTTGGGCACTGACAATTCCGTGGTGTTGTCGGGGAAATCATCGTCCTTTCCTTGGCTGCTCGCCTGTGTTGCCACCTGGATTCTGCGCGGGACGTCCTTCTGCTACGTCCCTTCGGCCCTCAATCCAGCGGACCTTCCTTCCCGCGGCCTGCTGCCGGCTCTGCGGCCTCTTCCGCGTCTTCGCCTTCGCCCTCAGACGAGTCGGATCTCCCTTTGGGCCGCCTCCCCGC | 62 |
WPRE(x) (돌연변이된 마멋 간염 조절 요소 - 버전 2) | TCAACCTCTGGATTACAAAATTTGTGAAAGATTGACTGGTATTCTTAACTATGTTGCTCCTTTTACGCTATGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATTGCTTCCCGTATGGCTTTCATTTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGAGTTGTGGCCCGTTGTCAGGCAACGTGGCGTGGTGTGCACTGTGTTTGCTGACGCAACCCCCACTGGTTGGGGCATTGCCACCACCTGTCAGCTCCTTTCCGGGACTTTCGCTTTCCCCCTCCCTATTGCCACGGCGGAACTCATCGCCGCCTGCCTTGCCCGCTGCTGGACAGGGGCTCGGCTGTTGGGCACTGACAATTCCGTGGTGTTGTCGGGGAAATCATCGTCCTTTCCTTGGCTGCTCGCCTGTGTTGCCACCTGGATTCTGCGCGGGACGTCCTTCTGCTACGTCCCTTCGGCCCTCAATCCAGCGGACCTTCCTTCCCGCGGCCTGCTGCCGGCTCTGCGGCCTCTTCCGCGTCTTCGCCTTCGCCCTCAGACGAGTCGGATCTCCCTTTGGGCCGCCTCCCCGCA | 63 |
WPRE(x) (돌연변이된 마멋 간염 조절 요소 - 버전 3) | TTCCTGTTAATCAACCTCTGGATTACAAAATTTGTGAAAGATTGACTGGTATTCTTAACTATGTTGCTCCTTTTACGCTATGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATTGCTTCCCGTATGGCTTTCATTTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGAGTTGTGGCCCGTTGTCAGGCAACGTGGCGTGGTGTGCACTGTGTTTGCTGACGCAACCCCCACTGGTTGGGGCATTGCCACCACCTGTCAGCTCCTTTCCGGGACTTTCGCTTTCCCCCTCCCTATTGCCACGGCGGAACTCATCGCCGCCTGCCTTGCCCGCTGCTGGACAGGGGCTCGGCTGTTGGGCACTGACAATTCCGTGGTGTTGTCGGGGAAGCTGACGTCCTTTCCGCGGCTGCTCGCCTGTGTTGCCACCTGGATTCTGCGCGGGACGTCCTTCTGCTACGTCCCTTCGGCCCTCAATCCAGCGGACCTTCCTTCCCGCGGCCTGCTGCCGGCTCTGCGGCCTCTTCCGCCTCTTCGCCTTCGCCCTCAGACGAGTCGGATCTCCCTTTGGGCCGCCTCCCCGCCCATGTATCTTTTTCACCTGTGCCTTGTTTTTGCCTGTGTTCCGCGTCCTACTTTTCAAGCCTCCAAGCTGTGCCTTGGGCGGCTTTGGGGCATGGACATAGATCCCTATAAAGAATTTGGTTCATCTTATCAGTTGTTGAATTTTCTTCCTTTGGAC | 64 |
CAAX | TGTGTGATAATG | 65 |
EES | CTGTTCTCATCACATCATATCAAGGTTATATACCATCAATATTGCCACAGATGTTACTTAGCCTTTTAATATTTCTCTAATTTAGTGTATATGCAATGATAGTTCTCTGATTTCTGAGATTGAGTTTCTCATGTGTAATGATTATTTAGAGTTTCTCTTTCATCTGTTCAAATTTTTGTCTAGTTTTATTTTTTACTGATTTGTAAGACTTCTTTTTATAATCTGCATATTACAATTCTCTTTACTGGGGTGTTGCAAATATTTTCTGTCATTCTATGGCCTGACTTTTCTTAATGGTTTTTTAATTTTAAAAATAAGTCTTAATATTCATGCAATCTAATTAACAATCTTTTCTTTGTGGTTAGGACTTTGAGTCATAAGAAATTTTTCTCTACACTGAAGTCATGATGGCATGCTTCTATATTATTTTCTAAAAGATTTAAAGTTTTGCCTTCTCCATTTAGACTTATAATTCACTGGAATTTTTTTGTGTGTATGGTATGACATATGGGTTCCCTTTTATTTTTTACATATAAATATATTTCCCTGTTTTTCTAAAAAAGAAAAAGATCATCATTTTCCCATTGTAAAATGCCATATTTTTTTCATAGGTCACTTACATATATCAATGGGTCTGTTTCTGAGCTCTACTCTATTTTATCAGCCTCACTGTCTATCCCCACACATCTCATGCTTTGCTCTAAATCTTGATATTTAGTGGAACATTCTTTCCCATTTTGTTCTACAAGAATATTTTTGTTATTGTCTTTGGGCTTTCTATATACATTTTGAAATGAGGTTGACAAGTTA | 66 |
HPRE | ATAACAGGCCTATTGATTGGAAAGTTTGTCAACGAATTGTGGGTCTTTTGGGGTTTGCTGCCCCTTTTACGCAATGTGGATATCCTGCTTTAATGCCTTTATATGCATGTATACAAGCAAAACAGGCTTTTACTTTCTCGCCAACTTACAAGGCCTTTCTCAGTAAACAGTATATGACCCTTTACCCCGTTGCTCGGCAACGGCCTGGTCTGTGCCAAGTGTTTGCTGACGCAACCCCCACTGGTTGGGGCTTGGCCATAGGCCATCAGCGCATGCGTGGAACCTTTGTGTCTCCTCTGCCGATCCATACTGCGGAACTCCTAGCCGCTTGTTTTGCTCGCAGCAGGTCTGGAGCAAACCTCATCGGGACCGACAATTCTGTCGTACTCTCCCGCAAGTATACATCGTTTCCATGGCTGCTAGGCTGTGCTGCCAACTGGATCCTGCGCGGGACGTCCTTTGTTTACGTCCCGTCGGCGCTGAATCCCGCGGACGACCCCTCCCGGGGCCGCTTGGGGCTCTACCGCCCGCTTCTCCGTCTGCCGTACCGTCCGACCACGGGGCGCACCTCTCTTTACGCGGACTCCCCGTCTGTGCCTTCTCATCTGCCGGACCGTGTGCACTTCGCTTCACCTCTGCACGTCGCATGGAGGCCACCGTGAACGCCCACCGGAACCTGCCCAAGGTCTTGCATAAGAGGACTCTTGGACTTTCAGCAATGTCATC | 67 |
R2V17 (HepB 유래 인핸서 요소) |
TTCCTGTAAACAGGCCTATTGATTGGAAAGTTTGTCAACGAATTGTGGGTCTTTTGGGGTTTGCTGCCCCTTTTACGCAATGTGGATATCCTGCTTTAATGCCTTTATATGCATGTATACAAGCAAAACAGGCTTTTACTTTCTCGCCAACTTACAAGGCCTTTCTCAGTAAACAGTATATGACCCTTTACCCCGTTGCTCGGCAACGGCCTGGTCTGTGCCAAGTGTTTGCTGACGCAACCCCCACTGGTTGGGGCTTGGCCATAGGCCATCAGCGCATGCGTGGAACCTTTGTGTCTCCTCTGCCGATCCATACTGCGGAACTCCTAGCCGCTTGTTTTGCTCGCAGCTGGACTGGAGCAAACCTCATCGGGACCGACAATTCTGTCGTACTCTCCCGCAAGCACTCACCGTTTCCGCGGCTGCTCGCCTGTGTTGCCACCTGGATTCTGCGCGGGACGTCCTTCTGCTACGTCCCTTCGGCCCTCAATCCAGCGGACCTTCCTTCCCGCGGCCTGCTGCCGGCTCTGCGGCCTCTTCCGCCTCTTCGCCTTCGCCCTCAGACGAGTCGGATCTCCCTTTGGGCCGCCTCCCCGCCCATGTATCTTTTTCACCTGTGCCTTGTTTTTGCCTGTGTTCCGCGTCCTACTTTTCAAGCCTCCAAGCTGTGCCTTGGGCGGCTTTGGGGCATGGACATAGATCCCTATAAAGAATTTGGTTCATCTTATCAGTTGTTGAATTTTCTTCCTTTGGAC | 68 |
3'UTR(글로빈) | GCTGGAGCCTCGGTAGCCGTTCCTCCTGCCCGCTGGGCCTCCCAACGGGCCCTCCTCCCCTCCTTGCACCGGCCCTTCCTGGTCTTTGAATAAA | 69 |
WPRE(r) | ATTCGAGCATCTTACCGCCATTTATTCCCATATTTGTTCTGTTTTTCTTGATTTGGGTATACATTTAAATGTTAATAAAACAAAATGGTGGGGCAATCATTTACATTTTTAGGGATATGTAATTACTAGTTCAGGTGTATTGCCACAAGACAAACATGTTAAGAAACTTTCCCGTTATTTACGCTCTGTTCCTGTTAATCAACCTCTGGATTACAAAATTTGTGAAAGATTGACTGATATTCTTAACTATGTTGCTCCTTTTACGCTGTGTGGATATGCTGCTTTAATGCCTCTGTATCATGCTATTGCTTCCCGTACGGCTTTCGTTTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGAGTTGTGGCCCGTTGTCCGTCAACGTGGCGTGGTGTGCTCTGTGTTTGCTGACGCAACCCCCACTGGCTGGGGCATTGCCACCACCTGTCAACTCCTTTCTGGGACTTTCGCTTTCCCCCTCCCGATCGCCACGGCAGAACTCATCGCCGCCTGCCTTGCCCGCTGCTGGACAGGGGCTAGGTTGCTGGGCACTGATAATTCCGTGGTGTTGTCGGGGAAGGGCC | 70 |
일부 실시예에서, 벡터는 표 6으로부터 선택된 폴리아데닐화(polyA) 신호를 포함한다. 일부 실시예에서, 폴리A 신호는 서열번호 71-75 중 어느 하나와 적어도 75%, 80%, 85%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 또는 100% 동일한 폴리뉴클레오티드 서열을 포함한다.
폴리-아데닐화 부위 | 서열 | 서열번호 |
토끼 글로빈 (pAGlobin-Oc) |
TGGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAATTTTTTGTGTCTCTCACTCGGAAGAACATATGGGAGGGCAAATCATTTAAAACATCAGAATGAGTATTTGGTTTAGAGTTTGGCAACATATGCCCATATGCTGGCTGCCATGAACAAAGGTTGGCTATAAAGAGGTCATCAGTATATGAAACAGCCCCCTGCTGTCCATTCCTTATTCCATAGAAAAGCCTTGACTTGAGGTTAGATTTTTTTTATATTTTGTTTTGTGTTATTTTTTTCTTTAACATCCCTAAAATTTTCCTTACATGTTTTACTAGCCAGATTTTTCCTCCTCTCCTGACTACTCCCAGTCATAGCTGTCCCTCTTCTCTTATGGAGATC | 71 |
소 성장 호르몬 (pAGH-Bt - 버전 1) |
TTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAATACAATAGCAGGCATGCTGGGGATGCGGTGGGCTCTATGGGTACCCAGGTGCTGAAGAATTGACCCGGTTCCTCCTGGG | 72 |
소 성장 호르몬 (pAGH-Bt - 버전 2) |
TTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCGGTGGGCTCTATGGGTACCCAGGTGCTGAAGAATTGACCCGGTTCCTCCTGGG | 73 |
소 성장 호르몬 (pAGH-Bt - 버전 3) |
CTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCGGTGGGCTCTATGG | 74 |
인간 성장 호르몬 (pAGH-Hs) | CTGCCCGGGTGGCATCCCTGTGACCCCTCCCCAGTGCCTCTCCTGGCCCTGGAAGTTGCCACTCCAGTGCCCACCAGCCTTGTCCTAATAAAATTAAGTTGCATCATTTTGTCTGACTAGGTGTCCTTCTATAATATTATGGGGTGGAGGGGGGTGGTATGGAGCAAGGGGCCCAAGTTGGGAAGAAACCTGTAGGGCCTGC | 75 |
예시적인 벡터 게놈은 도 2 내지 도 8에 도시되어 있고, 서열번호 17-25로서 제공되어 있다. 각 서열의 대문자로 표시된 부분은 발현 카세트이다 (서열번호 8-16, 서열번호 97, 서열번호 99, 및 서열번호 101). 일부 실시예에서, 벡터 게놈은 서열번호 8-16, 서열번호 97, 서열번호 99, 및 서열번호 101 중 어느 하나와 적어도 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 또는 100% 동일성을 공유하는 폴리뉴클레오티드 서열을 포함하거나, 이로 필수적으로 구성되거나, 이로 구성되며, 선택적으로 소문자로 표시된 ITR 서열을 포함하거나 포함하지 않는다. 코딩 서열은 밑줄이 그어져 있다. 발현 카세트는 대문자로 표시되어 있다.
아데노-연관 바이러스 벡터
아데노-연관 바이러스(AAV)는 복제-결핍 파보바이러스이며, 이의 단일-가닥 DNA 게놈은 2개의 ~145-뉴클레오티드 역위 말단 반복(ITR)을 포함하여 약 4.7 kb 길이이다. 항원 에피토프에 의해 분류될 때, 때때로 혈청형으로도 불리는, AAV의 다수의 공지된 변이체가 존재한다. AAV 혈청형의 게놈의 뉴클레오티드 서열은 알려져 있다. 예를 들어, AAV-1의 전체 게놈은 GenBank 수탁 번호 NC_002077에 제공되며; AAV-2의 전체 게놈은 GenBank 수탁 번호 NC_001401 및 Srivastava 등의 J. Virol., 45: 555-564 (1983)에 제공되며; AAV-3의 전체 게놈은 GenBank 수탁 번호 NC_1829에 제공되며; AAV-4의 전체 게놈은 GenBank 수탁 번호 NC_001829에 제공되며; AAV-5 게놈은 GenBank 수탁 번호 AF085716에 제공되며; AAV-6의 전체 게놈은 GenBank 수탁 번호 NC_00 1862에 제공되며; AAV-7 및 AAV-8 게놈의 적어도 일부는 GenBank 수탁 번호 AX753246 및 AX753249에 각각 제공되며; AAV-9 게놈은 Gao 등의 J. Virol., 78: 6381-6388 (2004)에 제공되며; AAV-10 게놈은 Mol. Ther., 13(1): 67-76 (2006)에 제공되며; 그리고 AAV-11 게놈은 Virology, 330(2): 375-383 (2004)에 제공된다. AAVrh.74 게놈의 서열은 본원에 참조로서 통합된, 미국 특허 제9,434,928호에 제공된다. 바이러스 DNA 복제(rep), 캡슐화/패키징 및 숙주 세포 염색체 통합을 지시하는 시스-작용 서열은 AAV ITR 내에 포함된다. 3개의 AAV 프로모터(상대 맵 위치에 대해 p5, p19 및 p40으로 명명됨)는 rep 및 cap 유전자를 암호화하는 2개의 AAV 내부 개방 해독 프레임의 발현을 유도한다. (뉴클레오티드 2107 및 2227에서) 단일 AAV 인트론의 차등적 스플라이싱과 결합된, 2개의 rep 프로모터(p5 및 p19)는 rep 유전자로부터 4개의 rep 단백질(rep78, rep68, rep52 및 rep40)을 생산한다. Rep 단백질은 궁극적으로 바이러스 게놈의 복제를 담당하는 다수의 효소 특성을 갖는다. cap 유전자는 p40 프로모터로부터 발현되고, 이는 3개의 캡시드 단백질 VP1, VP2, 및 VP3을 암호화한다. 대체 스플라이싱 및 비-컨센서스의 번역 시작 부위는 3개의 관련 캡시드 단백질의 생산을 담당한다. 단일 컨센서스 폴리아데닐화 부위는 AAV 게놈의 맵 위치 95에 위치한다. AAV의 수명 주기 및 유전학은 Muzyczka, Current Topics in Microbiology and Immunology, 158: 97-129 (1992)에서 검토된다.
AAV는, 예를 들어 유전자 요법에서 외래 DNA를 세포에 전달하기 위한 벡터로서 이를 매력적으로 만드는 고유한 특징을 갖는다. 배양물 내 세포의 AAV 감염은 비세포병변성이며, 인간 및 다른 동물의 자연 감염은 조용하고 무증상이다. 또한, AAV는 많은 포유류 세포를 감염시켜 많은 상이한 조직을 생체 내에서 표적화할 가능성을 허용한다. 또한, AAV는 서서히 분열하고 비분열 세포를 형질도입하며, 본질적으로 전사적으로 활성인 핵 에피솜(염색체 외 요소)으로서 이들 세포의 수명 동안 지속될 수 있다. AAV 프로바이러스 게놈은 플라스미드에 클로닝된 DNA로서 삽입되어, 재조합 게놈의 구축을 가능하게 한다. 또한, AAV 복제 및 게놈 캡슐화를 지시하는 신호가 AAV 게놈의 ITR 내에 포함되기 때문에, 게놈의 내부 약 4.3 kb의 일부 또는 전부(복제 및 구조적 캡시드 단백질, rep-cap을 암호화함)가 외래 DNA로 대체될 수 있다. AAV 벡터를 생성하기 위해, rep 및 cap 단백질이 트랜스로 제공될 수 있다. AAV의 또 다른 중요한 특징은 AAV가 매우 안정적이고 왕성한 바이러스라는 것이다. 이는 아데노바이러스를 불활성화하는 데 사용되는 조건(56° 내지 65°C에서 수시간 동안)을 쉽게 견디어 AAV의 저온 보존을 덜 중요하게 한다. AAV는 심지어 동결건조될 수도 있다. 마지막으로, AAV-감염 세포는 중복감염에 내성이 없다.
rAAV 게놈 내의 AAV DNA는 AAV 변이체 또는 혈청형 AAV-1, AAV-2, AAV-3, AAV-4, AAV-5, AAV-6, AAV-7, AAV-8, AAV-9, AAV-10, AAV-11, AAV-12, AAV-13 및 AAVrh10을 포함하지만 이에 한정되지 않는, 재조합 바이러스가 유도될 수 있는 임의의 AAV 변이체 또는 혈청형으로부터 유래될 수 있다. 위형화된 rAAV의 생산은, 예를 들어 WO 01/83692에 개시되어 있다. 다른 유형의 rAAV 변이체, 예를 들어 캡시드 돌연변이를 갖는 rAAV 또한 고려된다. 예를 들어, Marsic 등의 Molecular Therapy, 22(11): 1900-1909 (2014) 참조. 다양한 AAV 혈청형의 게놈의 뉴클레오티드 서열은 당 기술분야에 공지되어 있다.
일부 경우에, rAAV는 자가-상보적 게놈을 포함한다. 본원에서 정의된 바와 같이, "자기-상보적" 또는 "이중 가닥" 게놈을 포함하는 rAAV는, McCarty 등에 기재된 바와 같이, rAAV의 코딩 영역이 분자내 이중 가닥 DNA 주형을 형성하도록 구성되도록 조작된 rAAV를 지칭한다. 자가-상보적 재조합 아데노-연관 바이러스(scAAV) 벡터는 DNA 합성과 독립적으로 효율적인 형질도입을 촉진한다. Gene Therapy. 8 (16): 1248-54 (2001). 본 개시는, 일부 경우에, 자가-상보적 게놈을 포함하는 rAAV의 사용을 고려하는데, 그 이유는 감염(이러한 형질도입) 시, rAAV 게놈의 제2 가닥의 세포 매개 합성을 기다리기 보다는, 즉시 복제 및 전사할 준비가 된 하나의 이중 가닥 DNA(dsDNA) 유닛을 형성하기 위해 scAAV의 2개의 상보적 절반이 연관시킬 것이기 때문이다. rAAV(4.7-6 kb)에서 발견되는 전체 코딩 용량 대신에, 자가-상보적 게놈을 포함하는 rAAV는 그 양의 약 절반(2.4 kb)만 보유할 수 있다는 것을 이해할 것이다.
다른 경우에, rAAV 벡터는 단일 가닥 게놈을 포함한다. 본원에서 정의된 바와 같이, "단일 표준" 게놈은 자가-상보적이지 않은 게놈을 지칭한다. 대부분의 경우, 비-재조합 AAV는 단일 가닥 DNA 게놈을 갖는다. 세포의 효율적인 형질도입을 달성하기 위해 rAAV가 scAAV가 되어야 한다는 몇 가지 징후가 있었다. 그러나, 본 개시는, rAAV 벡터의 다른 유전적 변형이 표적 세포에서 최적의 유전자 전사를 얻는 데 유익할 수 있다는 것을 이해하면서, 자가-상보적 게놈보다는 단일 가닥 게놈을 가질 수 있는 rAAV 벡터를 고려한다. 일부 경우에, 본 개시는 마우스 눈의 전방 분절로의 효율적인 유전자 전달을 달성할 수 있는 단일 가닥 rAAV 벡터에 관한 것이다. Wang 등 참조. 단일 가닥 아데노-연관 바이러스는 마우스 눈의 앞부분으로 효율적인 유전자 전달을 달성한다. PLoS ONE 12(8): e0182473 (2017).
일부 경우에, rAAV 벡터는 혈청형 AAV1, AAV2, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV13, AAVrh10, 또는 AAVrh74이다. 위형화된 rAAV의 생산은, 예를 들어 WO- 01/83692에 개시되어 있다. 다른 유형의 rAAV 변이체, 예를 들어 캡시드 돌연변이를 갖는 rAAV 또한 고려된다. 예를 들어, Marsic 등의 Molecular Therapy, 22(11): 1900-1909 (2014) 참조. 일부 경우에, rAAV 벡터는 혈청형 AAV9이다. 일부 실시예에서, rAAV 벡터는 혈청형 AAV9이고 단일 가닥 게놈을 포함한다. 일부 실시예에서, rAAV 벡터는 혈청형 AAV9이고 자가-상보적 게놈을 포함한다. 일부 실시예에서, rAAV 벡터는 AAV2의 역위 말단 반복(ITR) 서열을 포함한다. 일부 실시예에서, rAAV 벡터는 rAAV 벡터가 AAV-2/9 벡터, AAV-2/6 벡터, 또는 AAV-2/8 벡터가 되도록, AAV2 게놈을 포함한다.
대부분의 공지된 AAV에 대한 캡시드 유전자에 대한 전장 서열 및 서열은 미국 특허 제8,524,446호에 제공되며, 이는 그 전체가 본원에 통합된다.
AAV 벡터는 야생형 AAV 서열을 포함할 수 있거나, 야생형 AAV 서열에 대한 하나 이상의 변형을 포함할 수 있다. 소정의 실시예에서, AAV 벡터는 캡시드 단백질, 예를 들어, VP1, VP2 및/또는 VP3 내에 하나 이상의 아미노산 변형, 예를 들어, 치환, 결실 또는 삽입을 포함한다. 특정 실시예에서, 변형은 AAV 벡터가 대상체에게 제공될 때 감소된 면역원성을 제공한다.
rAAV의 캡시드 단백질은, rAAV가 내피 세포 또는 보다 구체적으로는 내피 팁 세포와 같은 관심 있는 특정 표적 조직에 표적화되도록 변형될 수 있다. 일부 실시예에서, rAAV는 대상체의 뇌실내 공간에 직접 주사된다.
일부 실시예에서, rAAV 비리온은 AAV2 rAAV 비리온이다. 캡시드는 대부분 AAV2 캡시드 또는 이의 기능적 변이체이다. 일부 실시예에서, AAV2 캡시드는 기준 AAV2 캡시드, 예를 들어,
MAADGYLPDWLEDTLSEGIRQWWKLKPGPPPPKPAERHKDDSRGLVLPGYKYLGPFNGLDKGEPVNEADAAALEHDKAYDRQLDSGDNPYLKYNHADAEFQERLKEDTSFGGNLGRAVFQAKKRVLEPLGLVEEPVKTAPGKKRPVEHSPVEPDSSSGTGKAGQQPARKRLNFGQTGDADSVPDPQPLGQPPAAPSGLGTNTMATGSGAPMADNNEGADGVGNSSGNWHCDSTWMGDRVITTSTRTWALPTYNNHLYKQISSQSGASNDNHYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTQNDGTTTIANNLTSTVQVFTDSEYQLPYVLGSAHQGCLPPFPADVFMVPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTNTPSGTTTQSRLQFSQAGASDIRDQSRNWLPGPCYRQQRVSKTSADNNNSEYSWTGATKYHLNGRDSLVNPGPAMASHKDDEEKFFPQSGVLIFGKQGSEKTNVDIEKVMITDEEEIRTTNPVATEQYGSVSTNLQRGNRQAATADVNTQGVLPGMVWQDRDVYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPSTTFSAAKFASFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYNKSVNVDFTVDTNGVYSEPRPIGTRYLTRNL
(서열번호 76)와 적어도 98%, 99% 또는 100% 동일성을 공유한다.
일부 실시예에서, rAAV 비리온은 AAV9 rAAV 비리온이다. 캡시드는 대부분 AAV9 캡시드 또는 이의 기능적 변이체이다. 일부 실시예에서, AAV9 캡시드는 기준 AAV9 캡시드, 예를 들어,
MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGPGNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSFGGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPAKKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSSSGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFYCLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTINGSGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKVMITNEEEIKTTNPVATESYGQVATNHQSAQAQAQTGWVQNQGILPGMVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYSEPRPIGTRYLTRNL
(서열번호 77)와 적어도 98%, 99% 또는 100% 동일성을 공유한다.
일부 실시예에서, rAAV 비리온은 AAV6 rAAV 비리온이다. 캡시드는 대부분 AAV6 캡시드 또는 이의 기능적 변이체이다. 일부 실시예에서, AAV6 캡시드는 기준 AAV6 캡시드, 예를 들어,
MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLGPFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTSFGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPAKKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGNASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIANNLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQNQSGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNSNFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTALDNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRDVYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFITQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIGTRYLTRPL
(서열번호 78)와 적어도 98%, 99% 또는 100% 동일성을 공유한다.
일부 실시예에서, rAAV 비리온은 AAVrh.10 rAAV 비리온이다. 캡시드는 대부분 AAVrh.10 캡시드 또는 이의 기능적 변이체이다. 일부 실시예에서, AAVrh.10 캡시드는 기준 AAVrh.10 캡시드, 예를 들어,
MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLGPFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTSFGGNLGRAVFQAKKRVLEPLGLVEEGAKTAPGKKRPVEPSPQRSPDSSTGIGKKGQQPAKKRLNFGQTGDSESVPDPQPIGEPPAGPSGLGSGTMAAGGGAPMADNNEGADGVGSSSGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISNGTSGGSTNDNTYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTQNEGTKTIANNLTSTIQVFTDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFEFSYQFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTQSTGGTAGTQQLLFSQAGPNNMSAQAKNWLPGPCYRQQRVSTTLSQNNNSNFAWTGATKYHLNGRDSLVNPGVAMATHKDDEERFFPSSGVLMFGKQGAGKDNVDYSSVMLTSEEEIKTTNPVATEQYGVVADNLQQQNAAPIVGAVNSQGALPGMVWQNRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGLKHPPPQILIKNTPVPADPPTTFSQAKLASFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSTNVDFAVNTDGTYSEPRPIGTRYLTRNL
(서열번호 79)와 적어도 98%, 99% 또는 100% 동일성을 공유한다.
일부 실시예에서, rAAV 비리온은 AAV8 rAAV 비리온이다. 캡시드는 대부분 AAV8 캡시드 또는 이의 기능적 변이체이다. 일부 실시예에서, AAV8 캡시드는 기준 AAV8 캡시드, 예를 들어,
MAADGYLPDWLEDNLSEGIREWWALKPGAPKPKANQQKQDDGRGLVLPGYKYLGPFNGLDKGEPVNAADAAALEHDKAYDQQLQAGDNPYLRYNHADAEFQERLQEDTSFGGNLGRAVFQAKKRVLEPLGLVEEGAKTAPGKKRPVEPSPQRSPDSSTGIGKKGQQPARKRLNFGQTGDSESVPDPQPLGEPPAAPSGVGPNTMAAGGGAPMADNNEGADGVGSSSGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISNGTSGGATNDNTYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLSFKLFNIQVKEVTQNEGTKTIANNLTSTIQVFTDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFQFTYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTQTTGGTANTQTLGFSQGGPNTMANQAKNWLPGPCYRQQRVSTTTGQNNNSNFAWTAGTKYHLNGRNSLANPGIAMATHKDDEERFFPSNGILIFGKQNAARDNADYSDVMLTSEEEIKTTNPVATEEYGIVADNLQQQNTAPQIGTVNSQGALPGMVWQNRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGLKHPPPQILIKNTPVPADPPTTFNQSKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSTSVDFAVNTEGVYSEPRPIGTRYLTRNL
(서열번호 80)와 적어도 98%, 99% 또는 100% 동일성을 공유한다.
일부 실시예에서, rAAV 비리온은 AAVrh.74 rAAV 비리온이다. 캡시드는 대부분 AAVrh.74 캡시드 또는 이의 기능적 변이체이다. 일부 실시예에서, AAVrh.74 캡시드는 기준 AAVrh.74 캡시드, 예를 들어,
MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDNGRGLVLPGYKYLGPFNGLDKGEPVNAADAAALEHDKAYDQQLQAGDNPYLRYNHADAEFQERLQEDTSFGGNLGRAVFQAKKRVLEPLGLVESPVKTAPGKKRPVEPSPQRSPDSSTGIGKKGQQPAKKRLNFGQTGDSESVPDPQPIGEPPAGPSGLGSGTMAAGGGAPMADNNEGADGVGSSSGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISNGTSGGSTNDNTYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTQNEGTKTIANNLTSTIQVFTDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFEFSYNFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTQSTGGTAGTQQLLFSQAGPNNMSAQAKNWLPGPCYRQQRVSTTLSQNNNSNFAWTGATKYHLNGRDSLVNPGVAMATHKDDEERFFPSSGVLMFGKQGAGKDNVDYSSVMLTSEEEIKTTNPVATEQYGVVADNLQQQNAAPIVGAVNSQGALPGMVWQNRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGLKHPPPQILIKNTPVPADPPTTFNQAKLASFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSTNVDFAVNTEGTYSEPRPIGTRYLTRNL
(서열번호 81)와 적어도 98%, 99% 또는 100% 동일성을 공유한다.
일부 실시예에서, rAAV 비리온은 AAV-PHP.B rAAV 비리온 또는 이의 호중구 변이체, 예컨대 제한 없이 국제 특허 공개 번호 WO 2015/038958 A1 및 WO 2017/100671 A1에 개시된 것들이다. 예를 들어, AAV 캡시드는 서열 TLAVPFK(서열번호 83) 또는 KFPVALT(서열번호 84)로부터 적어도 4개의 연속 아미노산을 포함할 수 있으며, 예를 들어, AAV9의 아미노산 588 및 589를 암호화하는 서열 사이에 삽입되어 있다.
캡시드는 대부분 AAV-PHP.B 캡시드 또는 이의 기능적 변이체이다. 일부 실시예에서, AAV-PHP.B 캡시드는 기준 AAV-PHP.B 캡시드, 예를 들어,
MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGPGNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSFGGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPAKKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSSSGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFYCLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTINGSGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKVMITNEEEIKTTNPVATESYGQVATNHQSAQTLAVPFKAQAQTGWVQNQGILPGMVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYSEPRPIGTRYLTRNL
(서열번호 82)와 적어도 98%, 99% 또는 100% 동일성을 공유한다.
본 개시의 rAAV 비리온에 사용된 추가 AAV 캡시드는 특허 공개 번호 WO 2009/012176 A2 및 WO 2015/168666 A2에 개시된 것을 포함한다.
이론에 구속되지 않고, 본 발명자들은 AAV9 벡터 또는 AAVrh.10 벡터가 벡터의 광범위한 CNS 분포를 제공할 것이라고 결정하였다. 이론에 구속되지 않고, 본 발명자들은 AAV6 벡터가 표적화된 내피 세포에 일부 특이성을 제공할 수 있는 것으로 추가로 결정하였다. AAV8 및 AAVrh.10을 포함하지만 이에 한정되지 않는 다른 벡터 혈청형이 사용될 수 있다.
일부 실시예에서, rAAV 벡터는 AAV2 벡터가 아니다. 이론에 구속되지 않고, 본 발명자들은, 일부 경우에 AAV2 벡터의 사용이 내피 세포 이외에 또는 내피 세포 대신 신경 세포의 형질도입을 초래한다고 결정하였다. 이론에 구속되지 않고, 본 발명자들은 CNS 내에서 AAV2 벡터의 확산이 헤파란 설페이트 프로테오글리칸(HSPG) 수용체와의 상호작용에 의해 제한된다는 것을 추가로 결정하였다.
약학적 조성물 및 키트
일 측면에서, 본 개시는 본 개시의 rAAV 비리온 및 하나 이상의 약학적으로 허용 가능한 담체, 희석제 또는 부형제를 포함하는 약학적 조성물을 제공한다.
투여 목적을 위해, 예를 들어, 주사에 의해, 멸균 수용액과 같은, 다양한 용액이 사용될 수 있다. 이러한 수용액은 원하는 경우 완충될 수 있고, 액체 희석제는 식염수 또는 포도당으로 등장성으로 된다. 유리 산(DNA는 산성 인산염기를 함유함) 또는 약리학적으로 허용 가능한 염으로서의 rAAV의 용액은, 예를 들어, 0.001% 또는 0.01%로, 폴록사머 188과 같은 계면활성제와 적절히 혼합된 물에서 제조될 수 있다. rAAV의 분산액은 또한 글리세롤, 액체 폴리에틸렌 글리콜 및 이들의 혼합물 및 오일에서 제조될 수 있다. 일반적인 보관 및 사용 조건 하에서, 이들 제제는 미생물의 성장을 방지하기 위한 보존제를 함유한다. 이와 관련하여, 사용된 멸균 수성 매질은 당해 기술분야의 통상의 기술을 가진 자에게 주지된 표준 기술에 의해 모두 쉽게 수득될 수 있다.
주사용에 적합한 약학적 형태는 멸균 수용액 또는 분산액 및 멸균 주사용 용액 또는 분산액의 즉석 제조를 위한 멸균 분말을 포함하지만, 이에 한정되지 않는다. 모든 경우에, 형태는 멸균 상태이고, 쉽게 주사할 수 있는 정도로 유동적이어야 한다. 이는 제조 및 보관 조건 하에서 안정적이어야 하며, 박테리아 및 곰팡이와 같은 미생물의 오염 작용에 대해 보존되어야 한다. 담체는, 예를 들어, 물, 에탄올, 폴리올(예를 들어, 글리세롤, 프로필렌 글리콜, 액체 폴리에틸렌 글리콜 등), 이들의 적절한 혼합물, 및 식물성 오일을 함유하는 용매 또는 분산 매질일 수 있다. 적절한 유동성은, 예를 들어, 레시틴과 같은 코팅의 사용에 의해, 분산액의 경우에 요구되는 입자 크기의 유지에 의해, 및 계면활성제의 사용에 의해 유지될 수 있다. 미생물의 작용을 예방하는 것은 다양한 항균제 및 항진균제, 예를 들어 파라벤, 클로로부탄올, 페놀, 소르브산, 티메로살 등에 의해 이루어질 수 있다. 많은 경우에, 당류 또는 염화나트륨과 같은 등장화제를 포함하는 것이 바람직할 것이다. 주사용 조성물의 연장된 흡수는 흡수를 지연시키는 제제, 예를 들어, 알루미늄 모노스테아레이트 및 젤라틴의 사용에 의해 이루어질 수 있다.
멸균 주사용 용액은 필요에 따라 위에 열거된 다양한 다른 성분과 함께 적절한 용매에 필요한 양으로 rAAV를 혼입한 후 필터 멸균하여 제조할 수 있다. 일반적으로, 분산액은 멸균된 활성 성분을, 염기성 분산 매질 및 상기 열거된 것들로부터 요구되는 다른 성분을 함유하는 멸균 비히클에 혼입함으로써 제조된다. 멸균 주사용 용액의 제조를 위한 멸균 분말의 경우, 바람직한 제조 방법은 활성 성분에 이전에 멸균 여과된 용액으로부터 임의의 원하는 추가 성분을 더한 분말을 생성하는 진공 건조 및 동결건조 기술이다.
또 다른 측면에서, 본 개시는 본 개시의 rAAV 비리온 및 사용 지침을 포함하는 키트를 포함한다.
사용 방법
일 측면에서, 본 개시는 세포에서 GLUT1 활성을 증가시키는 방법을 제공하며, 상기 방법은 본 개시의 rAAV와 세포를 접촉시키는 단계를 포함한다. 또 다른 측면에서, 본 개시는 대상체에서 GLUT1 활성을 증가시키는 방법을 제공하며, 상기 방법은 본 개시의 rAAV에 투여하는 단계를 포함한다. 일부 실시예에서, 세포 및/또는 대상체는 SLC2A1 전령 RNA 또는 GLUT1 단백질 발현 수준 및/또는 활성이 결핍되어 있고/있거나 SLC2A1의 기능 상실 돌연변이를 포함한다. 세포는 내피 세포, 예를 들어 내피 팁 세포일 수 있다.
일부 실시예에서, 상기 방법은 내피 팁 세포의 정상적인 기능을 복원한다. 일부 실시예에서, 상기 방법은 세포 배양 및/또는 생체 내에서 GLUT1 수송자 단백질 발현 수준을 복원한다. 일부 실시예에서, 상기 방법은 세포 배양 및/또는 생체 내에서 정상적인 포도당 수송 및 대사(예: 당분해, 젖산염 생산)를 복원한다. 일부 실시예에서, 상기 방법은 중추 신경계(CNS)에서 정상적인 혈관신생 및/또는 미세혈관 구조의 발생을 복원한다.
치료 방법
또 다른 측면에서, 본 개시는 질환 또는 장애의 치료를 필요로 하는 대상체에서 이를 치료하는 방법을 제공하며, 상기 방법은 본 개시의 rAAV 비리온의 유효량을 대상체에게 투여하는 단계를 포함한다. 일부 실시예에서, 질환 또는 장애는 신경 질환 또는 장애이다. 일부 실시예에서, 대상체는 SLC2A1 발현 또는 기능의 유전적 파괴를 겪는다. 일부 실시예에서, 질환 또는 장애는 GLUT1 결핍 증후군(GLUT1 DS)이다.
CNS로의 AAV-매개 GLUT1 단백질 전달은 수명 연장을 증가시키고, 신경 변성, 조기 발작, 발달 지연, 후천성 소두증(뇌 성장 감소), 복합 운동 장애(경직, 운동실조, 근긴장이상), 발작성 안구-두 운동, 및/또는 뇌척수액 내 저 젖산염 및/또는 포도당 농도(저신경조증)를 예방, 감소, 완화 또는 약화시킬 수 있다. 일부 실시예에서, 상기 방법은 질환 과정에서, 예를 들어, 신생아, 유아 또는 청소년에서 조기에 치료를 제공한다.
본원에 개시된 방법은 뇌 및/또는 CNS에서 효율적인 생체분포를 제공할 수 있다. 이들은 내피 세포(예를 들어, 내피 팁 세포)의 전부 또는 실질적인 분획에서 지속된 발현을 초래할 수 있다. 특히, 본원에 개시된 방법은 대상체의 발달 및 노화 전반에 걸쳐 GLUT1 단백질의 장기적인 발현을 제공할 수 있다.
병용 요법 또한 본 발명에 의해 고려된다. 신규한 요법과의 조합에서와 마찬가지로, 표준 의학적 치료(예: 코르티코스테로이드 또는 국소 감압 약물)와 본 발명의 방법의 조합이 구체적으로 고려된다. 일부 경우에, 대상체는 본원에서 설명되는 rAAV의 투여에 대한 면역 반응을 예방하거나 감소시키기 위해 스테로이드 및/또는 면역 억제제의 조합으로 치료될 수 있다.
예를 들어, 뇌실내(ICV) 또는 대수조내(ICM) 주사를 위한, rAAV 벡터의 치료적 유효량은, 뇌 중량 기준, 약 1e12 vg/kg 내지 약 5e12 vg/kg, 또는 약 1e13 vg/kg 내지 약 5e13 vg/kg, 또는 약 1e14 vg/kg 내지 약 5e14 vg/kg, 또는 약 1e15 vg/kg 내지 약 5e15 vg/kg 범위의 rAAV의 투여량이다. 본 발명은 또한 이들 범위의 rAAV 벡터를 포함하는 조성물을 포함한다.
예를 들어, 특정 실시예에서, rAAV 벡터의 치료적 유효량은 약 1e10 vg, 약 2e10 vg, 약 3e10 vg, 약 4e10 vg, 약 5e10 vg, 약 6e10 vg, 약 7e10 vg, 약 8e10 vg, 약 9e10 vg, 약 1e12 vg, 약 2e12 vg, 약 3e12 vg, 약 4e12 vg, 약 4e13 vg 및 약 4e14 vg의 투여량이다. 본 발명은 또한 rAAV 벡터의 이들 투여량을 포함하는 조성물을 포함한다.
일부 실시예에서, 예를 들어, ICV 주사가 수행되는 경우, rAAV 벡터의 치료적 유효량은 1e10 vg/반구 내지 2e14 vg/반구, 또는 약 1e10 vg/반구, 약 1e11 vg/반구, 약 1e12 vg/반구, 1E13 vg/반구 또는 약 1e14 vg/반구 범위의 투여량이다. 일부 실시예에서, 예를 들어, ICM 주사가 수행되는 경우, rAAV 벡터의 치료적 유효량은 총 2e10 vg 내지 총 2e14 vg, 또는 총 약 2e10 vg, 총 약 2e11 vg, 총 약 2e12 vg, 총 약 2e13 vg, 또는 총 약 2e14 vg 범위의 투여량이다.
일부 실시예에서, 치료 조성물은 주사된 치료 조성물의 부피 당 rAAV 벡터의 약 1e9, 1e10, 또는 1e11 게놈을 포함한다. 실시예 경우에서, 치료 조성물은 mL당 rAAV 벡터의 대략 1e11, 1e12, 1e13, 또는 1e14 초과의 게놈을 포함한다. 소정의 실시예에서, 치료 조성물은 mL당 rAAV 벡터의 약 1e14, 1e13 또는 1e12 미만의 게놈을 포함한다.
환자의 기능적 개선, 임상적 이익 또는 효능의 증거는 발작성 안구-두 운동 분석, 발작 빈도 감소의 대용 마커(전신 강직성 간대 발작 및 근간대 발작), 뇌척수액(CSF) 내 젖산염 및/또는 포도당 농도, 발달 지연, 무도병, 근긴장이상 및 소두증의 평가에 의해 평가될 수 있다. Columbia Neurology 점수, 복합적 지적 추정, 적응 행동 복합적, 언어적 및 비언어적 인지 능력 및 시각운동 통합, 및 6분 보행 테스트와 같은, 표준 질환 평가 척도를 사용하여 인지, 운동, 말 및 언어 기능을 측정한다. 피바디 운동발달 단계 척도(Peabody Developmental Motor Scales) 제2판 (PDMS-2) 및 베일리 영아 발달 척도(Bayley Scales of Infant Development), 제3판을 포함한 인지 및 발달 평가를 아동의 장애 수준에 따라 적절하게 적용했다. 대근육 운동 기능 척도(GFMF-88), 장애 아동 평가도구(pediatric evaluation of disability inventory, PEDI). 이러한 척도 또는 유사한 척도뿐만 아니라, 3점 척도(평균 지속시간 감소, 변화 없음, 또는 증가)에서 발작 기간 변화에 대한 간병인 전반적 인상(CGICSD), PedsQL™(Pediatric Quality of Life Inventory) 및 Vineland 적응 거동 척도-2nd와 같은 삶의 질에 대한 환자 보고 결과는 질환의 구성요소 개선을 입증할 수 있다. 베이스라인 및 치료 후 뇌 자기 공명 영상은 연령 일치 환자 대조군 데이터 및 GLUT1 결핍 환자로부터의 이력 데이터와 비교하여 환자의 연령에 대한 개선되거나 정상화된 뇌 용적을 나타낼 수 있다.
수명 증가, 정상적인 신경발달 이정표 충족, CSF 내 정상 포도당 농도, 발작성 안구-두 운동의 빈도 또는 크기 감소, 간질 발작 활동의 감소 또는 부재(근간대성, 간대성, 전신 강직-간대 및/또는 간질 경련 포함), 경직, 근긴장이상 및/또는 운동실조 같은 복합 운동 장애의 발달 개선, 또는 이들의 결여, 및 컬럼비아 신경학 점수 및/또는 6분 보행 검사에서 개선되었거나 정상적인 수행 능력의 증가로 임상적 이점을 관찰할 수 있다. 신경보호 효과 및/또는 신경복원 효과의 증거는 전체 뇌 크기, 소두증의 결여 및/또는 피질 및/또는 소뇌 위축을 특성화함으로써 전술한 모든 메트릭 및/또는 자기 공명 영상(MRI)에서 명백할 수 있다.
일부 실시예에서, 방법은 내인성 Glut1 프로모터 또는 유비쿼터스 프로모터를 포함하는 벡터와 접촉한 세포 또는 벡터가 투여된 대상체의 세포와 비교하여 세포에 의해 증가된 포도당 흡수를 유발한다. 일부 경우에, 증가는 적어도 5%, 적어도 10%, 적어도 15%, 적어도 20%, 적어도 25%, 적어도 30%, 적어도 40%, 또는 적어도 50%이다. 일부 경우에, 증가는 적어도 1.1배, 적어도 1.2배, 적어도 1.3배, 적어도 1.4배, 적어도 1.5배, 적어도 1.6배, 적어도 1.7배, 또는 적어도 1.8배이다. 벡터는 본원에 개시된 임의의 벡터일 수 있다. 세포는 내피 세포 또는 신경 세포일 수 있다. 예를 들어, 상기 방법은 시험관 내 또는 생체 내, 인간 대뇌 미세혈관 내피 세포에 의한 포도당 흡수를 증가시킬 수 있다.
조성물의 투여
유효 투여량의 조성물의 투여는 정맥내, 뇌내, 척수강내, 대수조내, 또는 뇌실내 투여를 포함하지만 이에 한정되지 않는, 당 기술분야에서 표준 경로에 의해 이루어질 수 있다. 일부 경우에, 투여는 정맥내, 뇌내, 척수강내, 대수조내 또는 뇌실내 주사를 포함한다. 투여는 트렌델렌버그 경사를 사용하거나 사용하지 않고 척수강내 주사에 의해 수행될 수 있다. 대수조내(ICM) 전달은 척수강내(IT) 공간에서 카테터 진입을 통해 달성될 수 있다. 뇌실내 주사(들)는 자기 공명 영상(MRI) 가이드 신경외과 표적화를 통해 달성될 수 있다.
일부 실시예에서, 본 개시는 본 발명의 rAAV 및 조성물의 유효 투여량의 전신 투여를 제공한다. 예를 들어, 전신 투여는 전신이 영향을 받도록 순환계로의 투여일 수 있다. 전신 투여는 주사 또는 주입을 통한 정맥내 투여를 포함한다.
특히, 본 발명의 rAAV의 투여는 rAAV 재조합 벡터를 동물의 표적 조직 내로 수송할 임의의 물리적 방법을 사용함으로써 달성될 수 있다. 투여는 중추 신경계(CNS) 또는 뇌척수액(CSF) 내로의 및/또는 뇌로의 직접 주사를 포함하나 이에 한정되지 않는다.
일부 실시예에서, 본 개시의 방법은 뇌실내, 대수조내, 척수강내, 또는 실질내 전달을 포함한다. 주입 펌프를 사용하여 특수 캐뉼라, 카테터, 주사기/바늘을 사용하여 주입이 수행될 수 있다. 선택적으로, 주사 부위의 표적화는 MRI 유도 영상화를 통해 달성될 수 있다. 투여는 유효량의 rAAV 비리온, 또는 rAAV 비리온을 포함하는 약학적 조성물의 CNS로의 전달을 포함할 수 있다. 이는, 예를 들어, 편측 뇌실내 주사, 양측 뇌실내 주사, 트렌델렌부르크 틸팅 절차를 이용한 대수조내 주입, 또는 트렌델렌부르크 틸팅 절차가 없는 대수조내 주입, 트렌델렌부르크 틸팅 절차가 있는 척수강내 주입, 또는 트렌델렌부르크 대수조내 절차가 없는 척수강내 주입을 통해 달성될 수 있다. 본 개시의 조성물은 추가로 정맥내 투여될 수 있다.
CNS로의 직접 전달은 뇌실내 공간을, 편측 또는 양측으로, 특이적 신경 영역 또는 신경 표적을 함유하는 보다 일반적인 뇌 영역을 표적화하는 것을 포함할 수 있다. 개별 환자의 뇌실내 공간, 뇌 영역 및/또는 신경 표적(들) 선택 및 AAV의 후속 수술 중 전달은 다수의 영상화 기술(MRI, CT, MRI 병합과 조합된 CT)을 사용하고 임의의 수의 소프트웨어 계획 프로그램(예: Stealth 시스템, Clearpoint Neuronavigation 시스템, Brainlab, Neuroinspire 등)을 채용함으로써 달성될 수 있다. 뇌실내 공간 또는 뇌 영역 표적화 및 전달은 표준 정위 프레임(Leksell, CRW)의 사용 또는 수술 중 MRI를 사용하거나 사용하지 않고 프레임 없는 접근법의 사용이 관여할 수 있다. AAV의 실제 전달은 AAV 벡터의 흡착을 방지하기 위해 재료로 라이닝된 내부 루멘(inner lumen)을 갖거나 갖지 않는 바늘 또는 캐뉼라(예를 들어, Smartflow 캐뉼라, MRI 개입 캐뉼라)를 통한 주사에 의해 이루어질 수 있다. 전달 장치는 주사기(들) 및 사전 프로그래밍된 주입 속도 및 용량을 갖는 자동 주입 또는 미세주입 펌프로 구성된다. 주사기/바늘 조합 또는 바늘용 가이드 캐뉼라만이 정위 프레임과 직접 연결될 수 있다. 주입은 대류 전달 강화와 함께 일정한 유속 또는 다양한 속도를 포함할 수 있다.
예
예 1: 전임상 생체활성 및 효능
재조합 AAV 비리온은 도 2 내지 도 8에 개시된 벡터 게놈을 사용하여 생산된다. 이들은 GLUT1 결핍 질환의 결과로서 마우스 질병 모델에서 평가된다. 한 모델은 구성적 프로모터 또는 내피-특이적 프로모터(예를 들어, Tie-2)로부터 Cre/lox를 발현하는 유전자이식 동물과 교배된 flox-ed GLUT1 유전자를 사용한다. 생성된 마우스는 GLUT1 유전자좌에서 이형접합성 null이며, 인간 질환을 모방하는 발생 표현형을 나타낸다. GLUT1 DS의 두번째 마우스 모델은 마우스 GLUT-1 유전자의 프로모터 및 엑손 1 영역의 표적화된 파괴에 의해 생성된 이형접합 반수체부족성 마우스이다 (GLUT-1 +/- 마우스). 추가 동물 모델은 GLUT1 유전자가 S324P 점 돌연변이를 갖는 GLUT1 DS 모델을 포함할 수 있다.
유전자 발현 및 투여량-반응을 시험관 내 (내피 및 신경 세포주 사용) 및 생체 내 (야생형 및 GLUT1 DS 모델 마우스 사용)에서 평가한다. SLC2A1 발현 벡터로 형질감염된 배양된 세포(인간 배아 신장 세포 293, HEK293; 인간 제대 정맥 내피 세포, HUVEC; 인간 뇌-유래 내피 세포, bEND3; 인간 뇌 미세혈관 내피 세포, HBEC-5i; 인간 뇌 미세혈관 내피 세포주, hCMEC/D3 (혈액-뇌 장벽 모델); 인간 교세포 희소돌기아교세포 혼성 세포, MO3.13; 인간 신경아세포종, SH-SY5Y)는 정량적 실시간 PCR 분석에 의해 형질도입 효율을, ELISA 및/또는 웨스턴 블롯에 의해 GLUT1 수준을 밝힐 것이다. AAV 벡터 작제물(들)의 개념 및 효능 증명은, GLUT1 DS 돌연변이 마우스 대조군과 비교하여, 면역표지, CNS 내 뇌 모세혈관 밀도 및/또는 혈관 크기 증가, 양전자 방출 단층촬영(PET)을 사용한 뇌 포도당 흡수 증가, CSF 포도당 수준 또는 젖산염 수준 및/또는 CSF/혈당 비율의 증가, CSF 젖산염 수준 증가, 및 로타로드 및/또는 수직 극 검정과 같은 표준 검정을 사용한 운동 성능의 향상에 의해, CNS에서 이식유전자(GLUT1 단백질)의 발현에 의해 GLUT11 DS 마우스를 사용하여 생체 내에서 밝혀질 것이다. GLUT1 DS 마우스 모델(들)을 사용한 생체 내 유전자 발현 및 효능은, 이러한 투여 경로를 단독으로 및/또는 조합하여 사용하면서, 정맥내 또는 뇌실내 공간으로의 직접 주사에 의한 AAV 벡터 작제물(들)의 전달 후에 명백해질 것이다.
예 2: 내피 프로모터를 사용한 Glut1 발현의 시험관 내 평가
유전자 발현은 인간 대뇌 미세혈관 내피 세포(hCMEC/D3)를 사용하여 시험관 내에서 평가하였다. hFLT1, mTIE1, hGlut1, 또는 CMV 프로모터의 제어 하에 SLC2A1을 암호화하는 AAV9 벡터로 형질감염된 hCMEC/D3 세포에 의한 Glut1의 발현을 (도 10c에 도식화함) 평가하였다 (도 9). 내피 프로모터(hFLT1 및 mTIE1)로부터의 발현은 Glut1 프로모터로부터의 발현과 대등하였고, CMV 프로모터로부터의 발현보다 훨씬 더 낮았다. 이들 작제물 간의 유사한 발현 수준의 패턴을 면역형광 현미경에 의해 관찰하였다 (도 10a 및 도 10b).
놀랍게도, 내피 프로모터의 제어 하에 유전자로 형질감염 또는 형질도입된 인간 대뇌 미세혈관 내피 세포에 의한 2-디옥시-D-글루코오스(2-DG) 흡수는 대조군 Glut1 프로모터보다 컸으며, hFLT-1 프로모터는 2-DG(포도당) 흡수의 최고 수준을 나타냈다 (도 11a-11c, 도 12, 및 도 13). hFLT-1 프로모터 작제물에 의한 더 큰 2-DG(포도당) 흡수에 대한 이러한 소견은 또한 다양한 2-DG 농도(도 12a; 0, 0.1, 0.5, 및 1 mM) 및 형질감염 후 다양한 시점(도 12b)에 걸쳐 관찰되었고, 일부 경우에 CMV 프로모터에 대해 관찰된 것보다 대등하거나 약간 더 큰 것으로 밝혀졌다 (도 11a-11c; 도 12a, 12b; 도 13).
도 9 인간 대뇌 미세혈관 내피 세포(hCMEC/d3s)의 형질감염 후 이식유전자 단백질(Glut1-GFP)의 발현.
도 10a. Glut1-GFP 이식유전자의 발현을 지시하는 여러 내피 세포 프로모터 중 하나를 함유하는 작제물로 형질감염 후 72시간차 GFP 형광.
도 10b. 2개의 유비쿼터스 프로모터(CMV 또는 CAG) 중 하나를 함유하는 작제물로 형질감염 후, Glut1이 없는 대조군 벡터(CMV-GFP)로 형질감염 후 또는 형질감염이 없는 대조군 벡터(NFX 없음)의 72시간차 GFP 형광. Operetta CLS?? (PerkinElmer®)를 사용하여 획득한 이미지.
도 10c. 관심 프로모터(hFLT1, mTie, hTie 또는 hGlut1) 및 GLUT1(SLC2A1) 유전자(T2A 연결-GFP) 및 AAV2 역위 말단 반복(ITR)이 측면에 위치한 조절 요소를 함유하는 발현 카세트의 다이어그램.
도 11a-11c. 인간 GLUT1(SLC2A1)의 발현 후 hCMEC/d3 세포에서의 2-디옥시-D-글루코오스(포도당) 흡수. 인간 대뇌 미세혈관 내피 세포(hCMEC/d3s)를 CAG-GFP(CON; 음성 대조군) 또는 여러 내피-특이적 프로모터 중 하나(즉, hFLT1, mTie, hTie 또는 hGlut1)에 의해 또는 유비쿼터스 CMV 또는 CAG 프로모터에 의해 지시되는 hGLUT1-t2A-eGFP 이식유전자를 발현하는 플라스미드로 형질감염시켰다. 포도당 흡수는 배양 배지에서 0.5 mM 2-디옥시글루코오스(2-DG)로 발광 기반 키트(Promega®)를 사용하여 측정하였다. 포도당(2-DG) 흡수를 위상차 영상화를 사용하여 총 세포에 의해 정규화하였다 [오차 막대는 S.E.M을 나타냄; 병태 당 n=6 복제물].
도 11a. 제1 실험에서 형질감염 후 72시간차에 포도당(2-DG) 흡수를 측정하였다.
도 11b. 제2 실험에서 형질감염 후 72시간차에 포도당(2-DG) 흡수를 측정하였다.
도 11c. 형질감염 후 96시간차에 포도당(2-DG) 흡수를 측정하였다.
도 12a. 72시간 시점에서 인간 Glut1(SLC2A1)의 발현 후 hCMEC/D3 세포에서의 포도당(2-DG) 흡수를 보여준다.
도 12b. 96시간 시점에서 인간 Glut1(SLC2A1)의 발현 후 hCMEC/D3 세포에서 포도당(2-DG) 흡수를 보여준다.
도 13. hCMEC/D3 세포에서 hGLUT1(SLC2A1)의 AAV9-대개 발현 후 2-디옥시-D-글루코오스(포도당) 흡수. 인간 대뇌 미세혈관 내피 세포(hCMEC/d3s)를 CAG-GFP(음성 대조군) 또는 여러 내피-특이적 프로모터 중 하나(즉, hFLT1, mTie1 또는 hGlut1)에 의해 또는 유비쿼터스 CMV 프로모터에 의해 지시되는 hGLUT1 이식유전자를 발현하는 AAV9 벡터(3 x 105 벡터 게놈/세포)로 형질도입하였다. 포도당(2-DG) 흡수는 발광-기반 포도당 흡수-Glo 키트(Promega®)를 사용하여 형질도입 후 72시간차에 측정하였으며, 실시간-Glo MT 세포 생존력 검정(Promega®)을 사용하여 세포당 정규화하였다 [오차 막대는 S.E.M을 나타냄; 병태 당 n=4 복제물].
예 3: glut1 결핍 동물 모델에서 내피 프로모터를 사용한 AAV9-매개 Glut1 발현의 생체 내 평가
GLUT1 결핍 증후군(DS)의 마우스 모델에서 Glut1 수송자 단백질의 AAV9-매개 발현의 생체 내 효과를 평가하는 일련의 실험이 수행될 것이다. 이 모델은 마우스 GLUT-1 유전자(GLUT-1 +/- 마우스)의 프로모터 및 엑손 1 영역의 표적화된 파괴로 인해 이형접합 반수체부족성 마우스를 사용하며, 발작 활성, 저신경조증, 소뇌증 및 운동 기능 장애와 같은 인간 GLUT DS의 특징적인 특징을 나타낸다 (Wang 등, Hum Mol Gen, 2006; Tang 등, Nat Comm, 2016). AAV9 작제물은 유비쿼터스 프로모터(CMV) 또는 여러 내피 세포 프로모터 중 하나(hFLT-1, mTie, hGlut1)에 의해 지시되는 GLUT1 이식유전자의 발현을 사용해 상이한 투여량 및 상이한 투여 경로(정맥내 또는 뇌실내 투여)로 평가될 것이다. AAV9 벡터를 사용하여 전달 후 내피 세포 프로모터-매개 GLUT1 이식유전자 발현이 이러한 마우스 모델에서 기능적 및 병리학적 결함을 예방하거나 완화할 수 있는 정도를 평가할 것이다. 이형접합 반수체부족성 마우스에 투여될 때 AAV9-매개 Glut1 단백질 발현의 잠재적 유익한 효과는 미치료 GLUT-1 +/- 대조군 마우스와 비교함으로써 밝혀질 것이며, 이는 개선된 또는 정상화된 체중 증가, 운동 시험에 대한 행동 성과(예: 로타로드, 수직 극 검정), CSF 포도당 수준, 뇌 중량, 및 뇌 미세혈관 구조(예: 뇌 모세혈관 밀도, 혈관 크기, 혈관 분기점 수)의 무결성 및 크기로 구성될 것이다.
SEQUENCE LISTING
<110> Spacecraft Seven, LLC
<120> ADENO-ASSOCIATED VIRAL VECTOR FOR GLUT1 EXPRESSION AND USES
THEREOF
<130> ROPA-018/01WO 329592-2262
<150> US 63/061,726
<151> 2020-08-05
<160> 102
<170> PatentIn version 3.5
<210> 1
<211> 1037
<212> DNA
<213> Homo sapiens
<400> 1
tttgcttcta ggaagcagaa gactgaggaa atgacttggg cgggtgcatc aatgcggcca 60
aaaaagacac ggacacgctc ccctgggacc tgagctggtt cgcagtcttc ccaaaggtgc 120
caagcaagcg tcagttcccc tcaggcgctc caggttcagt gccttgtgcc gagggtctcc 180
ggtgccttcc tagacttctc gggacagtct gaaggggtca ggagcggcgg gacagcgcgg 240
gaagagcagg caaggggaga cagccggact gcgcctcagt cctccgtgcc aagaacaccg 300
tcgcggaggc gcggccagct tcccttggat cggactttcc gcccctaggg ccaggcggcg 360
gagcttcagc cttgtccctt ccccagtttc gggcggcccc cagagctgag taagccgggt 420
ggagggagtc tgcaaggatt tcctgagcgc gatgggcagg aggaggggca agggcaagag 480
ggcgcggagc aaagaccctg aacctgccgg ggccgcgctc ccgggcccgc gtcgccagca 540
cctccccacg cgcgctcggc cccgggccac ccgccctcgt cggcccccgc ccctctccgt 600
agccgcaggg aagcgagcct gggaggaaga agagggtagg tggggaggcg gatgaggggt 660
gggggacccc ttgacgtcac cagaaggagg tgccggggta ggaagtgggc tggggaaagg 720
ttataaatcg cccccgccct cggctgctct tcatcgaggt ccgcgggagg ctcggagcgc 780
gccaggcgga cactcctctc ggctcctccc cggcagcggc ggcggctcgg agcgggctcc 840
ggggctcggg tgcagcggcc agcgggcgcc tggcggcgag gattacccgg ggaagtggtt 900
gtctcctggc tggagccgcg agacgggcgc tcagggcgcg gggccggcgg cggcgaacaa 960
gaggacggac tctggcggcc gggtcgttgg ccgcggggag cgcgggcacc gggcgagcag 1020
gccgcgtcgc gctcacc 1037
<210> 2
<211> 1608
<212> DNA
<213> Homo sapiens
<400> 2
agctcctccc agcctcaggc ccaggaatgg gaatctctgt gggtcacaca tcagtaggga 60
ggtctttccc gatccttttc tatgctactc caggagtcaa agcgtctcct gggacttttc 120
agggcgcttc agaagagccc tgggcctaaa ccagctcaac caagctgcag ggacccagcc 180
tcctgagaaa agtgaatgtg agcccggtgc attcagagga gaatgaagcc ttcacccaga 240
acacactctg ggaagatgtc ccaggcccag ggggagggtt tgtactacca gacctaagtc 300
acctaaactg acaccaagtc tcatccatcc caaccattcc attccgggtc agaggggtca 360
tcgatttaac cagcaaggct gcccatccaa cggttgctcc ctctgctccc tggaagggcc 420
tcctcgtggg cgttctgtac ctacaggtct tgttccgttc tgggaactgc cagtggtggc 480
aagaggtgga gcaacgggtg ccagggcagg gagaggtgag tctgggaggg aagcagaggc 540
aagatccatg gggctttaga gactttgcca aagcagtgcg actgctccca ggttgttgtc 600
agccgtcaag agtgagtgca cctccctggg cagacttctg ctgccccagt gcccaggaat 660
aggcaggggt ttgccgcaaa atgaatgaca cctggcagac aataagctga agctttcatt 720
agcagcttaa gctgaggact atctatgcaa ccgatactcc ctgtgtgctc cccgggactg 780
cttaatgtga gcccttgtgg agcgattggc accaagaaag caaggactaa gtcagaagtt 840
caagtcccag ccttgccaca gcctcagggt gccctcgagc acagcaagcc tcagttttcc 900
catctgtaca atgagagagg tacacaaggt agactcgaag gctctttgtt gccagggccc 960
tgtgttcctt tgagtgtatg tgcttctcag gcccacagag gtcctttgtg tttcgtatgt 1020
gaactgctct ctaggaaacc catgtaactg tctgtgtcct ggggcacata catgaggact 1080
catgtgggcc gtattgtgtg tttgtgccgg ggggagggga gaccccagaa caatgtcccc 1140
caccccaccc ccctcctcaa taggcggaag ccactggctt cctccctttc ctgcctcctg 1200
cctcctttgt gccagcaaga ctgagtactg gagagagaca ggggatggga aaaatcagtc 1260
cagctgtccc caggtctgcc cttaccataa ccttcccccc acctcaagtg actcctccca 1320
ggccacaccc atccccagcc ttgtgggggc cagattgggg ggcctagagg ctcaaaggca 1380
gaatgagtcc tcccaccccc taccctgcca cccctcccac ccaagccacc tcatttcctc 1440
ttcctcccca gcaccgaccc acactgacca acacaggctg agcagtcagg cccacagcat 1500
ctgaccccag gcccagctcg tcctggctgg cctgggtcgg cctctggagt atggtctggc 1560
gggtgccccc tttcttgctc cccatcctct tcttggcttc tcatgtgg 1608
<210> 3
<211> 2510
<212> DNA
<213> Homo sapiens
<400> 3
ctagtagcag aaacaaggtc ctctggaaga gcaactgatg ctcttaggta ctgaagcatc 60
atcctgcccc agagaccact cgcatatgaa gcacacatat tcagtctgcc ttacttgtgt 120
taatgattgc cagtgtccct ctgacctcct agccctgaaa agtgtggcct gaaggtcatt 180
tcagagacgg ggagagctgc tcagagaagc caatcggcga gtctaggaca cacagacagg 240
atctagtccc agagttcgct agcctaggtg agcgtcccct ggccccttat accacttcct 300
tctccagctt gcatctaatc tgctctggca gaccatcgtg tttcctgtct tcctggcagc 360
ctccagcacg ctcagtgcta ctccctgcgc atgcgccctc ctcccagtac cttctctgac 420
tccagtgggc ttggagtgcg aggaggaagg gtgaggaagg ggtgaaatca ggtattggat 480
ccacaggggg tctgaagagc actagcctgg ccttttggga ctgaacttct gctatgaaga 540
cctccactgc catccctgga gtccggggca catccaaggc ttgctgtcca tcgtttactg 600
tttacagatg acaacaatga ctgtgttcgg ggcagaaata tccaccaggg ctagagtaca 660
aaaggagttt gcattgatgg ccggacaggc cctgtccctg gcagcctgcc agcgctgagt 720
atgagaccca gcgggaagtg ctaccctggc agacgtgtcc actgagtaca cagaccacca 780
aggcaggcag ctctcgggga agctgtctat gctgggccag cccaccttga gggcagggaa 840
cagaacagat tgtggcagag aggaaaatgt ggagcttctg tttgttcaca gacacacgca 900
ctcgcccacg cacgcacgca cgcacgcacg cacgcacgaa tgcacgcacg cagtagttga 960
atgctatgga ttccgctcag agctgagaac agccccagcg acagttccct ggcctctctc 1020
cttactctga tgtcctcatc tgtcttcaca tggtctcagg acgctaatac tccatcctaa 1080
tgtacactcc tttccctggg cctccgttcc agttcagttc tcagaggacc tggagggagt 1140
gattggctac accaactttg ctttcgttca ccaagcccat gtctctactt gggtgtctaa 1200
tgggcatctc caacattacc taccccaaac agaaaaccct ttcttccccc caaccacacc 1260
ccaccctacc cccacagtat tttctccatg cccggaaaga tctgctctct tatggtccct 1320
ctttgcctca ctgaaaagca ggacaagttg gggacttccc aaacttttat gcatgaagaa 1380
acccaggcaa tttgccaaaa ggtacactct gggggtctgt catttactct gagccagaac 1440
cctgaaattt ttactaaccc atcacataat gaatgaagag aatctttttc tttttttttt 1500
tttttctttt tttttggttt ttcgagacag ggtttctctg tatagccctg gctatcctgg 1560
aacacactct gtagaccagg ctggcctcga actcagaaat ccacctgcct ctgcctcccg 1620
agtgctggga ttaaaggcgt gcgccaccac gcctggctga atgaagagaa tcttgacctc 1680
atctccccag cctcttggtc ctgagggacc ctggtctacc tactgctttg ctgtcttctt 1740
agctcttctt acttttttgc tgactcagac ctatggctat ctccattata cagatgagga 1800
gactgaggca tggatccctg gttggtccat ggtcacgtga agcccatcac ccagtatttg 1860
taaagtgaga tgggccaggc tggtaccttg gaactgaaac tcacactgcc ctacctggaa 1920
gaatctgaca ggcaaaatct gctgctgaaa gtgattgtct gtcacgtttc tcagctgccc 1980
gactctgaga actccacagc cccctttcgt tccaccatac tacagagtcg ccacggaaag 2040
ccggctctgt ggagaagctg aggtagctgg gtttctgtct gggttactct gtccagcgag 2100
gaaacaagta ccttagaccc actaagcctc tgctttctga actgtaaagt gggggatatg 2160
acacctgcct cccagggatg gctgaatgct ctggcagaag cttagagccc ccacagctac 2220
ccctaggctc acagctcctc cgatgagacc tagaattgag gtatgagttg aataccccag 2280
gcaggtccaa ggcttccacg ggcccaggct gaccaagctg aggccgccca ccgtagggct 2340
tgcctatctg caggcagctc acaaaggaac aataacagga aaccatcccg aggggaagtg 2400
ggccagggcc agttggaaaa cctgcctccc tcccagcctg ggtgtggctc ccctctcccc 2460
tcctgaggca atcaactgtg ctctccacaa agctcggccc tggacagact 2510
<210> 4
<211> 94
<212> DNA
<213> Homo sapiens
<400> 4
gctggagcct cggtagccgt tcctcctgcc cgctgggcct cccaacgggc cctcctcccc 60
tccttgcacc ggcccttcct ggtctttgaa taaa 94
<210> 5
<211> 1476
<212> DNA
<213> Homo sapiens
<400> 5
atggagccca gcagcaagaa gctgacgggt cgcctcatgc tggccgtggg aggagcagtg 60
cttggctccc tgcagtttgg ctacaacact ggagtcatca atgcccccca gaaggtgatc 120
gaggagttct acaaccagac atgggtccac cgctatgggg agagcatcct gcccaccacg 180
ctcaccacgc tctggtccct ctcagtggcc atcttttctg ttgggggcat gattggctcc 240
ttctctgtgg gccttttcgt taaccgcttt ggccggcgga attcaatgct gatgatgaac 300
ctgctggcct tcgtgtccgc cgtgctcatg ggcttctcga aactgggcaa gtcctttgag 360
atgctgatcc tgggccgctt catcatcggt gtgtactgcg gcctgaccac aggcttcgtg 420
cccatgtatg tgggtgaagt gtcacccaca gcccttcgtg gggccctggg caccctgcac 480
cagctgggca tcgtcgtcgg catcctcatc gcccaggtgt tcggcctgga ctccatcatg 540
ggcaacaagg acctgtggcc cctgctgctg agcatcatct tcatcccggc cctgctgcag 600
tgcatcgtgc tgcccttctg ccccgagagt ccccgcttcc tgctcatcaa ccgcaacgag 660
gagaaccggg ccaagagtgt gctaaagaag ctgcgcggga cagctgacgt gacccatgac 720
ctgcaggaga tgaaggaaga gagtcggcag atgatgcggg agaagaaggt caccatcctg 780
gagctgttcc gctcccccgc ctaccgccag cccatcctca tcgctgtggt gctgcagctg 840
tcccagcagc tgtctggcat caacgctgtc ttctattact ccacgagcat cttcgagaag 900
gcgggggtgc agcagcctgt gtatgccacc attggctccg gtatcgtcaa cacggccttc 960
actgtcgtgt cgctgtttgt ggtggagcga gcaggccggc ggaccctgca cctcataggc 1020
ctcgctggca tggcgggttg tgccatactc atgaccatcg cgctagcact gctggagcag 1080
ctaccctgga tgtcctatct gagcatcgtg gccatctttg gctttgtggc cttctttgaa 1140
gtgggtcctg gccccatccc atggttcatc gtggctgaac tcttcagcca gggtccacgt 1200
ccagctgcca ttgccgttgc aggcttctcc aactggacct caaatttcat tgtgggcatg 1260
tgcttccagt atgtggagca actgtgtggt ccctacgtct tcatcatctt cactgtgctc 1320
ctggttctgt tcttcatctt cacctacttc aaagttcctg agactaaagg ccggaccttc 1380
gatgagatcg cttccggctt ccggcagggg ggagccagcc aaagtgacaa gacacccgag 1440
gagctgttcc atcccctggg ggctgattcc caagtg 1476
<210> 6
<211> 168
<212> DNA
<213> Adeno-associated virus 2
<400> 6
gcgcgctcgc tcgctcactg aggccgcccg ggcaaagccc gggcgtcggg cgacctttgg 60
tcgcccggcc tcagtgagcg agcgagcgcg cagagaggga gtggccaact ccatcactag 120
gggttccttg tagttaatga ttaacccgcc atgctactta tctacgta 168
<210> 7
<211> 168
<212> DNA
<213> Adeno-associated virus 2
<400> 7
tacgtagata agtagcatgg cgggttaatc attaactaca aggaacccct agtgatggag 60
ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc 120
cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc gagcgcgc 168
<210> 8
<211> 2963
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in Lab - part of expression cassette
<400> 8
ctctggagac gcgttacata cgttacataa cttacggtaa atggcccgcc tggctgaccg 60
cccaacgacc cccgcccatt gacgtcaata atgacgtatg ttcccatagt aacgccaata 120
gggactttcc attgacgtca atgggtggag tatttacggt aaactgccca cttggcagta 180
catcaagtgt atcatatgcc aagtacgccc cctattgacg tcaatgacgg taaatggccc 240
gcctggcatt atgcccagta catgacctta tgggactttc ctacttggca gtacatctac 300
gtattagtca tcgctattac catggtgatg cggttttggc agtacatcaa tgggcgtgga 360
tagcggtttg actcacgggg atttccaagt ctccacccca ttgacgtcaa tgggagtttg 420
ttttggcacc aaaatcaacg ggactttcca aaatgtcgta acaactccgc cccattgacg 480
caaatgggcg gtaggcgtgt acggtgggag gtctatataa gcagagctcg tttagtgaac 540
cgtcagatcg cctggagacg ccatccacgc tgttttgacc tccatagaag acaccgggac 600
cgatccagcc tccgcggatg gagcccagca gcaagaagct gacgggtcgc ctcatgctgg 660
ccgtgggagg agcagtgctt ggctccctgc agtttggcta caacactgga gtcatcaatg 720
ccccccagaa ggtgatcgag gagttctaca accagacatg ggtccaccgc tatggggaga 780
gcatcctgcc caccacgctc accacgctct ggtccctctc agtggccatc ttttctgttg 840
ggggcatgat tggctccttc tctgtgggcc ttttcgttaa ccgctttggc cggcggaatt 900
caatgctgat gatgaacctg ctggccttcg tgtccgccgt gctcatgggc ttctcgaaac 960
tgggcaagtc ctttgagatg ctgatcctgg gccgcttcat catcggtgtg tactgcggcc 1020
tgaccacagg cttcgtgccc atgtatgtgg gtgaagtgtc acccacagcc cttcgtgggg 1080
ccctgggcac cctgcaccag ctgggcatcg tcgtcggcat cctcatcgcc caggtgttcg 1140
gcctggactc catcatgggc aacaaggacc tgtggcccct gctgctgagc atcatcttca 1200
tcccggccct gctgcagtgc atcgtgctgc ccttctgccc cgagagtccc cgcttcctgc 1260
tcatcaaccg caacgaggag aaccgggcca agagtgtgct aaagaagctg cgcgggacag 1320
ctgacgtgac ccatgacctg caggagatga aggaagagag tcggcagatg atgcgggaga 1380
agaaggtcac catcctggag ctgttccgct cccccgccta ccgccagccc atcctcatcg 1440
ctgtggtgct gcagctgtcc cagcagctgt ctggcatcaa cgctgtcttc tattactcca 1500
cgagcatctt cgagaaggcg ggggtgcagc agcctgtgta tgccaccatt ggctccggta 1560
tcgtcaacac ggccttcact gtcgtgtcgc tgtttgtggt ggagcgagca ggccggcgga 1620
ccctgcacct cataggcctc gctggcatgg cgggttgtgc catactcatg accatcgcgc 1680
tagcactgct ggagcagcta ccctggatgt cctatctgag catcgtggcc atctttggct 1740
ttgtggcctt ctttgaagtg ggtcctggcc ccatcccatg gttcatcgtg gctgaactct 1800
tcagccaggg tccacgtcca gctgccattg ccgttgcagg cttctccaac tggacctcaa 1860
atttcattgt gggcatgtgc ttccagtatg tggagcaact gtgtggtccc tacgtcttca 1920
tcatcttcac tgtgctcctg gttctgttct tcatcttcac ctacttcaaa gttcctgaga 1980
ctaaaggccg gaccttcgat gagatcgctt ccggcttccg gcagggggga gccagccaaa 2040
gtgacaagac acccgaggag ctgttccatc ccctgggggc tgattcccaa gtgtgataat 2100
ggatcaacct ctggattaca aaatttgtga aagattgact ggtattctta actatgttgc 2160
tccttttacg ctatgtggat acgctgcttt aatgcctttg tatcatgcta ttgcttcccg 2220
tatggctttc attttctcct ccttgtataa atcctggttg ctgtctcttt atgaggagtt 2280
gtggcccgtt gtcaggcaac gtggcgtggt gtgcactgtg tttgctgacg caacccccac 2340
tggttggggc attgccacca cctgtcagct cctttccggg actttcgctt tccccctccc 2400
tattgccacg gcggaactca tcgccgcctg ccttgcccgc tgctggacag gggctcggct 2460
gttgggcact gacaattccg tggtgttgtc ggggaaatca tcgtcctttc cttggctgct 2520
cgcctgtgtt gccacctgga ttctgcgcgg gacgtccttc tgctacgtcc cttcggccct 2580
caatccagcg gaccttcctt cccgcggcct gctgccggct ctgcggcctc ttccgcgtct 2640
tcgccttcgc cctcagacga gtcggatctc cctttgggcc gcctccccgc atcattgcct 2700
gcccgggtgg catccctgtg acccctcccc agtgcctctc ctggccctgg aagttgccac 2760
tccagtgccc accagccttg tcctaataaa attaagttgc atcattttgt ctgactaggt 2820
gtccttctat aatattatgg ggtggagggg ggtggtatgg agcaaggggc ccaagttggg 2880
aagaaacctg tagggcctgc gttacccagg ctggagtgca gtggcacatt tctgctcact 2940
gcaacctcct cctccctggg ttc 2963
<210> 9
<400> 9
000
<210> 10
<211> 3414
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in Lab - part of expression cassette
<400> 10
ctctggagac gcgttacata acttacggta aatggcccgc ctggctgacc gcccaacgac 60
ccccgcccat tgacgtcaat aatgacgtat gttcccatag taacgccaat agggactttc 120
cattgacgtc aatgggtgga gtatttacgg taaactgccc acttggcagt acatcaagtg 180
tatcatatgc caagtacgcc ccctattgac gtcaatgacg gtaaatggcc cgcctggcat 240
tatgcccagt acatgacctt atgggacttt cctacttggc agtacatcta cgtattagtc 300
atcgctatta ccatggtcga ggtgagcccc acgttctgct tcactctccc catctccccc 360
ccctccccac ccccaatttt gtatttattt attttttaat tattttgtgc agcgatgggg 420
gcgggggggg ggggggcgcg cgccaggcgg ggcggggcgg ggcgaggggc ggggcggggc 480
gaggcggaga ggtgcggcgg cagccaatca gagcggcgcg ctccgaaagt ttccttttat 540
ggcgaggcgg cggcggcggc ggccctataa aaagcgaagc gcgcggcggg cgggagtcgc 600
tgcgcgctgc cttcgccccg tgccccgctc cgccgccgcc tcgcgccgcc cgccccggct 660
ctgactgacc gcgttactcc cacaggtgag cgggcgggac ggcccttctc ctccgggctg 720
taattagcgc ttggtttaat gacggcttgt ttcttttctg tggctgcgtg aaagccttga 780
ggggctccgg gagggccctt tgtgcggggg gagcggctcg gggggtgcgt gcgtgtgtgt 840
gtgcgtgggg agcgccgcgt gcggctccgc gctgcccggc ggctgtgagc gctgcgggcg 900
cggcgcgggg ctttgtgcgc tccgcagtgt gcgcgagggg agcgcggccg ggggcggtgc 960
cccgcggtgc ggggggggct gcgaggggaa caaaggctgc gtgcggggtg tgtgcgtggg 1020
ggggtgagca gggggtgtgg gcgcgtcggt cgggctgcaa ccccccctgc acccccctcc 1080
ccgagttgct gagcacggcc cggcttcggg tgcggggctc cgtacggggc gtggcgcggg 1140
gctcgccgtg ccgggcgggg ggtggcggca ggtgggggtg ccgggcgggg cggggccgcc 1200
tcgggccggg gagggctcgg gggaggggcg cggcggcccc cggagcgccg gcggctgtcg 1260
aggcgcggcg agccgcagcc attgcctttt atggtaatcg tgcgagaggg cgcagggact 1320
tcctttgtcc caaatctgtg cggagccgaa atctgggagg cgccgccgca ccccctctag 1380
cgggcgcggg gcgaagcggt gcggcgccgg caggaaggaa atgggcgggg agggccttcg 1440
tgcgtcgccg cgccgccgtc cccttctccc tctccagcct cggggctgtc cgcgggggga 1500
cggctgcctt cgggggggac ggggcagggc ggggttcggc ttctggcgtg tgaccggcgg 1560
ctctagagcc tctgctaacc atgttcatgc cttcttcttt ttcctacagc tcctgggcaa 1620
cgtgctggtt attgtgctgt ctcatcattt tggcaaagaa ttcatggagc ccagcagcaa 1680
gaagctgacg ggtcgcctca tgctggccgt gggaggagca gtgcttggct ccctgcagtt 1740
tggctacaac actggagtca tcaatgcccc ccagaaggtg atcgaggagt tctacaacca 1800
gacatgggtc caccgctatg gggagagcat cctgcccacc acgctcacca cgctctggtc 1860
cctctcagtg gccatctttt ctgttggggg catgattggc tccttctctg tgggcctttt 1920
cgttaaccgc tttggccggc ggaattcaat gctgatgatg aacctgctgg ccttcgtgtc 1980
cgccgtgctc atgggcttct cgaaactggg caagtccttt gagatgctga tcctgggccg 2040
cttcatcatc ggtgtgtact gcggcctgac cacaggcttc gtgcccatgt atgtgggtga 2100
agtgtcaccc acagcccttc gtggggccct gggcaccctg caccagctgg gcatcgtcgt 2160
cggcatcctc atcgcccagg tgttcggcct ggactccatc atgggcaaca aggacctgtg 2220
gcccctgctg ctgagcatca tcttcatccc ggccctgctg cagtgcatcg tgctgccctt 2280
ctgccccgag agtccccgct tcctgctcat caaccgcaac gaggagaacc gggccaagag 2340
tgtgctaaag aagctgcgcg ggacagctga cgtgacccat gacctgcagg agatgaagga 2400
agagagtcgg cagatgatgc gggagaagaa ggtcaccatc ctggagctgt tccgctcccc 2460
cgcctaccgc cagcccatcc tcatcgctgt ggtgctgcag ctgtcccagc agctgtctgg 2520
catcaacgct gtcttctatt actccacgag catcttcgag aaggcggggg tgcagcagcc 2580
tgtgtatgcc accattggct ccggtatcgt caacacggcc ttcactgtcg tgtcgctgtt 2640
tgtggtggag cgagcaggcc ggcggaccct gcacctcata ggcctcgctg gcatggcggg 2700
ttgtgccata ctcatgacca tcgcgctagc actgctggag cagctaccct ggatgtccta 2760
tctgagcatc gtggccatct ttggctttgt ggccttcttt gaagtgggtc ctggccccat 2820
cccatggttc atcgtggctg aactcttcag ccagggtcca cgtccagctg ccattgccgt 2880
tgcaggcttc tccaactgga cctcaaattt cattgtgggc atgtgcttcc agtatgtgga 2940
gcaactgtgt ggtccctacg tcttcatcat cttcactgtg ctcctggttc tgttcttcat 3000
cttcacctac ttcaaagttc ctgagactaa aggccggacc ttcgatgaga tcgcttccgg 3060
cttccggcag gggggagcca gccaaagtga caagacaccc gaggagctgt tccatcccct 3120
gggggctgat tcccaagtgt gatcattgcc tgcccgggtg gcatccctgt gacccctccc 3180
cagtgcctct cctggccctg gaagttgcca ctccagtgcc caccagcctt gtcctaataa 3240
aattaagttg catcattttg tctgactagg tgtccttcta taatattatg gggtggaggg 3300
gggtggtatg gagcaagggg cccaagttgg gaagaaacct gtagggcctg cgttacccag 3360
gctggagtgc agtggcacat ttctgctcac tgcaacctcc tcctccctgg gttc 3414
<210> 11
<400> 11
000
<210> 12
<211> 3409
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in Lab - part of expression cassette
<400> 12
ctctggagac gcgttacata tttgcttcta ggaagcagaa gactgaggaa atgacttggg 60
cgggtgcatc aatgcggcca aaaaagacac ggacacgctc ccctgggacc tgagctggtt 120
cgcagtcttc ccaaaggtgc caagcaagcg tcagttcccc tcaggcgctc caggttcagt 180
gccttgtgcc gagggtctcc ggtgccttcc tagacttctc gggacagtct gaaggggtca 240
ggagcggcgg gacagcgcgg gaagagcagg caaggggaga cagccggact gcgcctcagt 300
cctccgtgcc aagaacaccg tcgcggaggc gcggccagct tcccttggat cggactttcc 360
gcccctaggg ccaggcggcg gagcttcagc cttgtccctt ccccagtttc gggcggcccc 420
cagagctgag taagccgggt ggagggagtc tgcaaggatt tcctgagcgc gatgggcagg 480
aggaggggca agggcaagag ggcgcggagc aaagaccctg aacctgccgg ggccgcgctc 540
ccgggcccgc gtcgccagca cctccccacg cgcgctcggc cccgggccac ccgccctcgt 600
cggcccccgc ccctctccgt agccgcaggg aagcgagcct gggaggaaga agagggtagg 660
tggggaggcg gatgaggggt gggggacccc ttgacgtcac cagaaggagg tgccggggta 720
ggaagtgggc tggggaaagg ttataaatcg cccccgccct cggctgctct tcatcgaggt 780
ccgcgggagg ctcggagcgc gccaggcgga cactcctctc ggctcctccc cggcagcggc 840
ggcggctcgg agcgggctcc ggggctcggg tgcagcggcc agcgggcgcc tggcggcgag 900
gattacccgg ggaagtggtt gtctcctggc tggagccgcg agacgggcgc tcagggcgcg 960
gggccggcgg cggcgaacaa gaggacggac tctggcggcc gggtcgttgg ccgcggggag 1020
cgcgggcacc gggcgagcag gccgcgtcgc gctcaccgcc accatggagc ccagcagcaa 1080
gaagctgacg ggtcgcctca tgctggccgt gggaggagca gtgcttggct ccctgcagtt 1140
tggctacaac actggagtca tcaatgcccc ccagaaggtg atcgaggagt tctacaacca 1200
gacatgggtc caccgctatg gggagagcat cctgcccacc acgctcacca cgctctggtc 1260
cctctcagtg gccatctttt ctgttggggg catgattggc tccttctctg tgggcctttt 1320
cgttaaccgc tttggccggc ggaattcaat gctgatgatg aacctgctgg ccttcgtgtc 1380
cgccgtgctc atgggcttct cgaaactggg caagtccttt gagatgctga tcctgggccg 1440
cttcatcatc ggtgtgtact gcggcctgac cacaggcttc gtgcccatgt atgtgggtga 1500
agtgtcaccc acagcccttc gtggggccct gggcaccctg caccagctgg gcatcgtcgt 1560
cggcatcctc atcgcccagg tgttcggcct ggactccatc atgggcaaca aggacctgtg 1620
gcccctgctg ctgagcatca tcttcatccc ggccctgctg cagtgcatcg tgctgccctt 1680
ctgccccgag agtccccgct tcctgctcat caaccgcaac gaggagaacc gggccaagag 1740
tgtgctaaag aagctgcgcg ggacagctga cgtgacccat gacctgcagg agatgaagga 1800
agagagtcgg cagatgatgc gggagaagaa ggtcaccatc ctggagctgt tccgctcccc 1860
cgcctaccgc cagcccatcc tcatcgctgt ggtgctgcag ctgtcccagc agctgtctgg 1920
catcaacgct gtcttctatt actccacgag catcttcgag aaggcggggg tgcagcagcc 1980
tgtgtatgcc accattggct ccggtatcgt caacacggcc ttcactgtcg tgtcgctgtt 2040
tgtggtggag cgagcaggcc ggcggaccct gcacctcata ggcctcgctg gcatggcggg 2100
ttgtgccata ctcatgacca tcgcgctagc actgctggag cagctaccct ggatgtccta 2160
tctgagcatc gtggccatct ttggctttgt ggccttcttt gaagtgggtc ctggccccat 2220
cccatggttc atcgtggctg aactcttcag ccagggtcca cgtccagctg ccattgccgt 2280
tgcaggcttc tccaactgga cctcaaattt cattgtgggc atgtgcttcc agtatgtgga 2340
gcaactgtgt ggtccctacg tcttcatcat cttcactgtg ctcctggttc tgttcttcat 2400
cttcacctac ttcaaagttc ctgagactaa aggccggacc ttcgatgaga tcgcttccgg 2460
cttccggcag gggggagcca gccaaagtga caagacaccc gaggagctgt tccatcccct 2520
gggggctgat tcccaagtgt gataatggat caacctctgg attacaaaat ttgtgaaaga 2580
ttgactggta ttcttaacta tgttgctcct tttacgctat gtggatacgc tgctttaatg 2640
cctttgtatc atgctattgc ttcccgtatg gctttcattt tctcctcctt gtataaatcc 2700
tggttgctgt ctctttatga ggagttgtgg cccgttgtca ggcaacgtgg cgtggtgtgc 2760
actgtgtttg ctgacgcaac ccccactggt tggggcattg ccaccacctg tcagctcctt 2820
tccgggactt tcgctttccc cctccctatt gccacggcgg aactcatcgc cgcctgcctt 2880
gcccgctgct ggacaggggc tcggctgttg ggcactgaca attccgtggt gttgtcgggg 2940
aaatcatcgt cctttccttg gctgctcgcc tgtgttgcca cctggattct gcgcgggacg 3000
tccttctgct acgtcccttc ggccctcaat ccagcggacc ttccttcccg cggcctgctg 3060
ccggctctgc ggcctcttcc gcgtcttcgc cttcgccctc agacgagtcg gatctccctt 3120
tgggccgcct ccccgcatca ttgcctgccc gggtggcatc cctgtgaccc ctccccagtg 3180
cctctcctgg ccctggaagt tgccactcca gtgcccacca gccttgtcct aataaaatta 3240
agttgcatca ttttgtctga ctaggtgtcc ttctataata ttatggggtg gaggggggtg 3300
gtatggagca aggggcccaa gttgggaaga aacctgtagg gcctgcgtta cccaggctgg 3360
agtgcagtgg cacatttctg ctcactgcaa cctcctcctc cctgggttc 3409
<210> 13
<400> 13
000
<210> 14
<211> 3980
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in Lab - part of expression cassette
<400> 14
ctctggagac gcgttacata agctcctccc agcctcaggc ccaggaatgg gaatctctgt 60
gggtcacaca tcagtaggga ggtctttccc gatccttttc tatgctactc caggagtcaa 120
agcgtctcct gggacttttc agggcgcttc agaagagccc tgggcctaaa ccagctcaac 180
caagctgcag ggacccagcc tcctgagaaa agtgaatgtg agcccggtgc attcagagga 240
gaatgaagcc ttcacccaga acacactctg ggaagatgtc ccaggcccag ggggagggtt 300
tgtactacca gacctaagtc acctaaactg acaccaagtc tcatccatcc caaccattcc 360
attccgggtc agaggggtca tcgatttaac cagcaaggct gcccatccaa cggttgctcc 420
ctctgctccc tggaagggcc tcctcgtggg cgttctgtac ctacaggtct tgttccgttc 480
tgggaactgc cagtggtggc aagaggtgga gcaacgggtg ccagggcagg gagaggtgag 540
tctgggaggg aagcagaggc aagatccatg gggctttaga gactttgcca aagcagtgcg 600
actgctccca ggttgttgtc agccgtcaag agtgagtgca cctccctggg cagacttctg 660
ctgccccagt gcccaggaat aggcaggggt ttgccgcaaa atgaatgaca cctggcagac 720
aataagctga agctttcatt agcagcttaa gctgaggact atctatgcaa ccgatactcc 780
ctgtgtgctc cccgggactg cttaatgtga gcccttgtgg agcgattggc accaagaaag 840
caaggactaa gtcagaagtt caagtcccag ccttgccaca gcctcagggt gccctcgagc 900
acagcaagcc tcagttttcc catctgtaca atgagagagg tacacaaggt agactcgaag 960
gctctttgtt gccagggccc tgtgttcctt tgagtgtatg tgcttctcag gcccacagag 1020
gtcctttgtg tttcgtatgt gaactgctct ctaggaaacc catgtaactg tctgtgtcct 1080
ggggcacata catgaggact catgtgggcc gtattgtgtg tttgtgccgg ggggagggga 1140
gaccccagaa caatgtcccc caccccaccc ccctcctcaa taggcggaag ccactggctt 1200
cctccctttc ctgcctcctg cctcctttgt gccagcaaga ctgagtactg gagagagaca 1260
ggggatggga aaaatcagtc cagctgtccc caggtctgcc cttaccataa ccttcccccc 1320
acctcaagtg actcctccca ggccacaccc atccccagcc ttgtgggggc cagattgggg 1380
ggcctagagg ctcaaaggca gaatgagtcc tcccaccccc taccctgcca cccctcccac 1440
ccaagccacc tcatttcctc ttcctcccca gcaccgaccc acactgacca acacaggctg 1500
agcagtcagg cccacagcat ctgaccccag gcccagctcg tcctggctgg cctgggtcgg 1560
cctctggagt atggtctggc gggtgccccc tttcttgctc cccatcctct tcttggcttc 1620
tcatgtgggc caccatggag cccagcagca agaagctgac gggtcgcctc atgctggccg 1680
tgggaggagc agtgcttggc tccctgcagt ttggctacaa cactggagtc atcaatgccc 1740
cccagaaggt gatcgaggag ttctacaacc agacatgggt ccaccgctat ggggagagca 1800
tcctgcccac cacgctcacc acgctctggt ccctctcagt ggccatcttt tctgttgggg 1860
gcatgattgg ctccttctct gtgggccttt tcgttaaccg ctttggccgg cggaattcaa 1920
tgctgatgat gaacctgctg gccttcgtgt ccgccgtgct catgggcttc tcgaaactgg 1980
gcaagtcctt tgagatgctg atcctgggcc gcttcatcat cggtgtgtac tgcggcctga 2040
ccacaggctt cgtgcccatg tatgtgggtg aagtgtcacc cacagccctt cgtggggccc 2100
tgggcaccct gcaccagctg ggcatcgtcg tcggcatcct catcgcccag gtgttcggcc 2160
tggactccat catgggcaac aaggacctgt ggcccctgct gctgagcatc atcttcatcc 2220
cggccctgct gcagtgcatc gtgctgccct tctgccccga gagtccccgc ttcctgctca 2280
tcaaccgcaa cgaggagaac cgggccaaga gtgtgctaaa gaagctgcgc gggacagctg 2340
acgtgaccca tgacctgcag gagatgaagg aagagagtcg gcagatgatg cgggagaaga 2400
aggtcaccat cctggagctg ttccgctccc ccgcctaccg ccagcccatc ctcatcgctg 2460
tggtgctgca gctgtcccag cagctgtctg gcatcaacgc tgtcttctat tactccacga 2520
gcatcttcga gaaggcgggg gtgcagcagc ctgtgtatgc caccattggc tccggtatcg 2580
tcaacacggc cttcactgtc gtgtcgctgt ttgtggtgga gcgagcaggc cggcggaccc 2640
tgcacctcat aggcctcgct ggcatggcgg gttgtgccat actcatgacc atcgcgctag 2700
cactgctgga gcagctaccc tggatgtcct atctgagcat cgtggccatc tttggctttg 2760
tggccttctt tgaagtgggt cctggcccca tcccatggtt catcgtggct gaactcttca 2820
gccagggtcc acgtccagct gccattgccg ttgcaggctt ctccaactgg acctcaaatt 2880
tcattgtggg catgtgcttc cagtatgtgg agcaactgtg tggtccctac gtcttcatca 2940
tcttcactgt gctcctggtt ctgttcttca tcttcaccta cttcaaagtt cctgagacta 3000
aaggccggac cttcgatgag atcgcttccg gcttccggca ggggggagcc agccaaagtg 3060
acaagacacc cgaggagctg ttccatcccc tgggggctga ttcccaagtg tgataatgga 3120
tcaacctctg gattacaaaa tttgtgaaag attgactggt attcttaact atgttgctcc 3180
ttttacgcta tgtggatacg ctgctttaat gcctttgtat catgctattg cttcccgtat 3240
ggctttcatt ttctcctcct tgtataaatc ctggttgctg tctctttatg aggagttgtg 3300
gcccgttgtc aggcaacgtg gcgtggtgtg cactgtgttt gctgacgcaa cccccactgg 3360
ttggggcatt gccaccacct gtcagctcct ttccgggact ttcgctttcc ccctccctat 3420
tgccacggcg gaactcatcg ccgcctgcct tgcccgctgc tggacagggg ctcggctgtt 3480
gggcactgac aattccgtgg tgttgtcggg gaaatcatcg tcctttcctt ggctgctcgc 3540
ctgtgttgcc acctggattc tgcgcgggac gtccttctgc tacgtccctt cggccctcaa 3600
tccagcggac cttccttccc gcggcctgct gccggctctg cggcctcttc cgcgtcttcg 3660
ccttcgccct cagacgagtc ggatctccct ttgggccgcc tccccgcatc attgcctgcc 3720
cgggtggcat ccctgtgacc cctccccagt gcctctcctg gccctggaag ttgccactcc 3780
agtgcccacc agccttgtcc taataaaatt aagttgcatc attttgtctg actaggtgtc 3840
cttctataat attatggggt ggaggggggt ggtatggagc aaggggccca agttgggaag 3900
aaacctgtag ggcctgcgtt acccaggctg gagtgcagtg gcacatttct gctcactgca 3960
acctcctcct ccctgggttc 3980
<210> 15
<400> 15
000
<210> 16
<211> 4380
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in Lab - part of expression cassette
<400> 16
ctctggagac gcgttacata ctagtagcag aaacaaggtc ctctggaaga gcaactgatg 60
ctcttaggta ctgaagcatc atcctgcccc agagaccact cgcatatgaa gcacacatat 120
tcagtctgcc ttacttgtgt taatgattgc cagtgtccct ctgacctcct agccctgaaa 180
agtgtggcct gaaggtcatt tcagagacgg ggagagctgc tcagagaagc caatcggcga 240
gtctaggaca cacagacagg atctagtccc agagttcgct agcctaggtg agcgtcccct 300
ggccccttat accacttcct tctccagctt gcatctaatc tgctctggca gaccatcgtg 360
tttcctgtct tcctggcagc ctccagcacg ctcagtgcta ctccctgcgc atgcgccctc 420
ctcccagtac cttctctgac tccagtgggc ttggagtgcg aggaggaagg gtgaggaagg 480
ggtgaaatca ggtattggat ccacaggggg tctgaagagc actagcctgg ccttttggga 540
ctgaacttct gctatgaaga cctccactgc catccctgga gtccggggca catccaaggc 600
ttgctgtcca tcgtttactg tttacagatg acaacaatga ctgtgttcgg ggcagaaata 660
tccaccaggg ctagagtaca aaaggagttt gcattgatgg ccggacaggc cctgtccctg 720
gcagcctgcc agcgctgagt atgagaccca gcgggaagtg ctaccctggc agacgtgtcc 780
actgagtaca cagaccacca aggcaggcag ctctcgggga agctgtctat gctgggccag 840
cccaccttga gggcagggaa cagaacagat tgtggcagag aggaaaatgt ggagcttctg 900
tttgttcaca gacacacgca ctcgcccacg cacgcacgca cgcacgcacg cacgcacgaa 960
tgcacgcacg cagtagttga atgctatgga ttccgctcag agctgagaac agccccagcg 1020
acagttccct ggcctctctc cttactctga tgtcctcatc tgtcttcaca tggtctcagg 1080
acgctaatac tccatcctaa tgtacactcc tttccctggg cctccgttcc agttcagttc 1140
tcagaggacc tggagggagt gattggctac accaactttg ctttcgttca ccaagcccat 1200
gtctctactt gggtgtctaa tgggcatctc caacattacc taccccaaac agaaaaccct 1260
ttcttccccc caaccacacc ccaccctacc cccacagtat tttctccatg cccggaaaga 1320
tctgctctct tatggtccct ctttgcctca ctgaaaagca ggacaagttg gggacttccc 1380
aaacttttat gcatgaagaa acccaggcaa tttgccaaaa ggtacactct gggggtctgt 1440
catttactct gagccagaac cctgaaattt ttactaaccc atcacataat gaatgaagag 1500
aatctttttc tttttttttt tttttctttt tttttggttt ttcgagacag ggtttctctg 1560
tatagccctg gctatcctgg aacacactct gtagaccagg ctggcctcga actcagaaat 1620
ccacctgcct ctgcctcccg agtgctggga ttaaaggcgt gcgccaccac gcctggctga 1680
atgaagagaa tcttgacctc atctccccag cctcttggtc ctgagggacc ctggtctacc 1740
tactgctttg ctgtcttctt agctcttctt acttttttgc tgactcagac ctatggctat 1800
ctccattata cagatgagga gactgaggca tggatccctg gttggtccat ggtcacgtga 1860
agcccatcac ccagtatttg taaagtgaga tgggccaggc tggtaccttg gaactgaaac 1920
tcacactgcc ctacctggaa gaatctgaca ggcaaaatct gctgctgaaa gtgattgtct 1980
gtcacgtttc tcagctgccc gactctgaga actccacagc cccctttcgt tccaccatac 2040
tacagagtcg ccacggaaag ccggctctgt ggagaagctg aggtagctgg gtttctgtct 2100
gggttactct gtccagcgag gaaacaagta ccttagaccc actaagcctc tgctttctga 2160
actgtaaagt gggggatatg acacctgcct cccagggatg gctgaatgct ctggcagaag 2220
cttagagccc ccacagctac ccctaggctc acagctcctc cgatgagacc tagaattgag 2280
gtatgagttg aataccccag gcaggtccaa ggcttccacg ggcccaggct gaccaagctg 2340
aggccgccca ccgtagggct tgcctatctg caggcagctc acaaaggaac aataacagga 2400
aaccatcccg aggggaagtg ggccagggcc agttggaaaa cctgcctccc tcccagcctg 2460
ggtgtggctc ccctctcccc tcctgaggca atcaactgtg ctctccacaa agctcggccc 2520
tggacagact gccaccatgg agcccagcag caagaagctg acgggtcgcc tcatgctggc 2580
cgtgggagga gcagtgcttg gctccctgca gtttggctac aacactggag tcatcaatgc 2640
cccccagaag gtgatcgagg agttctacaa ccagacatgg gtccaccgct atggggagag 2700
catcctgccc accacgctca ccacgctctg gtccctctca gtggccatct tttctgttgg 2760
gggcatgatt ggctccttct ctgtgggcct tttcgttaac cgctttggcc ggcggaattc 2820
aatgctgatg atgaacctgc tggccttcgt gtccgccgtg ctcatgggct tctcgaaact 2880
gggcaagtcc tttgagatgc tgatcctggg ccgcttcatc atcggtgtgt actgcggcct 2940
gaccacaggc ttcgtgccca tgtatgtggg tgaagtgtca cccacagccc ttcgtggggc 3000
cctgggcacc ctgcaccagc tgggcatcgt cgtcggcatc ctcatcgccc aggtgttcgg 3060
cctggactcc atcatgggca acaaggacct gtggcccctg ctgctgagca tcatcttcat 3120
cccggccctg ctgcagtgca tcgtgctgcc cttctgcccc gagagtcccc gcttcctgct 3180
catcaaccgc aacgaggaga accgggccaa gagtgtgcta aagaagctgc gcgggacagc 3240
tgacgtgacc catgacctgc aggagatgaa ggaagagagt cggcagatga tgcgggagaa 3300
gaaggtcacc atcctggagc tgttccgctc ccccgcctac cgccagccca tcctcatcgc 3360
tgtggtgctg cagctgtccc agcagctgtc tggcatcaac gctgtcttct attactccac 3420
gagcatcttc gagaaggcgg gggtgcagca gcctgtgtat gccaccattg gctccggtat 3480
cgtcaacacg gccttcactg tcgtgtcgct gtttgtggtg gagcgagcag gccggcggac 3540
cctgcacctc ataggcctcg ctggcatggc gggttgtgcc atactcatga ccatcgcgct 3600
agcactgctg gagcagctac cctggatgtc ctatctgagc atcgtggcca tctttggctt 3660
tgtggccttc tttgaagtgg gtcctggccc catcccatgg ttcatcgtgg ctgaactctt 3720
cagccagggt ccacgtccag ctgccattgc cgttgcaggc ttctccaact ggacctcaaa 3780
tttcattgtg ggcatgtgct tccagtatgt ggagcaactg tgtggtccct acgtcttcat 3840
catcttcact gtgctcctgg ttctgttctt catcttcacc tacttcaaag ttcctgagac 3900
taaaggccgg accttcgatg agatcgcttc cggcttccgg caggggggag ccagccaaag 3960
tgacaagaca cccgaggagc tgttccatcc cctgggggct gattcccaag tgtgagctgg 4020
agcctcggta gccgttcctc ctgcccgctg ggcctcccaa cgggccctcc tcccctcctt 4080
gcaccggccc ttcctggtct ttgaataaac attgcctgcc cgggtggcat ccctgtgacc 4140
cctccccagt gcctctcctg gccctggaag ttgccactcc agtgcccacc agccttgtcc 4200
taataaaatt aagttgcatc attttgtctg actaggtgtc cttctataat attatggggt 4260
ggaggggggt ggtatggagc aaggggccca agttgggaag aaacctgtag ggcctgcgtt 4320
acccaggctg gagtgcagtg gcacatttct gctcactgca acctcctcct ccctgggttc 4380
<210> 17
<211> 3299
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in Lab - full polynucleotide sequence of vector genome
<400> 17
gcgcgctcgc tcgctcactg aggccgcccg ggcaaagccc gggcgtcggg cgacctttgg 60
tcgcccggcc tcagtgagcg agcgagcgcg cagagaggga gtggccaact ccatcactag 120
gggttccttg tagttaatga ttaacccgcc atgctactta tctacgtact ctggagacgc 180
gttacatacg ttacataact tacggtaaat ggcccgcctg gctgaccgcc caacgacccc 240
cgcccattga cgtcaataat gacgtatgtt cccatagtaa cgccaatagg gactttccat 300
tgacgtcaat gggtggagta tttacggtaa actgcccact tggcagtaca tcaagtgtat 360
catatgccaa gtacgccccc tattgacgtc aatgacggta aatggcccgc ctggcattat 420
gcccagtaca tgaccttatg ggactttcct acttggcagt acatctacgt attagtcatc 480
gctattacca tggtgatgcg gttttggcag tacatcaatg ggcgtggata gcggtttgac 540
tcacggggat ttccaagtct ccaccccatt gacgtcaatg ggagtttgtt ttggcaccaa 600
aatcaacggg actttccaaa atgtcgtaac aactccgccc cattgacgca aatgggcggt 660
aggcgtgtac ggtgggaggt ctatataagc agagctcgtt tagtgaaccg tcagatcgcc 720
tggagacgcc atccacgctg ttttgacctc catagaagac accgggaccg atccagcctc 780
cgcggatgga gcccagcagc aagaagctga cgggtcgcct catgctggcc gtgggaggag 840
cagtgcttgg ctccctgcag tttggctaca acactggagt catcaatgcc ccccagaagg 900
tgatcgagga gttctacaac cagacatggg tccaccgcta tggggagagc atcctgccca 960
ccacgctcac cacgctctgg tccctctcag tggccatctt ttctgttggg ggcatgattg 1020
gctccttctc tgtgggcctt ttcgttaacc gctttggccg gcggaattca atgctgatga 1080
tgaacctgct ggccttcgtg tccgccgtgc tcatgggctt ctcgaaactg ggcaagtcct 1140
ttgagatgct gatcctgggc cgcttcatca tcggtgtgta ctgcggcctg accacaggct 1200
tcgtgcccat gtatgtgggt gaagtgtcac ccacagccct tcgtggggcc ctgggcaccc 1260
tgcaccagct gggcatcgtc gtcggcatcc tcatcgccca ggtgttcggc ctggactcca 1320
tcatgggcaa caaggacctg tggcccctgc tgctgagcat catcttcatc ccggccctgc 1380
tgcagtgcat cgtgctgccc ttctgccccg agagtccccg cttcctgctc atcaaccgca 1440
acgaggagaa ccgggccaag agtgtgctaa agaagctgcg cgggacagct gacgtgaccc 1500
atgacctgca ggagatgaag gaagagagtc ggcagatgat gcgggagaag aaggtcacca 1560
tcctggagct gttccgctcc cccgcctacc gccagcccat cctcatcgct gtggtgctgc 1620
agctgtccca gcagctgtct ggcatcaacg ctgtcttcta ttactccacg agcatcttcg 1680
agaaggcggg ggtgcagcag cctgtgtatg ccaccattgg ctccggtatc gtcaacacgg 1740
ccttcactgt cgtgtcgctg tttgtggtgg agcgagcagg ccggcggacc ctgcacctca 1800
taggcctcgc tggcatggcg ggttgtgcca tactcatgac catcgcgcta gcactgctgg 1860
agcagctacc ctggatgtcc tatctgagca tcgtggccat ctttggcttt gtggccttct 1920
ttgaagtggg tcctggcccc atcccatggt tcatcgtggc tgaactcttc agccagggtc 1980
cacgtccagc tgccattgcc gttgcaggct tctccaactg gacctcaaat ttcattgtgg 2040
gcatgtgctt ccagtatgtg gagcaactgt gtggtcccta cgtcttcatc atcttcactg 2100
tgctcctggt tctgttcttc atcttcacct acttcaaagt tcctgagact aaaggccgga 2160
ccttcgatga gatcgcttcc ggcttccggc aggggggagc cagccaaagt gacaagacac 2220
ccgaggagct gttccatccc ctgggggctg attcccaagt gtgataatgg atcaacctct 2280
ggattacaaa atttgtgaaa gattgactgg tattcttaac tatgttgctc cttttacgct 2340
atgtggatac gctgctttaa tgcctttgta tcatgctatt gcttcccgta tggctttcat 2400
tttctcctcc ttgtataaat cctggttgct gtctctttat gaggagttgt ggcccgttgt 2460
caggcaacgt ggcgtggtgt gcactgtgtt tgctgacgca acccccactg gttggggcat 2520
tgccaccacc tgtcagctcc tttccgggac tttcgctttc cccctcccta ttgccacggc 2580
ggaactcatc gccgcctgcc ttgcccgctg ctggacaggg gctcggctgt tgggcactga 2640
caattccgtg gtgttgtcgg ggaaatcatc gtcctttcct tggctgctcg cctgtgttgc 2700
cacctggatt ctgcgcggga cgtccttctg ctacgtccct tcggccctca atccagcgga 2760
ccttccttcc cgcggcctgc tgccggctct gcggcctctt ccgcgtcttc gccttcgccc 2820
tcagacgagt cggatctccc tttgggccgc ctccccgcat cattgcctgc ccgggtggca 2880
tccctgtgac ccctccccag tgcctctcct ggccctggaa gttgccactc cagtgcccac 2940
cagccttgtc ctaataaaat taagttgcat cattttgtct gactaggtgt ccttctataa 3000
tattatgggg tggagggggg tggtatggag caaggggccc aagttgggaa gaaacctgta 3060
gggcctgcgt tacccaggct ggagtgcagt ggcacatttc tgctcactgc aacctcctcc 3120
tccctgggtt ctacgtagat aagtagcatg gcgggttaat cattaactac aaggaacccc 3180
tagtgatgga gttggccact ccctctctgc gcgctcgctc gctcactgag gccgggcgac 3240
caaaggtcgc ccgacgcccg ggctttgccc gggcggcctc agtgagcgag cgagcgcgc 3299
<210> 18
<400> 18
000
<210> 19
<211> 3750
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in Lab - full polynucleotide sequence of vector genome
<400> 19
gcgcgctcgc tcgctcactg aggccgcccg ggcaaagccc gggcgtcggg cgacctttgg 60
tcgcccggcc tcagtgagcg agcgagcgcg cagagaggga gtggccaact ccatcactag 120
gggttccttg tagttaatga ttaacccgcc atgctactta tctacgtact ctggagacgc 180
gttacataac ttacggtaaa tggcccgcct ggctgaccgc ccaacgaccc ccgcccattg 240
acgtcaataa tgacgtatgt tcccatagta acgccaatag ggactttcca ttgacgtcaa 300
tgggtggagt atttacggta aactgcccac ttggcagtac atcaagtgta tcatatgcca 360
agtacgcccc ctattgacgt caatgacggt aaatggcccg cctggcatta tgcccagtac 420
atgaccttat gggactttcc tacttggcag tacatctacg tattagtcat cgctattacc 480
atggtcgagg tgagccccac gttctgcttc actctcccca tctccccccc ctccccaccc 540
ccaattttgt atttatttat tttttaatta ttttgtgcag cgatgggggc gggggggggg 600
ggggcgcgcg ccaggcgggg cggggcgggg cgaggggcgg ggcggggcga ggcggagagg 660
tgcggcggca gccaatcaga gcggcgcgct ccgaaagttt ccttttatgg cgaggcggcg 720
gcggcggcgg ccctataaaa agcgaagcgc gcggcgggcg ggagtcgctg cgcgctgcct 780
tcgccccgtg ccccgctccg ccgccgcctc gcgccgcccg ccccggctct gactgaccgc 840
gttactccca caggtgagcg ggcgggacgg cccttctcct ccgggctgta attagcgctt 900
ggtttaatga cggcttgttt cttttctgtg gctgcgtgaa agccttgagg ggctccggga 960
gggccctttg tgcgggggga gcggctcggg gggtgcgtgc gtgtgtgtgt gcgtggggag 1020
cgccgcgtgc ggctccgcgc tgcccggcgg ctgtgagcgc tgcgggcgcg gcgcggggct 1080
ttgtgcgctc cgcagtgtgc gcgaggggag cgcggccggg ggcggtgccc cgcggtgcgg 1140
ggggggctgc gaggggaaca aaggctgcgt gcggggtgtg tgcgtggggg ggtgagcagg 1200
gggtgtgggc gcgtcggtcg ggctgcaacc ccccctgcac ccccctcccc gagttgctga 1260
gcacggcccg gcttcgggtg cggggctccg tacggggcgt ggcgcggggc tcgccgtgcc 1320
gggcgggggg tggcggcagg tgggggtgcc gggcggggcg gggccgcctc gggccgggga 1380
gggctcgggg gaggggcgcg gcggcccccg gagcgccggc ggctgtcgag gcgcggcgag 1440
ccgcagccat tgccttttat ggtaatcgtg cgagagggcg cagggacttc ctttgtccca 1500
aatctgtgcg gagccgaaat ctgggaggcg ccgccgcacc ccctctagcg ggcgcggggc 1560
gaagcggtgc ggcgccggca ggaaggaaat gggcggggag ggccttcgtg cgtcgccgcg 1620
ccgccgtccc cttctccctc tccagcctcg gggctgtccg cggggggacg gctgccttcg 1680
ggggggacgg ggcagggcgg ggttcggctt ctggcgtgtg accggcggct ctagagcctc 1740
tgctaaccat gttcatgcct tcttcttttt cctacagctc ctgggcaacg tgctggttat 1800
tgtgctgtct catcattttg gcaaagaatt catggagccc agcagcaaga agctgacggg 1860
tcgcctcatg ctggccgtgg gaggagcagt gcttggctcc ctgcagtttg gctacaacac 1920
tggagtcatc aatgcccccc agaaggtgat cgaggagttc tacaaccaga catgggtcca 1980
ccgctatggg gagagcatcc tgcccaccac gctcaccacg ctctggtccc tctcagtggc 2040
catcttttct gttgggggca tgattggctc cttctctgtg ggccttttcg ttaaccgctt 2100
tggccggcgg aattcaatgc tgatgatgaa cctgctggcc ttcgtgtccg ccgtgctcat 2160
gggcttctcg aaactgggca agtcctttga gatgctgatc ctgggccgct tcatcatcgg 2220
tgtgtactgc ggcctgacca caggcttcgt gcccatgtat gtgggtgaag tgtcacccac 2280
agcccttcgt ggggccctgg gcaccctgca ccagctgggc atcgtcgtcg gcatcctcat 2340
cgcccaggtg ttcggcctgg actccatcat gggcaacaag gacctgtggc ccctgctgct 2400
gagcatcatc ttcatcccgg ccctgctgca gtgcatcgtg ctgcccttct gccccgagag 2460
tccccgcttc ctgctcatca accgcaacga ggagaaccgg gccaagagtg tgctaaagaa 2520
gctgcgcggg acagctgacg tgacccatga cctgcaggag atgaaggaag agagtcggca 2580
gatgatgcgg gagaagaagg tcaccatcct ggagctgttc cgctcccccg cctaccgcca 2640
gcccatcctc atcgctgtgg tgctgcagct gtcccagcag ctgtctggca tcaacgctgt 2700
cttctattac tccacgagca tcttcgagaa ggcgggggtg cagcagcctg tgtatgccac 2760
cattggctcc ggtatcgtca acacggcctt cactgtcgtg tcgctgtttg tggtggagcg 2820
agcaggccgg cggaccctgc acctcatagg cctcgctggc atggcgggtt gtgccatact 2880
catgaccatc gcgctagcac tgctggagca gctaccctgg atgtcctatc tgagcatcgt 2940
ggccatcttt ggctttgtgg ccttctttga agtgggtcct ggccccatcc catggttcat 3000
cgtggctgaa ctcttcagcc agggtccacg tccagctgcc attgccgttg caggcttctc 3060
caactggacc tcaaatttca ttgtgggcat gtgcttccag tatgtggagc aactgtgtgg 3120
tccctacgtc ttcatcatct tcactgtgct cctggttctg ttcttcatct tcacctactt 3180
caaagttcct gagactaaag gccggacctt cgatgagatc gcttccggct tccggcaggg 3240
gggagccagc caaagtgaca agacacccga ggagctgttc catcccctgg gggctgattc 3300
ccaagtgtga tcattgcctg cccgggtggc atccctgtga cccctcccca gtgcctctcc 3360
tggccctgga agttgccact ccagtgccca ccagccttgt cctaataaaa ttaagttgca 3420
tcattttgtc tgactaggtg tccttctata atattatggg gtggaggggg gtggtatgga 3480
gcaaggggcc caagttggga agaaacctgt agggcctgcg ttacccaggc tggagtgcag 3540
tggcacattt ctgctcactg caacctcctc ctccctgggt tctacgtaga taagtagcat 3600
ggcgggttaa tcattaacta caaggaaccc ctagtgatgg agttggccac tccctctctg 3660
cgcgctcgct cgctcactga ggccgggcga ccaaaggtcg cccgacgccc gggctttgcc 3720
cgggcggcct cagtgagcga gcgagcgcgc 3750
<210> 20
<400> 20
000
<210> 21
<211> 3745
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in Lab - full polynucleotide sequence of vector genome
<400> 21
gcgcgctcgc tcgctcactg aggccgcccg ggcaaagccc gggcgtcggg cgacctttgg 60
tcgcccggcc tcagtgagcg agcgagcgcg cagagaggga gtggccaact ccatcactag 120
gggttccttg tagttaatga ttaacccgcc atgctactta tctacgtact ctggagacgc 180
gttacatatt tgcttctagg aagcagaaga ctgaggaaat gacttgggcg ggtgcatcaa 240
tgcggccaaa aaagacacgg acacgctccc ctgggacctg agctggttcg cagtcttccc 300
aaaggtgcca agcaagcgtc agttcccctc aggcgctcca ggttcagtgc cttgtgccga 360
gggtctccgg tgccttccta gacttctcgg gacagtctga aggggtcagg agcggcggga 420
cagcgcggga agagcaggca aggggagaca gccggactgc gcctcagtcc tccgtgccaa 480
gaacaccgtc gcggaggcgc ggccagcttc ccttggatcg gactttccgc ccctagggcc 540
aggcggcgga gcttcagcct tgtcccttcc ccagtttcgg gcggccccca gagctgagta 600
agccgggtgg agggagtctg caaggatttc ctgagcgcga tgggcaggag gaggggcaag 660
ggcaagaggg cgcggagcaa agaccctgaa cctgccgggg ccgcgctccc gggcccgcgt 720
cgccagcacc tccccacgcg cgctcggccc cgggccaccc gccctcgtcg gcccccgccc 780
ctctccgtag ccgcagggaa gcgagcctgg gaggaagaag agggtaggtg gggaggcgga 840
tgaggggtgg gggacccctt gacgtcacca gaaggaggtg ccggggtagg aagtgggctg 900
gggaaaggtt ataaatcgcc cccgccctcg gctgctcttc atcgaggtcc gcgggaggct 960
cggagcgcgc caggcggaca ctcctctcgg ctcctccccg gcagcggcgg cggctcggag 1020
cgggctccgg ggctcgggtg cagcggccag cgggcgcctg gcggcgagga ttacccgggg 1080
aagtggttgt ctcctggctg gagccgcgag acgggcgctc agggcgcggg gccggcggcg 1140
gcgaacaaga ggacggactc tggcggccgg gtcgttggcc gcggggagcg cgggcaccgg 1200
gcgagcaggc cgcgtcgcgc tcaccgccac catggagccc agcagcaaga agctgacggg 1260
tcgcctcatg ctggccgtgg gaggagcagt gcttggctcc ctgcagtttg gctacaacac 1320
tggagtcatc aatgcccccc agaaggtgat cgaggagttc tacaaccaga catgggtcca 1380
ccgctatggg gagagcatcc tgcccaccac gctcaccacg ctctggtccc tctcagtggc 1440
catcttttct gttgggggca tgattggctc cttctctgtg ggccttttcg ttaaccgctt 1500
tggccggcgg aattcaatgc tgatgatgaa cctgctggcc ttcgtgtccg ccgtgctcat 1560
gggcttctcg aaactgggca agtcctttga gatgctgatc ctgggccgct tcatcatcgg 1620
tgtgtactgc ggcctgacca caggcttcgt gcccatgtat gtgggtgaag tgtcacccac 1680
agcccttcgt ggggccctgg gcaccctgca ccagctgggc atcgtcgtcg gcatcctcat 1740
cgcccaggtg ttcggcctgg actccatcat gggcaacaag gacctgtggc ccctgctgct 1800
gagcatcatc ttcatcccgg ccctgctgca gtgcatcgtg ctgcccttct gccccgagag 1860
tccccgcttc ctgctcatca accgcaacga ggagaaccgg gccaagagtg tgctaaagaa 1920
gctgcgcggg acagctgacg tgacccatga cctgcaggag atgaaggaag agagtcggca 1980
gatgatgcgg gagaagaagg tcaccatcct ggagctgttc cgctcccccg cctaccgcca 2040
gcccatcctc atcgctgtgg tgctgcagct gtcccagcag ctgtctggca tcaacgctgt 2100
cttctattac tccacgagca tcttcgagaa ggcgggggtg cagcagcctg tgtatgccac 2160
cattggctcc ggtatcgtca acacggcctt cactgtcgtg tcgctgtttg tggtggagcg 2220
agcaggccgg cggaccctgc acctcatagg cctcgctggc atggcgggtt gtgccatact 2280
catgaccatc gcgctagcac tgctggagca gctaccctgg atgtcctatc tgagcatcgt 2340
ggccatcttt ggctttgtgg ccttctttga agtgggtcct ggccccatcc catggttcat 2400
cgtggctgaa ctcttcagcc agggtccacg tccagctgcc attgccgttg caggcttctc 2460
caactggacc tcaaatttca ttgtgggcat gtgcttccag tatgtggagc aactgtgtgg 2520
tccctacgtc ttcatcatct tcactgtgct cctggttctg ttcttcatct tcacctactt 2580
caaagttcct gagactaaag gccggacctt cgatgagatc gcttccggct tccggcaggg 2640
gggagccagc caaagtgaca agacacccga ggagctgttc catcccctgg gggctgattc 2700
ccaagtgtga taatggatca acctctggat tacaaaattt gtgaaagatt gactggtatt 2760
cttaactatg ttgctccttt tacgctatgt ggatacgctg ctttaatgcc tttgtatcat 2820
gctattgctt cccgtatggc tttcattttc tcctccttgt ataaatcctg gttgctgtct 2880
ctttatgagg agttgtggcc cgttgtcagg caacgtggcg tggtgtgcac tgtgtttgct 2940
gacgcaaccc ccactggttg gggcattgcc accacctgtc agctcctttc cgggactttc 3000
gctttccccc tccctattgc cacggcggaa ctcatcgccg cctgccttgc ccgctgctgg 3060
acaggggctc ggctgttggg cactgacaat tccgtggtgt tgtcggggaa atcatcgtcc 3120
tttccttggc tgctcgcctg tgttgccacc tggattctgc gcgggacgtc cttctgctac 3180
gtcccttcgg ccctcaatcc agcggacctt ccttcccgcg gcctgctgcc ggctctgcgg 3240
cctcttccgc gtcttcgcct tcgccctcag acgagtcgga tctccctttg ggccgcctcc 3300
ccgcatcatt gcctgcccgg gtggcatccc tgtgacccct ccccagtgcc tctcctggcc 3360
ctggaagttg ccactccagt gcccaccagc cttgtcctaa taaaattaag ttgcatcatt 3420
ttgtctgact aggtgtcctt ctataatatt atggggtgga ggggggtggt atggagcaag 3480
gggcccaagt tgggaagaaa cctgtagggc ctgcgttacc caggctggag tgcagtggca 3540
catttctgct cactgcaacc tcctcctccc tgggttctac gtagataagt agcatggcgg 3600
gttaatcatt aactacaagg aacccctagt gatggagttg gccactccct ctctgcgcgc 3660
tcgctcgctc actgaggccg ggcgaccaaa ggtcgcccga cgcccgggct ttgcccgggc 3720
ggcctcagtg agcgagcgag cgcgc 3745
<210> 22
<400> 22
000
<210> 23
<211> 4316
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in Lab - full polynucleotide sequence of vector genome
<400> 23
gcgcgctcgc tcgctcactg aggccgcccg ggcaaagccc gggcgtcggg cgacctttgg 60
tcgcccggcc tcagtgagcg agcgagcgcg cagagaggga gtggccaact ccatcactag 120
gggttccttg tagttaatga ttaacccgcc atgctactta tctacgtact ctggagacgc 180
gttacataag ctcctcccag cctcaggccc aggaatggga atctctgtgg gtcacacatc 240
agtagggagg tctttcccga tccttttcta tgctactcca ggagtcaaag cgtctcctgg 300
gacttttcag ggcgcttcag aagagccctg ggcctaaacc agctcaacca agctgcaggg 360
acccagcctc ctgagaaaag tgaatgtgag cccggtgcat tcagaggaga atgaagcctt 420
cacccagaac acactctggg aagatgtccc aggcccaggg ggagggtttg tactaccaga 480
cctaagtcac ctaaactgac accaagtctc atccatccca accattccat tccgggtcag 540
aggggtcatc gatttaacca gcaaggctgc ccatccaacg gttgctccct ctgctccctg 600
gaagggcctc ctcgtgggcg ttctgtacct acaggtcttg ttccgttctg ggaactgcca 660
gtggtggcaa gaggtggagc aacgggtgcc agggcaggga gaggtgagtc tgggagggaa 720
gcagaggcaa gatccatggg gctttagaga ctttgccaaa gcagtgcgac tgctcccagg 780
ttgttgtcag ccgtcaagag tgagtgcacc tccctgggca gacttctgct gccccagtgc 840
ccaggaatag gcaggggttt gccgcaaaat gaatgacacc tggcagacaa taagctgaag 900
ctttcattag cagcttaagc tgaggactat ctatgcaacc gatactccct gtgtgctccc 960
cgggactgct taatgtgagc ccttgtggag cgattggcac caagaaagca aggactaagt 1020
cagaagttca agtcccagcc ttgccacagc ctcagggtgc cctcgagcac agcaagcctc 1080
agttttccca tctgtacaat gagagaggta cacaaggtag actcgaaggc tctttgttgc 1140
cagggccctg tgttcctttg agtgtatgtg cttctcaggc ccacagaggt cctttgtgtt 1200
tcgtatgtga actgctctct aggaaaccca tgtaactgtc tgtgtcctgg ggcacataca 1260
tgaggactca tgtgggccgt attgtgtgtt tgtgccgggg ggaggggaga ccccagaaca 1320
atgtccccca ccccaccccc ctcctcaata ggcggaagcc actggcttcc tccctttcct 1380
gcctcctgcc tcctttgtgc cagcaagact gagtactgga gagagacagg ggatgggaaa 1440
aatcagtcca gctgtcccca ggtctgccct taccataacc ttccccccac ctcaagtgac 1500
tcctcccagg ccacacccat ccccagcctt gtgggggcca gattgggggg cctagaggct 1560
caaaggcaga atgagtcctc ccacccccta ccctgccacc cctcccaccc aagccacctc 1620
atttcctctt cctccccagc accgacccac actgaccaac acaggctgag cagtcaggcc 1680
cacagcatct gaccccaggc ccagctcgtc ctggctggcc tgggtcggcc tctggagtat 1740
ggtctggcgg gtgccccctt tcttgctccc catcctcttc ttggcttctc atgtgggcca 1800
ccatggagcc cagcagcaag aagctgacgg gtcgcctcat gctggccgtg ggaggagcag 1860
tgcttggctc cctgcagttt ggctacaaca ctggagtcat caatgccccc cagaaggtga 1920
tcgaggagtt ctacaaccag acatgggtcc accgctatgg ggagagcatc ctgcccacca 1980
cgctcaccac gctctggtcc ctctcagtgg ccatcttttc tgttgggggc atgattggct 2040
ccttctctgt gggccttttc gttaaccgct ttggccggcg gaattcaatg ctgatgatga 2100
acctgctggc cttcgtgtcc gccgtgctca tgggcttctc gaaactgggc aagtcctttg 2160
agatgctgat cctgggccgc ttcatcatcg gtgtgtactg cggcctgacc acaggcttcg 2220
tgcccatgta tgtgggtgaa gtgtcaccca cagcccttcg tggggccctg ggcaccctgc 2280
accagctggg catcgtcgtc ggcatcctca tcgcccaggt gttcggcctg gactccatca 2340
tgggcaacaa ggacctgtgg cccctgctgc tgagcatcat cttcatcccg gccctgctgc 2400
agtgcatcgt gctgcccttc tgccccgaga gtccccgctt cctgctcatc aaccgcaacg 2460
aggagaaccg ggccaagagt gtgctaaaga agctgcgcgg gacagctgac gtgacccatg 2520
acctgcagga gatgaaggaa gagagtcggc agatgatgcg ggagaagaag gtcaccatcc 2580
tggagctgtt ccgctccccc gcctaccgcc agcccatcct catcgctgtg gtgctgcagc 2640
tgtcccagca gctgtctggc atcaacgctg tcttctatta ctccacgagc atcttcgaga 2700
aggcgggggt gcagcagcct gtgtatgcca ccattggctc cggtatcgtc aacacggcct 2760
tcactgtcgt gtcgctgttt gtggtggagc gagcaggccg gcggaccctg cacctcatag 2820
gcctcgctgg catggcgggt tgtgccatac tcatgaccat cgcgctagca ctgctggagc 2880
agctaccctg gatgtcctat ctgagcatcg tggccatctt tggctttgtg gccttctttg 2940
aagtgggtcc tggccccatc ccatggttca tcgtggctga actcttcagc cagggtccac 3000
gtccagctgc cattgccgtt gcaggcttct ccaactggac ctcaaatttc attgtgggca 3060
tgtgcttcca gtatgtggag caactgtgtg gtccctacgt cttcatcatc ttcactgtgc 3120
tcctggttct gttcttcatc ttcacctact tcaaagttcc tgagactaaa ggccggacct 3180
tcgatgagat cgcttccggc ttccggcagg ggggagccag ccaaagtgac aagacacccg 3240
aggagctgtt ccatcccctg ggggctgatt cccaagtgtg ataatggatc aacctctgga 3300
ttacaaaatt tgtgaaagat tgactggtat tcttaactat gttgctcctt ttacgctatg 3360
tggatacgct gctttaatgc ctttgtatca tgctattgct tcccgtatgg ctttcatttt 3420
ctcctccttg tataaatcct ggttgctgtc tctttatgag gagttgtggc ccgttgtcag 3480
gcaacgtggc gtggtgtgca ctgtgtttgc tgacgcaacc cccactggtt ggggcattgc 3540
caccacctgt cagctccttt ccgggacttt cgctttcccc ctccctattg ccacggcgga 3600
actcatcgcc gcctgccttg cccgctgctg gacaggggct cggctgttgg gcactgacaa 3660
ttccgtggtg ttgtcgggga aatcatcgtc ctttccttgg ctgctcgcct gtgttgccac 3720
ctggattctg cgcgggacgt ccttctgcta cgtcccttcg gccctcaatc cagcggacct 3780
tccttcccgc ggcctgctgc cggctctgcg gcctcttccg cgtcttcgcc ttcgccctca 3840
gacgagtcgg atctcccttt gggccgcctc cccgcatcat tgcctgcccg ggtggcatcc 3900
ctgtgacccc tccccagtgc ctctcctggc cctggaagtt gccactccag tgcccaccag 3960
ccttgtccta ataaaattaa gttgcatcat tttgtctgac taggtgtcct tctataatat 4020
tatggggtgg aggggggtgg tatggagcaa ggggcccaag ttgggaagaa acctgtaggg 4080
cctgcgttac ccaggctgga gtgcagtggc acatttctgc tcactgcaac ctcctcctcc 4140
ctgggttcta cgtagataag tagcatggcg ggttaatcat taactacaag gaacccctag 4200
tgatggagtt ggccactccc tctctgcgcg ctcgctcgct cactgaggcc gggcgaccaa 4260
aggtcgcccg acgcccgggc tttgcccggg cggcctcagt gagcgagcga gcgcgc 4316
<210> 24
<400> 24
000
<210> 25
<211> 4716
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in Lab - full polynucleotide sequence of vector genome
<400> 25
gcgcgctcgc tcgctcactg aggccgcccg ggcaaagccc gggcgtcggg cgacctttgg 60
tcgcccggcc tcagtgagcg agcgagcgcg cagagaggga gtggccaact ccatcactag 120
gggttccttg tagttaatga ttaacccgcc atgctactta tctacgtact ctggagacgc 180
gttacatact agtagcagaa acaaggtcct ctggaagagc aactgatgct cttaggtact 240
gaagcatcat cctgccccag agaccactcg catatgaagc acacatattc agtctgcctt 300
acttgtgtta atgattgcca gtgtccctct gacctcctag ccctgaaaag tgtggcctga 360
aggtcatttc agagacgggg agagctgctc agagaagcca atcggcgagt ctaggacaca 420
cagacaggat ctagtcccag agttcgctag cctaggtgag cgtcccctgg ccccttatac 480
cacttccttc tccagcttgc atctaatctg ctctggcaga ccatcgtgtt tcctgtcttc 540
ctggcagcct ccagcacgct cagtgctact ccctgcgcat gcgccctcct cccagtacct 600
tctctgactc cagtgggctt ggagtgcgag gaggaagggt gaggaagggg tgaaatcagg 660
tattggatcc acagggggtc tgaagagcac tagcctggcc ttttgggact gaacttctgc 720
tatgaagacc tccactgcca tccctggagt ccggggcaca tccaaggctt gctgtccatc 780
gtttactgtt tacagatgac aacaatgact gtgttcgggg cagaaatatc caccagggct 840
agagtacaaa aggagtttgc attgatggcc ggacaggccc tgtccctggc agcctgccag 900
cgctgagtat gagacccagc gggaagtgct accctggcag acgtgtccac tgagtacaca 960
gaccaccaag gcaggcagct ctcggggaag ctgtctatgc tgggccagcc caccttgagg 1020
gcagggaaca gaacagattg tggcagagag gaaaatgtgg agcttctgtt tgttcacaga 1080
cacacgcact cgcccacgca cgcacgcacg cacgcacgca cgcacgaatg cacgcacgca 1140
gtagttgaat gctatggatt ccgctcagag ctgagaacag ccccagcgac agttccctgg 1200
cctctctcct tactctgatg tcctcatctg tcttcacatg gtctcaggac gctaatactc 1260
catcctaatg tacactcctt tccctgggcc tccgttccag ttcagttctc agaggacctg 1320
gagggagtga ttggctacac caactttgct ttcgttcacc aagcccatgt ctctacttgg 1380
gtgtctaatg ggcatctcca acattaccta ccccaaacag aaaacccttt cttcccccca 1440
accacacccc accctacccc cacagtattt tctccatgcc cggaaagatc tgctctctta 1500
tggtccctct ttgcctcact gaaaagcagg acaagttggg gacttcccaa acttttatgc 1560
atgaagaaac ccaggcaatt tgccaaaagg tacactctgg gggtctgtca tttactctga 1620
gccagaaccc tgaaattttt actaacccat cacataatga atgaagagaa tctttttctt 1680
tttttttttt tttctttttt tttggttttt cgagacaggg tttctctgta tagccctggc 1740
tatcctggaa cacactctgt agaccaggct ggcctcgaac tcagaaatcc acctgcctct 1800
gcctcccgag tgctgggatt aaaggcgtgc gccaccacgc ctggctgaat gaagagaatc 1860
ttgacctcat ctccccagcc tcttggtcct gagggaccct ggtctaccta ctgctttgct 1920
gtcttcttag ctcttcttac ttttttgctg actcagacct atggctatct ccattataca 1980
gatgaggaga ctgaggcatg gatccctggt tggtccatgg tcacgtgaag cccatcaccc 2040
agtatttgta aagtgagatg ggccaggctg gtaccttgga actgaaactc acactgccct 2100
acctggaaga atctgacagg caaaatctgc tgctgaaagt gattgtctgt cacgtttctc 2160
agctgcccga ctctgagaac tccacagccc cctttcgttc caccatacta cagagtcgcc 2220
acggaaagcc ggctctgtgg agaagctgag gtagctgggt ttctgtctgg gttactctgt 2280
ccagcgagga aacaagtacc ttagacccac taagcctctg ctttctgaac tgtaaagtgg 2340
gggatatgac acctgcctcc cagggatggc tgaatgctct ggcagaagct tagagccccc 2400
acagctaccc ctaggctcac agctcctccg atgagaccta gaattgaggt atgagttgaa 2460
taccccaggc aggtccaagg cttccacggg cccaggctga ccaagctgag gccgcccacc 2520
gtagggcttg cctatctgca ggcagctcac aaaggaacaa taacaggaaa ccatcccgag 2580
gggaagtggg ccagggccag ttggaaaacc tgcctccctc ccagcctggg tgtggctccc 2640
ctctcccctc ctgaggcaat caactgtgct ctccacaaag ctcggccctg gacagactgc 2700
caccatggag cccagcagca agaagctgac gggtcgcctc atgctggccg tgggaggagc 2760
agtgcttggc tccctgcagt ttggctacaa cactggagtc atcaatgccc cccagaaggt 2820
gatcgaggag ttctacaacc agacatgggt ccaccgctat ggggagagca tcctgcccac 2880
cacgctcacc acgctctggt ccctctcagt ggccatcttt tctgttgggg gcatgattgg 2940
ctccttctct gtgggccttt tcgttaaccg ctttggccgg cggaattcaa tgctgatgat 3000
gaacctgctg gccttcgtgt ccgccgtgct catgggcttc tcgaaactgg gcaagtcctt 3060
tgagatgctg atcctgggcc gcttcatcat cggtgtgtac tgcggcctga ccacaggctt 3120
cgtgcccatg tatgtgggtg aagtgtcacc cacagccctt cgtggggccc tgggcaccct 3180
gcaccagctg ggcatcgtcg tcggcatcct catcgcccag gtgttcggcc tggactccat 3240
catgggcaac aaggacctgt ggcccctgct gctgagcatc atcttcatcc cggccctgct 3300
gcagtgcatc gtgctgccct tctgccccga gagtccccgc ttcctgctca tcaaccgcaa 3360
cgaggagaac cgggccaaga gtgtgctaaa gaagctgcgc gggacagctg acgtgaccca 3420
tgacctgcag gagatgaagg aagagagtcg gcagatgatg cgggagaaga aggtcaccat 3480
cctggagctg ttccgctccc ccgcctaccg ccagcccatc ctcatcgctg tggtgctgca 3540
gctgtcccag cagctgtctg gcatcaacgc tgtcttctat tactccacga gcatcttcga 3600
gaaggcgggg gtgcagcagc ctgtgtatgc caccattggc tccggtatcg tcaacacggc 3660
cttcactgtc gtgtcgctgt ttgtggtgga gcgagcaggc cggcggaccc tgcacctcat 3720
aggcctcgct ggcatggcgg gttgtgccat actcatgacc atcgcgctag cactgctgga 3780
gcagctaccc tggatgtcct atctgagcat cgtggccatc tttggctttg tggccttctt 3840
tgaagtgggt cctggcccca tcccatggtt catcgtggct gaactcttca gccagggtcc 3900
acgtccagct gccattgccg ttgcaggctt ctccaactgg acctcaaatt tcattgtggg 3960
catgtgcttc cagtatgtgg agcaactgtg tggtccctac gtcttcatca tcttcactgt 4020
gctcctggtt ctgttcttca tcttcaccta cttcaaagtt cctgagacta aaggccggac 4080
cttcgatgag atcgcttccg gcttccggca ggggggagcc agccaaagtg acaagacacc 4140
cgaggagctg ttccatcccc tgggggctga ttcccaagtg tgagctggag cctcggtagc 4200
cgttcctcct gcccgctggg cctcccaacg ggccctcctc ccctccttgc accggccctt 4260
cctggtcttt gaataaacat tgcctgcccg ggtggcatcc ctgtgacccc tccccagtgc 4320
ctctcctggc cctggaagtt gccactccag tgcccaccag ccttgtccta ataaaattaa 4380
gttgcatcat tttgtctgac taggtgtcct tctataatat tatggggtgg aggggggtgg 4440
tatggagcaa ggggcccaag ttgggaagaa acctgtaggg cctgcgttac ccaggctgga 4500
gtgcagtggc acatttctgc tcactgcaac ctcctcctcc ctgggttcta cgtagataag 4560
tagcatggcg ggttaatcat taactacaag gaacccctag tgatggagtt ggccactccc 4620
tctctgcgcg ctcgctcgct cactgaggcc gggcgaccaa aggtcgcccg acgcccgggc 4680
tttgcccggg cggcctcagt gagcgagcga gcgcgc 4716
<210> 26
<211> 492
<212> PRT
<213> Homo sapiens
<400> 26
Met Glu Pro Ser Ser Lys Lys Leu Thr Gly Arg Leu Met Leu Ala Val
1 5 10 15
Gly Gly Ala Val Leu Gly Ser Leu Gln Phe Gly Tyr Asn Thr Gly Val
20 25 30
Ile Asn Ala Pro Gln Lys Val Ile Glu Glu Phe Tyr Asn Gln Thr Trp
35 40 45
Val His Arg Tyr Gly Glu Ser Ile Leu Pro Thr Thr Leu Thr Thr Leu
50 55 60
Trp Ser Leu Ser Val Ala Ile Phe Ser Val Gly Gly Met Ile Gly Ser
65 70 75 80
Phe Ser Val Gly Leu Phe Val Asn Arg Phe Gly Arg Arg Asn Ser Met
85 90 95
Leu Met Met Asn Leu Leu Ala Phe Val Ser Ala Val Leu Met Gly Phe
100 105 110
Ser Lys Leu Gly Lys Ser Phe Glu Met Leu Ile Leu Gly Arg Phe Ile
115 120 125
Ile Gly Val Tyr Cys Gly Leu Thr Thr Gly Phe Val Pro Met Tyr Val
130 135 140
Gly Glu Val Ser Pro Thr Ala Leu Arg Gly Ala Leu Gly Thr Leu His
145 150 155 160
Gln Leu Gly Ile Val Val Gly Ile Leu Ile Ala Gln Val Phe Gly Leu
165 170 175
Asp Ser Ile Met Gly Asn Lys Asp Leu Trp Pro Leu Leu Leu Ser Ile
180 185 190
Ile Phe Ile Pro Ala Leu Leu Gln Cys Ile Val Leu Pro Phe Cys Pro
195 200 205
Glu Ser Pro Arg Phe Leu Leu Ile Asn Arg Asn Glu Glu Asn Arg Ala
210 215 220
Lys Ser Val Leu Lys Lys Leu Arg Gly Thr Ala Asp Val Thr His Asp
225 230 235 240
Leu Gln Glu Met Lys Glu Glu Ser Arg Gln Met Met Arg Glu Lys Lys
245 250 255
Val Thr Ile Leu Glu Leu Phe Arg Ser Pro Ala Tyr Arg Gln Pro Ile
260 265 270
Leu Ile Ala Val Val Leu Gln Leu Ser Gln Gln Leu Ser Gly Ile Asn
275 280 285
Ala Val Phe Tyr Tyr Ser Thr Ser Ile Phe Glu Lys Ala Gly Val Gln
290 295 300
Gln Pro Val Tyr Ala Thr Ile Gly Ser Gly Ile Val Asn Thr Ala Phe
305 310 315 320
Thr Val Val Ser Leu Phe Val Val Glu Arg Ala Gly Arg Arg Thr Leu
325 330 335
His Leu Ile Gly Leu Ala Gly Met Ala Gly Cys Ala Ile Leu Met Thr
340 345 350
Ile Ala Leu Ala Leu Leu Glu Gln Leu Pro Trp Met Ser Tyr Leu Ser
355 360 365
Ile Val Ala Ile Phe Gly Phe Val Ala Phe Phe Glu Val Gly Pro Gly
370 375 380
Pro Ile Pro Trp Phe Ile Val Ala Glu Leu Phe Ser Gln Gly Pro Arg
385 390 395 400
Pro Ala Ala Ile Ala Val Ala Gly Phe Ser Asn Trp Thr Ser Asn Phe
405 410 415
Ile Val Gly Met Cys Phe Gln Tyr Val Glu Gln Leu Cys Gly Pro Tyr
420 425 430
Val Phe Ile Ile Phe Thr Val Leu Leu Val Leu Phe Phe Ile Phe Thr
435 440 445
Tyr Phe Lys Val Pro Glu Thr Lys Gly Arg Thr Phe Asp Glu Ile Ala
450 455 460
Ser Gly Phe Arg Gln Gly Gly Ala Ser Gln Ser Asp Lys Thr Pro Glu
465 470 475 480
Glu Leu Phe His Pro Leu Gly Ala Asp Ser Gln Val
485 490
<210> 27
<211> 1476
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in Lab - Codon-optimized polynucleotide encoding GLUT1
<400> 27
atggaaccat catccaaaaa gctgaccgga cgactgatgc ttgcagttgg cggtgcggtc 60
ttggggagcc tgcagtttgg gtacaatact ggcgtaatca atgccccgca gaaggttatt 120
gaagaatttt acaatcaaac gtgggtacat cgctacggtg aatccattct tcctacaact 180
ctgaccacac tctggagcct ttctgtagcg attttttccg tcgggggcat gataggatca 240
ttttccgtcg gtctttttgt gaaccgcttt ggccggagaa attccatgct gatgatgaat 300
cttctcgctt tcgtgagtgc cgtcctcatg ggatttagta aactgggtaa atctttcgag 360
atgttgatac tggggagatt tattatcggc gtgtattgtg gtttgaccac gggctttgta 420
ccaatgtatg ttggcgaggt ttctccgaca gcattgagag gtgcactcgg gaccttgcac 480
cagttgggca tcgtagtagg aatccttata gcgcaagttt tcgggctcga ttccatcatg 540
gggaacaaag atctctggcc attgctcctc tcaataattt ttataccggc attgcttcag 600
tgtattgttc ttcctttttg cccagagtcc cctaggttcc tgctcataaa caggaatgag 660
gagaatcgcg ctaagtccgt gttgaaaaaa cttaggggaa ctgcagacgt tactcacgat 720
ttgcaagaga tgaaggagga atctaggcaa atgatgcgcg agaagaaggt taccatactc 780
gaactcttcc gctcccccgc gtacaggcag cccattctta tcgcggtcgt cttgcagttg 840
tcacaacagt tgagtgggat taatgcagtt ttctattata gcacgtccat atttgaaaaa 900
gcaggcgtcc aacaacctgt ctatgcaact ataggctcag gcattgtaaa cacagcgttt 960
actgtagtat cactgtttgt cgttgagcgg gctggtcgaa ggaccttgca cctcatagga 1020
ctggcgggca tggcgggctg tgcgattctt atgacaattg cgctcgcgct gttggaacag 1080
cttccgtgga tgtcctatct ctctatagta gcaatatttg gatttgttgc attttttgaa 1140
gttgggcccg gacctatccc ctggttcatc gtcgcggagc tcttttccca aggcccaaga 1200
ccggctgcca ttgctgttgc aggcttctca aactggacga gtaatttcat agtaggtatg 1260
tgtttccagt atgttgaaca gctctgtggg ccctatgtct ttatcatctt tactgtgttg 1320
ctcgtgttgt tctttatctt cacttatttc aaagtacccg agacaaaggg caggacgttt 1380
gacgagattg catctggttt tagacaagga ggtgcctcac agagtgataa aaccccggag 1440
gaattgtttc atccgctggg agccgactca caggtc 1476
<210> 28
<211> 10
<212> DNA
<213> Artificial Sequence
<220>
<223> Kozak sequence motif
<400> 28
gccaccatgg 10
<210> 29
<211> 1482
<212> DNA
<213> Artificial Sequence
<220>
<223> Polynucleotide encoding GLUT1 with Kozak motif
<400> 29
gccaccatgg agcccagcag caagaagctg acgggtcgcc tcatgctggc cgtgggagga 60
gcagtgcttg gctccctgca gtttggctac aacactggag tcatcaatgc cccccagaag 120
gtgatcgagg agttctacaa ccagacatgg gtccaccgct atggggagag catcctgccc 180
accacgctca ccacgctctg gtccctctca gtggccatct tttctgttgg gggcatgatt 240
ggctccttct ctgtgggcct tttcgttaac cgctttggcc ggcggaattc aatgctgatg 300
atgaacctgc tggccttcgt gtccgccgtg ctcatgggct tctcgaaact gggcaagtcc 360
tttgagatgc tgatcctggg ccgcttcatc atcggtgtgt actgcggcct gaccacaggc 420
ttcgtgccca tgtatgtggg tgaagtgtca cccacagccc ttcgtggggc cctgggcacc 480
ctgcaccagc tgggcatcgt cgtcggcatc ctcatcgccc aggtgttcgg cctggactcc 540
atcatgggca acaaggacct gtggcccctg ctgctgagca tcatcttcat cccggccctg 600
ctgcagtgca tcgtgctgcc cttctgcccc gagagtcccc gcttcctgct catcaaccgc 660
aacgaggaga accgggccaa gagtgtgcta aagaagctgc gcgggacagc tgacgtgacc 720
catgacctgc aggagatgaa ggaagagagt cggcagatga tgcgggagaa gaaggtcacc 780
atcctggagc tgttccgctc ccccgcctac cgccagccca tcctcatcgc tgtggtgctg 840
cagctgtccc agcagctgtc tggcatcaac gctgtcttct attactccac gagcatcttc 900
gagaaggcgg gggtgcagca gcctgtgtat gccaccattg gctccggtat cgtcaacacg 960
gccttcactg tcgtgtcgct gtttgtggtg gagcgagcag gccggcggac cctgcacctc 1020
ataggcctcg ctggcatggc gggttgtgcc atactcatga ccatcgcgct agcactgctg 1080
gagcagctac cctggatgtc ctatctgagc atcgtggcca tctttggctt tgtggccttc 1140
tttgaagtgg gtcctggccc catcccatgg ttcatcgtgg ctgaactctt cagccagggt 1200
ccacgtccag ctgccattgc cgttgcaggc ttctccaact ggacctcaaa tttcattgtg 1260
ggcatgtgct tccagtatgt ggagcaactg tgtggtccct acgtcttcat catcttcact 1320
gtgctcctgg ttctgttctt catcttcacc tacttcaaag ttcctgagac taaaggccgg 1380
accttcgatg agatcgcttc cggcttccgg caggggggag ccagccaaag tgacaagaca 1440
cccgaggagc tgttccatcc cctgggggct gattcccaag tg 1482
<210> 30
<211> 13
<212> DNA
<213> Artificial Sequence
<220>
<223> Kozak sequence motif
<400> 30
gccgccrcca ugg 13
<210> 31
<211> 10
<212> DNA
<213> Artificial Sequence
<220>
<223> Kozak sequence motif
<400> 31
gacaccaugg 10
<210> 32
<211> 141
<212> DNA
<213> Adeno-associated virus
<400> 32
cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccgggcaaag cccgggcgtc 60
gggcgacctt tggtcgcccg gcctcagtga gcgagcgagc gcgcagagag ggagtggcca 120
actccatcac taggggttcc t 141
<210> 33
<211> 170
<212> DNA
<213> Adeno-associated virus
<400> 33
ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct tgtagttaat gattaacccg ccatgctact tatctacgta 170
<210> 34
<211> 141
<212> DNA
<213> Adeno-associated viurs
<400> 34
aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg 60
ccgggcgacc aaaggtcgcc cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc 120
gagcgcgcag ctgcctgcag g 141
<210> 35
<211> 124
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in Lab - vector filler sequence
<400> 35
gcggcaattc agtcgataac tataacggtc ctaaggtagc gatttaaata cgcgctctct 60
taaggtagcc ccgggacgcg tcaattgact acaaaccgag tatctgcaga gggccctgcg 120
tatg 124
<210> 36
<211> 84
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in Lab - vector filler sequence
<400> 36
cttctgaggc ggaaagaacc agatcctctc ttaaggtagc atcgagattt aaattaggga 60
taacagggta atggcgcggg ccgc 84
<210> 37
<211> 63
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in Lab - vector filler sequence
<400> 37
gttacccagg ctggagtgca gtggcacatt tctgctcact gcaacctcct cctccctggg 60
ttc 63
<210> 38
<211> 573
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in lab - CAG promoter in part Human betaherpesvirus 5
<400> 38
acttacggta aatggcccgc ctggctgacc gcccaacgac ccccgcccat tgacgtcaat 60
aatgacgtat gttcccatag taacgccaat agggactttc cattgacgtc aatgggtgga 120
gtatttacgg taaactgccc acttggcagt acatcaagtg tatcatatgc caagtacgcc 180
ccctattgac gtcaatgacg gtaaatggcc cgcctggcat tatgcccagt acatgacctt 240
atgggacttt cctacttggc agtacatcta cgtattagtc atcgctatta ccatggtcga 300
ggtgagcccc acgttctgct tcactctccc catctccccc ccctccccac ccccaatttt 360
gtatttattt attttttaat tattttgtgc agcgatgggg gcgggggggg ggggggcgcg 420
cgccaggcgg ggcggggcgg ggcgaggggc ggggcggggc gaggcggaga ggtgcggcgg 480
cagccaatca gagcggcgcg ctccgaaagt ttccttttat ggcgaggcgg cggcggcggc 540
ggccctataa aaagcgaagc gcgcggcggg cgg 573
<210> 39
<211> 253
<212> DNA
<213> Homo sapiens
<400> 39
gcccagcacc ccaaggcggc caacgccaaa actctccctc ctcctcttcc tcaatctcgc 60
tctcgctctt tttttttttc gcaaaaggag gggagagggg gtaaaaaaat gctgcactgt 120
gcggcgaagc cggtgagtga gcggcgcggg gccaatcagc gtgcgccgtt ccgaaagttg 180
ccttttatgg ctcgagcggc cgcggcggcg ccctataaaa cccagcggcg cgacgcgcca 240
ccaccgccga gtc 253
<210> 40
<211> 281
<212> DNA
<213> Gallus gallus
<400> 40
ggtcgaggtg agccccacgt tctgcttcac tctccccatc tcccccccct ccccaccccc 60
aattttgtat ttatttattt tttaattatt ttgtgcagcg atgggggcgg gggggggggg 120
ggcgcgcgcc aggcggggcg gggcggggcg aggggcgggg cggggcgagg cggagaggtg 180
cggcggcagc caatcagagc ggcgcgctcc gaaagtttcc ttttatggcg aggcggcggc 240
ggcggcggcc ctataaaaag cgaagcgcgc ggcgggcggg a 281
<210> 41
<211> 220
<212> DNA
<213> Human betaherpesvirus 5
<400> 41
tggtgatgcg gttttggcag tacaccaatg ggcgtggata gcggtttgac tcacggggat 60
ttccaagtct ccaccccatt gacgtcaatg ggagtttgtt ttggcaccaa aatcaacggg 120
actttccaaa atgtcgtaat aaccccgccc cgttgacgca aatgggcggt aggcgtgtac 180
ggtgggaggt ctatataagc agagctcgtt tagtgaaccg 220
<210> 42
<211> 583
<212> DNA
<213> Human betaherpesvirus 5
<400> 42
tagttattaa tagtaatcaa ttacggggtc attagttcat agcccatata tggagttccg 60
cgttacataa cttacggtaa atggcccgcc tggctgaccg cccaacgacc cccgcccatt 120
gacgtcaata atgacgtatg ttcccatagt aacgccaata gggactttcc attgacgtca 180
atgggtggag tatttacggt aaactgccca cttggcagta catcaagtgt atcatatgcc 240
aagtacgccc cctattgacg tcaatgacgg taaatggccc gcctggcatt atgcccagta 300
catgacctta tgggactttc ctacttggca gtacatctac gtattagtca tcgctattac 360
catggtgatg cggttttggc agtacatcaa tgggcgtgga tagcggtttg actcacgggg 420
atttccaagt ctccacccca ttgacgtcaa tgggagtttg ttttggcacc aaaatcaacg 480
ggactttcca aaatgtcgta acaactccgc cccattgacg caaatgggcg gtaggcgtgt 540
acggtgggag gtctatataa gcagagctgg tttagtgaac cgt 583
<210> 43
<211> 508
<212> DNA
<213> Human betaherpesvirus 5
<400> 43
cgttacataa cttacggtaa atggcccgcc tggctgaccg cccaacgacc cccgcccatt 60
gacgtcaata atgacgtatg ttcccatagt aacgccaata gggactttcc attgacgtca 120
atgggtggag tatttacggt aaactgccca cttggcagta catcaagtgt atcatatgcc 180
aagtacgccc cctattgacg tcaatgacgg taaatggccc gcctggcatt atgcccagta 240
catgacctta tgggactttc ctacttggca gtacatctac gtattagtca tcgctattac 300
catggtgatg cggttttggc agtacatcaa tgggcgtgga tagcggtttg actcacgggg 360
atttccaagt ctccacccca ttgacgtcaa tgggagtttg ttttggcacc aaaatcaacg 420
ggactttcca aaatgtcgta acaactccgc cccattgacg caaatgggcg gtaggcgtgt 480
acggtgggag gtctatataa gcagagct 508
<210> 44
<211> 573
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in lab - CAG promoter in part Human betaherpesvirus 5
<400> 44
acttacggta aatggcccgc ctggctgacc gcccaacgac ccccgcccat tgacgtcaat 60
aatgacgtat gttcccatag taacgccaat agggactttc cattgacgtc aatgggtgga 120
gtatttacgg taaactgccc acttggcagt acatcaagtg tatcatatgc caagtacgcc 180
ccctattgac gtcaatgacg gtaaatggcc cgcctggcat tatgcccagt acatgacctt 240
atgggacttt cctacttggc agtacatcta cgtattagtc atcgctatta ccatggtcga 300
ggtgagcccc acgttctgct tcactctccc catctccccc ccctccccac ccccaatttt 360
gtatttattt attttttaat tattttgtgc agcgatgggg gcgggggggg ggggggcgcg 420
cgccaggcgg ggcggggcgg ggcgaggggc ggggcggggc gaggcggaga ggtgcggcgg 480
cagccaatca gagcggcgcg ctccgaaagt ttccttttat ggcgaggcgg cggcggcggc 540
ggccctataa aaagcgaagc gcgcggcggg cgg 573
<210> 45
<211> 580
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in lab - CAG promoter in part Human betaherpesvirus 5
<400> 45
cgttacataa cttacggtaa atggcccgcc tggctgaccg cccaacgacc cccgcccatt 60
gacgtcaata atgacgtatg ttcccatagt aacgccaata gggactttcc attgacgtca 120
atgggtggag tatttacggt aaactgccca cttggcagta catcaagtgt atcatatgcc 180
aagtacgccc cctattgacg tcaatgacgg taaatggccc gcctggcatt atgcccagta 240
catgacctta tgggactttc ctacttggca gtacatctac gtattagtca tcgctattac 300
catgtcgagg tgagccccac gttctgcttc actctcccca tctccccccc ctccccaccc 360
ccaattttgt atttatttat tttttaatta ttttgtgcag cgatgggggc gggggggggg 420
ggggcgcgcg ccaggcgggg cggggcgggg cgaggggcgg ggcggggcga ggcggagagg 480
tgcggcggca gccaatcaga gcggcgcgct ccgaaagttt ccttttatgg cgaggcggcg 540
gcggcggcgg ccctataaaa agcgaagcgc gcggcgggcg 580
<210> 46
<211> 455
<212> DNA
<213> Homo sapiens
<400> 46
caacctttgg agctaagcca gcaatggtag agggaagatt ctgcacgtcc cttccaggcg 60
gcctccccgt caccaccccc cccaacccgc cccgaccgga gctgagagta attcatacaa 120
aaggactcgc ccctgccttg gggaatccca gggaccgtcg ttaaactccc actaacgtag 180
aacccagaga tcgctgcgtt cccgccccct cacccgcccg ctctcgtcat cactgaggtg 240
gagaatagca tgcgtgaggc tccggtgccc gtcagtgggc agagcgcaca tcgcccacag 300
tccccgagaa gttgggggga ggggtcggca attgaacggg tgcctagaga aggtggcgcg 360
gggtaaactg ggaaagtgat gtcgtgtact ggctccgcct ttttcccgag ggtgggggag 420
aaccgtatat aagtgcagta gtcgccgtga acgtt 455
<210> 47
<211> 401
<212> DNA
<213> Homo sapiens
<400> 47
agtgcaagtg ggttttagga ccaggatgag gcggggtggg ggtgcctacc tgacgaccga 60
ccccgaccca ctggacaagc acccaacccc cattccccaa attgcgcatc ccctatcaga 120
gagggggagg ggaaacagga tgcggcgagg cgcgtgcgca ctgccagctt cagcaccgcg 180
gacagtgcct tcgcccccgc ctggcggcgc gcgccaccgc cgcctcagca ctgaaggcgc 240
gctgacgtca ctcgccggtc ccccgcaaac tccccttccc ggccaccttg gtcgcgtccg 300
cgccgccgcc ggcccagccg gaccgcacca cgcgaggcgc gagatagggg ggcacgggcg 360
cgaccatctg cgctgcggcg ccggcgactc agcgctgcct c 401
<210> 48
<211> 448
<212> DNA
<213> Homo sapiens
<400> 48
agtgcaagtg ggttttagga ccaggatgag gcggggtggg ggtgcctacc tgacgaccga 60
ccccgaccca ctggacaagc acccaacccc cattccccaa attgcgcatc ccctatcaga 120
gagggggagg ggaaacagga tgcggcgagg cgcgtgcgca ctgccagctt cagcaccgcg 180
gacagtgcct tcgcccccgc ctggcggcgc gcgccaccgc cgcctcagca ctgaaggcgc 240
gctgacgtca ctcgccggtc ccccgcaaac tccccttccc ggccaccttg gtcgcgtccg 300
cgccgccgcc ggcccagccg gaccgcacca cgcgaggcgc gagatagggg ggcacgggcg 360
cgaccatctg cgctgcggcg ccggcgactc agcgctgcct cagtctgcgg tgggcagcgg 420
aggagtcgtg tcgtgcctga gagcgcag 448
<210> 49
<211> 422
<212> DNA
<213> Homo sapiens
<400> 49
ctgcagaggg ccctgcgtat gagtgcaagt gggttttagg accaggatga ggcggggtgg 60
gggtgcctac ctgacgaccg accccgaccc actggacaag cacccaaccc ccattcccca 120
aattgcgcat cccctatcag agagggggag gggaaacagg atgcggcgag gcgcgtgcgc 180
actgccagct tcagcaccgc ggacagtgcc ttcgcccccg cctggcggcg cgcgccaccg 240
ccgcctcagc actgaaggcg cgctgacgtc actcgccggt cccccgcaaa ctccccttcc 300
cggccacctt ggtcgcgtcc gcgccgccgc cggcccagcc ggaccgcacc acgcgaggcg 360
cgagataggg gggcacgggc gcgaccatct gcgctgcggc gccggcgact cagcgctgcc 420
tc 422
<210> 50
<211> 281
<212> DNA
<213> Homo sapiens
<400> 50
acttgtggac aaagtttgct ctattccacc tcctccaggc cctccttggg tccatcaccc 60
caggggtgct gggtccatcc cacccccagg cccacacagg cttgcagtat tgtgtgcggt 120
atggtcaggg cgtccgagag caggtttcgc agtggaaggc aggcaggtgt tggggaggca 180
gttaccgggg caacgggaac agggcgtttt ggaggtggtt gccatgggga cctggatgct 240
gacgaaggct cgcgaggctg tgagcagcca cagtgccctg c 281
<210> 51
<211> 851
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in Lab - eSYN promoter polynucleotide
<400> 51
gacattgatt attgactagt tattaatagt aatcaattac ggggtcatta gttcatagcc 60
catatatgga gttccgcgtt acataactta cggtaaatgg cccgcctggc tgaccgccca 120
acgacccccg cccattgacg tcaataatga cgtatgttcc catagtaacg ccaataggga 180
ctttccattg acgtcaatgg gtggactatt tacggtaaac tgcccacttg gcagtacatc 240
aagtgtatca tatgccaagt acgcccccta ttgacgtcaa tgacggtaaa tggcccgcct 300
ggcattatgc ccagtacatg accttatggg actttcctac ttggcagtac atctacgtat 360
tagtcatcgc tattaccatg gctgcagagg gccctgcgta tgagtgcaag tgggttttag 420
gaccaggatg aggcggggtg ggggtgccta cctgacgacc gaccccgacc cactggacaa 480
gcacccaacc cccattcccc aaattgcgca tcccctatca gagaggggga ggggaaacag 540
gatgcggcga ggcgcgtcgc gactgccagc ttcagcaccg cggacagtgc cttcgccccc 600
gcctggcggc gcgcgccacc gccgcctcag cactgaaggc gcgctgacgt cactcgccgg 660
tcccccgcaa actccccttc ccggccacct tggtcgcgtc cgcgccgccg ccggcccagc 720
cggaccgcac cacgcgaggc gcgagatagg ggggcacggg cgcgaccatc tgcgctgcgg 780
cgccggcgac tcagcgctgc ctcagtctgc ggtgggcagc ggaggagtcg tgtcgtgcct 840
gagagcgcag g 851
<210> 52
<211> 304
<212> DNA
<213> Human betaherpesvirus 5
<400> 52
cgttacataa cttacggtaa atggcccgcc tggctgaccg cccaacgacc cccgcccatt 60
gacgtcaata atgacgtatg ttcccatagt aacgccaata gggactttcc attgacgtca 120
atgggtggag tatttacggt aaactgccca cttggcagta catcaagtgt atcatatgcc 180
aagtacgccc cctattgacg tcaatgacgg taaatggccc gcctggcatt atgcccagta 240
catgacctta tgggactttc ctacttggca gtacatctac gtattagtca tcgctattac 300
catg 304
<210> 53
<211> 953
<212> DNA
<213> Homo sapiens
<400> 53
cgcgtccgcc cgcgagcaca gagcctcgcc tttgccgatc cgccgcccgt ccacacccgc 60
cgccaggtaa gcccggccag ccgaccgggg catgcggccg cggcccttcg cccgtgcaga 120
gccgccgtct gggccgcagc ggggggcgca tggggcggaa ccggaccgcc gtggggggcg 180
cgggagaagc ccctgggcct ccggagatgg gggacacccc acgccagttc gcaggcgcga 240
ggccgcgctc gggcgggcgc gctccggggg tgccgctctc ggggcggggg caaccggcgg 300
ggtctttgtc tgagccgggc tcttgccaat ggggatcgca cggtgggcgc ggcgtagccc 360
ccgtcaggcc cggtgggggc tggggcgcca tgcgcgtgcg cgctggtcct ttgggcgcta 420
actgcgtgcg cgctgggaat tggcgctaat tgcgcgtgcg cgctgggact caatggcgct 480
aatcgcgcgt gcgttctggg gcccgggcgc ttgcgccact tcctgcccga gccgctggcg 540
cccgagggtg tggccgctgc gtgcgcgcgc gcgacccggt cgctgtttga accgggcgga 600
ggcggggctg gcgcccggtt gggagggggt tggggcctgg cttcctgccg cgcgccgcgg 660
ggacgcctcc gaccagtgtt tgccttttat ggtaataacg cggccggccc ggcttccttt 720
gtccccaatc tgggcgcgcg ccggcgcccc ctggcggcct aaggactcgg cgcgccggaa 780
gtggccaggg cggcagcggc tgctcttggc ggccccgagg tgactatagc cttcttttgt 840
gtcttgatag ttcgccagcc tctgctaacc atgttcatgc cttcttcttt ttcctacagc 900
tcctgggcaa cgtgctggtt attgtgctgt ctcatcattt tggcaaagaa ttc 953
<210> 54
<211> 1068
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in Lab - Chicken beta-actin exon/intron plus rabbit globin
intron
<400> 54
gtcgctgcgc gctgccttcg ccccgtgccc cgctccgccg ccgcctcgcg ccgcccgccc 60
cggctctgac tgaccgcgtt actcccacag gtgagcgggc gggacggccc ttctcctccg 120
ggctgtaatt agcgcttggt ttaatgacgg cttgtttctt ttctgtggct gcgtgaaagc 180
cttgaggggc tccgggaggg ccctttgtgc ggggggagcg gctcgggggg tgcgtgcgtg 240
tgtgtgtgcg tggggagcgc cgcgtgcggc tccgcgctgc ccggcggctg tgagcgctgc 300
gggcgcggcg cggggctttg tgcgctccgc agtgtgcgcg aggggagcgc ggccgggggc 360
ggtgccccgc ggtgcggggg gggctgcgag gggaacaaag gctgcgtgcg gggtgtgtgc 420
gtgggggggt gagcaggggg tgtgggcgcg tcggtcgggc tgcaaccccc cctgcacccc 480
cctccccgag ttgctgagca cggcccggct tcgggtgcgg ggctccgtac ggggcgtggc 540
gcggggctcg ccgtgccggg cggggggtgg cggcaggtgg gggtgccggg cggggcgggg 600
ccgcctcggg ccggggaggg ctcgggggag gggcgcggcg gcccccggag cgccggcggc 660
tgtcgaggcg cggcgagccg cagccattgc cttttatggt aatcgtgcga gagggcgcag 720
ggacttcctt tgtcccaaat ctgtgcggag ccgaaatctg ggaggcgccg ccgcaccccc 780
tctagcgggc gcggggcgaa gcggtgcggc gccggcagga aggaaatggg cggggagggc 840
cttcgtgcgt cgccgcgccg ccgtcccctt ctccctctcc agcctcgggg ctgtccgcgg 900
ggggacggct gccttcgggg gggacggggc agggcggggt tcggcttctg gcgtgtgacc 960
ggcggctcta gagcctctgc taaccatgtt catgccttct tctttttcct acagctcctg 1020
ggcaacgtgc tggttattgt gctgtctcat cattttggca aagaattc 1068
<210> 55
<211> 126
<212> DNA
<213> Homo sapiens
<400> 55
agtctgcggt gggcagcgga ggagtcgtgt cgtgcctgag agcgcagctg tgctcctggg 60
caccgcgcag tccgcccccg cggctcctgg ccagaccacc cctaggaccc cctgccccaa 120
gtcgca 126
<210> 56
<211> 121
<212> DNA
<213> Human betaherpesvirus 5
<400> 56
tcagatcgcc tggagaggcc atccacgctg ttttgacctc catagtggac accgggaccg 60
atccagcctc cgcggccggg aacggtgcat tggaacgcgg attccccgtg ccaagagtga 120
c 121
<210> 57
<211> 512
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in Lab - adenovirus derived enhancer element
<400> 57
ctcactctct tccgcatcgc tgtctgcgag ggccagctgt tgggctcgcg gttgaggaca 60
aactcttcgc ggtctttcca gtactcttgg atcggaaacc cgtcggcctc cgaacggtac 120
tccgccaccg agggacctga gcgagtccgc atcgaccgga tcggaaaacc tctcgagaaa 180
ggcgtctaac cagtcacagt cgcaaggtag gctgagcacc gtggcgggcg gcagcgggtg 240
gcggtcgggg ttgtttctgg cggaggtgct gctgatgatg taattaaagt aggcggtctt 300
gagacggcgg atggtcgagg tgaggtgtgg caggcttgag atccagctgt tggggtgagt 360
actccctctc aaaagcgggc attacttctg cgctaagatt gtcagtttcc aaaaacgagg 420
aggatttgat attcacctgg cccgatctgg ccatacactt gagtgacaat gacatccact 480
ttgcctttct ctccacaggt gtccactccc ag 512
<210> 58
<211> 956
<212> DNA
<213> Homo sapiens
<400> 58
ctttttcgca acgggtttgc cgccagaaca caggtaagtg ccgtgtgtgg ttcccgcggg 60
cctggcctct ttacgggtta tggcccttgc gtgccttgaa ttacttccac ctggctccag 120
tacgtgattc ttgatcccga gctggagcca ggggcgggcc ttgcgcttta ggagcccctt 180
cgcctcgtgc ttgagttgag gcctggcctg ggcgctgggg ccgccgcgtg cgaatctggt 240
ggcaccttcg cgcctgtctc gctgctttcg ataagtctct agccatttaa aatttttgat 300
gacgtgctgc gacgcttttt ttctggcaag atagtcttgt aaatgcgggc caggatctgc 360
acactggtat ttcggttttt gggcccgcgg ccggcgacgg ggcccgtgcg tcccagcgca 420
catgttcggc gaggcggggc ctgcgagcgc ggccaccgag aatcggacgg gggtagtctc 480
aagctggccg gcctgctctg gtgcctggcc tcgcgccgcc gtgtatcgcc ccgccctggg 540
cggcaaggct ggcccggtcg gcaccagttg cgtgagcgga aagatggccg cttcccggcc 600
ctgctccagg gggctcaaaa tggaggacgc ggcgctcggg agagcgggcg ggtgagtcac 660
ccacacaaag gaaaagggcc tttccgtcct cagccgtcgc ttcatgtgac tccacggagt 720
accgggcgcc gtccaggcac ctcgattagt tctggagctt ttggagtacg tcgtctttag 780
gttgggggga ggggttttat gcgatggagt ttccccacac tgagtgggtg gagactgaag 840
ttaggccagc ttggcacttg atgtaattct ccttggaatt tggccttttt gagtttggat 900
cttggttcat tctcaagcct cagacagtgg ttcaaagttt ttttcttcca tttcag 956
<210> 59
<211> 939
<212> DNA
<213> Homo sapiens
<400> 59
gtaagtgccg tgtgtggttc ccgcgggcct ggcctcttta cgggttatgg cccttgcgtg 60
ccttgaatta cttccacctg gctgcagtac gtgattcttg atcccgagct tcgggttgga 120
agtgggtggg agagttcgag gccttgcgct taaggagccc cttcgcctcg tgcttgagtt 180
gaggcctggc ctgggcgctg gggccgccgc gtgcgaatct ggtggcacct tcgcgcctgt 240
ctcgctgctt tcgataagtc tctagccatt taaaattttt gatgacctgc tgcgacgctt 300
tttttctggc aagatagtct tgtaaatgcg ggccaagatc tgcacactgg tatttcggtt 360
tttggggccg cgggcggcga cggggcccgt gcgtcccagc gcacatgttc ggcgaggcgg 420
ggcctgcgag cgcggccacc gagaatcgga cgggggtagt ctcaagctgg ccggcctgct 480
ctggtgcctg gcctcgcgcc gccgtgtatc gccccgccct gggcggcaag gctggcccgg 540
tcggcaccag ttgcgtgagc ggaaagatgg ccgcttcccg gccctgctgc agggagctca 600
aaatggagga cgcggcgctc gggagagcgg gcgggtgagt cacccacaca aaggaaaagg 660
gcctttccgt cctcagccgt cgcttcatgt gactccacgg agtaccgggc gccgtccagg 720
cacctcgatt agttctcgag cttttggagt acgtcgtctt taggttgggg ggaggggttt 780
tatgcgatgg agtttcccca cactgagtgg gtggagactg aagttaggcc agcttggcac 840
ttgatgtaat tctccttgga atttgccctt tttgagtttg gatcttggtt cattctcaag 900
cctcagacag tggttcaaag tttttttctt ccatttcag 939
<210> 60
<211> 83
<212> DNA
<213> Homo sapiens
<400> 60
tcagaagccc cgggctcgtc agtcaaaccg gttctctgtt tgcactcggc agcacgggca 60
ggcaagtggt ccctaggttc ggg 83
<210> 61
<211> 476
<212> DNA
<213> Homo sapiens
<400> 61
gtgagtctat gggacccttg atgttttctt tccccttctt ttctatggtt aagttcatgt 60
cataggaagg ggagaagtaa cagggtacac atattgacca aatcagggta attttgcatt 120
tgtaatttta aaaaatgctt tcttctttta atatactttt ttgtttatct tatttctaat 180
actttcccta atctctttct ttcagggcaa taatgataca atgtatcatg cctctttgca 240
ccattctaaa gaataacagt gataatttct gggttaaggc aatagcaata tttctgcata 300
taaatatttc tgcatataaa ttgtaactga tgtaagaggt ttcatattgc taatagcagc 360
tacaatccag ctaccattct gcttttattt tatggttggg ataaggctgg attattctga 420
gtccaagcta ggcccttttg ctaatcatgt tcatacctct tatcttcctc ccacag 476
<210> 62
<211> 589
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in Lab - mutated woodchuck hepatitis regulatory element
<400> 62
aatcaacctc tggattacaa aatttgtgaa agattgactg gtattcttaa ctatgttgct 60
ccttttacgc tatgtggata cgctgcttta atgcctttgt atcatgctat tgcttcccgt 120
atggctttca ttttctcctc cttgtataaa tcctggttgc tgtctcttta tgaggagttg 180
tggcccgttg tcaggcaacg tggcgtggtg tgcactgtgt ttgctgacgc aacccccact 240
ggttggggca ttgccaccac ctgtcagctc ctttccggga ctttcgcttt ccccctccct 300
attgccacgg cggaactcat cgccgcctgc cttgcccgct gctggacagg ggctcggctg 360
ttgggcactg acaattccgt ggtgttgtcg gggaaatcat cgtcctttcc ttggctgctc 420
gcctgtgttg ccacctggat tctgcgcggg acgtccttct gctacgtccc ttcggccctc 480
aatccagcgg accttccttc ccgcggcctg ctgccggctc tgcggcctct tccgcgtctt 540
cgccttcgcc ctcagacgag tcggatctcc ctttgggccg cctccccgc 589
<210> 63
<211> 588
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in Lab - mutated woodchuck hepatitis regulatory element
<400> 63
tcaacctctg gattacaaaa tttgtgaaag attgactggt attcttaact atgttgctcc 60
ttttacgcta tgtggatacg ctgctttaat gcctttgtat catgctattg cttcccgtat 120
ggctttcatt ttctcctcct tgtataaatc ctggttgctg tctctttatg aggagttgtg 180
gcccgttgtc aggcaacgtg gcgtggtgtg cactgtgttt gctgacgcaa cccccactgg 240
ttggggcatt gccaccacct gtcagctcct ttccgggact ttcgctttcc ccctccctat 300
tgccacggcg gaactcatcg ccgcctgcct tgcccgctgc tggacagggg ctcggctgtt 360
gggcactgac aattccgtgg tgttgtcggg gaaatcatcg tcctttcctt ggctgctcgc 420
ctgtgttgcc acctggattc tgcgcgggac gtccttctgc tacgtccctt cggccctcaa 480
tccagcggac cttccttccc gcggcctgct gccggctctg cggcctcttc cgcgtcttcg 540
ccttcgccct cagacgagtc ggatctccct ttgggccgcc tccccgca 588
<210> 64
<211> 755
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in Lab - mutated woodchuck hepatitis regulatory element
<400> 64
ttcctgttaa tcaacctctg gattacaaaa tttgtgaaag attgactggt attcttaact 60
atgttgctcc ttttacgcta tgtggatacg ctgctttaat gcctttgtat catgctattg 120
cttcccgtat ggctttcatt ttctcctcct tgtataaatc ctggttgctg tctctttatg 180
aggagttgtg gcccgttgtc aggcaacgtg gcgtggtgtg cactgtgttt gctgacgcaa 240
cccccactgg ttggggcatt gccaccacct gtcagctcct ttccgggact ttcgctttcc 300
ccctccctat tgccacggcg gaactcatcg ccgcctgcct tgcccgctgc tggacagggg 360
ctcggctgtt gggcactgac aattccgtgg tgttgtcggg gaagctgacg tcctttccgc 420
ggctgctcgc ctgtgttgcc acctggattc tgcgcgggac gtccttctgc tacgtccctt 480
cggccctcaa tccagcggac cttccttccc gcggcctgct gccggctctg cggcctcttc 540
cgcctcttcg ccttcgccct cagacgagtc ggatctccct ttgggccgcc tccccgccca 600
tgtatctttt tcacctgtgc cttgtttttg cctgtgttcc gcgtcctact tttcaagcct 660
ccaagctgtg ccttgggcgg ctttggggca tggacataga tccctataaa gaatttggtt 720
catcttatca gttgttgaat tttcttcctt tggac 755
<210> 65
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> CAAX motif
<400> 65
tgtgtgataa tg 12
<210> 66
<211> 810
<212> DNA
<213> Homo sapiens
<400> 66
ctgttctcat cacatcatat caaggttata taccatcaat attgccacag atgttactta 60
gccttttaat atttctctaa tttagtgtat atgcaatgat agttctctga tttctgagat 120
tgagtttctc atgtgtaatg attatttaga gtttctcttt catctgttca aatttttgtc 180
tagttttatt ttttactgat ttgtaagact tctttttata atctgcatat tacaattctc 240
tttactgggg tgttgcaaat attttctgtc attctatggc ctgacttttc ttaatggttt 300
tttaatttta aaaataagtc ttaatattca tgcaatctaa ttaacaatct tttctttgtg 360
gttaggactt tgagtcataa gaaatttttc tctacactga agtcatgatg gcatgcttct 420
atattatttt ctaaaagatt taaagttttg ccttctccat ttagacttat aattcactgg 480
aatttttttg tgtgtatggt atgacatatg ggttcccttt tattttttac atataaatat 540
atttccctgt ttttctaaaa aagaaaaaga tcatcatttt cccattgtaa aatgccatat 600
ttttttcata ggtcacttac atatatcaat gggtctgttt ctgagctcta ctctatttta 660
tcagcctcac tgtctatccc cacacatctc atgctttgct ctaaatcttg atatttagtg 720
gaacattctt tcccattttg ttctacaaga atatttttgt tattgtcttt gggctttcta 780
tatacatttt gaaatgaggt tgacaagtta 810
<210> 67
<211> 726
<212> DNA
<213> Hepatitis B virus
<400> 67
ataacaggcc tattgattgg aaagtttgtc aacgaattgt gggtcttttg gggtttgctg 60
ccccttttac gcaatgtgga tatcctgctt taatgccttt atatgcatgt atacaagcaa 120
aacaggcttt tactttctcg ccaacttaca aggcctttct cagtaaacag tatatgaccc 180
tttaccccgt tgctcggcaa cggcctggtc tgtgccaagt gtttgctgac gcaaccccca 240
ctggttgggg cttggccata ggccatcagc gcatgcgtgg aacctttgtg tctcctctgc 300
cgatccatac tgcggaactc ctagccgctt gttttgctcg cagcaggtct ggagcaaacc 360
tcatcgggac cgacaattct gtcgtactct cccgcaagta tacatcgttt ccatggctgc 420
taggctgtgc tgccaactgg atcctgcgcg ggacgtcctt tgtttacgtc ccgtcggcgc 480
tgaatcccgc ggacgacccc tcccggggcc gcttggggct ctaccgcccg cttctccgtc 540
tgccgtaccg tccgaccacg gggcgcacct ctctttacgc ggactccccg tctgtgcctt 600
ctcatctgcc ggaccgtgtg cacttcgctt cacctctgca cgtcgcatgg aggccaccgt 660
gaacgcccac cggaacctgc ccaaggtctt gcataagagg actcttggac tttcagcaat 720
gtcatc 726
<210> 68
<211> 755
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in Lab - HepB derived enhancer element
<400> 68
ttcctgtaaa caggcctatt gattggaaag tttgtcaacg aattgtgggt cttttggggt 60
ttgctgcccc ttttacgcaa tgtggatatc ctgctttaat gcctttatat gcatgtatac 120
aagcaaaaca ggcttttact ttctcgccaa cttacaaggc ctttctcagt aaacagtata 180
tgacccttta ccccgttgct cggcaacggc ctggtctgtg ccaagtgttt gctgacgcaa 240
cccccactgg ttggggcttg gccataggcc atcagcgcat gcgtggaacc tttgtgtctc 300
ctctgccgat ccatactgcg gaactcctag ccgcttgttt tgctcgcagc tggactggag 360
caaacctcat cgggaccgac aattctgtcg tactctcccg caagcactca ccgtttccgc 420
ggctgctcgc ctgtgttgcc acctggattc tgcgcgggac gtccttctgc tacgtccctt 480
cggccctcaa tccagcggac cttccttccc gcggcctgct gccggctctg cggcctcttc 540
cgcctcttcg ccttcgccct cagacgagtc ggatctccct ttgggccgcc tccccgccca 600
tgtatctttt tcacctgtgc cttgtttttg cctgtgttcc gcgtcctact tttcaagcct 660
ccaagctgtg ccttgggcgg ctttggggca tggacataga tccctataaa gaatttggtt 720
catcttatca gttgttgaat tttcttcctt tggac 755
<210> 69
<211> 94
<212> DNA
<213> Homo sapiens
<400> 69
gctggagcct cggtagccgt tcctcctgcc cgctgggcct cccaacgggc cctcctcccc 60
tccttgcacc ggcccttcct ggtctttgaa taaa 94
<210> 70
<211> 596
<212> DNA
<213> Woodchuck hepatitis virus
<400> 70
attcgagcat cttaccgcca tttattccca tatttgttct gtttttcttg atttgggtat 60
acatttaaat gttaataaaa caaaatggtg gggcaatcat ttacattttt agggatatgt 120
aattactagt tcaggtgtat tgccacaaga caaacatgtt aagaaacttt cccgttattt 180
acgctctgtt cctgttaatc aacctctgga ttacaaaatt tgtgaaagat tgactgatat 240
tcttaactat gttgctcctt ttacgctgtg tggatatgct gctttaatgc ctctgtatca 300
tgctattgct tcccgtacgg ctttcgtttt ctcctccttg tataaatcct ggttgctgtc 360
tctttatgag gagttgtggc ccgttgtccg tcaacgtggc gtggtgtgct ctgtgtttgc 420
tgacgcaacc cccactggct ggggcattgc caccacctgt caactccttt ctgggacttt 480
cgctttcccc ctcccgatcg ccacggcaga actcatcgcc gcctgccttg cccgctgctg 540
gacaggggct aggttgctgg gcactgataa ttccgtggtg ttgtcgggga agggcc 596
<210> 71
<211> 387
<212> DNA
<213> Oryctolagus cuniculus
<400> 71
tggctaataa aggaaattta ttttcattgc aatagtgtgt tggaattttt tgtgtctctc 60
actcggaaga acatatggga gggcaaatca tttaaaacat cagaatgagt atttggttta 120
gagtttggca acatatgccc atatgctggc tgccatgaac aaaggttggc tataaagagg 180
tcatcagtat atgaaacagc cccctgctgt ccattcctta ttccatagaa aagccttgac 240
ttgaggttag atttttttta tattttgttt tgtgttattt ttttctttaa catccctaaa 300
attttcctta catgttttac tagccagatt tttcctcctc tcctgactac tcccagtcat 360
agctgtccct cttctcttat ggagatc 387
<210> 72
<211> 251
<212> DNA
<213> Bos taurus
<400> 72
ttgccagcca tctgttgttt gcccctcccc cgtgccttcc ttgaccctgg aaggtgccac 60
tcccactgtc ctttcctaat aaaatgagga aattgcatcg cattgtctga gtaggtgtca 120
ttctattctg gggggtgggg tggggcagga cagcaagggg gaggattggg aatacaatag 180
caggcatgct ggggatgcgg tgggctctat gggtacccag gtgctgaaga attgacccgg 240
ttcctcctgg g 251
<210> 73
<211> 251
<212> DNA
<213> Bos taurus
<400> 73
ttgccagcca tctgttgttt gcccctcccc cgtgccttcc ttgaccctgg aaggtgccac 60
tcccactgtc ctttcctaat aaaatgagga aattgcatcg cattgtctga gtaggtgtca 120
ttctattctg gggggtgggg tggggcagga cagcaagggg gaggattggg aagacaatag 180
caggcatgct ggggatgcgg tgggctctat gggtacccag gtgctgaaga attgacccgg 240
ttcctcctgg g 251
<210> 74
<211> 225
<212> DNA
<213> Bos taurus
<400> 74
ctgtgccttc tagttgccag ccatctgttg tttgcccctc ccccgtgcct tccttgaccc 60
tggaaggtgc cactcccact gtcctttcct aataaaatga ggaaattgca tcgcattgtc 120
tgagtaggtg tcattctatt ctggggggtg gggtggggca ggacagcaag ggggaggatt 180
gggaagacaa tagcaggcat gctggggatg cggtgggctc tatgg 225
<210> 75
<211> 202
<212> DNA
<213> Homo sapiens
<400> 75
ctgcccgggt ggcatccctg tgacccctcc ccagtgcctc tcctggccct ggaagttgcc 60
actccagtgc ccaccagcct tgtcctaata aaattaagtt gcatcatttt gtctgactag 120
gtgtccttct ataatattat ggggtggagg ggggtggtat ggagcaaggg gcccaagttg 180
ggaagaaacc tgtagggcct gc 202
<210> 76
<211> 735
<212> PRT
<213> Adeno-associated virus 2
<400> 76
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Arg Gln Ala Ala Thr
580 585 590
Ala Asp Val Asn Thr Gln Gly Val Leu Pro Gly Met Val Trp Gln Asp
595 600 605
Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr
610 615 620
Asp Gly His Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu Lys
625 630 635 640
His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala Asn
645 650 655
Pro Ser Thr Thr Phe Ser Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln
660 665 670
Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln Lys
675 680 685
Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr
690 695 700
Asn Lys Ser Val Asn Val Asp Phe Thr Val Asp Thr Asn Gly Val Tyr
705 710 715 720
Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
725 730 735
<210> 77
<211> 736
<212> PRT
<213> Adeno-associated virus 9
<400> 77
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Ala Gln Ala Gln
580 585 590
Thr Gly Trp Val Gln Asn Gln Gly Ile Leu Pro Gly Met Val Trp Gln
595 600 605
Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His
610 615 620
Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Met
625 630 635 640
Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala
645 650 655
Asp Pro Pro Thr Ala Phe Asn Lys Asp Lys Leu Asn Ser Phe Ile Thr
660 665 670
Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln
675 680 685
Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn
690 695 700
Tyr Tyr Lys Ser Asn Asn Val Glu Phe Ala Val Asn Thr Glu Gly Val
705 710 715 720
Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
725 730 735
<210> 78
<211> 736
<212> PRT
<213> Adeno-associated virus 6
<400> 78
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Asp Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Phe Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ser Gly Ile Gly
145 150 155 160
Lys Thr Gly Gln Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro Pro
180 185 190
Ala Thr Pro Ala Ala Val Gly Pro Thr Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ala
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Ala Ser Thr Gly Ala Ser Asn Asp Asn His
260 265 270
Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe
275 280 285
His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn
290 295 300
Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln
305 310 315 320
Val Lys Glu Val Thr Thr Asn Asp Gly Val Thr Thr Ile Ala Asn Asn
325 330 335
Leu Thr Ser Thr Val Gln Val Phe Ser Asp Ser Glu Tyr Gln Leu Pro
340 345 350
Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala
355 360 365
Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly
370 375 380
Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro
385 390 395 400
Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe
405 410 415
Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp
420 425 430
Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Asn Arg
435 440 445
Thr Gln Asn Gln Ser Gly Ser Ala Gln Asn Lys Asp Leu Leu Phe Ser
450 455 460
Arg Gly Ser Pro Ala Gly Met Ser Val Gln Pro Lys Asn Trp Leu Pro
465 470 475 480
Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Lys Thr Asp Asn
485 490 495
Asn Asn Ser Asn Phe Thr Trp Thr Gly Ala Ser Lys Tyr Asn Leu Asn
500 505 510
Gly Arg Glu Ser Ile Ile Asn Pro Gly Thr Ala Met Ala Ser His Lys
515 520 525
Asp Asp Lys Asp Lys Phe Phe Pro Met Ser Gly Val Met Ile Phe Gly
530 535 540
Lys Glu Ser Ala Gly Ala Ser Asn Thr Ala Leu Asp Asn Val Met Ile
545 550 555 560
Thr Asp Glu Glu Glu Ile Lys Ala Thr Asn Pro Val Ala Thr Glu Arg
565 570 575
Phe Gly Thr Val Ala Val Asn Leu Gln Ser Ser Ser Thr Asp Pro Ala
580 585 590
Thr Gly Asp Val His Val Met Gly Ala Leu Pro Gly Met Val Trp Gln
595 600 605
Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His
610 615 620
Thr Asp Gly His Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu
625 630 635 640
Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala
645 650 655
Asn Pro Pro Ala Glu Phe Ser Ala Thr Lys Phe Ala Ser Phe Ile Thr
660 665 670
Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln
675 680 685
Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Val Gln Tyr Thr Ser Asn
690 695 700
Tyr Ala Lys Ser Ala Asn Val Asp Phe Thr Val Asp Asn Asn Gly Leu
705 710 715 720
Tyr Thr Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Pro Leu
725 730 735
<210> 79
<211> 738
<212> PRT
<213> Non-human primate Adeno-associated virus
<400> 79
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Asp Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro
180 185 190
Pro Ala Gly Pro Ser Gly Leu Gly Ser Gly Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ser Thr Asn Asp
260 265 270
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn
305 310 315 320
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Glu Phe Ser Tyr
405 410 415
Gln Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
Ser Arg Thr Gln Ser Thr Gly Gly Thr Ala Gly Thr Gln Gln Leu Leu
450 455 460
Phe Ser Gln Ala Gly Pro Asn Asn Met Ser Ala Gln Ala Lys Asn Trp
465 470 475 480
Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Leu Ser
485 490 495
Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Gly Ala Thr Lys Tyr His
500 505 510
Leu Asn Gly Arg Asp Ser Leu Val Asn Pro Gly Val Ala Met Ala Thr
515 520 525
His Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Ser Gly Val Leu Met
530 535 540
Phe Gly Lys Gln Gly Ala Gly Lys Asp Asn Val Asp Tyr Ser Ser Val
545 550 555 560
Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr
565 570 575
Glu Gln Tyr Gly Val Val Ala Asp Asn Leu Gln Gln Gln Asn Ala Ala
580 585 590
Pro Ile Val Gly Ala Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val
595 600 605
Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
610 615 620
Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
625 630 635 640
Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val
645 650 655
Pro Ala Asp Pro Pro Thr Thr Phe Ser Gln Ala Lys Leu Ala Ser Phe
660 665 670
Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu
675 680 685
Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr
690 695 700
Ser Asn Tyr Tyr Lys Ser Thr Asn Val Asp Phe Ala Val Asn Thr Asp
705 710 715 720
Gly Thr Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
725 730 735
Asn Leu
<210> 80
<211> 738
<212> PRT
<213> Adeno-associated virus 8
<400> 80
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Gln Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro
180 185 190
Pro Ala Ala Pro Ser Gly Val Gly Pro Asn Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ala Thr Asn Asp
260 265 270
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Ser Phe Lys Leu Phe Asn
305 310 315 320
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Thr Tyr
405 410 415
Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
Ser Arg Thr Gln Thr Thr Gly Gly Thr Ala Asn Thr Gln Thr Leu Gly
450 455 460
Phe Ser Gln Gly Gly Pro Asn Thr Met Ala Asn Gln Ala Lys Asn Trp
465 470 475 480
Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Thr Gly
485 490 495
Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Ala Gly Thr Lys Tyr His
500 505 510
Leu Asn Gly Arg Asn Ser Leu Ala Asn Pro Gly Ile Ala Met Ala Thr
515 520 525
His Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Asn Gly Ile Leu Ile
530 535 540
Phe Gly Lys Gln Asn Ala Ala Arg Asp Asn Ala Asp Tyr Ser Asp Val
545 550 555 560
Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr
565 570 575
Glu Glu Tyr Gly Ile Val Ala Asp Asn Leu Gln Gln Gln Asn Thr Ala
580 585 590
Pro Gln Ile Gly Thr Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val
595 600 605
Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
610 615 620
Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
625 630 635 640
Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val
645 650 655
Pro Ala Asp Pro Pro Thr Thr Phe Asn Gln Ser Lys Leu Asn Ser Phe
660 665 670
Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu
675 680 685
Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr
690 695 700
Ser Asn Tyr Tyr Lys Ser Thr Ser Val Asp Phe Ala Val Asn Thr Glu
705 710 715 720
Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
725 730 735
Asn Leu
<210> 81
<211> 738
<212> PRT
<213> Non-human primate Adeno-associated virus
<400> 81
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Asp Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asn Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Gln Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Ser Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro
180 185 190
Pro Ala Gly Pro Ser Gly Leu Gly Ser Gly Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ser Thr Asn Asp
260 265 270
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn
305 310 315 320
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Glu Phe Ser Tyr
405 410 415
Asn Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
Ser Arg Thr Gln Ser Thr Gly Gly Thr Ala Gly Thr Gln Gln Leu Leu
450 455 460
Phe Ser Gln Ala Gly Pro Asn Asn Met Ser Ala Gln Ala Lys Asn Trp
465 470 475 480
Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Leu Ser
485 490 495
Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Gly Ala Thr Lys Tyr His
500 505 510
Leu Asn Gly Arg Asp Ser Leu Val Asn Pro Gly Val Ala Met Ala Thr
515 520 525
His Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Ser Gly Val Leu Met
530 535 540
Phe Gly Lys Gln Gly Ala Gly Lys Asp Asn Val Asp Tyr Ser Ser Val
545 550 555 560
Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr
565 570 575
Glu Gln Tyr Gly Val Val Ala Asp Asn Leu Gln Gln Gln Asn Ala Ala
580 585 590
Pro Ile Val Gly Ala Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val
595 600 605
Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
610 615 620
Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
625 630 635 640
Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val
645 650 655
Pro Ala Asp Pro Pro Thr Thr Phe Asn Gln Ala Lys Leu Ala Ser Phe
660 665 670
Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu
675 680 685
Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr
690 695 700
Ser Asn Tyr Tyr Lys Ser Thr Asn Val Asp Phe Ala Val Asn Thr Glu
705 710 715 720
Gly Thr Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
725 730 735
Asn Leu
<210> 82
<211> 743
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic construct - AAV9 variant
<400> 82
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Arg Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Thr Leu Ala Val
580 585 590
Pro Phe Lys Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 83
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide insert
<400> 83
Thr Leu Ala Val Pro Phe Lys
1 5
<210> 84
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide insert
<400> 84
Lys Phe Pro Val Ala Leu Thr
1 5
<210> 85
<211> 940
<212> DNA
<213> Homo sapiens
<400> 85
tggagccgcc aaatattttg ggaaatagcg ggaatgttgg cgaactgggc aagtgcgttt 60
tctgattaag agcaaccaga ttcagctttt taaactacaa ttatactggc caaacaaaat 120
acccttatac aaaaaccaaa actactggca ggagtcgctg ccagcttgcg acccggcata 180
cttggctgag tatccgcttc tcccttgtgg ctccaaactg ctgcagattc tcggccactt 240
cagacgcgcg cgatggcgaa gagggtcctg cactttgacg cgcctggtga gggagcgctg 300
ctcttcgcag cgctcctggt gatgctcccc aaatttcggg gaccggcaag cgattaaatc 360
ttggagttgc tcagcgcccg ttaccgagta ctttttattt acaccagaaa caaagttgtt 420
gctctgggat gttctctcct gggcgacttg gggcccagcg cagtccagtt gtgtggggaa 480
atggggagat gtaaatgggc ttggggagct ggagatcgcc gccgggtacc cgggtgaggg 540
gcggggctgg ccgcacggga gagcccctcc tccgctccgg ccccgccccg catggccccg 600
cctccgcgct ctagagtttc ggcaccagct cccaccctgc actgagtccc gggaccccgg 660
gagagcggtc aatgtgtggt cgctgcgttt cctctgcctg cgccgggcat cacttgcgcg 720
ccgcagaaag tccgtctggc agcctggata tcctctccta ccggcacccg cagacgcccc 780
tgcagccgcg gtcggcgccc gggctcccta gccctgtgcg ctcaactgtc ctgcgctgcg 840
gggtgccgcg agttccacct ccgcgcctcc ttctctagac aggcgctggg agaaagaacc 900
ggctcccgag ttctgggcat ttcgcccggc tcgaggtgca 940
<210> 86
<211> 1142
<212> DNA
<213> Mus musculus
<400> 86
aagcttccga ccgttagtca gagaactgta agtgctcaga gcctggctga caatgatctg 60
gaatgaacca gataacaaca taataaaatc tcagtaaaat aatttaacag ttagcttgga 120
agctggtcag ctctggggaa atcagggtaa attgtgctgt catgaactgt cccacactga 180
catcggccaa agtgaatatg aactttggta gatccaatgc ctgttctatt tatttttcca 240
gtgaaaagta ttttgataga gcttttcatt ttgtaaatac actgagttaa ccaaaatatc 300
atggatttcc gtttgttctt aagacatgca actcgtctac ggctatacca ctctgaacgc 360
gcccgatctc ggaagacatg caactcaaat gtaaatacag tagaatatta cttaggtaga 420
aactcctggt gattttaaaa gattggaaaa gaatatgagg aagagttgaa taatgcaaat 480
tctagtgtgt gtgctaccga agtgaacact taatgcacag tctacagact aggacatttt 540
atcgtgtgtt gtaaaattgg gtagaaactt gtgtttgtga aaactgagca ttaaaacctt 600
acagagaccg tttcttgttt acttttgaaa aaaaaaagag tcacgtgagc ctcattttgt 660
atttgtgtgt gtgtgtgtgt gtgtgtctcc cctcctccca gcgtgtgtgt gctgggagga 720
ggggagaccc cagaacaatg tcctgcctcc aaaccttctc aataggcgga agccactggc 780
ttcctccctt tcctgtctcc cgtgctccag caatgcagat ggaagggacc gaagggatgg 840
gagagagagc ccaaccatcc ccagatctgt ccttgtcaca acctgcctcc cacctctaat 900
gccccccctt ccagagactt ccaggccaca cccatcccgg gcttgtgggg gctggacacg 960
ggaggactac aggcgacaac tcttcccacc ctctctccct gccacccctc ctaccctaac 1020
catcatttcc tcttcctccc cagcaccgag gtgcactgag ctggacaggc tgaacactca 1080
gacccacagc aactgacccc gggcccagct ggccttggct ggcccagggc agcttccaga 1140
gt 1142
<210> 87
<211> 2079
<212> DNA
<213> Homo sapiens
<400> 87
gctggagtgc agtggcacga tctcggctca ctgcaacctc tgcctcccag gttcaaacaa 60
ttctcctgcc tcagcctcca gagtagctgg ggttacaggt gcacgccagc aagcacagct 120
aaattttgta tttttagtag agatggggtt ttgccatgtt ggccaggctg gtctcaaact 180
cctgacctca ggtgatccac tcccaaagtg ctgggattat aggcgtgagc cactgtgcca 240
ggcccactgt ttttgttttt ttttttcgtg atgacaaatt taaagtcatc tcataggaat 300
agaaaatagc tttttagtag aagctcttgg aatttaaatt gagactgaat ggaaagatga 360
aagaaaataa acttattaac atttaatgag aaccttcaaa gaactaggca tagtaccaaa 420
tggttttata tttttaaacc tcatttattc ctctcaaaac acctgggaag gagatatttt 480
tgccatttca cagctgttga aactgaggct caaaaagact aagtaacttt tctcagctac 540
acatgtggct gagccagtat ttgaacccag ttctgtttgc agacagaacc tgggcttttt 600
cacacctgca aactggaaac attaattggt tcttaagatc atcatcgatg tgataaaacc 660
tgggacagaa attagtcaag actagctgca tctgcctttt cctctggtgg gtaggaaaag 720
gaggagtata atgatttcct caggcatgaa ggtcgatgat gagcaaagtg tatactctct 780
aatctaatgt cataattcat attgtggagt aattatctgg ataagtgtag ggtctctgac 840
ctcattctag atattgtaca ttccatggct attttcattt tggtccatga actctctttg 900
ctctcatgag caccattttt atcccaatct aatcctgtat gtttgtgttt ttacacagat 960
tagtttttaa atgttatata taatttgctt ctgaaacacc attgctcaat gactaccaaa 1020
tctttctcat taccaaaatc cttctatgcc aacttcttca agaaatttga tcacctttag 1080
atgaattgtt aatgaaaatt aaagctatag ccggcaacat gggtatcttt gggctaatgg 1140
ccaaccaaca ggccatctgt gtgaaagaaa acaggctaac aattttggac tctggtctct 1200
tggggctaca ttgagcattg acctcaccgg tgctcactga aattaattgc ttttcaggtt 1260
gtattttctc atcacggaaa ccttcttctc ccaattcaaa ccatgtgggt taaaatgaga 1320
aaacaaaagc caaaacggct tcccacaccc aaaagctcct tctgtcagag atcccagtag 1380
ccccgggaga gctgttagaa gtctgagaag gattggtcat catcgcatac catacatagg 1440
tggagggctt gttattctca gtttcccgcc tatgagagga tacccctatt gtttctgaaa 1500
atgctgaccg ggacccacac ttccaacaaa aattcctctg cccctacagc agcagcaaaa 1560
gcagcagcag aagcaacagc aacagataag tgttttgatg aattgcgaga tggatagggc 1620
ttgagtgccc ccagccctgc tgataccaaa tgcctttaag atacagcctt tcccatccta 1680
atctacaaag gaaacaggaa aaaggaactt aaaactccct gtgctcagac agaaatgaga 1740
ctgttacagc ctgcttctgt gctgttcctt cttgcctcta acttgtaaac aagacgtagt 1800
aggacgatgc taatggaaag tcacaaaccg ctgggttttt gaaaggatcc ttgggacctc 1860
atgcacattt gtggaaactg gatggagaga tttggggaag catggactct ttagccagct 1920
tagttctctg tggagtcagc ttgctccttt ctggtaaggt ttggctttat tttttttaat 1980
ttagtatttt aaaaaacaga gttagtgatt tctgggtgct ctccccaaat ctcatcagtg 2040
ctgatgaaca aggggtggct gtagcaaagg caccatttc 2079
<210> 88
<211> 1559
<212> DNA
<213> Homo sapiens
<400> 88
catccatgcc catggcctca gatgccagcc ataagctgtt gggttccaaa cctcgactcc 60
aggctggact cacccctgtc tcccccacca gcctgacacc tccacctggg tatctaacga 120
gcatctcaaa ctcaacctgc ctgagacaga ggaatcacta tcccctcctc ctccaaaaat 180
atccttccat cacactcccc atcttgtgct ctgatttact aaacggccct gggccctctc 240
tttctcaggg tctctgcttg cccagctata taataaaaca agtttgggac ttcccaacca 300
ttcacccatg gaaaaacaga agcaactctt caaaggacag attcccagga tctgccctgg 360
gagattccaa atcagttgat ctggggtgag cccagtcctc tgtagttttt agaagctcct 420
cctatgtctc tcctggtcag cagaatcttg gcccctccct tccccccagc ctcttggttc 480
ttctgggctc tgatccagcc tcagcgtcac tgtcttccac gcccctcttt gattctcgtt 540
tatgtcaaaa gccttgtgag gatgaggctg tgattatccc cattttacag atgaggaaac 600
tgtggctcca ggatgacaca actggccaga ggtcacatca gaagcagagc tgggtcactt 660
gactccaccc aatatcccta aatgcaaaca tcccctacag accgaggctg gcaccttaga 720
gctggagtcc atgcccgctc tgaccaggag aagccaacct ggtcctccag agccaagagc 780
ttctgtccct ttcccatctc ctgaagcctc cctgtcacct ttaaagtcca ttcccacaaa 840
gacatcatgg gatcaccaca gaaaatcaag ctctggggct aggctgaccc cagctagatt 900
tttggctctt ttatacccca gctgggtgga caagcacctt aaacccgctg agcctcagct 960
tcccgggcta taaaatgggg gtgatgacac ctgcctgtag cattccaagg agggttaaat 1020
gtgatgctgc agccaagggt ccccacagcc aggctctttg caggtgctgg gttcagagtc 1080
ccagagctga ggccgggagt aggggttcaa gtggggtgcc ccaggcaggg tccagtgcca 1140
gccctctgtg gagacagcca tccggggccg aggcagccgc ccaccgcagg gcctgcctat 1200
ctgcagccag cccagccctc acaaaggaac aataacagga aaccatccca gggggaagtg 1260
ggccagggcc agctggaaaa cctgaagggg aggcagccag gcctccctcg ccagcggggt 1320
gtggctcccc tccaaagacg gtcggctgac aggctccaca gagctccact cacgctcagc 1380
cctggacgga caggcagtcc aacggaacag aaacatccct cagcccacag gcacggtgag 1440
tgggggctcc cacactcccc tccaccccaa acccgccacc ctgcgcccaa gatgggaggg 1500
tcctcagctt ccccatctgt agaatgggca tcgtcccact cccatgacag agaggctcc 1559
<210> 89
<211> 399
<212> DNA
<213> Homo sapiens
<400> 89
gtctcccagg catgactcca acaatgcatc ccatgggatt tggggttccc cagatctggg 60
gcttgtaggc ctgactctcc cctgtgcaca cgtctcatac acgcatgcgt gcacccattg 120
cctgccccgc cccttgcaca gggagtcagc agggaggact gggttatgcc ctgcttatca 180
gcagcttccc agcttcctct gcctggattc ttagaggcct ggggtcctag aacgagctgg 240
tgcacgtggc ttcccaaaga tctctcagat aatgagagga aatgcagtca tcagtttgca 300
gaaggctagg gattctgggc catagctcag acctgcgccc accatctccc tccaggcagc 360
ccttggctgg tccctgcgag cccgtggaga ctgccagtc 399
<210> 90
<211> 735
<212> DNA
<213> Homo sapiens
<400> 90
atctttagcc gatccattca accctggcca ggatccaaat ggactgtttt tgtcagggcc 60
aggaccggat ccttcatacc tggggtgcat aggaagtgtt agtactcccc ttcctccaaa 120
cacagcagca aaattggctc aggttgaggt gtttttctca acttccctgg agtccagccc 180
tggaagctgg atcaggaagc tgtgttgttc tactgtgatt ccccctggcc tgtatcagct 240
tgccctgaaa caaccagcat tcctggttat cccacacagg tggggcactc taggaagacc 300
agggatcaag tgtgggggtg tagggatagg gggtgtttgg ggagggcaag gcagttaatt 360
aaggcagctg ccaggaggtc tccctccaaa ctctacaaag ctttatcagc ttggaggtac 420
ttctaatacc atttcctttc attgtttcct tttggtaatt aaaaggaggc caatcccctg 480
ttgtggcagc tcacagctat tgtggtggga aagggagggt ggttggtgga tgtcacagct 540
tgggctttat ctcccccagc agtggggact ccacagcccc tgggctacat aacagcaaga 600
cagtccggag ctgtagcaga cctgattgag cctttgcagc agctgagagc atggcctagg 660
gtgggcggca ccattgtcca gcagctgagt ttcccaggga ccttggagat agccgcagcc 720
ctcatttgca gggga 735
<210> 91
<211> 1132
<212> DNA
<213> Homo sapiens
<400> 91
tggcttccgg agggtggcct gggggctggg gtgccaggga caccatcgcc actggtggga 60
gggcagggca cagcccctcc gtgtcccttt gtctctcctg tctgaaggcc agagcaggct 120
gctaggcctg gggccaccac tgcccctggg tgctacaccc agtgtgctgg gtcactggga 180
acttcctgaa gtggtgtcac ctgaactggg cccccaagga tggggtgcgg gcagtaccgc 240
aggaagagga gcagcccctg tgaagattga gaggtctggg aagcccctgc ggcttgggag 300
agtgggggtc gccaggcagg gggaaagccc ctgtgccacc gctttttgcc agagactcag 360
gctccagaga ggcagtgagt ggcatggggg gtgaggctgg ggccctgggc ctgacctcca 420
cacgcctgcc tggcctctct gtttgccatg ggatgagaga gacagtgctg ggactcagag 480
cggggctgga gagtgagagt gcgagaaagg gcctgggtgg ggcttggacc ccggggcggg 540
ctttctggag agccccccta cgagggcctc tacggcggtg acggggtggg gggcttctgc 600
aaaccttggt cagggaagtg gagctggctc gagtggaaga gaccacccgg ctcagtcggg 660
gatgtgggag tggactgggt ggtgcagact gggggtcgag cgccttctga agtgacgggg 720
ccgggacgcg cagggaggcg gcccaagaag cgcgccctag gccagcccag aatgcgctcg 780
gccgcgacta ggacaacggc gggtggggct gggggcggct gccgggcggg gagcggtccc 840
gcgccctcag ctacccctca agagccgttg tttccctaac ttcagctgcc agaggctctg 900
tgattggctg cggcacgatg acccgcgcac ggattggctg cttcgggccg gggggccggg 960
cccgggggac agaatccgcc cccgaacctt caaagagggt accccccggc aggagctggc 1020
agacccagga ggtgcgacag acccgcgggg caaacggact ggggccaaga gccgggagcg 1080
cgggcgcaaa ggcaccaggg cccgcccagg gcgccgcgca gcacggcctt gg 1132
<210> 92
<211> 888
<212> DNA
<213> Homo sapiens
<400> 92
cgccttgctg tgccactttg ggacttccct ccctagcctg agcttcagtt ttcctgcctg 60
ttaggcagcc ccatgtcaac tgcacttagt aggccgggtt tgatgcccga caagacgtga 120
agtggtggag gtgggcagga tcccagcgct accatcttct tgaaccagtg atctcaacac 180
atcggatttc tgtttcctca tctgcaaaat gggatcagtg agctcaggtg ggtcacaaat 240
tctacaggaa ctactttagc caagcccggc cccctgaaag ttcccctcgg tgggctgtta 300
gggtgattgt tttcatctgt ggggctccct gatgcgtccc acccaccagc cttggagagg 360
gtgggatggg agggtggggt gcttggggag acaagcctag agcctgggcc ctcccacccc 420
actgcctccc cccatcccag ggccccccac ccagtgacaa agcccgtggc acttcctcta 480
cccggttggc aggcggcctg gcccagcccc ttctctaagg aagcgcattt cctgcctccc 540
tgggccggcc gggctggatg agccgggagc tccctgctgc cggtcatacc acagccttca 600
tctgcgccct ggggccagga ctgctgctgt cactgccatc cattggagcc cagcaccccc 660
tccccgccca tccttcggac agcaactcca gcccagcccc gcgtccctgt gtccacttct 720
cctgacccct cggccgccac cccagaaggc tggagcaggg acgccgtcgc tccggccgcc 780
tgctcccctc gggtccccgt gcgagcccac gccggccccg gtgcccgccc gcagccctgc 840
cactggacac aggataaggc ccagcgcaca ggcccccacg tggacacc 888
<210> 93
<211> 1658
<212> DNA
<213> Homo sapiens
<400> 93
gcccaggctg gagtgcagtg gcacagtcac aactcactgc agcctcaaac tcctgggctc 60
aaaacgatcc acagtctcct gagtagctgg gactacagga gcttgttacc acacccagct 120
ccagtttata aattcatctc cagtttataa aggaggaaac cgaggtactg agaggttaaa 180
aaaccttcct gcagacactt gtccagcaag tggccactcc aggatttgga ccaaggtgat 240
gtgtcttcag gctgtgtctc tgccactgtg ccacgctgct gggtggtagg cagcagtggg 300
tgggtgcctg cagtggtctg taaagaccac ctgagatgtc cttcctcctc tgttccaccc 360
tgtccaggtc caagaagaca gtctatgaag agagagcagg tgtgactctc tcagtgtgct 420
cctctgtgag aagcaggctg acatcccaaa gggaagggcg gataacagag acagtgcaag 480
cggaggagat gagggtgcct caaagccggg aggctgggtg atgcaggagc ctgcgtgtcc 540
cgaggggggt gctgggccca gtgtgagtac gtgtgactgt gactgagaca gtgtgactgc 600
tgaaggcagg gacacagcag ctccctgact gggggcagaa ggcgttaact gtgtgaaggc 660
tggttgtggg tgggtgggct ctgggcctcg aacccggggg ctgagggaga tagtaaacag 720
cagggtgact gacgggaaga tcatgttggt agccctgcga agatgctgca gggctgtggg 780
ggtttgtgtg actttgcagt tcaacaaatt caaattcagc caacgctggc agggcctgtt 840
gtgccaggca accagctagg aggaggagac tcggacccag cttgcagctg aagggcgctg 900
gctgccgggt tctgtgggtt caccttgcgg tgtcttccct tgctaacact gagtccttac 960
aatagcccca tctccaggtt gaggctagat ggaggggaca gagggaagtg acttgcccaa 1020
ggtgacccaa gctcccgagt gccagggcag gatctgaatt caggctctca gactgcagag 1080
cctgagtccc tccctgccat gcctgtgcca gggtggaaat gtctggtcct ggaggggagc 1140
gtggactcct ggccttggct ctggagacat ccccctagac cacgtgggct cctaacctgt 1200
ccatggtcac tgtgctgagg ggcgggacgg tgggtcaccc ctagttcttt tttccccagg 1260
gccagattca tggactgaag ggttgctcgg ctctcagaga ccccctaagc gccccgccct 1320
ggccccaagc cctcccccag ctcccgcgtc ccccccctcc tggcgctgac tccgggccag 1380
aagaggaaag gctgtctcca cccacctctc gcactctccc ttctccttta taaaggccgg 1440
aacagctgaa agggtggcaa cttctcctcc tgcagccggg agcggcctgc ctgcctccct 1500
gcgcacccgc agcctccccc gctgcctccc tagggctccc ctccggccgc cagcgcccat 1560
ttttcattcc ctagatagag atactttgcg cgcacacaca tacatacgcg cgcaaaaagg 1620
aaaaaaaaaa aaaaaagccc accctccagc ctcgctgc 1658
<210> 94
<211> 1455
<212> DNA
<213> Homo sapiens
<400> 94
acatccaatg cccgctctgc ctcatcttct atgggaaaca agaattttag aggtcaggta 60
gcctaacacc atcaattctc aaaagaggaa gctgaggcca agagaagtcc tgtgaatttc 120
ttacagctca tttgtgacag accaagaatt acccacttta ctgggttgtt atttactaag 180
tgacagtgag tctatatctc ttttgacaag tgaggtgggg gcatggaatt cggcatgtgg 240
ttggtgtaag aactcccctc tctcctcttt aaccttactt aataagaccc tggcacagtt 300
gatattttaa gagggctact ctgttttccc agagggacct aggcacggta accctcttag 360
catgcagacc ttgtttcctg aggggtaatg tttcccttcc ctgtgacttg tttcttgggg 420
gctgtgttct gattttcctg ctgagccact tgttgccttg ggctggctgc cgcgcttggc 480
agtttttagt gagggctctg atagatgcca ggaggtgagg ggaagggctc tgggtggact 540
ccgtcattgg acaagcagac ttagtgatgg atgagccttc ccctgaggaa gttttggatc 600
agaagtccaa ctgataagtt tttccagaat tgagtaaccc agaagcagtg ccgaaaggat 660
cttacctctc ttgtggcttt ttgtattgat tttaaaagaa attctcagag gcagttccac 720
attgtactgg aagcacagct atatccacaa taggcttaga tatatgtaac atgaattgct 780
ttagaaataa catttgagga gaggggtgag aggaaggaag agagggtctt aaaaaatagc 840
cctatcaaaa tattttcttt cttctaagta ttgaaaagac acaatataac cctttcttct 900
ttcaaatgat ctcatagcta tttgttgagg ggaaatacca aatgtttatt attttttttg 960
aagaagcttc ttcggtcctg atgattcatg ttgatatcat tttcctcctg actacagagg 1020
ctctgagaca aagctacacc tcaagtgata tgccagggtc agaacaattc ccgtcctgaa 1080
ggagggtgtg caaccttctt tatccctcct tcacagacgt ccttgagccc ttgagacgga 1140
tgtgagtgag tttttcagtc ctcatgcaaa acaaccatct aaacataaca gatgacatca 1200
gcttgggctt ttcaattcct ggatggcagc agcgtgttaa tccagccttc atcctggatt 1260
tcataaacca aaacaagaga gcctggcagg aggacagcgc tgctgctggg ttgaggaaat 1320
tgatgacggg aaagcatgcg ggcaacccag tgtataaaac tcataaacgt gtaggcagag 1380
gctcagctac cagtttggac ggctgcttcc caccagcaaa gaccacgact ggagagccga 1440
gccggaggca gctgg 1455
<210> 95
<211> 1389
<212> DNA
<213> Homo sapiens
<400> 95
tggcacacac gcaccctgtc caatgtatct tttgtgtaaa tctggactta acacttcaag 60
caaactgcct ggcttgctga aaggtggaga cacctttcga ttcagtcttt taatatgtgt 120
tgagtgccac ctatgtgcag agcaagatat tggggacttt ggagagatcc agaagagtga 180
gaagacagta tcctacctta gggggttccc agtccaatga gggaagcagc cccatgcctt 240
gggagctccc aagctataga agcagctaac aatcgagtct ggaaaggcaa acaacttcag 300
gacccgcttc taaagcggaa tcgcaagtac acgcaaaatg aatccagcct tgactgtgtg 360
gagttgggta aaccacctgc ctcttacgtt gatggggaac tagaatgagg acagctccag 420
ggaacaagaa agggtagacc ataggagctg tcccatgtcc caacagtggg gaggagctga 480
tgggcggccc ctgctggatt agtgttatcc tgagaaggct tctggatgcg atgggatttg 540
aggtgctgct gcaaagaatg aattgctcac ggaagggtgg ggtgggggca ttccaggtag 600
agggtgcctc ctgggggatg cagggaacat gaggggcctg ggcaattaat caagccttgg 660
gcacaagcct aggcagtcac ccccaattca aagccagttg aaaatgcaga ggagagagga 720
gggccagtgt ttggttgtct tgaccaaacc cttgaagctg gccagcggca agggcaagga 780
ccagggtcag aggtagaggg cgtgagtgaa ggcaacccag actgagtcct tccctaagcg 840
cccaggtttc ctgacagctg ttaaggaagc aaggtgagaa agggttaagt gtgcccctcc 900
accgccccaa atgcttcctg tgtttgaaat ccttcaggtc tctgcaaacc ctctggcccc 960
cggccaggcg ggcattgtcc ggggagcggt tgtaggttgt cagagaggcc gcgcagcctt 1020
tgttgtgggg ccacctcggg gttccctctc gcgctcacgc tcgggctggg gctgcagagt 1080
gcgtgcctgg aggggggcgg tgcgggaggc tcgctccctc tccctcttcc tgccccccct 1140
ctagccctcc cgatgaccac atgaccaagt gggctcgcgg ccaagccaca agctacaaaa 1200
tgcagcccct ggagtgagcg gggagcattc tctctggcag ccggggtcac gggcagttgc 1260
agccgcggcc gagcagccag ccgctaagaa agagctcgcc gctgccgctc ccggagccgc 1320
cgaggccagc ttcgcggcgc tgccccgcgg cgggagagga ggctgcagaa gagcggaggc 1380
ggccagcgg 1389
<210> 96
<211> 4258
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in Lab - full polynucleotide sequence of vector genome
<400> 96
gcgcgctcgc tcgctcactg aggccgcccg ggcaaagccc gggcgtcggg cgacctttgg 60
tcgcccggcc tcagtgagcg agcgagcgcg cagagaggga gtggccaact ccatcactag 120
gggttccttg tagttaatga ttaacccgcc atgctactta tctacgtact ctggagacgc 180
gttacataag ctcctcccag cctcaggccc aggaatggga atctctgtgg gtcacacatc 240
agtagggagg tctttcccga tccttttcta tgctactcca ggagtcaaag cgtctcctgg 300
gacttttcag ggcgcttcag aagagccctg ggcctaaacc agctcaacca agctgcaggg 360
acccagcctc ctgagaaaag tgaatgtgag cccggtgcat tcagaggaga atgaagcctt 420
cacccagaac acactctggg aagatgtccc aggcccaggg ggagggtttg tactaccaga 480
cctaagtcac ctaaactgac accaagtctc atccatccca accattccat tccgggtcag 540
aggggtcatc gatttaacca gcaaggctgc ccatccaacg gttgctccct ctgctccctg 600
gaagggcctc ctcgtgggcg ttctgtacct acaggtcttg ttccgttctg ggaactgcca 660
gtggtggcaa gaggtggagc aacgggtgcc agggcaggga gaggtgagtc tgggagggaa 720
gcagaggcaa gatccatggg gctttagaga ctttgccaaa gcagtgcgac tgctcccagg 780
ttgttgtcag ccgtcaagag tgagtgcacc tccctgggca gacttctgct gccccagtgc 840
ccaggaatag gcaggggttt gccgcaaaat gaatgacacc tggcagacaa taagctgaag 900
ctttcattag cagcttaagc tgaggactat ctatgcaacc gatactccct gtgtgctccc 960
cgggactgct taatgtgagc ccttgtggag cgattggcac caagaaagca aggactaagt 1020
cagaagttca agtcccagcc ttgccacagc ctcagggtgc cctcgagcac agcaagcctc 1080
agttttccca tctgtacaat gagagaggta cacaaggtag actcgaaggc tctttgttgc 1140
cagggccctg tgttcctttg agtgtatgtg cttctcaggc ccacagaggt cctttgtgtt 1200
tcgtatgtga actgctctct aggaaaccca tgtaactgtc tgtgtcctgg ggcacataca 1260
tgaggactca tgtgggccgt attgtgtgtt tgtgccgggg ggaggggaga ccccagaaca 1320
atgtccccca ccccaccccc ctcctcaata ggcggaagcc actggcttcc tccctttcct 1380
gcctcctgcc tcctttgtgc cagcaagact gagtactgga gagagacagg ggatgggaaa 1440
aatcagtcca gctgtcccca ggtctgccct taccataacc ttccccccac ctcaagtgac 1500
tcctcccagg ccacacccat ccccagcctt gtgggggcca gattgggggg cctagaggct 1560
caaaggcaga atgagtcctc ccacccccta ccctgccacc cctcccaccc aagccacctc 1620
atttcctctt cctccccagc accgacccac actgaccaac acaggctgag cagtcaggcc 1680
cacagcatct gaccccaggc ccagctcgtc ctggctggcc tgggtcggcc tctggagtgc 1740
caccatggag cccagcagca agaagctgac gggtcgcctc atgctggccg tgggaggagc 1800
agtgcttggc tccctgcagt ttggctacaa cactggagtc atcaatgccc cccagaaggt 1860
gatcgaggag ttctacaacc agacatgggt ccaccgctat ggggagagca tcctgcccac 1920
cacgctcacc acgctctggt ccctctcagt ggccatcttt tctgttgggg gcatgattgg 1980
ctccttctct gtgggccttt tcgttaaccg ctttggccgg cggaattcaa tgctgatgat 2040
gaacctgctg gccttcgtgt ccgccgtgct catgggcttc tcgaaactgg gcaagtcctt 2100
tgagatgctg atcctgggcc gcttcatcat cggtgtgtac tgcggcctga ccacaggctt 2160
cgtgcccatg tatgtgggtg aagtgtcacc cacagccctt cgtggggccc tgggcaccct 2220
gcaccagctg ggcatcgtcg tcggcatcct catcgcccag gtgttcggcc tggactccat 2280
catgggcaac aaggacctgt ggcccctgct gctgagcatc atcttcatcc cggccctgct 2340
gcagtgcatc gtgctgccct tctgccccga gagtccccgc ttcctgctca tcaaccgcaa 2400
cgaggagaac cgggccaaga gtgtgctaaa gaagctgcgc gggacagctg acgtgaccca 2460
tgacctgcag gagatgaagg aagagagtcg gcagatgatg cgggagaaga aggtcaccat 2520
cctggagctg ttccgctccc ccgcctaccg ccagcccatc ctcatcgctg tggtgctgca 2580
gctgtcccag cagctgtctg gcatcaacgc tgtcttctat tactccacga gcatcttcga 2640
gaaggcgggg gtgcagcagc ctgtgtatgc caccattggc tccggtatcg tcaacacggc 2700
cttcactgtc gtgtcgctgt ttgtggtgga gcgagcaggc cggcggaccc tgcacctcat 2760
aggcctcgct ggcatggcgg gttgtgccat actcatgacc atcgcgctag cactgctgga 2820
gcagctaccc tggatgtcct atctgagcat cgtggccatc tttggctttg tggccttctt 2880
tgaagtgggt cctggcccca tcccatggtt catcgtggct gaactcttca gccagggtcc 2940
acgtccagct gccattgccg ttgcaggctt ctccaactgg acctcaaatt tcattgtggg 3000
catgtgcttc cagtatgtgg agcaactgtg tggtccctac gtcttcatca tcttcactgt 3060
gctcctggtt ctgttcttca tcttcaccta cttcaaagtt cctgagacta aaggccggac 3120
cttcgatgag atcgcttccg gcttccggca ggggggagcc agccaaagtg acaagacacc 3180
cgaggagctg ttccatcccc tgggggctga ttcccaagtg tgataatgga tcaacctctg 3240
gattacaaaa tttgtgaaag attgactggt attcttaact atgttgctcc ttttacgcta 3300
tgtggatacg ctgctttaat gcctttgtat catgctattg cttcccgtat ggctttcatt 3360
ttctcctcct tgtataaatc ctggttgctg tctctttatg aggagttgtg gcccgttgtc 3420
aggcaacgtg gcgtggtgtg cactgtgttt gctgacgcaa cccccactgg ttggggcatt 3480
gccaccacct gtcagctcct ttccgggact ttcgctttcc ccctccctat tgccacggcg 3540
gaactcatcg ccgcctgcct tgcccgctgc tggacagggg ctcggctgtt gggcactgac 3600
aattccgtgg tgttgtcggg gaaatcatcg tcctttcctt ggctgctcgc ctgtgttgcc 3660
acctggattc tgcgcgggac gtccttctgc tacgtccctt cggccctcaa tccagcggac 3720
cttccttccc gcggcctgct gccggctctg cggcctcttc cgcgtcttcg ccttcgccct 3780
cagacgagtc ggatctccct ttgggccgcc tccccgcatc attgcctgcc cgggtggcat 3840
ccctgtgacc cctccccagt gcctctcctg gccctggaag ttgccactcc agtgcccacc 3900
agccttgtcc taataaaatt aagttgcatc attttgtctg actaggtgtc cttctataat 3960
attatggggt ggaggggggt ggtatggagc aaggggccca agttgggaag aaacctgtag 4020
ggcctgcgtt acccaggctg gagtgcagtg gcacatttct gctcactgca acctcctcct 4080
ccctgggttc tacgtagata agtagcatgg cgggttaatc attaactaca aggaacccct 4140
agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc 4200
aaaggtcgcc cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc gagcgcgc 4258
<210> 97
<211> 3922
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in Lab - part of expression cassette
<400> 97
ctctggagac gcgttacata agctcctccc agcctcaggc ccaggaatgg gaatctctgt 60
gggtcacaca tcagtaggga ggtctttccc gatccttttc tatgctactc caggagtcaa 120
agcgtctcct gggacttttc agggcgcttc agaagagccc tgggcctaaa ccagctcaac 180
caagctgcag ggacccagcc tcctgagaaa agtgaatgtg agcccggtgc attcagagga 240
gaatgaagcc ttcacccaga acacactctg ggaagatgtc ccaggcccag ggggagggtt 300
tgtactacca gacctaagtc acctaaactg acaccaagtc tcatccatcc caaccattcc 360
attccgggtc agaggggtca tcgatttaac cagcaaggct gcccatccaa cggttgctcc 420
ctctgctccc tggaagggcc tcctcgtggg cgttctgtac ctacaggtct tgttccgttc 480
tgggaactgc cagtggtggc aagaggtgga gcaacgggtg ccagggcagg gagaggtgag 540
tctgggaggg aagcagaggc aagatccatg gggctttaga gactttgcca aagcagtgcg 600
actgctccca ggttgttgtc agccgtcaag agtgagtgca cctccctggg cagacttctg 660
ctgccccagt gcccaggaat aggcaggggt ttgccgcaaa atgaatgaca cctggcagac 720
aataagctga agctttcatt agcagcttaa gctgaggact atctatgcaa ccgatactcc 780
ctgtgtgctc cccgggactg cttaatgtga gcccttgtgg agcgattggc accaagaaag 840
caaggactaa gtcagaagtt caagtcccag ccttgccaca gcctcagggt gccctcgagc 900
acagcaagcc tcagttttcc catctgtaca atgagagagg tacacaaggt agactcgaag 960
gctctttgtt gccagggccc tgtgttcctt tgagtgtatg tgcttctcag gcccacagag 1020
gtcctttgtg tttcgtatgt gaactgctct ctaggaaacc catgtaactg tctgtgtcct 1080
ggggcacata catgaggact catgtgggcc gtattgtgtg tttgtgccgg ggggagggga 1140
gaccccagaa caatgtcccc caccccaccc ccctcctcaa taggcggaag ccactggctt 1200
cctccctttc ctgcctcctg cctcctttgt gccagcaaga ctgagtactg gagagagaca 1260
ggggatggga aaaatcagtc cagctgtccc caggtctgcc cttaccataa ccttcccccc 1320
acctcaagtg actcctccca ggccacaccc atccccagcc ttgtgggggc cagattgggg 1380
ggcctagagg ctcaaaggca gaatgagtcc tcccaccccc taccctgcca cccctcccac 1440
ccaagccacc tcatttcctc ttcctcccca gcaccgaccc acactgacca acacaggctg 1500
agcagtcagg cccacagcat ctgaccccag gcccagctcg tcctggctgg cctgggtcgg 1560
cctctggagt gccaccatgg agcccagcag caagaagctg acgggtcgcc tcatgctggc 1620
cgtgggagga gcagtgcttg gctccctgca gtttggctac aacactggag tcatcaatgc 1680
cccccagaag gtgatcgagg agttctacaa ccagacatgg gtccaccgct atggggagag 1740
catcctgccc accacgctca ccacgctctg gtccctctca gtggccatct tttctgttgg 1800
gggcatgatt ggctccttct ctgtgggcct tttcgttaac cgctttggcc ggcggaattc 1860
aatgctgatg atgaacctgc tggccttcgt gtccgccgtg ctcatgggct tctcgaaact 1920
gggcaagtcc tttgagatgc tgatcctggg ccgcttcatc atcggtgtgt actgcggcct 1980
gaccacaggc ttcgtgccca tgtatgtggg tgaagtgtca cccacagccc ttcgtggggc 2040
cctgggcacc ctgcaccagc tgggcatcgt cgtcggcatc ctcatcgccc aggtgttcgg 2100
cctggactcc atcatgggca acaaggacct gtggcccctg ctgctgagca tcatcttcat 2160
cccggccctg ctgcagtgca tcgtgctgcc cttctgcccc gagagtcccc gcttcctgct 2220
catcaaccgc aacgaggaga accgggccaa gagtgtgcta aagaagctgc gcgggacagc 2280
tgacgtgacc catgacctgc aggagatgaa ggaagagagt cggcagatga tgcgggagaa 2340
gaaggtcacc atcctggagc tgttccgctc ccccgcctac cgccagccca tcctcatcgc 2400
tgtggtgctg cagctgtccc agcagctgtc tggcatcaac gctgtcttct attactccac 2460
gagcatcttc gagaaggcgg gggtgcagca gcctgtgtat gccaccattg gctccggtat 2520
cgtcaacacg gccttcactg tcgtgtcgct gtttgtggtg gagcgagcag gccggcggac 2580
cctgcacctc ataggcctcg ctggcatggc gggttgtgcc atactcatga ccatcgcgct 2640
agcactgctg gagcagctac cctggatgtc ctatctgagc atcgtggcca tctttggctt 2700
tgtggccttc tttgaagtgg gtcctggccc catcccatgg ttcatcgtgg ctgaactctt 2760
cagccagggt ccacgtccag ctgccattgc cgttgcaggc ttctccaact ggacctcaaa 2820
tttcattgtg ggcatgtgct tccagtatgt ggagcaactg tgtggtccct acgtcttcat 2880
catcttcact gtgctcctgg ttctgttctt catcttcacc tacttcaaag ttcctgagac 2940
taaaggccgg accttcgatg agatcgcttc cggcttccgg caggggggag ccagccaaag 3000
tgacaagaca cccgaggagc tgttccatcc cctgggggct gattcccaag tgtgataatg 3060
gatcaacctc tggattacaa aatttgtgaa agattgactg gtattcttaa ctatgttgct 3120
ccttttacgc tatgtggata cgctgcttta atgcctttgt atcatgctat tgcttcccgt 3180
atggctttca ttttctcctc cttgtataaa tcctggttgc tgtctcttta tgaggagttg 3240
tggcccgttg tcaggcaacg tggcgtggtg tgcactgtgt ttgctgacgc aacccccact 3300
ggttggggca ttgccaccac ctgtcagctc ctttccggga ctttcgcttt ccccctccct 3360
attgccacgg cggaactcat cgccgcctgc cttgcccgct gctggacagg ggctcggctg 3420
ttgggcactg acaattccgt ggtgttgtcg gggaaatcat cgtcctttcc ttggctgctc 3480
gcctgtgttg ccacctggat tctgcgcggg acgtccttct gctacgtccc ttcggccctc 3540
aatccagcgg accttccttc ccgcggcctg ctgccggctc tgcggcctct tccgcgtctt 3600
cgccttcgcc ctcagacgag tcggatctcc ctttgggccg cctccccgca tcattgcctg 3660
cccgggtggc atccctgtga cccctcccca gtgcctctcc tggccctgga agttgccact 3720
ccagtgccca ccagccttgt cctaataaaa ttaagttgca tcattttgtc tgactaggtg 3780
tccttctata atattatggg gtggaggggg gtggtatgga gcaaggggcc caagttggga 3840
agaaacctgt agggcctgcg ttacccaggc tggagtgcag tggcacattt ctgctcactg 3900
caacctcctc ctccctgggt tc 3922
<210> 98
<211> 3850
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in Lab - full polynucleotide sequence of vector genome
<400> 98
gcgcgctcgc tcgctcactg aggccgcccg ggcaaagccc gggcgtcggg cgacctttgg 60
tcgcccggcc tcagtgagcg agcgagcgcg cagagaggga gtggccaact ccatcactag 120
gggttccttg tagttaatga ttaacccgcc atgctactta tctacgtact ctggagacgc 180
gttacataaa gcttccgacc gttagtcaga gaactgtaag tgctcagagc ctggctgaca 240
atgatctgga atgaaccaga taacaacata ataaaatctc agtaaaataa tttaacagtt 300
agcttggaag ctggtcagct ctggggaaat cagggtaaat tgtgctgtca tgaactgtcc 360
cacactgaca tcggccaaag tgaatatgaa ctttggtaga tccaatgcct gttctattta 420
tttttccagt gaaaagtatt ttgatagagc ttttcatttt gtaaatacac tgagttaacc 480
aaaatatcat ggatttccgt ttgttcttaa gacatgcaac tcgtctacgg ctataccact 540
ctgaacgcgc ccgatctcgg aagacatgca actcaaatgt aaatacagta gaatattact 600
taggtagaaa ctcctggtga ttttaaaaga ttggaaaaga atatgaggaa gagttgaata 660
atgcaaattc tagtgtgtgt gctaccgaag tgaacactta atgcacagtc tacagactag 720
gacattttat cgtgtgttgt aaaattgggt agaaacttgt gtttgtgaaa actgagcatt 780
aaaaccttac agagaccgtt tcttgtttac ttttgaaaaa aaaaagagtc acgtgagcct 840
cattttgtat ttgtgtgtgt gtgtgtgtgt gtgtctcccc tcctcccagc gtgtgtgtgc 900
tgggaggagg ggagacccca gaacaatgtc ctgcctccaa accttctcaa taggcggaag 960
ccactggctt cctccctttc ctgtctcccg tgctccagca atgcagatgg aagggaccga 1020
agggatggga gagagagccc aaccatcccc agatctgtcc ttgtcacaac ctgcctccca 1080
cctctaatgc ccccccttcc agagacttcc aggccacacc catcccgggc ttgtgggggc 1140
tggacacggg aggactacag gcgacaactc ttcccaccct ctctccctgc cacccctcct 1200
accctaacca tcatttcctc ttcctcccca gcaccgaggt gcactgagct ggacaggctg 1260
aacactcaga cccacagcaa ctgaccccgg gcccagctgg ccttggctgg cccagggcag 1320
cttccagagt gccaccatgg agcccagcag caagaagctg acgggtcgcc tcatgctggc 1380
cgtgggagga gcagtgcttg gctccctgca gtttggctac aacactggag tcatcaatgc 1440
cccccagaag gtgatcgagg agttctacaa ccagacatgg gtccaccgct atggggagag 1500
catcctgccc accacgctca ccacgctctg gtccctctca gtggccatct tttctgttgg 1560
gggcatgatt ggctccttct ctgtgggcct tttcgttaac cgctttggcc ggcggaattc 1620
aatgctgatg atgaacctgc tggccttcgt gtccgccgtg ctcatgggct tctcgaaact 1680
gggcaagtcc tttgagatgc tgatcctggg ccgcttcatc atcggtgtgt actgcggcct 1740
gaccacaggc ttcgtgccca tgtatgtggg tgaagtgtca cccacagccc ttcgtggggc 1800
cctgggcacc ctgcaccagc tgggcatcgt cgtcggcatc ctcatcgccc aggtgttcgg 1860
cctggactcc atcatgggca acaaggacct gtggcccctg ctgctgagca tcatcttcat 1920
cccggccctg ctgcagtgca tcgtgctgcc cttctgcccc gagagtcccc gcttcctgct 1980
catcaaccgc aacgaggaga accgggccaa gagtgtgcta aagaagctgc gcgggacagc 2040
tgacgtgacc catgacctgc aggagatgaa ggaagagagt cggcagatga tgcgggagaa 2100
gaaggtcacc atcctggagc tgttccgctc ccccgcctac cgccagccca tcctcatcgc 2160
tgtggtgctg cagctgtccc agcagctgtc tggcatcaac gctgtcttct attactccac 2220
gagcatcttc gagaaggcgg gggtgcagca gcctgtgtat gccaccattg gctccggtat 2280
cgtcaacacg gccttcactg tcgtgtcgct gtttgtggtg gagcgagcag gccggcggac 2340
cctgcacctc ataggcctcg ctggcatggc gggttgtgcc atactcatga ccatcgcgct 2400
agcactgctg gagcagctac cctggatgtc ctatctgagc atcgtggcca tctttggctt 2460
tgtggccttc tttgaagtgg gtcctggccc catcccatgg ttcatcgtgg ctgaactctt 2520
cagccagggt ccacgtccag ctgccattgc cgttgcaggc ttctccaact ggacctcaaa 2580
tttcattgtg ggcatgtgct tccagtatgt ggagcaactg tgtggtccct acgtcttcat 2640
catcttcact gtgctcctgg ttctgttctt catcttcacc tacttcaaag ttcctgagac 2700
taaaggccgg accttcgatg agatcgcttc cggcttccgg caggggggag ccagccaaag 2760
tgacaagaca cccgaggagc tgttccatcc cctgggggct gattcccaag tgtgataatg 2820
gatcaacctc tggattacaa aatttgtgaa agattgactg gtattcttaa ctatgttgct 2880
ccttttacgc tatgtggata cgctgcttta atgcctttgt atcatgctat tgcttcccgt 2940
atggctttca ttttctcctc cttgtataaa tcctggttgc tgtctcttta tgaggagttg 3000
tggcccgttg tcaggcaacg tggcgtggtg tgcactgtgt ttgctgacgc aacccccact 3060
ggttggggca ttgccaccac ctgtcagctc ctttccggga ctttcgcttt ccccctccct 3120
attgccacgg cggaactcat cgccgcctgc cttgcccgct gctggacagg ggctcggctg 3180
ttgggcactg acaattccgt ggtgttgtcg gggaaatcat cgtcctttcc ttggctgctc 3240
gcctgtgttg ccacctggat tctgcgcggg acgtccttct gctacgtccc ttcggccctc 3300
aatccagcgg accttccttc ccgcggcctg ctgccggctc tgcggcctct tccgcgtctt 3360
cgccttcgcc ctcagacgag tcggatctcc ctttgggccg cctccccgca tcattgcctg 3420
cccgggtggc atccctgtga cccctcccca gtgcctctcc tggccctgga agttgccact 3480
ccagtgccca ccagccttgt cctaataaaa ttaagttgca tcattttgtc tgactaggtg 3540
tccttctata atattatggg gtggaggggg gtggtatgga gcaaggggcc caagttggga 3600
agaaacctgt agggcctgcg ttacccaggc tggagtgcag tggcacattt ctgctcactg 3660
caacctcctc ctccctgggt tctacgtaga taagtagcat ggcgggttaa tcattaacta 3720
caaggaaccc ctagtgatgg agttggccac tccctctctg cgcgctcgct cgctcactga 3780
ggccgggcga ccaaaggtcg cccgacgccc gggctttgcc cgggcggcct cagtgagcga 3840
gcgagcgcgc 3850
<210> 99
<211> 3514
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in Lab - part of expression cassette
<400> 99
ctctggagac gcgttacata aagcttccga ccgttagtca gagaactgta agtgctcaga 60
gcctggctga caatgatctg gaatgaacca gataacaaca taataaaatc tcagtaaaat 120
aatttaacag ttagcttgga agctggtcag ctctggggaa atcagggtaa attgtgctgt 180
catgaactgt cccacactga catcggccaa agtgaatatg aactttggta gatccaatgc 240
ctgttctatt tatttttcca gtgaaaagta ttttgataga gcttttcatt ttgtaaatac 300
actgagttaa ccaaaatatc atggatttcc gtttgttctt aagacatgca actcgtctac 360
ggctatacca ctctgaacgc gcccgatctc ggaagacatg caactcaaat gtaaatacag 420
tagaatatta cttaggtaga aactcctggt gattttaaaa gattggaaaa gaatatgagg 480
aagagttgaa taatgcaaat tctagtgtgt gtgctaccga agtgaacact taatgcacag 540
tctacagact aggacatttt atcgtgtgtt gtaaaattgg gtagaaactt gtgtttgtga 600
aaactgagca ttaaaacctt acagagaccg tttcttgttt acttttgaaa aaaaaaagag 660
tcacgtgagc ctcattttgt atttgtgtgt gtgtgtgtgt gtgtgtctcc cctcctccca 720
gcgtgtgtgt gctgggagga ggggagaccc cagaacaatg tcctgcctcc aaaccttctc 780
aataggcgga agccactggc ttcctccctt tcctgtctcc cgtgctccag caatgcagat 840
ggaagggacc gaagggatgg gagagagagc ccaaccatcc ccagatctgt ccttgtcaca 900
acctgcctcc cacctctaat gccccccctt ccagagactt ccaggccaca cccatcccgg 960
gcttgtgggg gctggacacg ggaggactac aggcgacaac tcttcccacc ctctctccct 1020
gccacccctc ctaccctaac catcatttcc tcttcctccc cagcaccgag gtgcactgag 1080
ctggacaggc tgaacactca gacccacagc aactgacccc gggcccagct ggccttggct 1140
ggcccagggc agcttccaga gtgccaccat ggagcccagc agcaagaagc tgacgggtcg 1200
cctcatgctg gccgtgggag gagcagtgct tggctccctg cagtttggct acaacactgg 1260
agtcatcaat gccccccaga aggtgatcga ggagttctac aaccagacat gggtccaccg 1320
ctatggggag agcatcctgc ccaccacgct caccacgctc tggtccctct cagtggccat 1380
cttttctgtt gggggcatga ttggctcctt ctctgtgggc cttttcgtta accgctttgg 1440
ccggcggaat tcaatgctga tgatgaacct gctggccttc gtgtccgccg tgctcatggg 1500
cttctcgaaa ctgggcaagt cctttgagat gctgatcctg ggccgcttca tcatcggtgt 1560
gtactgcggc ctgaccacag gcttcgtgcc catgtatgtg ggtgaagtgt cacccacagc 1620
ccttcgtggg gccctgggca ccctgcacca gctgggcatc gtcgtcggca tcctcatcgc 1680
ccaggtgttc ggcctggact ccatcatggg caacaaggac ctgtggcccc tgctgctgag 1740
catcatcttc atcccggccc tgctgcagtg catcgtgctg cccttctgcc ccgagagtcc 1800
ccgcttcctg ctcatcaacc gcaacgagga gaaccgggcc aagagtgtgc taaagaagct 1860
gcgcgggaca gctgacgtga cccatgacct gcaggagatg aaggaagaga gtcggcagat 1920
gatgcgggag aagaaggtca ccatcctgga gctgttccgc tcccccgcct accgccagcc 1980
catcctcatc gctgtggtgc tgcagctgtc ccagcagctg tctggcatca acgctgtctt 2040
ctattactcc acgagcatct tcgagaaggc gggggtgcag cagcctgtgt atgccaccat 2100
tggctccggt atcgtcaaca cggccttcac tgtcgtgtcg ctgtttgtgg tggagcgagc 2160
aggccggcgg accctgcacc tcataggcct cgctggcatg gcgggttgtg ccatactcat 2220
gaccatcgcg ctagcactgc tggagcagct accctggatg tcctatctga gcatcgtggc 2280
catctttggc tttgtggcct tctttgaagt gggtcctggc cccatcccat ggttcatcgt 2340
ggctgaactc ttcagccagg gtccacgtcc agctgccatt gccgttgcag gcttctccaa 2400
ctggacctca aatttcattg tgggcatgtg cttccagtat gtggagcaac tgtgtggtcc 2460
ctacgtcttc atcatcttca ctgtgctcct ggttctgttc ttcatcttca cctacttcaa 2520
agttcctgag actaaaggcc ggaccttcga tgagatcgct tccggcttcc ggcagggggg 2580
agccagccaa agtgacaaga cacccgagga gctgttccat cccctggggg ctgattccca 2640
agtgtgataa tggatcaacc tctggattac aaaatttgtg aaagattgac tggtattctt 2700
aactatgttg ctccttttac gctatgtgga tacgctgctt taatgccttt gtatcatgct 2760
attgcttccc gtatggcttt cattttctcc tccttgtata aatcctggtt gctgtctctt 2820
tatgaggagt tgtggcccgt tgtcaggcaa cgtggcgtgg tgtgcactgt gtttgctgac 2880
gcaaccccca ctggttgggg cattgccacc acctgtcagc tcctttccgg gactttcgct 2940
ttccccctcc ctattgccac ggcggaactc atcgccgcct gccttgcccg ctgctggaca 3000
ggggctcggc tgttgggcac tgacaattcc gtggtgttgt cggggaaatc atcgtccttt 3060
ccttggctgc tcgcctgtgt tgccacctgg attctgcgcg ggacgtcctt ctgctacgtc 3120
ccttcggccc tcaatccagc ggaccttcct tcccgcggcc tgctgccggc tctgcggcct 3180
cttccgcgtc ttcgccttcg ccctcagacg agtcggatct ccctttgggc cgcctccccg 3240
catcattgcc tgcccgggtg gcatccctgt gacccctccc cagtgcctct cctggccctg 3300
gaagttgcca ctccagtgcc caccagcctt gtcctaataa aattaagttg catcattttg 3360
tctgactagg tgtccttcta taatattatg gggtggaggg gggtggtatg gagcaagggg 3420
cccaagttgg gaagaaacct gtagggcctg cgttacccag gctggagtgc agtggcacat 3480
ttctgctcac tgcaacctcc tcctccctgg gttc 3514
<210> 100
<211> 3010
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in Lab - full polynucleotide sequence of vector genome
<400> 100
gcgcgctcgc tcgctcactg aggccgcccg ggcaaagccc gggcgtcggg cgacctttgg 60
tcgcccggcc tcagtgagcg agcgagcgcg cagagaggga gtggccaact ccatcactag 120
gggttccttg tagttaatga ttaacccgcc atgctactta tctacgtact ctggagacgc 180
gttacataac cattttgcta gagaaggccg cggaggctca gagaggtgcg cacacttgcc 240
ctgagtcaca cagcgaatgc cctccgcggt cccaacgcag agagaacgag ccgatcggca 300
gcctgagcga ggcagtggtt agggggggcc ccggccccgg ccactcccct caccccctcc 360
ccgcagagcg ccgcccagga caggctgggc cccaggcccc gccccgaggt cctgcccaca 420
cacccctgac acaccggcgt cgccagccaa tggccggggt cctataaacg ctacggtccg 480
cgcgctctct gccaccatgg agcccagcag caagaagctg acgggtcgcc tcatgctggc 540
cgtgggagga gcagtgcttg gctccctgca gtttggctac aacactggag tcatcaatgc 600
cccccagaag gtgatcgagg agttctacaa ccagacatgg gtccaccgct atggggagag 660
catcctgccc accacgctca ccacgctctg gtccctctca gtggccatct tttctgttgg 720
gggcatgatt ggctccttct ctgtgggcct tttcgttaac cgctttggcc ggcggaattc 780
aatgctgatg atgaacctgc tggccttcgt gtccgccgtg ctcatgggct tctcgaaact 840
gggcaagtcc tttgagatgc tgatcctggg ccgcttcatc atcggtgtgt actgcggcct 900
gaccacaggc ttcgtgccca tgtatgtggg tgaagtgtca cccacagccc ttcgtggggc 960
cctgggcacc ctgcaccagc tgggcatcgt cgtcggcatc ctcatcgccc aggtgttcgg 1020
cctggactcc atcatgggca acaaggacct gtggcccctg ctgctgagca tcatcttcat 1080
cccggccctg ctgcagtgca tcgtgctgcc cttctgcccc gagagtcccc gcttcctgct 1140
catcaaccgc aacgaggaga accgggccaa gagtgtgcta aagaagctgc gcgggacagc 1200
tgacgtgacc catgacctgc aggagatgaa ggaagagagt cggcagatga tgcgggagaa 1260
gaaggtcacc atcctggagc tgttccgctc ccccgcctac cgccagccca tcctcatcgc 1320
tgtggtgctg cagctgtccc agcagctgtc tggcatcaac gctgtcttct attactccac 1380
gagcatcttc gagaaggcgg gggtgcagca gcctgtgtat gccaccattg gctccggtat 1440
cgtcaacacg gccttcactg tcgtgtcgct gtttgtggtg gagcgagcag gccggcggac 1500
cctgcacctc ataggcctcg ctggcatggc gggttgtgcc atactcatga ccatcgcgct 1560
agcactgctg gagcagctac cctggatgtc ctatctgagc atcgtggcca tctttggctt 1620
tgtggccttc tttgaagtgg gtcctggccc catcccatgg ttcatcgtgg ctgaactctt 1680
cagccagggt ccacgtccag ctgccattgc cgttgcaggc ttctccaact ggacctcaaa 1740
tttcattgtg ggcatgtgct tccagtatgt ggagcaactg tgtggtccct acgtcttcat 1800
catcttcact gtgctcctgg ttctgttctt catcttcacc tacttcaaag ttcctgagac 1860
taaaggccgg accttcgatg agatcgcttc cggcttccgg caggggggag ccagccaaag 1920
tgacaagaca cccgaggagc tgttccatcc cctgggggct gattcccaag tgtgataatg 1980
gatcaacctc tggattacaa aatttgtgaa agattgactg gtattcttaa ctatgttgct 2040
ccttttacgc tatgtggata cgctgcttta atgcctttgt atcatgctat tgcttcccgt 2100
atggctttca ttttctcctc cttgtataaa tcctggttgc tgtctcttta tgaggagttg 2160
tggcccgttg tcaggcaacg tggcgtggtg tgcactgtgt ttgctgacgc aacccccact 2220
ggttggggca ttgccaccac ctgtcagctc ctttccggga ctttcgcttt ccccctccct 2280
attgccacgg cggaactcat cgccgcctgc cttgcccgct gctggacagg ggctcggctg 2340
ttgggcactg acaattccgt ggtgttgtcg gggaaatcat cgtcctttcc ttggctgctc 2400
gcctgtgttg ccacctggat tctgcgcggg acgtccttct gctacgtccc ttcggccctc 2460
aatccagcgg accttccttc ccgcggcctg ctgccggctc tgcggcctct tccgcgtctt 2520
cgccttcgcc ctcagacgag tcggatctcc ctttgggccg cctccccgca tcattgcctg 2580
cccgggtggc atccctgtga cccctcccca gtgcctctcc tggccctgga agttgccact 2640
ccagtgccca ccagccttgt cctaataaaa ttaagttgca tcattttgtc tgactaggtg 2700
tccttctata atattatggg gtggaggggg gtggtatgga gcaaggggcc caagttggga 2760
agaaacctgt agggcctgcg ttacccaggc tggagtgcag tggcacattt ctgctcactg 2820
caacctcctc ctccctgggt tctacgtaga taagtagcat ggcgggttaa tcattaacta 2880
caaggaaccc ctagtgatgg agttggccac tccctctctg cgcgctcgct cgctcactga 2940
ggccgggcga ccaaaggtcg cccgacgccc gggctttgcc cgggcggcct cagtgagcga 3000
gcgagcgcgc 3010
<210> 101
<211> 2611
<212> DNA
<213> Artificial Sequence
<220>
<223> Made in Lab - part of expression cassette
<400> 101
ctctggagac gcgttacata accattttgc tagagaaggc cgcggaggct cagagaggtg 60
cgcacacttg ccctgagtca cacagcgaat gccctccgcg gtcccaacgc agagagaacg 120
agccgatcgg cagcctgagc gaggcagtgg ttaggggggg ccccggcccc ggccactccc 180
ctcaccccct ccccgcagag cgccgcccag gacaggctgg gccccaggcc ccgccccgag 240
gtcctgccca cacacccctg acacaccggc gtcgccagcc aatggccggg gtcctataaa 300
cgctacggtc cgcgcgctct ctgccaccat ggagcccagc agcaagaagc tgacgggtcg 360
cctcatgctg gccgtgggag gagcagtgct tggctccctg cagtttggct acaacactgg 420
agtcatcaat gccccccaga aggtgatcga ggagttctac aaccagacat gggtccaccg 480
ctatggggag agcatcctgc ccaccacgct caccacgctc tggtccctct cagtggccat 540
cttttctgtt gggggcatga ttggctcctt ctctgtgggc cttttcgtta accgctttgg 600
ccggcggaat tcaatgctga tgatgaacct gctggccttc gtgtccgccg tgctcatggg 660
cttctcgaaa ctgggcaagt cctttgagat gctgatcctg ggccgcttca tcatcggtgt 720
gtactgcggc ctgaccacag gcttcgtgcc catgtatgtg ggtgaagtgt cacccacagc 780
ccttcgtggg gccctgggca ccctgcacca gctgggcatc gtcgtcggca tcctcatcgc 840
ccaggtgttc ggcctggact ccatcatggg caacaaggac ctgtggcccc tgctgctgag 900
catcatcttc atcccggccc tgctgcagtg catcgtgctg cccttctgcc ccgagagtcc 960
ccgcttcctg ctcatcaacc gcaacgagga gaaccgggcc aagagtgtgc taaagaagct 1020
gcgcgggaca gctgacgtga cccatgacct gcaggagatg aaggaagaga gtcggcagat 1080
gatgcgggag aagaaggtca ccatcctgga gctgttccgc tcccccgcct accgccagcc 1140
catcctcatc gctgtggtgc tgcagctgtc ccagcagctg tctggcatca acgctgtctt 1200
ctattactcc acgagcatct tcgagaaggc gggggtgcag cagcctgtgt atgccaccat 1260
tggctccggt atcgtcaaca cggccttcac tgtcgtgtcg ctgtttgtgg tggagcgagc 1320
aggccggcgg accctgcacc tcataggcct cgctggcatg gcgggttgtg ccatactcat 1380
gaccatcgcg ctagcactgc tggagcagct accctggatg tcctatctga gcatcgtggc 1440
catctttggc tttgtggcct tctttgaagt gggtcctggc cccatcccat ggttcatcgt 1500
ggctgaactc ttcagccagg gtccacgtcc agctgccatt gccgttgcag gcttctccaa 1560
ctggacctca aatttcattg tgggcatgtg cttccagtat gtggagcaac tgtgtggtcc 1620
ctacgtcttc atcatcttca ctgtgctcct ggttctgttc ttcatcttca cctacttcaa 1680
agttcctgag actaaaggcc ggaccttcga tgagatcgct tccggcttcc ggcagggggg 1740
agccagccaa agtgacaaga cacccgagga gctgttccat cccctggggg ctgattccca 1800
agtgtgataa tggatcaacc tctggattac aaaatttgtg aaagattgac tggtattctt 1860
aactatgttg ctccttttac gctatgtgga tacgctgctt taatgccttt gtatcatgct 1920
attgcttccc gtatggcttt cattttctcc tccttgtata aatcctggtt gctgtctctt 1980
tatgaggagt tgtggcccgt tgtcaggcaa cgtggcgtgg tgtgcactgt gtttgctgac 2040
gcaaccccca ctggttgggg cattgccacc acctgtcagc tcctttccgg gactttcgct 2100
ttccccctcc ctattgccac ggcggaactc atcgccgcct gccttgcccg ctgctggaca 2160
ggggctcggc tgttgggcac tgacaattcc gtggtgttgt cggggaaatc atcgtccttt 2220
ccttggctgc tcgcctgtgt tgccacctgg attctgcgcg ggacgtcctt ctgctacgtc 2280
ccttcggccc tcaatccagc ggaccttcct tcccgcggcc tgctgccggc tctgcggcct 2340
cttccgcgtc ttcgccttcg ccctcagacg agtcggatct ccctttgggc cgcctccccg 2400
catcattgcc tgcccgggtg gcatccctgt gacccctccc cagtgcctct cctggccctg 2460
gaagttgcca ctccagtgcc caccagcctt gtcctaataa aattaagttg catcattttg 2520
tctgactagg tgtccttcta taatattatg gggtggaggg gggtggtatg gagcaagggg 2580
cccaagttgg gaagaaacct gtagggcctg c 2611
<210> 102
<211> 302
<212> DNA
<213> Homo sapiens
<400> 102
accattttgc tagagaaggc cgcggaggct cagagaggtg cgcacacttg ccctgagtca 60
cacagcgaat gccctccgcg gtcccaacgc agagagaacg agccgatcgg cagcctgagc 120
gaggcagtgg ttaggggggg ccccggcccc ggccactccc ctcaccccct ccccgcagag 180
cgccgcccag gacaggctgg gccccaggcc ccgccccgag gtcctgccca cacacccctg 240
acacaccggc gtcgccagcc aatggccggg gtcctataaa cgctacggtc cgcgcgctct 300
ct 302
Claims (45)
- 프로모터에 작동 가능하게 연결된, GLUT1 또는 이의 기능적 변이체를 암호화하는 폴리뉴클레오티드 서열을 포함하는, 발현 카세트.
- 제1항에 있어서, 상기 프로모터는 내피 프로모터, 선택적으로 Tie-1 프로모터, Tie-2(TEK) 프로모터, FLT-1 프로모터, FLK-1(KDR) 프로모터, ICAM-2 프로모터, VE-카드헤린(CDH5) 프로모터, VWF 프로모터, ENG 프로모터, PDGFB 프로모터, ESM1 프로모터, APLN 프로모터, 또는 Claudin-5(Ple261) 프로모터이며, 단, 상기 내피 프로모터는 Glut1 프로모터가 아닌, 발현 카세트.
- 제1항 또는 제2항에 있어서, 상기 프로모터는 FLT-1 프로모터인, 발현 카세트.
- 제3항에 있어서, 상기 FLT-1 프로모터는 인간 FLT-1(hFLT-1) 프로모터인, 발현 카세트.
- 제4항에 있어서, 상기 hFLT-1 프로모터는 서열번호 1과 적어도 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 또는 100% 동일성을 공유하는, 발현 카세트.
- 제1항 또는 제2항에 있어서, 상기 프로모터는 Tie-1 프로모터인, 발현 카세트.
- 제6항에 있어서, 상기 Tie-1 프로모터는 인간 Tie-1(hTie-1) 프로모터인, 발현 카세트.
- 제7항에 있어서, 상기 hTie-1 프로모터는 서열번호 2과 적어도 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 또는 100% 동일성을 공유하는, 발현 카세트.
- 제1항 또는 제2항에 있어서, 상기 프로모터는 혈관 내피-카드헤린(VE-카드헤린) 프로모터인, 발현 카세트.
- 제9항에 있어서, 상기 VE-카드헤린 프로모터는 인간 VE-카드헤린(hVE-카드헤린) 프로모터인, 발현 카세트.
- 제10항에 있어서, 상기 hVE-카드헤린 프로모터는 서열번호 3과 적어도 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 또는 100% 동일성을 공유하는, 발현 카세트.
- 제1항에 있어서, 상기 프로모터는 유비쿼터스 프로모터인, 발현 카세트.
- 제1항 또는 제12항에 있어서, 상기 프로모터는 CMV 프로모터인, 발현 카세트.
- 제1항 또는 제12항에 있어서, 상기 프로모터는 CAG 프로모터인, 발현 카세트.
- 제1항 내지 제14항 중 어느 한 항에 있어서, 상기 발현 카세트는 폴리A 신호, 선택적으로 인간 성장 호르몬(hGH) 폴리A를 포함하는, 발현 카세트.
- 제1항 내지 제15항 중 어느 한 항에 있어서, 상기 발현 카세트는 마멋 간염 바이러스 전사후 조절 요소(WPRE), 선택적으로 WPRE(x)를 포함하는, 발현 카세트.
- 제1항 내지 제16항 중 어느 한 항에 있어서, 상기 발현 카세트는 서열번호 4과 적어도 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 또는 100% 동일성을 공유하는 서열을 포함하는 3' 미번역 영역(3' UTR)을 포함하는, 발현 카세트.
- 제1항 내지 제17항 중 어느 한 항에 있어서, 상기 GLUT1을 암호화하는 폴리뉴클레오티드 서열은 SLC2A1 폴리뉴클레오티드인, 발현 카세트.
- 제18항에 있어서, 상기 SLC2A1 폴리뉴클레오티드는 인간 SLC2A1 폴리뉴클레오티드인, 발현 카세트.
- 제17항 내지 제19항 중 어느 한 항에 있어서, 상기 GLUT1을 암호화하는 폴리뉴클레오티드 서열은 서열번호 5과 적어도 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 또는 100% 동일성을 공유하는, 발현 카세트.
- 제1항 내지 제20항 중 어느 한 항에 있어서, 상기 발현 카세트는 5' 및 3' 역위 말단 반복(ITR), 선택적으로 AAV2 ITR, 선택적으로 서열번호 6 또는 서열번호 7와 적어도 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 또는 100% 동일성을 공유하는 ITR이 측면에 위치하는, 발현 카세트.
- 제1항 내지 제21항 중 어느 한 항에 있어서, 상기 발현 카세트는 서열번호 8-16, 서열번호 97, 서열번호 99, 및 서열번호 101 중 어느 하나와 적어도 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 또는 100% 동일성을 공유하는, 발현 카세트.
- 제1항 내지 제21항 중 어느 한 항의 발현 카세트를 포함하는 유전자 요법 벡터.
- 제23항에 있어서, 상기 유전자 요법 벡터는 재조합 아데노-연관 바이러스(rAAV) 벡터인, 벡터.
- 제24항에 있어서, 상기 rAAV 벡터는 AAV6, AAV8, AAV9, AAVrh.74, 또는 AAVrh.10 벡터, 또는 이의 기능적 변이체인, 벡터.
- 제24항 또는 제25항에 있어서, 상기 rAAV 벡터는 AAV2 벡터가 아닌, 벡터.
- 제24항 내지 제26항 중 어느 한 항에 있어서, 상기 rAAV 벡터는 서열번호 15-17 중 어느 하나와 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 또는 100% 동일성을 공유하는 캡시드 단백질을 포함하는, 벡터.
- 질환 또는 장애의 치료 및/또는 예방을 필요로 하는 대상체에서 이를 치료 및/또는 예방하는 방법으로서, 제23항 내지 제27항 중 어느 한 항의 벡터를 대상체에게 투여하는 단계를 포함하는, 방법.
- 제28항에 있어서, 질환 또는 장애는 신경 장애인, 방법.
- 제28항 또는 제29항에 있어서, 질환 또는 장애는 포도당 수송자 1 결핍 증후군(GLUT1DS) 또는 드 비보 질환인, 방법.
- 제28항 내지 제30항 중 어느 한 항에 있어서, 벡터는 뇌실내(ICV) 주사에 의해 투여되는, 방법.
- 제28항 내지 제31항 중 어느 한 항에 있어서, 상기 투여는, 선택적으로 기준 rAAV 벡터와 비교하여 증가된 수준으로, 뇌에서 GLUT1을 암호화하는 폴리뉴클레오티드 서열의 발현을 초래하는, 방법.
- 제28항 내지 제32항 중 어느 한 항에 있어서, 상기 투여는, 선택적으로 기준 rAAV 벡터에 비해 증가된 수준으로, 뇌에서 GLUT1 단백질의 발현 증가 및/또는 CSF에서 포도당 수준 및/또는 젖산염 수준의 증가를 초래하고, 선택적으로, 상기 증가는 적어도 약 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% 또는 그 이상의 증가인, 방법.
- 제28항 내지 제33항 중 어느 한 항에 있어서, 벡터는 1E12 벡터 게놈(vg), 1E13 vg, 1E14 vg, 또는 3E14 vg의 투여량으로 투여되는, 방법.
- 제28항 내지 제34항 중 어느 한 항에 있어서, 상기 방법은 내인성 Glut1 프로모터 또는 유비쿼터스 프로모터를 사용하여 수행된 방법에 비해 대뇌 미세혈관 내피 세포에 의한 포도당 흡수 증가를 유발하는, 방법.
- 세포에서 GLUT1을 발현하는 방법으로서, 제23항 내지 제27항 중 어느 한 항의 벡터와 상기 세포를 접촉시키는 단계를 포함하는, 방법.
- 제36항에 있어서, 상기 세포는 내피 세포인, 방법.
- 제37항에 있어서, 상기 내피 세포는 대뇌 미세혈관 내피 세포인, 방법.
- 제37항 또는 제38항에 있어서, 상기 내피 세포는 생체 내 내피 세포인, 방법.
- 제36항에 있어서, 상기 세포는 뉴런인, 방법.
- 제40항에 있어서, 상기 뉴런은 생체 내 뉴런인, 방법.
- 제36항 내지 제40항 중 어느 한 항에 있어서, 상기 방법은 벡터를 대상체에게 생체 내 투여하는 단계를 포함하는, 방법.
- 제36항 내지 제41항 중 어느 한 항에 있어서, 상기 벡터는 내인성 Glut1 프로모터 또는 유비쿼터스 프로모터를 포함하는 벡터와 접촉된 세포와 비교하여 세포에 의한 포도당 흡수 증가를 유발하는, 방법.
- 제23항 내지 제27항 중 어느 한 항의 벡터를 포함하는 약학적 조성물.
- 제23항 내지 제27항 중 어느 한 항의 벡터 또는 제43항의 약학적 조성물 및 선택적으로 사용 지침을 포함하는 키트.
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