KR20220110781A - 재조합 aav를 생산하기 위한 신규 조성물 및 방법 - Google Patents
재조합 aav를 생산하기 위한 신규 조성물 및 방법 Download PDFInfo
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- KR20220110781A KR20220110781A KR1020227022189A KR20227022189A KR20220110781A KR 20220110781 A KR20220110781 A KR 20220110781A KR 1020227022189 A KR1020227022189 A KR 1020227022189A KR 20227022189 A KR20227022189 A KR 20227022189A KR 20220110781 A KR20220110781 A KR 20220110781A
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Abstract
높은 효력의 재조합 AAV 캡시드를 고수율로 생산하기 위한 핵산 구축물, 숙주 곤충 세포, 및 방법이 본원에 제공된다.
Description
관련 출원에 대한 상호 참조
본 출원은 2019년 12월 4일에 출원된 미국 가출원 62/943,715를 우선권 주장하며, 그의 내용은 그 전문이 본원에 참조로 포함된다.
서열 목록
본 출원은 ASCII 포맷으로 전자 제출된 서열 목록을 함유한다. 서열 목록은 그 전문이 본원에 참조로 포함된다. 2020년 11월 30일에 생성된 ASCII 카피는 025297_WO 015_SL.txt로 명명되고, 111,015 바이트 크기이다.
발명의 배경
아데노-연관 바이러스 (AAV)는 파르보비리다에(Parvoviridae) 과 및 데펜도파르보바이러스(Dependoparvovirus) 속에 속하는 소형 외피 비보유 바이러스이다. AAV는 3종의 캡시드 단백질 - 바이러스 단백질 (VP) 1, VP2, 및 VP3 - 로부터 대략 1:1:10의 몰비로 조립된 캡시드 내로 패키징된 단일-가닥 DNA 게놈으로 구성된다 (Berns and Parrish (2007) Parvoviridae in Fields Virology (Knipe and Howley, eds., 5th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins); Wang et al., Nat Rev Drug Discov. (2019) 18(5):358-78). 캡시드 단백질은 단일 캡시드 (cap) 유전자에 의해 코딩되고, 선택적 스플라이싱 및 차별적 코돈 용법에 의해 생성된다 (id.). VP1은 가장 큰 캡시드 단백질 (81.6 kD)이다. VP2 (66.6 kD)는 VP1의 N-말단 말단절단된 형태이다. VP3 (59.9 kD)은 VP2의 N-말단 말단절단된 형태이다. 예를 들어, 문헌 [Cecchini et al., Hum Gene Ther. (2011) 22:1021-30]을 참조한다.
재조합 AAV (rAAV)는 인간에서의 유전자 요법 및 DNA 백신을 위한 벡터로서 집중적으로 연구되었다. 포유동물 세포에서의 rAAV 생산을 위해, 헬퍼 바이러스 (예를 들어, 아데노바이러스, 백시니아 또는 헤르페스바이러스)가 필요하다. 수년에 걸쳐, (1) 헬퍼 단백질 (아데노바이러스 E1, E2A, E4 및 VA)의 최소 세트를 확인하고, 클로닝하고, (2) AAV Rep (Rep78, Rep68, Rep52 및 Rep40) 및 캡시드 단백질을 트랜스로 제공하고, (3) AAV 역전된 말단 반복부 (ITR)에 의해 플랭킹된 DNA 서열의 패키징을 허용하는 트랜스진 시스템을 개발하는 것을 포함하는, rAAV 생산을 용이하게 하기 위한 여러 변형이 이루어졌다 (Samulski et al., J Virol. (1989) 63(9):3822-8). 이들 3가지 성분이 포유동물 세포 내로 도입되는 경우에, 관심 트랜스진을 함유하는 rAAV는 용이하게 정제될 수 있다. 이렇게 생산된 재조합 AAV는 임상 시험에 사용되었다 (Clement and Grieger, Mol Ther Methods Clin Dev. (2016) 3:16002).
보다 큰 규모의 임상 시험 및 상업화를 위해 규모 확장된 rAAV 생산이 필요함에 따라, Rep 및 캡시드 단백질을 발현하고 rAAV 캡시드 내로 패키징되는 트랜스진 함유 AAV 벡터 게놈에 대한 코딩 서열을 보유하기 위해 바큘로바이러스 벡터를 이용하는 곤충 세포-기반 생산 시스템의 개발이 이루어졌다. 재조합 AAV (rAAV)의 곤충 세포-기반 제조는 비-부착성 세포의 확장성 및 무혈청 성장 조건의 사용으로 인한 비용 절감을 포함하여, 포유동물 세포-기반 rAAV 제조에 비해 여러 이점을 제공한다. 이러한 시스템은 또한 아데노바이러스 헬퍼 기능을 필요로 하지 않는다 (예를 들어, 문헌 [Urabe et al., Hum Gene Ther. (2002) 13:1935-43; Urabe et al., J Vir. (2006) 80(4):1874-85; Chen et al., Mol Ther. (2008) 16(5):924-30; Smith et al., Mol Ther. (2009) 17(11):1888-96; 및 Mietzsch et al., Hum Gene Ther Methods (2017) 28(1):15-22)] 참조). 바큘로바이러스-곤충 세포 시스템이 배수 규모로 rAAV 생산에 성공적으로 이용되었지만, 곤충 세포에서 생성된 rAAV는 포유동물 세포에서 생산된 rAAV와 비교하여 감소된 VP1 함량 (예를 들어, 대략 1:1:30 내지 1:1:60의 VP1:VP2:VP3 비를 가짐) 및 결과적으로 감소된 효력을 갖는 것으로 관찰되었다 (예를 들어, 문헌 [Urabe et al., 2002, 상기 문헌; Kohlbrenner et al., Mol Ther. (2005) 12(6):1217-25; Urabe et al., 2006, 상기 문헌; Aslanidi et al., Proc Natl Acad Sci USA (2009) 106(13):5059-64; Kondratov et al., Mol Ther. (2017) 25(12):2661-75; 및 Mietzsch et al., 상기 문헌] 참조). VP1의 개시 코돈 콘텍스트를 변형시킴으로써 캡시드 비를 개선시키기 위한 여러 노력이 이루어졌다 (예를 들어, 문헌 [Kondratov et al., 상기 문헌; Mietzsch et al., 상기 문헌] 참조).
따라서, rAAV를 산업적 규모로 생산하기 위한 개선된 바큘로바이러스-곤충 세포 시스템에 대한 필요가 남아있다.
발명의 개요
본 개시내용은 강력한 재조합 AAV를 고수율로 생산하기 위한 바큘로바이러스-곤충 세포 시스템을 제공한다. 한 측면에서, 본 개시내용은 Rep78에 대한 발현 카세트를 포함하는 제1 바큘로바이러스 벡터 및 Rep52에 대한 발현 카세트를 포함하는 제2 바큘로바이러스 벡터를 포함하는 곤충 세포 (예를 들어, Sf9 또는 Sf21 세포)를 제공하며, 여기서 제1 벡터 및 제2 벡터는 각각 (i) VP1에 대한 발현 카세트 및 VP2/VP3에 대한 발현 카세트; 또는 (ii) 각각 VP2/VP3에 대한 발현 카세트 및 VP1에 대한 발현 카세트를 추가로 포함한다. 일부 실시양태에서, 제1 및 제2 벡터 중 하나 또는 둘 다는 곤충 세포의 게놈 내로 안정하게 통합된다.
일부 실시양태에서, Rep78 발현 카세트 및 Rep52 발현 카세트는 동일한 곤충 프로모터를 포함한다. 일부 실시양태에서, Rep78 발현 카세트는 Rep78 코딩 서열에 대한 비-정규 개시 코돈을 포함하며, 여기서 코돈은 임의로 ACG, TTG, GTG 또는 CTG이다.
일부 실시양태에서, VP1 발현 카세트 및 VP2/VP3 발현 카세트는 동일한 곤충 프로모터를 포함한다. 일부 실시양태에서, VP1, VP2, 및 VP3 단백질은 동일한 AAV 혈청형으로부터의, 또는 1종 초과의 AAV 혈청형으로부터의 아미노산 서열을 포함한다. 특정 실시양태에서, VP1, VP2, 및/또는 VP3 단백질은 AAV1, AAV2, AAV3 (예를 들어, AAV3B), AAV6, 및/또는 AAV9로부터의 아미노산 서열을 포함한다. 특정 실시양태에서, Rep78 및 Rep52 단백질은 VP1, VP2, 및/또는 VP3 단백질과 상이한 AAV 혈청형으로부터 유래된다.
일부 실시양태에서, Rep78, Rep52, VP1, 및 VP2/VP3 발현 카세트 각각은 폴리헤드론 프로모터, IE-1 프로모터, 및 p10 프로모터로부터 선택된 곤충 프로모터를 포함한다.
본원의 곤충 세포는 재조합 AAV 게놈에 대한 코딩 서열을 추가로 포함할 수 있으며, 여기서 재조합 AAV 게놈은 포유동물 프로모터의 전사 제어 하에 있는 관심 트랜스진에 대한 발현 카세트, 및 양쪽 말단 상의 AAV 역전된 말단 반복부 (ITR)를 포함한다. 일부 실시양태에서, 재조합 AAV 게놈에 대한 코딩 서열은 제1 또는 제2 벡터 상에 위치하거나, 또는 제3 벡터 상에 위치한다. 관심 트랜스진은, 예를 들어 유전 질환 (예를 들어, 리소솜 축적 질환, 또는 혈우병)에서 기능이 결여 또는 결핍된 단백질, 예컨대 효소 (효소 대체 요법에서 사용하기 위한 것) 및 혈액 응고 인자 (대체 인자로서 사용하기 위한 것); 및 유전자 발현을 조절하기 위한 단백질 (예를 들어, 아연 핑거 단백질 (ZFP) 전사 인자)을 비제한적으로 포함하는 치료 단백질을 코딩할 수 있다. 관심 트랜스진은 또한 유전자 편집 단백질, 예컨대 아연 핑거 뉴클레아제 (ZFN), ZFP 데아미나제, ZFP 레콤비나제, TALEN, CRISPR Cas 단백질, 및 CRISPR Cpf 단백질을 코딩할 수 있다. 트랜스진은 또한 간섭 RNA 분자, 예컨대 소형 헤어핀 RNA를 코딩할 수 있다.
일부 실시양태에서, VP1 단백질 및/또는 VP2 단백질은 각각 야생형 VP1 및 VP2 단백질에 비해 잔기 157, 162, 164, 179, 188, 194, 196, 197, 200, 및 201 (서열식별번호(SEQ ID NO): 1에 따른 넘버링)에서 2개 이상의 돌연변이를 포함한다. 본원에 사용된 "서열식별번호: 1에 따른 넘버링"은 서열식별번호: 1에서의 아미노산 잔기 위치, 또는 상이한 VP1 서열 (예를 들어, AAV6 이외의 혈청형으로부터의 VP1 서열)에서의 상응하는 아미노산 잔기 위치를 의미한다. 일부 실시양태에서, VP1 단백질 및/또는 VP2 단백질은 S157A, T162S, Q164A, S179T, L188I, T194A, A196S, A197G, P200S, 및 T201L (서열식별번호: 1에 따른 넘버링)로 이루어진 군으로부터 선택된 2개 이상의 돌연변이를 포함한다. 추가 실시양태에서, VP1 단백질 및/또는 VP2 단백질은 이들 10가지 돌연변이 모두를 포함한다.
일부 실시양태에서, VP1 단백질은 야생형 VP1 단백질에 비해 잔기 67, 81, 84, 85, 및 92 (서열식별번호: 1에 따른 넘버링)에서 1개 이상의 돌연변이를 추가로 포함한다. 특정 실시양태에서, VP1 단백질은 A67E, Q81R, K84D, A85S, 및 R92K로 이루어진 군으로부터 선택된 1개 이상의 돌연변이를 포함한다. 추가 실시양태에서, VP1 단백질은 이들 5가지 돌연변이 모두를 포함한다.
일부 실시양태에서, 본원에 개시된 VP1 단백질 및 VP2 단백질은 돌연변이를 제외하고는 AAV6의 VP1 단백질 및 VP2 단백질과 각각 동일하다. 특정한 실시양태에서, VP1 단백질 및/또는 VP2 단백질은 AAV6으로부터 유래되고, 각각 야생형 AAV6 VP1 및 VP2 단백질에 비해 돌연변이 S157A, T162S, Q164A, S179T, L188I, T194A, A196S, A197G, P200S, 및 T201L을 포함한다.
일부 실시양태에서, VP1-발현 벡터는 또한 조립-활성화 단백질 (AAP)에 대한 발현 카세트를 포함하며, 여기서 AAP는 야생형 AAP 단백질에 비해 잔기 8, 10, 12, 17, 21 및 22 (서열식별번호: 10에 따른 넘버링)에서 1개 이상의 돌연변이를 포함한다. 본원에 사용된 "서열식별번호: 10에 따른 넘버링"은 서열식별번호: 10에서의 아미노산 잔기 위치, 또는 상이한 AAP 서열 (예를 들어, AAV6 이외의 혈청형으로부터의 AAP 서열)에서의 상응하는 아미노산 잔기 위치를 의미한다. 특정 실시양태에서, AAP는 P8Q, H10L, L12Q, Q17P, L21Q 및 L22V로 이루어진 군으로부터 선택된 1개 이상의 (예를 들어, 모든) 돌연변이를 포함한다. 특정한 실시양태에서, AAP는 AAP 돌연변이를 제외하고는 AAV6의 야생형 AAP와 동일하다.
특정한 실시양태에서, VP1 발현 카세트는 제1 아미노산을 갖거나 갖지 않는 서열식별번호: 7에 대한 코딩 서열 (예를 들어, 서열식별번호: 14의 뉴클레오티드 18-151)을 포함한다. 추가 실시양태에서, 캡시드 발현 카세트는 서열식별번호: 14의 10개 이상 (예를 들어, 20개 이상, 30개 이상, 40개 이상, 50개 이상, 75개 이상, 100개 이상, 125개 이상, 또는 150개 이상)의 인접 뉴클레오티드, 또는 전체 뉴클레오티드 서열을 포함한다.
일부 실시양태에서, VP1 단백질은 야생형 VP1 단백질에 비해 잔기 81, 84, 85, 및 92 (서열식별번호: 1에 따른 넘버링)에서 1개 이상의 돌연변이를 포함한다. 일부 실시양태에서, VP1 단백질은 Q81R, K84D, A85S, 및 R92K로 이루어진 군으로부터 선택된 1개 이상의 돌연변이를 포함한다. 추가 실시양태에서, VP1 단백질은 이들 4가지 돌연변이 모두를 포함한다. 특정한 실시양태에서, VP1 단백질은 잔기 67에서의 돌연변이, 예를 들어 A67E 돌연변이를 추가로 포함한다. 일부 실시양태에서, VP1 단백질은 돌연변이(들)를 제외하고는 AAV6의 VP1 단백질과 동일하다. 특정 실시양태에서, VP1 단백질은 야생형 AAV6 VP1에 비해 돌연변이 A67E, Q81R, K84D, A85S, 및 R92K를 포함한다.
본 곤충 세포 AAV 생산 시스템의 특정한 실시양태에서, VP1은 제1 아미노산 잔기를 갖거나 갖지 않는 서열식별번호: 1, 7, 또는 16을 포함하고; VP2는 서열식별번호: 1 또는 7의 아미노산 잔기 138-736 또는 139-736을 포함하거나, 또는 제1 아미노산 잔기를 갖거나 갖지 않는 서열식별번호: 18을 포함하고; VP3은 서열식별번호: 1의 아미노산 잔기 204-736 또는 205-736 또는 서열식별번호: 7의 아미노산 잔기 203-736 또는 204-736을 포함하거나, 또는 제1 아미노산 잔기를 갖거나 갖지 않는 서열식별번호: 19를 포함한다.
일부 실시양태에서, VP1은 제1 아미노산 잔기를 갖거나 갖지 않는 서열식별번호: 24를 포함하고; VP2는 서열식별번호: 24의 아미노산 잔기 138-736 또는 139-736을 포함하고; VP3은 서열식별번호: 24의 203-736 또는 204-736의 아미노산 잔기를 포함한다.
일부 실시양태에서, VP1은 제1 아미노산 잔기를 갖거나 갖지 않는 서열식별번호: 25를 포함하고; VP2는 서열식별번호: 25의 아미노산 잔기 138-735 또는 139-735를 포함하고; VP3은 서열식별번호: 25의 203-735 또는 204-735를 포함한다.
일부 실시양태에서, VP1은 제1 아미노산 잔기를 갖거나 갖지 않는 서열식별번호: 26을 포함하고; VP2는 서열식별번호: 26의 아미노산 잔기 138-736 또는 139-736을 포함하고; VP3은 서열식별번호: 26의 203-736 또는 204-736의 아미노산 잔기를 포함한다.
일부 실시양태에서, VP1은 제1 아미노산 잔기를 갖거나 갖지 않는 서열식별번호: 27을 포함하고; VP2는 서열식별번호: 27의 아미노산 잔기 138-736 또는 139-736을 포함하고; VP3은 서열식별번호: 27의 203-736 또는 204-736의 아미노산 잔기를 포함한다.
일부 실시양태에서, Rep78은 제1 아미노산 잔기를 갖거나 갖지 않는 서열식별번호: 21을 포함하고/거나; Rep52는 제1 아미노산 잔기를 갖거나 갖지 않는 서열식별번호: 23을 포함한다.
이들 실시양태는, 생산 세포가 제1 아미노산 잔기를 절단하는 것으로 인해 코딩 서열에 의해 코딩되는 제1 아미노산 잔기 (즉, 개시 코돈에 의해 코딩되는 아미노산)를 함유하지 않는 헬퍼 단백질 (Rep78, Rep52, VP1, VP2, 및 VP3)을 포괄한다. 이들 실시양태는 또한 그의 제1 아미노산 잔기가 비-정규 개시 코돈, 예컨대 본원에 기재되거나 또는 관련 기술분야에 달리 공지된 것에 의해 코딩되는 헬퍼 단백질을 포괄한다.
또 다른 측면에서, 본 개시내용은 또한 본원의 곤충 세포에서 생산된 재조합 AAV 비리온, 트랜스진을 필요로 하는 인간 환자의 치료에서의 그의 용도, 이러한 치료를 위한 의약의 제조에서의 그의 용도, 및 재조합 AAV 비리온 및 제약상 허용되는 담체를 포함하는 제약 조성물을 제공한다.
또 다른 측면에서, 본 개시내용은 본원의 곤충 세포를 제공하는 단계, 재조합 AAV 게놈의 발현 및 VP1, VP2, 및 VP3 단백질을 포함하는 AAV 캡시드 내의 재조합 AAV 게놈의 패키징을 허용하는 조건 하에 곤충 세포를 배양하는 단계, 및 배양물로부터 재조합 AAV를 단리하는 단계를 포함하는, 재조합 AAV 비리온을 생산하는 방법을 제공한다. 곤충 세포에서 AAV 비리온을 제조하기 위한 발현 카세트의 조합물 (예를 들어, 조성물)이 또한 제공된다.
본 발명의 다른 특징, 목적 및 이점은 하기 상세한 설명에서 명백하다. 그러나, 상세한 설명은 본 발명의 실시양태 및 측면을 나타내지만, 제한이 아니라 단지 예시로서 주어지는 것으로 이해되어야 한다. 본 발명의 범위 내의 다양한 변화 및 변형은 상세한 설명으로부터 관련 기술분야의 통상의 기술자에게 명백해질 것이다.
도 1a는 아미노산 잔기 155와 207 (컨센서스 서열에 기초한 넘버링) 사이의 AAV 혈청형 3B, 5, 6, 8, 및 9로부터의 VP1/VP2 아미노산 서열의 정렬을 보여준다. AAV6 VP1/VP2 내의 단백질분해적 절단 부위를 확인하기 위해 SDS-PAGE 겔 중심부로부터 잘라낸 단백질분해적 절단 산물에 대해 N-말단 에드만(Edman) 분해 서열분석을 수행하였다. 절단 부위는 잔기 G190E191로 맵핑된다. 지니우스(Geneious) 소프트웨어 패키지 및 클러스탈W(ClustalW) 정렬을 위한 디폴트 설정을 사용하여 다중 서열 정렬을 생성하였다. VP3 개시 부위는 잔기 205에서 삼각형으로 표시된다. 도 1a는 출현 순서로 각각 서열식별번호: 28-33을 개시한다.
도 1b는 아미노산 잔기 155와 205 (컨센서스 서열에 기초한 넘버링) 사이의 AAV 혈청형 1, 2, 3B, 4, 및 6-11로부터의 VP1/VP2 아미노산 서열의 정렬을 보여준다. 지니우스 소프트웨어 패키지 및 ClustalW 정렬을 위한 디폴트 설정을 사용하여 다중 서열 정렬을 생성하였다. 도 1b는 출현 순서로 각각 서열식별번호: 34-38, 73, 및 39-43을 개시한다.
도 1c는 도 1b에 정렬된 바와 같은 아미노산 잔기 158-203 사이의 AAV 혈청형 1, 4, 6, 7, 8, 및 11로부터의 상응하는 아미노산 위치를 비교하는 표이다. 표는 이들 혈청형에서 단백질분해적 절단을 방지할 수 있는 아미노산 돌연변이를 나타낸다. 아미노산 잔기 번호는 도 1b에 제시된 컨센서스 서열에 기초한다.
도 2는 AAV6 VP1/VP2 서열 (서열식별번호: 3)에서의 상응하는 영역에 대한 AAV9 VP1/VP2 (서열식별번호: 4)의 45개 아미노산 스트레치의 치환을 보여주며, 이는 생성된 키메라 VP1/VP2 단백질 ("AAV6/9 VP1/VP2")의 단백질분해적 절단을 무효화한다. 도면은 이식된 AAV9 Cap 뉴클레오티드 서열 및 AAV9 이식체에서 대체된 AAV6 Cap 뉴클레오티드 서열의 정렬을 보여주고; 화살표 "A"는 AAP 개시 코돈을 나타낸다. AAV9 이식체: AAV6 Cap 유전자가 AAV9 Cap 유전자로부터의 서열을 함유하는 바큘로바이러스 헬퍼 벡터. 도 2는 출현 순서로 각각 서열식별번호: 44-45를 개시한다.
도 3a 및 3b는 AAV6/9 VP1/VP2의 변이체가 절단을 방지하였음을 도시한다. 도 3a: AAV6/9 VP1/VP2의 변이체 1, 2, 3, 및 4의 서열 정렬 (서열식별번호: 1에 따른 넘버링). 도 3b: AAV6, AAV9 이식체, 변이체 1, 변이체 2, 변이체 3, 및 변이체 4의 cap/AAP 뉴클레오티드 서열 및 AAP 아미노산 서열 (직사각형내)의 부분 정렬. AAV9 이식체의 AAP 아미노산 서열은 표시된 영역에서 AAP6의 것에 비해 6개의 돌연변이 (P8Q, H10L, L12Q, Q17P, L21Q, 및 L22V)를 갖는 반면, 변이체 1-3의 AAP 아미노산 서열은 각각 단 2개의 돌연변이 (L21Q 및 L22V)만을 갖는다. 변이체 4는 표시된 영역에서 천연 AAP6 서열을 갖는다. 도 3a는 출현 순서로 모두 각각 서열식별번호: 46-51을 개시하고, 도 3b는 서열식별번호: 52, 67, 53, 68, 54, 69, 55, 70, 56, 71, 57, 및 72를 개시한다.
도 4a는 표시된 영역에서의 AAV 혈청형 1, 2, 3B, 4, 및 6-11로부터의 조립-활성화 단백질 (AAP) 아미노산 서열의 정렬을 보여준다. 아미노산 잔기 번호는 컨센서스 서열에 기초한다. 지니우스 소프트웨어 패키지 및 ClustalW 정렬을 위한 디폴트 설정을 사용하여 다중 서열 정렬을 생성하였다. 도 4a는 출현 순서로 각각 서열식별번호: 58-62, 8, 63-64, 9, 및 65-66을 개시한다.
도 4b는 (i) AAV1, AAV2, AAV4, AAV6, AAV7, AAV8, AAV10, 또는 AAV11과 (ii) AAV9 또는 AAV3B 사이의, 표시된 AAP 영역에서의 아미노산 차이 (컨센서스 넘버링)를 보여주는 것이다. 아미노산 잔기 번호는 도 4a에 제시된 컨센서스 서열에 기초한다.
도 5는 곤충 세포에서 AAV를 생산하기 위한 2개의 바큘로바이러스 헬퍼 시스템을 보여주는 개략 다이아그램이다. Rep78, Rep52, VP1, 및 VP2/VP3 코딩 서열에 대한 개시 코돈이 그의 전사 방향과 함께 제시된다. 두 시스템 모두 2개의 바큘로바이러스 벡터를 포함한다. 한 쌍의 AAV 역전된 말단 반복부 (ITR)가 플랭킹된 관심 유전자 (GOI)를 포함하는 재조합 AAV 게놈에 대한 코딩 서열은 별개의 바큘로바이러스 벡터 상에 놓일 수 있거나, 또는 Rep52 코딩 서열과 동일한 벡터 상에 놓일 수 있다.
도 1b는 아미노산 잔기 155와 205 (컨센서스 서열에 기초한 넘버링) 사이의 AAV 혈청형 1, 2, 3B, 4, 및 6-11로부터의 VP1/VP2 아미노산 서열의 정렬을 보여준다. 지니우스 소프트웨어 패키지 및 ClustalW 정렬을 위한 디폴트 설정을 사용하여 다중 서열 정렬을 생성하였다. 도 1b는 출현 순서로 각각 서열식별번호: 34-38, 73, 및 39-43을 개시한다.
도 1c는 도 1b에 정렬된 바와 같은 아미노산 잔기 158-203 사이의 AAV 혈청형 1, 4, 6, 7, 8, 및 11로부터의 상응하는 아미노산 위치를 비교하는 표이다. 표는 이들 혈청형에서 단백질분해적 절단을 방지할 수 있는 아미노산 돌연변이를 나타낸다. 아미노산 잔기 번호는 도 1b에 제시된 컨센서스 서열에 기초한다.
도 2는 AAV6 VP1/VP2 서열 (서열식별번호: 3)에서의 상응하는 영역에 대한 AAV9 VP1/VP2 (서열식별번호: 4)의 45개 아미노산 스트레치의 치환을 보여주며, 이는 생성된 키메라 VP1/VP2 단백질 ("AAV6/9 VP1/VP2")의 단백질분해적 절단을 무효화한다. 도면은 이식된 AAV9 Cap 뉴클레오티드 서열 및 AAV9 이식체에서 대체된 AAV6 Cap 뉴클레오티드 서열의 정렬을 보여주고; 화살표 "A"는 AAP 개시 코돈을 나타낸다. AAV9 이식체: AAV6 Cap 유전자가 AAV9 Cap 유전자로부터의 서열을 함유하는 바큘로바이러스 헬퍼 벡터. 도 2는 출현 순서로 각각 서열식별번호: 44-45를 개시한다.
도 3a 및 3b는 AAV6/9 VP1/VP2의 변이체가 절단을 방지하였음을 도시한다. 도 3a: AAV6/9 VP1/VP2의 변이체 1, 2, 3, 및 4의 서열 정렬 (서열식별번호: 1에 따른 넘버링). 도 3b: AAV6, AAV9 이식체, 변이체 1, 변이체 2, 변이체 3, 및 변이체 4의 cap/AAP 뉴클레오티드 서열 및 AAP 아미노산 서열 (직사각형내)의 부분 정렬. AAV9 이식체의 AAP 아미노산 서열은 표시된 영역에서 AAP6의 것에 비해 6개의 돌연변이 (P8Q, H10L, L12Q, Q17P, L21Q, 및 L22V)를 갖는 반면, 변이체 1-3의 AAP 아미노산 서열은 각각 단 2개의 돌연변이 (L21Q 및 L22V)만을 갖는다. 변이체 4는 표시된 영역에서 천연 AAP6 서열을 갖는다. 도 3a는 출현 순서로 모두 각각 서열식별번호: 46-51을 개시하고, 도 3b는 서열식별번호: 52, 67, 53, 68, 54, 69, 55, 70, 56, 71, 57, 및 72를 개시한다.
도 4a는 표시된 영역에서의 AAV 혈청형 1, 2, 3B, 4, 및 6-11로부터의 조립-활성화 단백질 (AAP) 아미노산 서열의 정렬을 보여준다. 아미노산 잔기 번호는 컨센서스 서열에 기초한다. 지니우스 소프트웨어 패키지 및 ClustalW 정렬을 위한 디폴트 설정을 사용하여 다중 서열 정렬을 생성하였다. 도 4a는 출현 순서로 각각 서열식별번호: 58-62, 8, 63-64, 9, 및 65-66을 개시한다.
도 4b는 (i) AAV1, AAV2, AAV4, AAV6, AAV7, AAV8, AAV10, 또는 AAV11과 (ii) AAV9 또는 AAV3B 사이의, 표시된 AAP 영역에서의 아미노산 차이 (컨센서스 넘버링)를 보여주는 것이다. 아미노산 잔기 번호는 도 4a에 제시된 컨센서스 서열에 기초한다.
도 5는 곤충 세포에서 AAV를 생산하기 위한 2개의 바큘로바이러스 헬퍼 시스템을 보여주는 개략 다이아그램이다. Rep78, Rep52, VP1, 및 VP2/VP3 코딩 서열에 대한 개시 코돈이 그의 전사 방향과 함께 제시된다. 두 시스템 모두 2개의 바큘로바이러스 벡터를 포함한다. 한 쌍의 AAV 역전된 말단 반복부 (ITR)가 플랭킹된 관심 유전자 (GOI)를 포함하는 재조합 AAV 게놈에 대한 코딩 서열은 별개의 바큘로바이러스 벡터 상에 놓일 수 있거나, 또는 Rep52 코딩 서열과 동일한 벡터 상에 놓일 수 있다.
발명의 상세한 설명
본 개시내용은 강력한 rAAV 캡시드를 고수율로 생산하기 위한 개선된 바큘로바이러스-곤충 세포 시스템 및 관련 조성물을 제공한다. 본 rAAV 생산 시스템은 이중 바큘로바이러스 헬퍼 벡터를 이용한다. 제1 벡터는 Rep78에 대한 발현 카세트 및 VP1 또는 VP2/VP3에 대한 발현 카세트를 보유하는 한편, 제2 벡터는 Rep52에 대한 발현 카세트 및 나머지 캡시드 단백질(들)에 대한 발현 카세트 (제1 벡터가 VP1을 발현하는 경우 VP2/VP3, 또는 제1 벡터가 VP2/VP3을 발현하는 경우 VP1)를 보유한다. 일부 실시양태에서, Rep78 카세트는 Rep52 카세트 내의 프로모터와 동일한 (또는 유사한 강도를 갖는) 프로모터를 사용하고, 임의로 준최적 개시 코돈을 가져, Rep78 및 Rep52 단백질이 최적 화학량론으로 생산될 수 있다. 다른 실시양태에서, Rep78 카세트는 Rep52 카세트 내의 프로모터보다 더 약한 프로모터를 사용하지만, 정규 개시 코돈을 가져, Rep78 및 Rep52 단백질이 최적의 화학량론으로 생산될 수 있다.
일부 실시양태에서, VP1 카세트는 VP2/VP3 카세트 내의 프로모터와 동일한 (또는 유사한 강도를 갖는) 프로모터를 사용하고, 임의로 준최적 개시 코돈을 가져, 3개의 캡시드 단백질이 최적의 화학량론으로 생산될 수 있다. 다른 실시양태에서, VP1 카세트는 VP2/VP3 카세트 내의 프로모터보다 더 약한 프로모터를 사용하지만, 정규 개시 코돈을 가져, 캡시드 단백질이 최적의 화학량론으로 생산될 수 있다.
rAAV-생산 세포를 형질도입하는 데 필요한 바큘로바이러스 벡터의 수를 감소시키기 위해, rAAV 게놈에 대한 코딩 서열이 또한 2개의 벡터 중 하나에, 예를 들어 제2 벡터 (즉, Rep52 발현 카세트를 보유하는 벡터)에 포함될 수 있다.
본 발명자들은 별개의 카세트로부터 Rep78 및 Rep52를 발현시키고 별개의 카세트로부터 VP1 및 VP2/VP3을 발현시키는 것이 곤충 세포 시스템에서 생산된 rAAV의 효력 및/또는 수율을 크게 개선시킨다는 것을 발견하였다. 하기 작업 실시예에서 입증된 바와 같이, 본 발명의 시스템은, 캡시드 단백질이 단일 Cap 유전자로부터 생산되고 Rep 단백질이 단일 Rep 유전자로부터 생산되는 우세한 1-벡터 시스템으로부터 캡시드 단백질이 생산되는 생산 시스템과 비교하여, 효력 및/또는 수율이 다중-배수 증가되어 rAAV를 생산한다.
본 발명의 생산 시스템은 임의의 혈청형, 예컨대 AAV1, AAV2, AAV3, AAV3A, AAV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AAV8.2, AAV9, AAVrh10, 또는 조작된 혈청형의 rAAV를 생산하는 데 사용될 수 있다. 캡시드 단백질의 코딩 서열은 임의의 목적하는 혈청형으로부터 유래될 수 있다.
본 발명의 시스템은 또한 유사형, 예컨대 AAV2/8, AAV2/5, 또는 AAV2/6의 rAAV를 생산하는 데 사용될 수 있다. "유사형", "유사형화" 또는 "교차-패키징된" rAAV는, 예를 들어 바이러스의 형질도입 효능 또는 향성 프로파일을 변경시키기 위해 그의 캡시드가 또 다른 AAV 혈청형의 캡시드로 대체된 재조합 AAV를 의미한다 (예를 들어, 문헌 [Balaji et al., J Surg Res. (2013) 184(1):691-8] 참조). 예를 들어, AAV2/8 유사형화 AAV는 AAV8의 캡시드 및 AAV2로부터 유래된 ITR을 함유한다.
본 발명의 시스템은 또한 키메라 또는 하이브리드 AAV를 생산하는 데 사용될 수 있다. "키메라" 또는 "하이브리드" rAAV는 그의 캡시드가 상이한 혈청형으로부터 유래된 캡시드 단백질로부터 조립되고/거나 그의 캡시드 단백질이 상이한 혈청형 (예를 들어, 혈청형 1 및 2; 예를 들어, 문헌 [Hauck et al., Mol Ther. (2003) 7(3):419-25] 참조)으로부터 유래된 서열을 갖는 키메라 단백질인 재조합 AAV를 의미한다.
I. 캡시드 단백질 발현 카세트
포유동물 세포에서, Cap 유전자는 포유동물 p40 프로모터의 제어 하에 2개의 mRNA로 전사된다. 하나의 mRNA는 VP1로 번역되고, 다른 것은 VP2 및 VP3으로 번역된다. VP2에 대한 번역 개시 코돈은 종종 리보솜 스킵을 유발하는 준최적 개시 코돈인 ACG인 반면, VP3에 대한 개시 코돈은 정규 ATG이다. 선택적 스플라이싱 및 약한 VP2 개시 코돈의 상호작용을 통해, Cap 유전자는 VP1, VP2, 및 VP3을 1:1:10의 겉보기 단백질 비로 생산한다 (예를 들어, 상기 문헌 [Berns and Parrish] 참조).
선행 곤충 세포 시스템이 rAAV를 높은 수율 및 효력으로 생산하지 못하는 것은 부분적으로 이들 시스템이 캡시드 단백질의 최적 화학량론을 달성하지 못한 것에 기인하였다. 본 발명의 rAAV 생산 시스템에서, 2개의 별개의 발현 카세트가 VP1 및 VP2/VP3을 발현하는 데 사용된다. VP1 및 VP2/VP3에 대한 별개의 발현 카세트의 사용은 놀랍게도 강력한 rAAV의 고수율 생산으로 이어진다.
일부 실시양태에서, VP1에 대한 발현 카세트 및 VP2/VP3에 대한 발현 카세트는 동일하거나 유사한 강도의 곤충 프로모터를 사용한다. 예를 들어, 2개의 카세트는 동일한 프로모터를 사용할 수 있다. 사용될 수 있는 곤충 프로모터의 예는 p10 프로모터, p35 프로모터, 폴리헤드론 (폴리h) 프로모터, E1 프로모터, ΔE1 프로모터, 4×Hsp27 EcRE+최소 Hsp70 프로모터, 및 염기성 프로모터이다.
발현 카세트는 추가의 조절 요소, 예컨대 코작(Kozak) 서열; 전사 개시 및 종결 부위 (변형 또는 비변형됨); mRNA 스플라이스 부위 (폴리펩티드 코딩 서열 내에서 또는 그에 인접하여 변형 또는 비변형됨); 및 mRNA의 스플라이싱, 핵 유출, 국재화, 안정화 또는 번역을 제어하는 바이러스, 진핵 또는 원핵 RNA 요소 (예를 들어, 우드척(Woodchuck) 간염 바이러스 전사후 조절 요소 (WPRE) (Zufferey et al., J Virol. (1999) 73(4):2886-92), MMLV/MPMV, 진핵 구성적 수송 요소 (CTE) (Li et al., Nature (2006) 443(7108):234-7), RNA 지프코드(zipcode) (Jambhekar and DeRisi, RNA (2007) 13(5):625-42), 및 번역 효율을 증가시키는 오메가 또는 다른 5'-UTR RNA 요소)를 함유할 수 있다.
일부 실시양태에서, 캡시드 단백질에 대한 코딩 서열은 AAV 수율 및 효력을 추가로 증진시키도록 변형될 수 있다. 예를 들어, 코딩 서열은 곤충 세포에서 mRNA 안정성, 번역 효율 및/또는 DNA 벡터 안정성을 증가시키기 위해 코돈-변형될 수 있다. 코딩 서열의 개시 코돈 영역은 또한 캡시드 단백질의 발현 수준을 추가로 미세 조정하기 위하여 변형될 수 있는데; 예를 들어 VP1 개시 코돈은 야생형 ATG에서 VP1 발현 수준이 더 낮도록 VP2의 개시 코돈 (ACG)과 같은 준최적 코돈으로 변화될 수 있다. VP1 개시 코돈은 또한 다른 준최적 개시 코돈, 예컨대 TTG, CTG, 및 GTG로 변화될 수 있다.
VP1 발현 카세트로부터의 VP2 및 VP3 또는 임의의 다른 부산물 펩티드의 생산을 피하기 위해, VP1 코딩 서열을 돌연변이시켜 포매된 VP2 및 VP3 ORF에 대한 천연 개시 코돈, 임의의 아웃-오브-프레임 ATG 부위, 임의의 바람직하지 않은 스플라이스 수용자 부위, 임의의 잠재 프로모터 서열, 및/또는 임의의 탈안정화 요소를 제거할 수 있다 (예를 들어, 상기 문헌 [Smith et al.] 참조).
일부 실시양태에서, 본 생산 시스템은 rAAV6을 생산한다. AAV6 VP1 단백질의 완전한 아미노산 서열이 하기에 제시되며, 여기서 VP2의 개시 부위 (T) 및 VP3의 돌연변이된 개시 부위 (천연 M으로부터 변화됨)는 볼드체 및 밑줄표시된다:
상기 서열에서, 위치 1에서의 X는 M (야생형; 공급원: 진뱅크(GenBank) AAB95450.1), T, L, 또는 V일 수 있다. 다른 실시양태에서, VP1 개시 잔기는 비-정규 개시 코돈, 예컨대 준최적 개시 코돈에 의해 코딩된 또 다른 아미노산일 수 있다 (예를 들어, 문헌 [Kearse et al., Genes Dev. (2017) 31:1717-31] 참조). 일부 실시양태에서, VP1 단백질 내의 돌연변이된 VP3 개시 부위는 상기 제시된 V 이외의 아미노산이다. 일부 실시양태에서, 본원에서 생산된 AAV6 VP2 단백질은 VP3 개시 부위가 돌연변이되지 않은 (즉, 천연 메티오닌인) 서열식별번호: 1의 아미노산 138 내지 736에 걸친 서열을 포함하고, AAV6 VP3 단백질은 N-말단 아미노산이 천연 M인 서열식별번호: 1의 아미노산 204-736에 걸친 서열을 포함한다.
코딩 서열 변형의 추가의 비제한적 예가 하기 기재된다. 또한, WO 2020/168145를 참조하며, 그의 개시내용은 그 전문이 본원에 참조로 포함된다.
A. VP1 및 VP2의 단백질분해적 분해를 감소시키기 위한 변형
일부 실시양태에서, VP1 및 VP2 코딩 서열은 2개 이상의 코돈에서 돌연변이되어 그에 의해 코딩된 VP1 및 VP2 단백질이 생산 프로세스 동안 단백질분해적 분해에 저항성이도록 할 수 있다. VP1 코딩 서열은 또한 AAP에 대한 오픈 리딩 프레임을 함유하기 때문에, 코돈 변화는 또한 AAP에서 돌연변이를 유발할 수 있다. VP1 및 VP2에서의 이들 돌연변이는 rAAV의 감염성, 즉 효력을 추가로 개선시킨다.
일부 실시양태에서, 본 발명의 개선된 바큘로바이러스-곤충 세포 시스템은 곤충 세포에서 단백질분해에 감수성인 임의의 AAV 혈청형을 생산하는 데 사용될 수 있다. 이러한 AAV 혈청형은, 예를 들어 AAV1, AAV6, AAV8 또는 그의 변이체, 또는 VP1 및 VP2 단백질이 곤충 세포에서 단백질분해에 감수성인 임의의 유사형화 또는 키메라 rAAV를 포함할 수 있다.
본 개시내용의 개선된 AAV 생산 시스템에서, 곤충 세포에서 단백질분해에 감수성인 부위를 제거하기 위해, 예를 들어 AAV1, AAV4, AAV6, AAV7, AAV8, 또는 AAV11로부터 유래된 AAV VP1 및 VP2 단백질에 2개 이상의 점 돌연변이가 도입된다. 도입된 점 돌연변이는 AAV2, AAV3, AAV5, AAV9, 또는 AAV10 내의 상응하는 위치에서의 잔기와 동일한 잔기일 수 있다.
"상응하는" 아미노산 잔기 또는 영역이란, 잔기 또는 영역을 함유하는 대상 서열 및 참조 서열을 최대 상동성 (관련 기술분야에서 인식되는 갭을 허용함)을 달성하도록 정렬하였을 때, 참조 잔기 또는 영역과 (반드시 동일하지는 않지만) 정렬되는 아미노산 잔기 또는 영역을 의미한다. 예를 들어, AAV8 VP1의 아미노산 잔기 189 (L)는 AAV6 VP1의 아미노산 잔기 188에 상응한다.
이들 시스템에서, VP1 및 VP2 단백질에 의해 공유되는 중첩 영역은 단백질분해 부위를 제거하기 위해 돌연변이될 수 있다. 예를 들어, rAAV6 VP1 및/또는 VP2는 서열식별번호: 1의 잔기 138-203 (예를 들어, 잔기 151-201, 잔기 157-201, 또는 잔기 185-194 (즉, PQPLGEPPAT (서열식별번호: 2), 여기서 절단은 G와 E 사이에 제시됨))에 상응하는 영역 내의 2개 이상의 잔기에서 야생형에 비해 돌연변이를 포함할 수 있으며, 여기서 돌연변이된 잔기는 잔기 157, 162, 164, 179, 188, 194, 196, 197, 200, 및 201로 이루어진 군으로부터 선택된다. 일부 실시양태에서, AAV6 VP1 및/또는 VP2 단백질은 S157A, T162S, Q164A, S179T, L188I, T194A, A196S, A197G, P200S, 및 T201L (서열식별번호: 1에 따른 넘버링)로 이루어진 군으로부터 선택된 2개 이상의 돌연변이를 포함한다. 예를 들어, AAV6 VP1 및/또는 VP2는 돌연변이 (i) S179T, L188I, T194A, A196S, A197G, P200S, 및 T201L ("변이체 1"); (ii) S179T, L188I, T194A, A196S, 및 A197G ("변이체 2"); (iii) T194A, A196S, A197G, P200S, 및 T201L ("변이체 3"); (iv) S157A, T162S, 및 Q164A ("변이체 4"); 또는 (v) P200S 및 T201L을 가질 수 있다. 편의상, 본원에서는 VP1 내의 잔기 번호만을 언급한다. VP2 내의 상응하는 잔기의 번호는 상기 서열식별번호: 1로부터 쉽게 파악될 수 있다. 예를 들어, VP1 내의 잔기 S157은 VP2 내의 잔기 S20이다.
특정한 실시양태에서, AAV6 VP1 및/또는 VP2는 군 내에 돌연변이 L188I 및 1개 이상의 다른 돌연변이를 포함한다. 예를 들어, AAV6 VP1 및/또는 VP2는 돌연변이 L188I, P200S, 및 T201L을 가질 수 있다.
일부 실시양태에서, AAV6 VP1 및/또는 VP2는 S157A, T162S, Q164A, S179T, L188I, T194A, A196S, A197G, P200S, 및 T201L의 모든 10개의 돌연변이를 포함하여, 서열식별번호: 1에서의 잔기 157-201에 상응하는 영역 내의 그의 서열은 하기와 같다.
상기 서열은 AAV9 VP1 및 VP2의 상응하는 영역 내의 서열과 동일하다.
따라서, 변형된 VP1 코딩 서열을 생성하기 위해, 널리 공지된 분자 클론 기술을 사용하여 VP1의 잔기 157-201 (즉, VP2의 잔기 20-64; 서열식별번호: 3)에 대한 코딩 서열을 AAV9의 상응하는 아미노산 서열 (서열식별번호: 4)에 대한 코딩 서열로 대체할 수 있고; 생성된 변형된 바큘로바이러스 AAV6 헬퍼 벡터는 본원에서 "AAV9 이식체"로 지칭되고, 생성된 VP1 단백질은 본원에서 "AAV6/9 VP1"로 지칭된다. 동일한 이식으로 VP2에서 동일한 영역을 돌연변이시켜 AAV6/9 VP2를 생성할 수 있다. 일부 실시양태에서, 대체된 AAV6 VP1 유전자 서열의 부분은 하기에 제시된 밑줄표시된 서열을 포함한다 (또한 도 2 참조):
특정 실시양태에서, 서열식별번호: 13에서 밑줄표시된 부분은 AAV9로부터의 상응하는 Cap 유전자 서열로 대체되어 본원에 개시된 AAV9 이식체를 생성한다. 특정한 실시양태에서, AAV9 이식체에서 AAV6 Cap 유전자에 이식된 AAV9 Cap 서열은 하기에 제시된 밑줄표시된 서열을 포함한다 (또한 도 2 참조):
다른 실시양태에서, 바큘로바이러스 AAV6 헬퍼 구축물 내의 변형된 cap6 유전자는 서열식별번호: 1의 VP1의 잔기 157-201에 대한 코딩 서열 (즉, VP2의 잔기 20-64; 서열식별번호: 3)을 VP1 및/또는 VP2가 곤충 세포에서의 단백질분해적 절단에 저항성인 혈청형, 예를 들어 AAV2, AAV3, AAV5, 또는 AAV10으로부터의 상응하는 아미노산 서열에 대한 코딩 서열로 대체함으로써 생성될 수 있다.
다른 실시양태에서, AAV 혈청형, 예컨대 AAV1, AAV4, AAV7, AAV8, 또는 AAV11의 VP1/VP2 단백질은 이들이 도 1c에 제시된 1개 이상의 돌연변이를 함유하도록 돌연변이될 수 있다. 생성된 단백질은 곤충 세포에서 단백질분해에 대해 보다 저항성일 것으로 예상된다. 다양한 AAV 혈청형으로부터의 조작된 VP1/VP2 단백질의 비제한적 예는 하기에 제시된다:
(1) 조작된 AAV1 VP1/VP2 단백질은 하기 돌연변이: S158T/A, I160T/V, T163A/S/K, Q165K/A, K169R, S180A/T, L189E/I, T195A, A197S/T, A198S/G, V199L, P201T/S, 및 T202N/L 중 1개 이상을 함유할 수 있고;
(2) 조작된 AAV4 VP1/VP2 단백질은 하기 돌연변이: T158S/A, I160T/V, K163A/S, K165Q/A, K169R, K171R, V173N, E175G, D176Q/E, E177T, T178G, G179D/E, A180S/T, G181D/E, D182S, G183V, E189L/I, S191Q/E, T192P, S193P, G194A, M196P, S197T, D200G, D201T/S, S202N/L, 및 E203T 중 1개 이상을 함유할 수 있고;
(3) 조작된 AAV6 VP1/VP2 단백질은 하기 돌연변이: S158T/A, I160T/V, T163A/S/K, Q165K/A, K169R, S180A/T, L189E/I, T195A, A197S/T, A198S/G, V199L, P201T/S, 및 T202N/L 중 1개 이상을 함유할 수 있고;
(4) 조작된 AAV7 VP1/VP2 단백질은 하기 돌연변이: T158S/A, I160T/V, K163A/S, Q165K/A, R169K, S180A/T, L189E/I, S197T, S198G, V199L, 및 G202N/L 중 1개 이상을 함유할 수 있고;
(5) 조작된 AAV8 VP1/VP2 단백질은 하기 돌연변이: T158S/A, I160T/V, K163A/S, Q165K/A, R169K, S180A/T, L189E/I, S197T, G198S, V199L, P201T/S, 및 N202L 중 1개 이상을 함유할 수 있고;
(6) 조작된 AAV11 VP1/VP2 단백질은 하기 돌연변이: S158T/A, I160T/V, K163A/S, K165Q/A, R169K, E175G, E176Q, D177T, T178G, G179D/E, A180S/T, G181D/E, D182S, G183V, E189L/I, S191Q/E, D192P, T193P, S194A, M196P, S197T, S200G, D201T/S, I202N/L, 및 E203T 중 1개 이상을 함유할 수 있다 (컨센서스 넘버링; 도 1c 참조).
일부 실시양태에서, 곤충 세포에서 단백질분해에 감수성인 AAV 혈청형으로부터의 VP1/VP2 단백질은 하기 아미노산 잔기 (도 1c에서의 컨센서스 넘버링): 158, 163, 165, 180, 189, 195, 197, 198, 201, 및 202에서 1개 이상의 돌연변이를 함유하도록 돌연변이된다 (이들 잔기는 각각 서열식별번호: 1 (AAV6)의 넘버링에 따른 아미노산 잔기 157, 162, 164, 179, 188, 194, 196, 197, 200, 및 201 또는 서열식별번호: 1에 대해 최대 상동성을 나타내도록 정렬된 또 다른 혈청형으로부터의 상응하는 서열에 상응한다). 추가 실시양태에서, VP1/VP2 단백질은 하기 아미노산 잔기 (도 1c에서의 컨센서스 넘버링): 160, 169, 171-179, 181-183, 191-194, 196, 199 및 203에서 1개 이상의 돌연변이를 추가로 함유할 수 있다.
일부 실시양태에서, 곤충 세포에서 단백질분해에 감수성인 AAV 혈청형으로부터의 VP1/VP2 단백질은 1개 이상의 돌연변이: S158T/A, I160T/V, K/T163S/A/T, Q165K/A, K169R, K171R, V173N, E175G, D176Q/E, D/E177T, T178G, G179D/E, S180A/T, G181D/E, D182S, G183V, L189E/I, Q/S191E, T/D192P, S/T193P, G/S194A, T/G195A, M196P, A197S/T, A198G/S, V199L, S200G, D/P201S/T, T/S202N/L, 및 E203T (도 1c에서의 컨센서스 넘버링)를 함유하도록 돌연변이된다.
일부 실시양태에서, 조작된 VP1/VP2 단백질은 하기 돌연변이: S158A, T163S, Q165A, S180T, L189I, T195A, A197S, A198G, P201S 및 T202L (도 1c에서의 컨센서스 번호) 중 1개 이상을 함유할 수 있다 (이들 잔기는 각각 서열식별번호: 1 (AAV6)의 넘버링에 따른 아미노산 잔기 S157A, T162S, Q164A, S179T, L188I, T194A, A196S, A197G, P200S 및 T201L 또는 서열식별번호: 1에 대해 최대 상동성을 나타내도록 정렬된 또 다른 혈청형으로부터의 상응하는 서열에 상응한다).
본원에 기재된 돌연변이는 곤충 세포에서의 단백질분해적 절단에 감수성인 AAV 캡시드 단백질 내의 부위를 제거한다. 따라서, 변형된 Cap 유전자를 함유하는 헬퍼 구축물은 보다 높은 순도 및 균일성의 rAAV 생성물, 뿐만 아니라 개선된 캡시드 단백질을 생성할 것이다.
놀랍게도, AAV VP1/VP2 고유 영역 (즉, VP1 및 VP2에 공통적이지만 VP3에는 부재하는 영역)에 대해 본원에 도입된 점 돌연변이가 또한 단백질분해적 절단의 방지에만 의존하지 않는 메카니즘을 통해 rAAV의 효력을 유의하게 개선시킬 수 있는 것으로 밝혀졌다.
B. rAAV 생산 수율의 추가 개선을 위한 변형
추가적으로 또는 대안적으로, 바큘로바이러스 헬퍼 구축물 내의 VP1 코딩 서열은 조작된 PLA2 도메인이 보다 높은 효소적 활성을 획득하도록 VP1 PLA2 도메인을 코딩하는 영역 내의 1개 이상의 코돈에서 돌연변이된다. 보다 높은 PLA2 효소적 활성은 곤충 세포 생산 시스템에서 보다 높은 수율의 rAAV로 이어질 수 있는 것으로 밝혀졌다.
본 개시내용은 곤충 세포에서 rAAV의 생산 수율을 개선시키기 위해 VP1 코딩 서열이 VP1 고유 영역 (즉, VP1에 존재하지만 VP2 또는 VP3에는 존재하지 않는 영역)에서 변경된 바큘로바이러스-곤충 시스템을 제공한다. VP1 고유 영역 (서열식별번호: 1의 잔기 1-137에 상응함)은 PLA2 도메인을 함유하고, 영역 내의 돌연변이는 생성된 VP1 단백질에서 PLA2 도메인의 효소적 활성을 증가시킬 수 있다.
일부 실시양태에서, 본 개시내용의 바큘로바이러스 헬퍼 구축물은 rAAV6 또는 rAAV9의 생산을 위한 헬퍼 기능을 제공하고, 헬퍼 구축물 상의 VP1 발현 카세트는 돌연변이된 PLA2 도메인을 갖는 변형된 AAV6 또는 AAV9 Cap 유전자 (각각 Cap6 또는 Cap9)를 포함한다. 돌연변이된 PLA2 도메인은 서열식별번호: 1의 잔기 1-137 (예를 들어, 52-97 또는 67-92)에 상응하는 영역 내의 1개 이상의 위치에서 야생형에 비해 돌연변이를 포함할 수 있고, 여기서 위치는 잔기 67, 81, 84, 85, 및 92 (서열식별번호: 1의 넘버링)로 이루어진 군으로부터 선택된다. 일부 실시양태에서, AAV6 VP1 단백질은 A67E, Q81R, K84D, A85S, 및 R92K (서열식별번호: 1에 따른 넘버링)로 이루어진 군으로부터 선택된 1개 이상의 돌연변이를 포함한다. 특정한 실시양태에서, AAV6 VP1 단백질은 5개의 돌연변이 모두를 포함하고, 이에 의해 서열식별번호: 1에서의 잔기 52-97 (서열식별번호: 5)에 상응하는 영역 내의 그의 서열은 하기와 같다.
이러한 서열은 AAV2 VP1 내의 상응하는 영역 내의 서열과 동일하다. 따라서, 바큘로바이러스 AAV6 헬퍼 구축물에서 변형된 cap6 유전자를 생성하기 위해, 널리 공지된 분자 클로닝 기술을 사용하여 VP1의 잔기 52-97 또는 67-92에 대한 코딩 서열을 AAV2의 상응하는 아미노산 서열에 대한 코딩 서열로 대체할 수 있다.
놀랍게도, AAV VP1 고유 영역에 본원에 도입된 점 돌연변이가 VP1 PLA2 도메인의 효소적 활성을 유의하게 개선시킬 수 있고, 또한 곤충 세포에서 생산된 rAAV의 수율의 유의한 개선 (예를 들어, 2배 이상, 3배 이상, 4배 이상, 또는 5배 이상)으로 이어질 수 있는 것으로 밝혀졌다.
특정한 실시양태에서, 조작된 Cap 유전자는 PLA2 도메인에서의 상기 언급된 돌연변이 및 단백질분해 부위를 제거하는 상기 언급된 돌연변이 둘 다를 함유하는 AAV6 VP1 단백질을 코딩한다. 하나의 예시적인 변형된 AAV6 VP1 단백질 ("AAV6/2/9 VP1")은 하기 서열을 갖는다 (여기서 V203은 대신 M203 또는 또 다른 아미노산일 수 있음):
다른 예시적인 변형된 AAV6 VP1 단백질은 위치 1에서의 개시 잔기가 존재하지 않거나, 또는 T, L, V 또는 비-정규 개시 코돈, 예컨대 준최적 개시 코돈에 의해 코딩되는 또 다른 아미노산인 것을 제외하고는 서열식별번호: 7과 동일한 서열을 갖는다. 이들 변형된 AAV6 VP1 단백질 중 하나를 코딩하는 바큘로바이러스 헬퍼 구축물은 곤충 세포에서 개선된 효력 및 수율을 갖는 rAAV6 또는 유사형화 또는 키메라 rAAV를 생산하는 데 사용될 수 있다.
일부 실시양태에서, 조작된 Cap 유전자는 AAV2 PLA2 도메인을 함유하는 AAV9 VP1 단백질을 코딩한다. 야생형 AAV9 VP1 서열 (유니프롯KB(UniProtKB) - Q6JC40 (Q6JC40_9VIRU))은 하기에 제시되고, 여기서 PLA2 도메인 내의 AAV9/2 VP1 내의 상응하는 것과 상이한 5개의 아미노산 잔기는 볼드체 및 박스로 표시된다:
상기 영역 내의 야생형 AAV9 및 AAV2 서열 (서열식별번호: 11의 잔기 52-97)은 하기에 제시되고, 여기서 AAV2 서열 이식 후에 야생형 AAV9와 비교한 5개의 아미노산 변화는 볼드체 및 박스로 표시된다:
일부 실시양태에서, 서열식별번호: 11에서의 M203은 V203 또는 비정규 개시 코돈에 의해 코딩되는 또 다른 아미노산에 의해 대체될 수 있다.
C. AAP에 대한 변형
일부 실시양태에서, VP1 코딩 서열은 또한 캡시드 단백질을 안정화시키고 캡시드 조립을 용이하게 하는 개선된 능력을 갖는 조작된 AAP를 코딩한다. AAV6 AAP의 잔기 1-30 ("AAP6")이 AAV9 AAP의 잔기 1-30 ("AAP9")으로 변화된 경우에, 조작된 헬퍼 구축물로 생산된 rAAV의 효력은 유의하게 증가되는 것으로 밝혀졌다. AAP6 및 AAP9의 잔기 1-30은 하기에 제시되며, 여기서 야생형 AAP6과 비교한 야생형 AAP9에서의 6개의 아미노산 차이는 볼드체 및 박스로 표시된다:
완전한 AAV6 AAP 야생형 서열은 하기에 제시된다:
일부 실시양태에서, 조작된 AAP 단백질은 잔기 8, 10, 12, 17, 21, 및 22 (도 4a의 컨센서스 서열에 기초한 넘버링)에서 1개 이상의 돌연변이를 포함한다. 추가 실시양태에서, 조작된 AAP 단백질은 하기 아미노산 잔기: Q8, L10, Q12, P17, Q21, 및 V22 중 1개 이상을 포함할 수 있다. 일부 실시양태에서, 조작된 AAP 단백질은 야생형 AAP 서열에 비해 하기 돌연변이: P8Q, H10L, L12Q, Q17P, L21Q 및 L22V 중 1개 이상을 포함할 수 있다. 조작되고 개선된 AAP 단백질의 비제한적인 예는 하기에 제시된다:
(1) 하기 돌연변이: P8Q, I9T, H10L, L12Q, L16H, Q17P, L21Q, L22V, 및 L26I 중 1개 이상을 포함하는 조작된 AAP1 (혈청형 1의 AAP);
(2) 하기 돌연변이: E2A, T5S, Y7S, L8Q, P10L, S11N, L12Q, D14E, S15N, H16L, Q17P, L21Q, E24D, I26L, 및 R27Q 중 1개 이상을 포함하는 조작된 AAP2 (혈청형 2의 AAP);
(3) 하기 돌연변이: E2A, Q3T, A4Q, T5S, D6Q, P7S, L12Q, R13S, D14E, Q15N, L16H, P17Q, E18Q, C22V, L23W, M24D, T25L, V26I/L, R27Q 및 C28W 중 1개 이상을 포함하는 조작된 AAP4 (혈청형 4의 AAP);
(4) 하기 돌연변이: P8Q, H10L, L12Q, L16H, Q17P, L21Q, L22V, 및 L26I 중 1개 이상을 포함하는 조작된 AAP6 (혈청형 6의 AAP);
(5) 하기 돌연변이: P8Q, L12Q, L16H, Q17P, L21Q, L22V, 및 L26I 중 1개 이상을 포함하는 조작된 AAP7 (혈청형 7의 AAP);
(6) 하기 돌연변이: F7S, L12Q, L16H, Q17P, R19P, L21Q 및 I26L 중 1개 이상을 포함하는 조작된 AAP8 (혈청형 8의 AAP);
(7) 하기 돌연변이: S3T, P8Q, Q12L, L16H, Q17P, A19P, L21Q 및 V26I/L 중 1개 이상을 포함하는 조작된 AAP10 (혈청형 10의 AAP); 및
(8) 하기 돌연변이: E2A, P3T, E4Q, T5S, D6Q, P7S, L12Q, R13S, D14E, Q15N, I16L/H, P17Q, A18Q, C22V, L23W, Q24D, T25L, L26I, K27Q 및 C28W 중 1개 이상을 포함하는 조작된 AAP11 (혈청형 11의 AAP) (또한 도 4b 참조).
조작된 AAP 단백질을 생성하기 위해, 점 돌연변이를 수행할 수 있다. AAP를 코딩하는 오픈 리딩 프레임은 Cap 유전자에 포매되고 단지 프레임시프트에 의해 번역되기 때문에, AAP의 N 말단 부분에 대한 코딩 서열 (예를 들어, 잔기 1-30, 잔기 1-28, 잔기 2-30, 잔기 2-28 등)을 함유하는 Cap 유전자의 부분을 또 다른 혈청형으로부터 이식할 수도 있다. 일부 실시양태에서, AAV9 VP1/VP2 고유 영역 (즉, VP1 및 VP2에 공통적이지만 VP3에는 부재하는 영역), 예를 들어 서열식별번호: 14의 뉴클레오티드 18-151을 포함하는 cap9 서열을 코딩하는 AAV9 Cap 유전자 부분이 cap6의 상응하는 영역으로 치환되어, AAV9 VP1의 부분을 갖는 조작된 AAV6 VP1을 발현하는 조작된 VP1 발현 카세트 (예를 들어, 상기 논의된 바와 같은 단백질분해 부위(들)를 제거하도록) 뿐만 아니라 N-말단 1-30개의 아미노산 잔기가 이제 AAP9의 것과 동일한 조작된 AAP6을 생성한다. 일부 실시양태에서, AAP 돌연변이는 AAV9 Cap 유전자 이식에 대해 상기 기재된 바와 동일한 방법에 의해 생성된다.
캡시드 단백질의 추가의 예는 하기 실시예에 기재되어 있다.
II. Rep 단백질 발현 카세트
포유동물 세포에서, Rep 유전자는 포유동물 p5 프로모터의 제어 하에 Rep78-코딩 RNA 및 Rep78 ORF 내에 위치한 포유동물 p19 프로모터 하에 Rep52-코딩 RNA로 전사된다 (예를 들어, 상기 문헌 [Urabe et al., 2002] 참조). Rep78 및 Rep52 둘 다에 대한 개시 코돈은 ATG이다. Rep52에 비해 Rep78의 과다발현은 rAAV의 수율에 불리한 영향을 미치는 것으로 밝혀졌다.
선행 곤충 세포 시스템이 rAAV를 고수율로 생산하지 못하는 것은 부분적으로 이들 시스템이 Rep 단백질의 최적 화학량론을 달성하지 못한 것에 기인하였다. 본 발명의 rAAV 생산 시스템에서, 2개의 별개의 발현 카세트가 Rep78 및 Rep52를 발현시키는 데 사용된다. 일부 실시양태에서, Rep78에 대한 발현 카세트 및 Rep52에 대한 발현 카세트는 동일하거나 유사한 강도의 곤충 프로모터를 사용하지만; Rep78에 대한 보다 약한 개시 코돈 (예를 들어, CTG, TTG, GTG, 및 ACG)을 사용하는 것은 목적하는 Rep78:Rep52 단백질 비 및 높은 AAV 수율을 달성하도록 돕는다. 특정 실시양태에서, 2개의 카세트는 동일한 프로모터, 예컨대 캡시드 발현 카세트에 대해 상기 열거된 것을 사용할 수 있다. 다른 실시양태에서, Rep78 발현 카세트는 정규 개시 코돈 (ATG)을 갖지만, 목적하는 화학량론을 달성하기 위해 Rep52 발현 카세트보다 더 약한 프로모터를 사용한다.
일부 실시양태에서, Rep 발현 카세트는 추가의 조절 요소, 예컨대 캡시드 단백질 발현 카세트에 대해 상기 기재된 것들을 함유할 수 있다.
일부 실시양태에서, Rep 단백질에 대한 코딩 서열은 AAV 수율 및 효력을 추가로 증진시키도록 변형될 수 있다. 예를 들어, 코딩 서열은 곤충 세포에서 mRNA 안정성, 번역 효율 또는 DNA 벡터 안정성을 증가시키기 위해 코돈-변형될 수 있다. Rep52 또는 Rep78 발현 카세트로부터의 임의의 다른 부산물 펩티드의 생산을 피하기 위해, Rep78 코딩 서열을 돌연변이시켜 포매된 Rep52 ORF에 대한 개시 코돈, 임의의 오프-프레임 ATG 부위, 임의의 바람직하지 않은 스플라이스 수용자 부위, 임의의 잠재 프로모터 서열, 및/또는 임의의 탈안정화 요소를 제거할 수 있다 (예를 들어, 상기 문헌 [Smith et al.] 참조). 반대로, Rep52 코딩 서열을 트리밍하여 Rep52 개시 코돈 상류의 임의의 Rep78 코딩 서열을 제거할 수 있다.
Rep78에 대한 준최적 개시 코돈의 사용과 함께, Rep78 및 Rep52에 대한 별개의 발현 카세트의 사용은 놀랍게도 강력한 rAAV의 고수율 생산으로 이어진다.
III. 곤충 세포에서의 rAAV 생산
곤충 세포에서의 rAAV 생산은 이전에 기재된 바와 같이 수행될 수 있다. 예를 들어, 문헌 [Urabe et al., 2002 and 2006, 상기 문헌; Chen et al., 상기 문헌; Smith et al., 상기 문헌; Mietzsch et al., 상기 문헌]; WO 2007/046703, WO 2007/148971, WO 2009/104964, WO 2013/036118 및 WO 2008/024998을 참조하며, 이들 모두는 그 전문이 본원에 참조로 포함된다.
본 개시내용의 생산 방법에서의 곤충 세포는 본원에 기재된 이중 바큘로바이러스 헬퍼 벡터를 포함한다. 곤충 세포는, 비제한적으로, 배양된 세포주 예컨대 트리코플루시아 니(Trichoplusia ni)로부터 유래된 BTI-TN-5B1-4 (하이 파이브(High Five)™, 써모 피셔 사이언티픽(Thermo Fisher Scientific), 캘리포니아주 칼스배드), Sf9 세포 또는 Sf21 세포 (둘 다 스포도프테라 프루기페르다(Spodoptera frugiperda)로부터 유래됨), 포유동물-유형 글리칸 프로파일을 갖는 Sf9 또는 TN368 세포 (글리코박(GlycoBac)), 또는 Sf-RVN 세포 (밀리포어시그마(MilliporeSigma)), Sf9-13F12 세포 (라도바이러스-무함유 세포; 문헌 [Ma et al., Virology (2019) 536:125-33])일 수 있다.
rAAV는 그의 캡시드 내에 관심 트랜스진을 함유하는 AAV 벡터를 포함할 수 있다. 트랜스진은 생화학적 (루시페라제, SEAP) 또는 영상화 (GFP, 비너스(Venus), dTomato) 기술을 사용한 검출을 위해 리포터 단백질을 코딩할 수 있다. 트랜스진은 키메라 항원 수용체 (CAR), C-펩티드 또는 인슐린, 콜라겐 VII, IGF-I, 지단백질 리파제, 피브리노겐, 프로트롬빈, 인자 V, 인자 VIII, 인자 IX, 인자 XI, 인자 XII, 인자 XIII, 폰 빌레브란트 인자, 프리칼리크레인, 고분자량 키니노겐 (피츠제랄드 인자), 피브로넥틴, 항트롬빈 III, 헤파린 보조인자 II, 단백질 C, 단백질 S, 단백질 Z, 단백질 Z-관련 프로테아제 억제제, 플라스미노겐, 알파 2-항플라스민, 조직 플라스미노겐 활성화제, 우로키나제, 플라스미노겐 활성화제 억제제-1, 플라스미노겐 활성화제 억제제-2, 또는 리소솜 축적 질환, 예컨대 알파-갈락토시다제 A를 치료하기 위한 (파브리병을 치료하기 위한) 임의의 효소를 포함하나 이에 제한되지는 않는 치료 단백질을 코딩할 수 있다. 트랜스진은 서열-특이적 결합 단백질 (예를 들어, ZFP, TALE, TALEN, 또는 dCas9)을 코딩할 수 있다. 일부 실시양태에서, ZFP는 ZFP 전사 인자 (예를 들어, ZFP 도메인이 전사 인자에 융합된 융합 단백질), 아연 핑거 뉴클레아제 (예를 들어, ZFP 도메인이 뉴클레아제에 융합된 융합 단백질), 또는 ZFP 염기 편집제 (예를 들어, ZFP 도메인이 핵염기 편집제에 융합된 융합 단백질)일 수 있다. 트랜스진은 상동 재조합 또는 비-상동 말단 연결에 의해 숙주 게놈 (공여자) 내의 특정 부위 내로 혼입될 수 있는 서열을 보유할 수 있다. 트랜스진은 백신접종을 위한 면역원성 단백질 (예를 들어, 종양 항원)을 코딩할 수 있다.
AAV 벡터는 인간 세포에서 트랜스진의 발현을 지시하고 조절할 수 있는 전사 조절 요소 (예를 들어, 프로모터 및 인핸서)를 포함할 수 있다. AAV 벡터는 또한 트랜스진 발현 카세트의 한쪽 또는 양쪽 말단 상에 AAV 완전 또는 부분 역전된 말단 반복부 (ITR)를 포함할 수 있다. ITR은 패키징 및 숙주 (인간) 게놈 내로의 바이러스 통합에 필요하다. AAV 벡터는 단일-가닥 또는 자기-상보적일 수 있다.
IV. rAAV의 제약 조성물
본 방법에 의해 생산된 rAAV 캡시드는 제약 조성물로서 제약상 허용되는 담체와 함께 제제화될 수 있다. 제제는 액체 또는 유화된 액체 중의 현탁제를 포함하나 이에 제한되지 않는다. 제약상 허용되는 담체는 예를 들어, 물, 염수, 덱스트로스, 글리세롤, 수크로스 등 및 그의 조합을 포함한다. 추가로, 조성물은 예컨대, 습윤제 또는 유화제, pH 완충제, 안정화제, 또는 rAAV 제약 조성물의 유효성을 증진시키는 다른 시약과 같은 보조 물질을 함유할 수 있다.
rAAV 제약 조성물은 예를 들어, 전신 투여 (예를 들어, 정맥내, 복강내, 근육내, 피하, 척수강내 또는 두개내 주입) 또는 국부 주사에 의해 환자에게 투여함으로써 생체내 전달될 수 있다. 대안적으로, rAAV는 환자로부터 체외이식된 세포 (예를 들어, 림프구, 골수 흡인물, 또는 조직 생검) 또는 동종 세포 (예를 들어, 범용 CAR T 세포와 같은 범용 공여자 세포)와 같은 생체외 세포로 전달된 후, 이어서, 통상적으로, rAAV 벡터가 도입된 세포에 대한 선별 후에, 처리된 세포는 환자에게 도입될 수 있다.
본원에서 달리 정의되지 않는 한, 본 발명과 관련하여 사용된 과학 기술 용어는 관련 기술분야의 통상의 기술자에 의해 일반적으로 이해되는 의미를 가질 것이다. 예시적인 방법 및 물질이 하기에 기재되지만, 본원에 기재된 것과 유사하거나 동등한 방법 및 물질이 또한 본 발명의 실시 또는 시험에 사용될 수 있다. 상충되는 경우에, 정의를 포함한 본 명세서가 우선할 것이다. 일반적으로, 본원에 기재된 세포 및 조직 배양, 분자 생물학, 바이러스학, 면역학, 미생물학, 유전학, 분석 화학, 합성 유기 화학, 의약 및 제약 화학, 및 단백질 및 핵산 화학 및 하이브리드화와 관련하여 사용된 명명법 및 그의 기술은 관련 기술분야에 널리 공지되어 있고 통상적으로 사용되는 것이다. 효소적 반응 및 정제 기술은 제조업체의 설명서에 따라, 관련 기술분야에서 통상적으로 달성되는 바와 같이 또는 본원에 기재된 바와 같이 수행된다. 추가로, 문맥상 달리 요구되지 않는 한, 단수 용어는 복수를 포함할 것이고, 복수 용어는 단수를 포함할 것이다. 본 명세서 및 실시양태 전반에 걸쳐, 단어 "갖는다" 및 "포함한다", 또는 변형어, 예컨대 "갖는다(has)", "갖는", "포함한다(comprises)" 또는 "포함하는"은 언급된 정수 또는 정수의 군을 포함하지만, 임의의 다른 정수 또는 정수의 군을 배제하지 않음을 암시하는 것으로 이해될 것이다. 본원에 언급된 모든 간행물 및 다른 참고문헌은 그 전문이 참조로 포함된다. 다수의 문헌이 본원에 인용되지만, 이러한 인용은 이들 문헌 중 임의의 것이 관련 기술분야의 통상의 일반 지식의 일부를 형성한다는 것을 인정하는 것은 아니다.
본 발명을 보다 잘 이해할 수 있도록 하기 위해, 하기 실시예를 기재한다. 이들 실시예는 단지 예시를 위한 것이며, 어떠한 방식으로도 본 발명의 범주를 제한하는 것으로 해석되어서는 안된다.
실시예
실시예 1: Sf9 곤충 세포에서의 AAV 생산
현재, Sf9 AAV 제조에 사용되는 헬퍼 시스템은 AAV 생산에 요구되는 모든 Rep 및 캡시드 단백질을 발현하기 위해 누출 스캐닝, 선택적 스플라이싱, 및/또는 내부 프로모터에 의존한다 (Smith et al., 상기 문헌; Chen et al., 상기 문헌). 이용가능한 캡시드 단백질의 화학량론에 기초하여 AAV 캡시드가 조립되기 때문에 (Berns and Parrish, 상기 문헌), 본 발명자들은 rAAV 생산 동안 발현된 VP1의 양에 대해 보다 큰 제어를 발휘하는 것이 rAAV 캡시드 내로 혼입된 VP1의 양을 증가시키고, 그에 의해 바이러스 효력을 증가시킬 수 있다고 가정하였다.
이 가설을 시험하기 위해, 본 발명자들은 독립적 프로모터의 제어 하에 개별 캡시드 단백질에 대한 코딩 서열을 개별 바큘로바이러스 벡터 내로 클로닝하였다. Rep 단백질에 대한 보다 큰 제어를 가능하게 하기 위해, 본 발명자들은 또한 개별 Rep 단백질에 대한 코딩 서열을 개별 바큘로바이러스 벡터 내로 클로닝하였다. 상이한 벡터 상의 Rep 및 Cap 코딩 서열의 다양한 가능한 조합을 시험하기 위해, 본 발명자들은 2가지 버전의 바큘로바이러스 헬퍼 시스템을 구축하였다 (도 5).
제1 버전에서, 본 발명자들은 Rep78 발현 카세트를 VP1 발현 카세트와 쌍형성시키고, Rep52 발현 카세트를 VP2/VP3 발현 카세트와 쌍형성시켰다. 제2 버전에서, 본 발명자들은 Rep52 발현 카세트를 VP1 발현 카세트와 쌍형성시키고, Rep78 발현 카세트를 VP2/VP3 발현 카세트와 쌍형성시켰다. Rep 발현 카세트 둘 다는 폴리헤드린 프로모터의 제어 하에 있었다. VP1 및 VP2/3 발현 카세트 둘 다는 p10 프로모터의 제어 하에 있었다. AAV 복제의 자연적 맥락에서와 동일한 누출 스캐닝 메카니즘을 이용하는 VP2/3 유전자를 제외하고는, 이들 헬퍼 벡터 내 Rep 코딩 서열 및 VP1 코딩 서열 중 어느 것도 발현을 위해 누출 스캐닝 또는 선택적 스플라이싱에 의존하지 않는다. rAAV 생산에 필요한 바큘로바이러스 벡터의 수를 감소시키기 위해, 본 발명자들은 AAV 미니게놈에 대한 코딩 서열을 Rep52-발현 벡터 내로 둘 다의 버전으로 혼입시켰다 (도 5). 본 연구를 위해, AAV 미니게놈은 알파-갈락토시다제 A (GLA) 또는 아연 핑거 단백질 (ZFP)에 대한 발현 카세트를 함유하였다 (SBS#65918 및 SBS#57890, 이들의 코딩 서열은 트랜스진 발현 카세트에서 T2A 자기-절단 펩티드를 코딩하는 뉴클레오티드 링커에 의해 분리되었다; WO 2018/102665 및 WO 2020/072677 참조). GLA-코딩 rAAV는 파브리병에 대한 유전자 요법에 유용할 수 있다. ZFP는 마우스 미세관-연관 단백질 타우 (Mapt) 유전자에 결합하여 그의 발현을 억제하였다.
발현 카세트 내의 코딩 서열 및 코딩된 폴리펩티드 서열은 다음과 같다. VP1 코딩 서열에서, 천연 VP3 ORF에 대한 ATG 개시 코돈을 GTG로 변화시켜 M에서 V로의 치환을 발생시켰다. Rep78 코딩 서열에서, 천연 Rep58 ORF에 대한 ATG 개시 코돈을 GTG로 변화시켜 M에서 V로의 치환을 또한 발생시켰다. 본원의 연구를 위해, Rep 유전자는 AAV2로부터 유래되었다.
rAAV의 생성 및 상대 수율의 결정
나이브 Sf9 곤충 세포에 바큘로바이러스-감염된 곤충 세포 (2개의 바큘로바이러스 벡터에 의해 각각 감염된 세포에 대해 BIIC1 및 BIIC2)를 접종하였다. 접종을 위한 BIIC1:BIIC2:나이브 Sf9 세포의 비는 1:1:10000이었다. 세포 배양물을 6일 동안 인큐베이션하였다. 이어서, 세포를 수거하고, 재현탁시키고, 3회 동결/해동시켰다. 세포 용해물을 벤조나제로 처리하였다. 세포 파편을 원심분리에 의해 제거하였다. AAV를 PEG 및 NaCl의 첨가에 의해 농축시킨 후, 얼음 상에서 인큐베이션하고, 침전된 바이러스를 원심분리하였다. 농축된 바이러스를 재현탁시키고, CsCl 구배에 적용한 후, 밤새 초원심분리하였다. 밴딩된 AAV를 수집하고, 투석하였다. 이어서, qPCR을 수행하여 벡터 게놈 (vg) 함량을 적정하였다. 본원에서 시험된 rAAV6 (GLA-코딩 트랜스진을 포함함) 및 rAAV9 (ZFP-코딩 트랜스진을 포함함)를 이들 방법에 의해 수득하였다. vg/mL에 샘플의 총 mL을 곱하여 총 AAV 수율을 계산하고, AAV2 레플리카제 및 AAV6 캡시드 단백질을 발현하고 상기 문헌 [Smith et al.]에 기재된 1-벡터 시스템을 사용하는 표준 헬퍼 시스템 1의 수율과 비교하여 표현하였다.
추가의 rAAV 혈청형, rAAV1, rAAV2, 및 rAAV3B를 도 5에 예시된 버전 2 방법에 의해 수득하였다. rAAV1 및 rAAV3B 바이러스에서의 VP1은 상기 기재된 바와 같은 AAV2 PLA2 도메인을 함유하였다. rAAV1의 경우에, VP1 및 VP2는 단백질분해 부위를 제거하기 위해 상기 기재된 바와 같은 AAV9 이식체를 추가로 함유하였다. AAV2 및 AAV3B는 AAV1 및 AAV6에서 관찰된 바와 같이 단백질분해적 절단에 감수성인 것으로 보이지 않았고; 따라서, 그의 VP1/VP2는 이식된 AAV9 VP 서열을 함유하도록 조작되지 않았다. 이들 3종의 바이러스는 또한 rAAV9와 동일한 ZFP 트랜스진을 보유하였다.
연구에서, AAV 게놈은 AAV2로부터의 ITR (역전된 말단 반복부)을 포함하였고, 곤충 세포는 AAV2 레플리카제를 발현하였다.
본원의 rAAV6, rAAV9, rAAV1, rAAV2, 및 rAAV3B 바이러스의 캡시드 단백질 서열은 하기에 제시된다. rAAV6의 캡시드 단백질은 상기 상세히 기재된 바와 같은 AAV2 및 AAV9로부터의 서열을 함유하였다. rAAV9, rAAV1, 및 rAAV3B의 캡시드 단백질을 또한 하기 나타낸 바와 같이 다른 AAV 혈청형으로부터의 서열을 함유하도록 조작하였다.
rAAV6 효력의 결정
본 실시예에서 상기 기재된 방법에 의해 수득된 rAAV6을 900K의 감염 다중도 (vg 역가에 기초한 MOI 또는 바이러스/세포)로 HepG2 세포에 적용하였다. 세포를 5일 동안 인큐베이션하였다. 조직 배양물 상청액을 수집하고, GLA 기질로부터 방출된 형광 리포터 4-메틸움벨리페릴 (4-MU)의 수준을 측정함으로써 GLA 효소 활성에 대해 검정하였다. 효소적 활성을 표준 헬퍼 시스템 1에 의해 생산된 rAAV 샘플을 사용한 활성과 비교하여 계산하였다.
rAAV9 효력의 결정
본 실시예에서 상기 기재된 방법에 의해 수득된 rAAV9를 30K의 MOI로 마우스 피질 뉴런에 적용하고, 6일 동안 인큐베이션하였다. 세포를 총 RNA에 대해 수거하고, cDNA를 생성하는 데 사용하였다. cDNA를 AAV 트랜스진에 의해 코딩되는 마우스 Mapt mRNA 및 아연 핑거 단백질 (ZFP) mRNA의 발현에 대해 qPCR에 의해 분석하였다. mRNA 발현을 숙주 세포 RNA에 대해 정규화한 후, 효력을 AAV9 표준 헬퍼 시스템 (하기)에 의해 생산된 rAAV9와 비교하여 계산하였다. rAAV1, rAAV2, 및 rAAV3B 바이러스의 효력은 또한 동일한 방식으로 시험될 수 있다.
Rep 및 캡시드 단백질의 서열
본원에서 시험된 rAAV6, rAAV1, rAAV2, rAAV3B, 및 rAAV9 바이러스에 대한 아미노산 및 코딩 서열이 하기에 제시된다.
rAAV6 VP1 코딩 서열:
rAAV6 VP1 폴리펩티드:
rAAV6 VP2/VP3 코딩 서열:
rAAV6 VP2 폴리펩티드 서열:
rAAV6 VP3 폴리펩티드 서열:
rAAV1 VP1/VP2/VP3 폴리펩티드 서열 (이식된 AAV2 PLA2 도메인은 박스로 제시되고; 이식된 AAV9 VP2/VP3 단백질분해적 저항성 도메인은 이탤릭체 및 볼드체표시되고; VP2 및 VP3의 제1 아미노산 (서열식별번호: 24에서 각각 T138 및 V203)은 볼드체 및 밑줄표시됨):
rAAV2 VP1/VP2/VP3 폴리펩티드 서열 (VP2 및 VP3의 제1 아미노산 (서열식별번호: 25에서 각각 T138 및 V203)은 볼드체 및 밑줄표시됨):
rAAV3B VP1/VP2/VP3 폴리펩티드 서열 (이식된 AAV2 PLA2 도메인은 박스로 제시되고; VP2 및 VP3의 제1 아미노산 (서열식별번호: 26에서 각각 T138 및 V203)은 볼드체 및 밑줄표시됨):
rAAV9 VP1/VP2/VP3 폴리펩티드 서열 (이식된 AAV2 PLA2 도메인은 박스로 제시되고; VP2 및 VP3의 제1 아미노산 (서열식별번호: 27에서 각각 T138 및 V203)은 볼드체 및 밑줄표시됨):
AAV2 Rep78 코딩 서열:
AAV2 Rep78 폴리펩티드:
AAV2 Rep52 코딩 서열:
AAV2 Rep52 폴리펩티드:
결과
본 발명자들은 rAAV6을 생산하는 도 5의 각각의 버전의 능력, 및 표준 헬퍼 시스템 1 및 그의 캡시드 발현 카세트가 상기 기재된 AAV6/2/9 하이브리드 서열을 사용한다는 점에서 표준 헬퍼 시스템 1과 상이한 표준 헬퍼 시스템 2에 대해 생성된 rAAV의 효력을 시험하였다. 놀랍게도, Rep 및 Cap 유전자의 쌍형성은 수율 및 효력 둘 다에 유의한 영향을 미쳤다. 버전 1은 수율에서 대략 2배 감소 및 효력에서 8배 증가를 나타냈고, 반면에 버전 2는 수율에서 대략 4배 증가 및 효력에서 5배 증가를 나타냈다 (표 1). 캡시드 비의 비교는 버전 1 rAAV6이 매우 적은 VP2 및 야생형 AAV에서 관찰된 것 (1:10)과 유사한 VP1:VP3 비를 갖는다는 것을 보여주었다. 버전 2 시스템에 의해 생산된 재조합 AAV는 표준 헬퍼 시스템 2에 의해 관찰된 것과 유사한 캡시드 비를 가졌다 (표 1).
표 1 rAAV6의 특징화*
*수율 및 효력 수치는 3개의 독립적인 생산 로트의 평균이다. 캡시드 비는 단일 생산 로트로부터의 것이다.
rAAV9에 대해, 버전 1은 표준 헬퍼 시스템 1과 비교하여 수율에서 대략 3배 감소 및 유사한 효력을 나타냈고, 반면에 버전 2는 수율에서 대략 4배 증가 및 효력에서 2배 감소를 나타냈다 (표 2). 캡시드 비의 비교는 버전 1 rAAV9가 AAV9 표준 헬퍼 시스템의 절반만큼의 VP2 및 야생형 AAV에서 관찰된 것 (1:10)의 절반인 VP1:VP3 비를 갖는다는 것을 보여주었다. 버전 2 시스템에 의해 생산된 재조합 AAV9는 AAV9 표준 헬퍼 시스템에 의해 제공된 rAAV9에 의해 관찰된 것과 유사한 캡시드 비를 가졌다 (표 2). AAV9 표준 헬퍼 시스템은, AAV6/2/9 하이브리드 캡시드 단백질을 생산하는 대신에, VP1 단백질이 상기 기재된 바와 같이 AAV2 PLA2 도메인을 함유하도록 조작된 하이브리드 AAV9 캡시드 단백질을 생산한 것을 제외하고는 AAV6 표준 헬퍼 시스템 2와 동일하였다.
표 2 rAAV9의 특징화*
*수율 및 효력 수치 및 캡시드 비는 6개의 비독립적인 생산 로트로부터의 것이다.
추가의 혈청형 rAAV1, rAAV2 및 rAAV3B는 도 5의 버전 2 방법에 의해 성공적으로 생산되었다.
이들 데이터는 헬퍼 벡터 상의 Rep 및 Cap 발현 카세트의 쌍형성이 생산된 rAAV의 수율 및 효력에 영향을 미친다는 것을 시사한다. 또한, 데이터는 Rep 및 Cap 단백질이 2개의 별개의 바큘로바이러스 벡터로부터 성공적으로 발현될 수 있고, 감염성 rAAV를 고수율로 생산하는 것을 도울 수 있음을 입증한다. 마지막으로, 이들 데이터는 본원에 기재된 생산 시스템이 상이한 AAV 혈청형에 광범위하게 적용가능하고, 보다 광범위하게 시험된 AAV6 및 AAV9 버전으로 제한되지 않는다는 것을 입증한다.
표 3 서열의 목록
SEQUENCE LISTING
<110> SANGAMO THERAPEUTICS, INC.
<120> NOVEL COMPOSITIONS AND METHODS FOR PRODUCING RECOMBINANT AAV
<130> 025297.WO015
<140>
<141>
<150> 62/943,715
<151> 2019-12-04
<160> 73
<170> PatentIn version 3.5
<210> 1
<211> 737
<212> PRT
<213> Unknown
<220>
<221> source
<223> /note="Description of Unknown:
VP1 protein sequence"
<220>
<221> VARIANT
<222> (1)..(1)
<223> /replace="Thr" or "Leu" or "Val"
<220>
<221> SITE
<222> (1)..(737)
<223> /note="Variant residues given in the sequence have no
preference with respect to those in the annotations
for variant positions"
<400> 1
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 Val Val Ala Ser Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn
210 215 220
Ala 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 Ser Ala Ser Thr Gly Ala Ser Asn Asp Asn
260 265 270
His 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 Thr Asn Asp Gly Val Thr Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Ser Asp Ser Glu Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Gln 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 Asn
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 Thr Phe Ser Tyr Thr
405 410 415
Phe Glu Asp 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 Asn
435 440 445
Arg Thr Gln Asn Gln Ser Gly Ser Ala Gln Asn Lys Asp Leu Leu Phe
450 455 460
Ser Arg Gly Ser Pro Ala Gly Met Ser Val Gln Pro Lys Asn Trp Leu
465 470 475 480
Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Lys Thr Asp
485 490 495
Asn Asn Asn Ser Asn Phe Thr Trp Thr Gly Ala Ser Lys Tyr Asn Leu
500 505 510
Asn Gly Arg Glu Ser Ile Ile Asn Pro Gly Thr Ala Met Ala Ser His
515 520 525
Lys Asp Asp Lys Asp Lys Phe Phe Pro Met Ser Gly Val Met Ile Phe
530 535 540
Gly Lys Glu Ser Ala Gly Ala Ser Asn Thr Ala Leu Asp Asn Val Met
545 550 555 560
Ile Thr Asp Glu Glu Glu Ile Lys Ala Thr Asn Pro Val Ala Thr Glu
565 570 575
Arg Phe Gly Thr Val Ala Val Asn Leu Gln Ser Ser Ser Thr Asp Pro
580 585 590
Ala Thr Gly Asp Val His Val Met Gly Ala Leu Pro Gly Met Val Trp
595 600 605
Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro
610 615 620
His Thr Asp Gly His Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly
625 630 635 640
Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro
645 650 655
Ala Asn Pro Pro Ala Glu Phe Ser Ala Thr Lys Phe Ala Ser Phe Ile
660 665 670
Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu
675 680 685
Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Val Gln Tyr Thr Ser
690 695 700
Asn Tyr Ala Lys Ser Ala Asn Val Asp Phe Thr Val Asp Asn Asn Gly
705 710 715 720
Leu Tyr Thr Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Pro
725 730 735
Leu
<210> 2
<211> 10
<212> PRT
<213> Adeno-associated virus 6
<400> 2
Pro Gln Pro Leu Gly Glu Pro Pro Ala Thr
1 5 10
<210> 3
<211> 45
<212> PRT
<213> Adeno-associated virus 6
<400> 3
Ser Gly Ile Gly Lys Thr Gly Gln Gln Pro Ala Lys Lys Arg Leu Asn
1 5 10 15
Phe Gly Gln Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu
20 25 30
Gly Glu Pro Pro Ala Thr Pro Ala Ala Val Gly Pro Thr
35 40 45
<210> 4
<211> 45
<212> PRT
<213> Adeno-associated virus 9
<400> 4
Ala Gly Ile Gly Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn
1 5 10 15
Phe Gly Gln Thr Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile
20 25 30
Gly Glu Pro Pro Ala Ala Pro Ser Gly Val Gly Ser Leu
35 40 45
<210> 5
<211> 46
<212> PRT
<213> Adeno-associated virus 6
<400> 5
Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro Val Asn Ala
1 5 10 15
Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp Gln Gln Leu
20 25 30
Lys Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala Asp
35 40 45
<210> 6
<211> 46
<212> PRT
<213> Adeno-associated virus 2
<400> 6
Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro Val Asn Glu
1 5 10 15
Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp Arg Gln Leu
20 25 30
Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala Asp
35 40 45
<210> 7
<211> 736
<212> PRT
<213> Unknown
<220>
<221> source
<223> /note="Description of Unknown:
VP1 protein sequence"
<400> 7
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 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 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 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 Val 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> 8
<211> 30
<212> PRT
<213> Adeno-associated virus 6
<400> 8
Met Ala Thr Gln Ser Gln Ser Pro Thr His Asn Leu Ser Glu Asn Leu
1 5 10 15
Gln Gln Pro Pro Leu Leu Trp Asp Leu Leu Gln Trp Leu Gln
20 25 30
<210> 9
<211> 30
<212> PRT
<213> Adeno-associated virus 9
<400> 9
Met Ala Thr Gln Ser Gln Ser Gln Thr Leu Asn Gln Ser Glu Asn Leu
1 5 10 15
Pro Gln Pro Pro Gln Val Trp Asp Leu Leu Gln Trp Leu Gln
20 25 30
<210> 10
<211> 196
<212> PRT
<213> Adeno-associated virus 6
<400> 10
Met Ala Thr Gln Ser Gln Ser Pro Thr His Asn Leu Ser Glu Asn Leu
1 5 10 15
Gln Gln Pro Pro Leu Leu Trp Asp Leu Leu Gln Trp Leu Gln Ala Val
20 25 30
Ala His Gln Trp Gln Thr Ile Thr Lys Ala Pro Thr Glu Trp Val Met
35 40 45
Pro Gln Glu Ile Gly Ile Ala Ile Pro His Gly Trp Ala Thr Glu Ser
50 55 60
Ser Pro Pro Ala Pro Glu His Gly Pro Cys Pro Pro Ile Thr Thr Thr
65 70 75 80
Ser Thr Ser Lys Ser Pro Val Leu Gln Arg Gly Pro Ala Thr Thr Thr
85 90 95
Thr Thr Ser Ala Thr Ala Pro Pro Gly Gly Ile Leu Ile Ser Thr Asp
100 105 110
Ser Thr Ala Ile Ser His His Val Thr Gly Ser Asp Ser Ser Thr Thr
115 120 125
Ile Gly Asp Ser Gly Pro Arg Asp Ser Thr Ser Ser Ser Ser Thr Ser
130 135 140
Lys Ser Arg Arg Ser Arg Arg Met Met Ala Ser Arg Pro Ser Leu Ile
145 150 155 160
Thr Leu Pro Ala Arg Phe Lys Ser Ser Arg Thr Arg Ser Thr Ser Cys
165 170 175
Arg Thr Ser Ser Ala Leu Arg Thr Arg Ala Ala Ser Leu Arg Ser Arg
180 185 190
Arg Thr Cys Ser
195
<210> 11
<211> 736
<212> PRT
<213> Adeno-associated virus 9
<400> 11
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> 12
<211> 46
<212> PRT
<213> Adeno-associated virus 9
<400> 12
Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro Val Asn Ala
1 5 10 15
Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp Gln Gln Leu
20 25 30
Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala Asp
35 40 45
<210> 13
<211> 183
<212> DNA
<213> Adeno-associated virus 6
<400> 13
aagagccaga ctcctcctcg ggcattggca agacaggcca gcagcccgct aaaaagagac 60
tcaattttgg tcagactggc gactcagagt cagtccccga cccacaacct ctcggagaac 120
ctccagcaac ccccgctgct gtgggaccta ctacaatggc ttcaggcggt ggcgcaccaa 180
tgg 183
<210> 14
<211> 183
<212> DNA
<213> Adeno-associated virus 9
<400> 14
aagagccaga ctcctccgcg ggtattggca aatcgggtgc acagcccgct aaaaagagac 60
tcaatttcgg tcagactggc gacacagagt cagtcccaga ccctcaacca atcggagaac 120
ctcccgcagc cccctcaggt gtgggatctc ttacaatggc ttcaggcggt ggcgcaccaa 180
tgg 183
<210> 15
<211> 2211
<212> DNA
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polynucleotide"
<400> 15
acggctgccg acggttatct acccgattgg ctcgaggaca acctctctga gggcattcgc 60
gagtggtggg acctcaaacc tggagccccg aaacccaaag ccaaccagca aaagcaggac 120
gacggccggg gtctggtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttcaagaaga tacgtctttt gggggcaacc tcgggcgagc agtcttccag 360
gccaagaaga gggttctcga accttttggt ctggttgagg aaggtgctaa gaccgctcct 420
ggaaagaaac gtccggtaga gcagtcgcca caagagccag actcctccgc gggtattggc 480
aaatcgggtg cacagcccgc taaaaagaga ctcaatttcg gtcagactgg cgacacagag 540
tcagtcccag accctcaacc aatcggagaa cctcccgcag ccccctcagg tgtgggatct 600
cttacagtgg cttcaggcgg tggcgcacca gtggcagaca ataacgaagg cgccgacgga 660
gtgggtaatg cctcaggaaa ttggcattgc gattccacat ggctgggcga cagagtcatc 720
accaccagca cccgaacatg ggccttgccc acctataaca accacctcta caagcaaatc 780
tccagtgctt caacgggggc cagcaacgac aaccactact tcggctacag caccccctgg 840
gggtattttg atttcaacag attccactgc catttctcac cacgtgactg gcagcgactc 900
atcaacaaca attggggatt ccggcccaag agactcaact tcaagctctt caacatccaa 960
gtcaaggagg tcacgacgaa tgatggcgtc acgaccatcg ctaataacct taccagcacg 1020
gttcaagtct tctcggactc ggagtaccag ttgccgtacg tcctcggctc tgcgcaccag 1080
ggctgcctcc ctccgttccc ggcggacgtg ttcatgattc cgcagtacgg ctacctaacg 1140
ctcaacaatg gcagccaggc agtgggacgg tcatcctttt actgcctgga atatttccca 1200
tcgcagatgc tgagaacggg caataacttt accttcagct acaccttcga ggacgtgcct 1260
ttccacagca gctacgcgca cagccagagc ctggaccggc tgatgaatcc tctcatcgac 1320
cagtacctgt attacctgaa cagaactcag aatcagtccg gaagtgccca aaacaaggac 1380
ttgctgttta gccgggggtc tccagctggc atgtctgttc agcccaaaaa ctggctacct 1440
ggaccctgtt accggcagca gcgcgtttct aaaacaaaaa cagacaacaa caacagcaac 1500
tttacctgga ctggtgcttc aaaatataac cttaatgggc gtgaatctat aatcaaccct 1560
ggcactgcta tggcctcaca caaagacgac aaagacaagt tctttcccat gagcggtgtc 1620
atgatttttg gaaaggagag cgccggagct tcaaacactg cattggacaa tgtcatgatc 1680
acagacgaag aggaaatcaa agccactaac cccgtggcca ccgaaagatt tgggactgtg 1740
gcagtcaatc tccagagcag cagcacagac cctgcgaccg gagatgtgca tgttatggga 1800
gccttacctg gaatggtgtg gcaagacaga gacgtatatc tgcagggtcc tatttgggcc 1860
aaaattcctc acacggatgg acactttcac ccgtctcctc tcatgggcgg ctttggactt 1920
aagcacccgc ctcctcagat cctcatcaaa aacacgcctg ttcctgcgaa tcctccggca 1980
gagttttcgg ctacaaagtt tgcttcattc atcacccagt attccacagg acaagtgagc 2040
gtggagattg aatgggagct gcagaaagaa aacagcaaac gctggaatcc cgaagtgcag 2100
tatacatcta actatgcaaa atctgccaac gttgatttca ctgtggacaa caatggactt 2160
tatactgagc ctcgccccat tggcacccgt tacctcaccc gtcccctgta a 2211
<210> 16
<211> 736
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<220>
<221> VARIANT
<222> (1)..(1)
<223> /replace="Thr"
<220>
<221> SITE
<222> (1)..(736)
<223> /note="Variant residues given in the sequence have no
preference with respect to those in the annotations
for variant positions"
<400> 16
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 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 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 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 Val Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val 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> 17
<211> 1800
<212> DNA
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polynucleotide"
<400> 17
acggctcctg gaaagaaacg tccggtagag cagtcgccac aagagccaga ctcctccgcg 60
ggtattggca aatcgggtgc acagcccgct aaaaagagac tcaatttcgg tcagactggc 120
gacacagagt cagtcccaga ccctcaacca atcggagaac ctcccgcagc cccctcaggt 180
gtgggatctc ttacaatggc ttcaggcggt ggcgcaccag tggcagacaa taacgaaggc 240
gccgacggag tgggtaatgc ctcaggaaat tggcattgcg attccacatg gctgggcgac 300
agagtcatca ccaccagcac ccgaacatgg gccttgccca cctataacaa ccacctctac 360
aagcaaatct ccagtgcttc aacgggggcc agcaacgaca accactactt cggctacagc 420
accccctggg ggtattttga tttcaacaga ttccactgcc atttctcacc acgtgactgg 480
cagcgactca tcaacaacaa ttggggattc cggcccaaga gactcaactt caagctcttc 540
aacatccaag tcaaggaggt cacgacgaat gatggcgtca cgaccatcgc taataacctt 600
accagcacgg ttcaagtctt ctcggactcg gagtaccagt tgccgtacgt cctcggctct 660
gcgcaccagg gctgcctccc tccgttcccg gcggacgtgt tcatgattcc gcagtacggc 720
tacctaacgc tcaacaatgg cagccaggca gtgggacggt catcctttta ctgcctggaa 780
tatttcccat cgcagatgct gagaacgggc aataacttta ccttcagcta caccttcgag 840
gacgtgcctt tccacagcag ctacgcgcac agccagagcc tggaccggct gatgaatcct 900
ctcatcgacc agtacctgta ttacctgaac agaactcaga atcagtccgg aagtgcccaa 960
aacaaggact tgctgtttag ccgggggtct ccagctggca tgtctgttca gcccaaaaac 1020
tggctacctg gaccctgtta ccggcagcag cgcgtttcta aaacaaaaac agacaacaac 1080
aacagcaact ttacctggac tggtgcttca aaatataacc ttaatgggcg tgaatctata 1140
atcaaccctg gcactgctat ggcctcacac aaagacgaca aagacaagtt ctttcccatg 1200
agcggtgtca tgatttttgg aaaggagagc gccggagctt caaacactgc attggacaat 1260
gtcatgatca cagacgaaga ggaaatcaaa gccactaacc ccgtggccac cgaaagattt 1320
gggactgtgg cagtcaatct ccagagcagc agcacagacc ctgcgaccgg agatgtgcat 1380
gttatgggag ccttacctgg aatggtgtgg caagacagag acgtatatct gcagggtcct 1440
atttgggcca aaattcctca cacggatgga cactttcacc cgtctcctct catgggcggc 1500
tttggactta agcacccgcc tcctcagatc ctcatcaaaa acacgcctgt tcctgcgaat 1560
cctccggcag agttttcggc tacaaagttt gcttcattca tcacccagta ttccacagga 1620
caagtgagcg tggagattga atgggagctg cagaaagaaa acagcaaacg ctggaatccc 1680
gaagtgcagt atacatctaa ctatgcaaaa tctgccaacg ttgatttcac tgtggacaac 1740
aatggacttt atactgagcc tcgccccatt ggcacccgtt acctcacccg tcccctgtaa 1800
<210> 18
<211> 599
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<220>
<221> VARIANT
<222> (1)..(1)
<223> /replace="Thr"
<220>
<221> SITE
<222> (1)..(599)
<223> /note="Variant residues given in the sequence have no
preference with respect to those in the annotations
for variant positions"
<400> 18
Met Ala Pro Gly Lys Lys Arg Pro Val Glu Gln Ser Pro Gln Glu Pro
1 5 10 15
Asp Ser Ser Ala Gly Ile Gly Lys Ser Gly Ala Gln Pro Ala Lys Lys
20 25 30
Arg Leu Asn Phe Gly Gln Thr Gly Asp Thr Glu Ser Val Pro Asp Pro
35 40 45
Gln Pro Ile Gly Glu Pro Pro Ala Ala Pro Ser Gly Val Gly Ser Leu
50 55 60
Thr Met Ala Ser Gly Gly Gly Ala Pro Val Ala Asp Asn Asn Glu Gly
65 70 75 80
Ala Asp Gly Val Gly Asn Ala Ser Gly Asn Trp His Cys Asp Ser Thr
85 90 95
Trp Leu Gly Asp Arg Val Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu
100 105 110
Pro Thr Tyr Asn Asn His Leu Tyr Lys Gln Ile Ser Ser Ala Ser Thr
115 120 125
Gly Ala Ser Asn Asp Asn His Tyr Phe Gly Tyr Ser Thr Pro Trp Gly
130 135 140
Tyr Phe Asp Phe Asn Arg Phe His Cys His Phe Ser Pro Arg Asp Trp
145 150 155 160
Gln Arg Leu Ile Asn Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn
165 170 175
Phe Lys Leu Phe Asn Ile Gln Val Lys Glu Val Thr Thr Asn Asp Gly
180 185 190
Val Thr Thr Ile Ala Asn Asn Leu Thr Ser Thr Val Gln Val Phe Ser
195 200 205
Asp Ser Glu Tyr Gln Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly
210 215 220
Cys Leu Pro Pro Phe Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly
225 230 235 240
Tyr Leu Thr Leu Asn Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe
245 250 255
Tyr Cys Leu Glu Tyr Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn
260 265 270
Phe Thr Phe Ser Tyr Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr
275 280 285
Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln
290 295 300
Tyr Leu Tyr Tyr Leu Asn Arg Thr Gln Asn Gln Ser Gly Ser Ala Gln
305 310 315 320
Asn Lys Asp Leu Leu Phe Ser Arg Gly Ser Pro Ala Gly Met Ser Val
325 330 335
Gln Pro Lys Asn Trp Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val
340 345 350
Ser Lys Thr Lys Thr Asp Asn Asn Asn Ser Asn Phe Thr Trp Thr Gly
355 360 365
Ala Ser Lys Tyr Asn Leu Asn Gly Arg Glu Ser Ile Ile Asn Pro Gly
370 375 380
Thr Ala Met Ala Ser His Lys Asp Asp Lys Asp Lys Phe Phe Pro Met
385 390 395 400
Ser Gly Val Met Ile Phe Gly Lys Glu Ser Ala Gly Ala Ser Asn Thr
405 410 415
Ala Leu Asp Asn Val Met Ile Thr Asp Glu Glu Glu Ile Lys Ala Thr
420 425 430
Asn Pro Val Ala Thr Glu Arg Phe Gly Thr Val Ala Val Asn Leu Gln
435 440 445
Ser Ser Ser Thr Asp Pro Ala Thr Gly Asp Val His Val Met Gly Ala
450 455 460
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
465 470 475 480
Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro Ser Pro
485 490 495
Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile
500 505 510
Lys Asn Thr Pro Val Pro Ala Asn Pro Pro Ala Glu Phe Ser Ala Thr
515 520 525
Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
530 535 540
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
545 550 555 560
Glu Val Gln Tyr Thr Ser Asn Tyr Ala Lys Ser Ala Asn Val Asp Phe
565 570 575
Thr Val Asp Asn Asn Gly Leu Tyr Thr Glu Pro Arg Pro Ile Gly Thr
580 585 590
Arg Tyr Leu Thr Arg Pro Leu
595
<210> 19
<211> 534
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<400> 19
Met Ala Ser Gly Gly Gly Ala Pro Val Ala Asp Asn Asn Glu Gly Ala
1 5 10 15
Asp Gly Val Gly Asn Ala Ser Gly Asn Trp His Cys Asp Ser Thr Trp
20 25 30
Leu Gly Asp Arg Val Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro
35 40 45
Thr Tyr Asn Asn His Leu Tyr Lys Gln Ile Ser Ser Ala Ser Thr Gly
50 55 60
Ala Ser Asn Asp Asn His Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr
65 70 75 80
Phe Asp Phe Asn Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln
85 90 95
Arg Leu Ile Asn Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe
100 105 110
Lys Leu Phe Asn Ile Gln Val Lys Glu Val Thr Thr Asn Asp Gly Val
115 120 125
Thr Thr Ile Ala Asn Asn Leu Thr Ser Thr Val Gln Val Phe Ser Asp
130 135 140
Ser Glu Tyr Gln Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys
145 150 155 160
Leu Pro Pro Phe Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr
165 170 175
Leu Thr Leu Asn Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr
180 185 190
Cys Leu Glu Tyr Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe
195 200 205
Thr Phe Ser Tyr Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala
210 215 220
His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr
225 230 235 240
Leu Tyr Tyr Leu Asn Arg Thr Gln Asn Gln Ser Gly Ser Ala Gln Asn
245 250 255
Lys Asp Leu Leu Phe Ser Arg Gly Ser Pro Ala Gly Met Ser Val Gln
260 265 270
Pro Lys Asn Trp Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser
275 280 285
Lys Thr Lys Thr Asp Asn Asn Asn Ser Asn Phe Thr Trp Thr Gly Ala
290 295 300
Ser Lys Tyr Asn Leu Asn Gly Arg Glu Ser Ile Ile Asn Pro Gly Thr
305 310 315 320
Ala Met Ala Ser His Lys Asp Asp Lys Asp Lys Phe Phe Pro Met Ser
325 330 335
Gly Val Met Ile Phe Gly Lys Glu Ser Ala Gly Ala Ser Asn Thr Ala
340 345 350
Leu Asp Asn Val Met Ile Thr Asp Glu Glu Glu Ile Lys Ala Thr Asn
355 360 365
Pro Val Ala Thr Glu Arg Phe Gly Thr Val Ala Val Asn Leu Gln Ser
370 375 380
Ser Ser Thr Asp Pro Ala Thr Gly Asp Val His Val Met Gly Ala Leu
385 390 395 400
Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile
405 410 415
Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro Ser Pro Leu
420 425 430
Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys
435 440 445
Asn Thr Pro Val Pro Ala Asn Pro Pro Ala Glu Phe Ser Ala Thr Lys
450 455 460
Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu
465 470 475 480
Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu
485 490 495
Val Gln Tyr Thr Ser Asn Tyr Ala Lys Ser Ala Asn Val Asp Phe Thr
500 505 510
Val Asp Asn Asn Gly Leu Tyr Thr Glu Pro Arg Pro Ile Gly Thr Arg
515 520 525
Tyr Leu Thr Arg Pro Leu
530
<210> 20
<211> 1866
<212> DNA
<213> Adeno-associated virus 2
<400> 20
ctggcggggt tttacgagat tgtgattaag gtccccagcg accttgacga gcatctgccc 60
ggcatttctg acagctttgt gaactgggtg gccgagaagg agtgggagtt gccgccagat 120
tctgacttgg atctgaatct gattgagcag gcacccctga ccgtggccga gaagctgcag 180
cgcgactttc tgacggagtg gcgccgtgtg agtaaggccc cggaggccct tttctttgtg 240
caatttgaga agggagagag ctacttccac ttacacgtgc tcgtggaaac caccggggtg 300
aaatccttag ttttgggacg tttcctgagt cagattcgcg aaaaactgat tcagagaatt 360
taccgcggga tcgagccgac tttgccaaac tggttcgcgg tcacaaagac cagaaacggc 420
gccggaggcg ggaacaaggt ggtggacgag tgctacatcc ccaattactt gctccccaaa 480
acccagcctg agctccagtg ggcgtggact aatttagaac agtatttaag cgcctgtttg 540
aatctcacgg agcgtaaacg gttggtggcg cagcatctga cgcacgtgtc gcagacgcag 600
gagcagaaca aagagaatca gaatcccaat tctgacgcgc cggtgatcag atcaaaaact 660
tcagccaggt acgtggagct ggtcgggtgg ctcgtggaca aggggattac ctcggagaag 720
cagtggatcc aggaggacca ggcctcatac atctccttca atgcggcctc caactcgcgg 780
tcccaaatca aggctgcctt ggacaatgcg ggaaagatta tgagcctgac taaaaccgcc 840
cccgactacc tggtgggcca gcagcccgtg gaggacattt ccagcaatcg gatttataaa 900
attttggaac taaacgggta cgatccccaa tatgcggctt ccgtctttct gggatgggcc 960
acgaaaaagt tcggcaagag gaacaccatc tggctgtttg ggcctgcaac taccgggaag 1020
accaacatcg cggaggccat agcccacact gtgcccttct acgggtgcgt aaactggacc 1080
aatgagaact ttcccttcaa cgactgtgtc gacaagatgg tgatctggtg ggaggagggg 1140
aagatgaccg ccaaggtcgt ggagtcggcc aaagccattc tcggaggaag caaggtgcgc 1200
gtggaccaga aatgcaagtc ctcggcccag atagacccga ctcccgtgat cgtcacctcc 1260
aacaccaaca tgtgcgccgt gattgacggg aactcaacga ccttcgaaca ccagcagccg 1320
ttgcaagacc ggatgttcaa atttgaactc acccgccgtc tggatcatga ctttgggaag 1380
gtcaccaagc aggaagtcaa agactttttc cggtgggcaa aggatcacgt ggttgaggtg 1440
gagcatgaat tctacgtcaa aaagggtgga gccaagaaaa gacccgcccc cagtgacgca 1500
gatataagtg agcccaaacg ggtgcgcgag tcagttgcgc agccatcgac gtcagacgcg 1560
gaagcttcga tcaactacgc agacaggtac caaaacaaat gttctcgtca cgtgggcatg 1620
aatctgatgc tgtttccctg cagacaatgc gagagaatga atcagaattc aaatatctgc 1680
ttcactcacg gacagaaaga ctgtttagag tgctttcccg tgtcagaatc tcaacccgtt 1740
tctgtcgtca aaaaggcgta tcagaaactg tgctacattc atcatatcat gggaaaggtg 1800
ccagacgctt gcactgcctg cgatctggtc aatgtggatt tggatgactg catctttgaa 1860
caataa 1866
<210> 21
<211> 621
<212> PRT
<213> Adeno-associated virus 2
<220>
<221> VARIANT
<222> (1)..(1)
<223> /replace="Leu"
<220>
<221> SITE
<222> (1)..(621)
<223> /note="Variant residues given in the sequence have no
preference with respect to those in the annotations
for variant positions"
<400> 21
Met Ala Gly Phe Tyr Glu Ile Val Ile Lys Val Pro Ser Asp Leu Asp
1 5 10 15
Glu His Leu Pro Gly Ile Ser Asp Ser Phe Val Asn Trp Val Ala Glu
20 25 30
Lys Glu Trp Glu Leu Pro Pro Asp Ser Asp Leu Asp Leu Asn Leu Ile
35 40 45
Glu Gln Ala Pro Leu Thr Val Ala Glu Lys Leu Gln Arg Asp Phe Leu
50 55 60
Thr Glu Trp Arg Arg Val Ser Lys Ala Pro Glu Ala Leu Phe Phe Val
65 70 75 80
Gln Phe Glu Lys Gly Glu Ser Tyr Phe His Leu His Val Leu Val Glu
85 90 95
Thr Thr Gly Val Lys Ser Leu Val Leu Gly Arg Phe Leu Ser Gln Ile
100 105 110
Arg Glu Lys Leu Ile Gln Arg Ile Tyr Arg Gly Ile Glu Pro Thr Leu
115 120 125
Pro Asn Trp Phe Ala Val Thr Lys Thr Arg Asn Gly Ala Gly Gly Gly
130 135 140
Asn Lys Val Val Asp Glu Cys Tyr Ile Pro Asn Tyr Leu Leu Pro Lys
145 150 155 160
Thr Gln Pro Glu Leu Gln Trp Ala Trp Thr Asn Leu Glu Gln Tyr Leu
165 170 175
Ser Ala Cys Leu Asn Leu Thr Glu Arg Lys Arg Leu Val Ala Gln His
180 185 190
Leu Thr His Val Ser Gln Thr Gln Glu Gln Asn Lys Glu Asn Gln Asn
195 200 205
Pro Asn Ser Asp Ala Pro Val Ile Arg Ser Lys Thr Ser Ala Arg Tyr
210 215 220
Val Glu Leu Val Gly Trp Leu Val Asp Lys Gly Ile Thr Ser Glu Lys
225 230 235 240
Gln Trp Ile Gln Glu Asp Gln Ala Ser Tyr Ile Ser Phe Asn Ala Ala
245 250 255
Ser Asn Ser Arg Ser Gln Ile Lys Ala Ala Leu Asp Asn Ala Gly Lys
260 265 270
Ile Met Ser Leu Thr Lys Thr Ala Pro Asp Tyr Leu Val Gly Gln Gln
275 280 285
Pro Val Glu Asp Ile Ser Ser Asn Arg Ile Tyr Lys Ile Leu Glu Leu
290 295 300
Asn Gly Tyr Asp Pro Gln Tyr Ala Ala Ser Val Phe Leu Gly Trp Ala
305 310 315 320
Thr Lys Lys Phe Gly Lys Arg Asn Thr Ile Trp Leu Phe Gly Pro Ala
325 330 335
Thr Thr Gly Lys Thr Asn Ile Ala Glu Ala Ile Ala His Thr Val Pro
340 345 350
Phe Tyr Gly Cys Val Asn Trp Thr Asn Glu Asn Phe Pro Phe Asn Asp
355 360 365
Cys Val Asp Lys Met Val Ile Trp Trp Glu Glu Gly Lys Met Thr Ala
370 375 380
Lys Val Val Glu Ser Ala Lys Ala Ile Leu Gly Gly Ser Lys Val Arg
385 390 395 400
Val Asp Gln Lys Cys Lys Ser Ser Ala Gln Ile Asp Pro Thr Pro Val
405 410 415
Ile Val Thr Ser Asn Thr Asn Met Cys Ala Val Ile Asp Gly Asn Ser
420 425 430
Thr Thr Phe Glu His Gln Gln Pro Leu Gln Asp Arg Met Phe Lys Phe
435 440 445
Glu Leu Thr Arg Arg Leu Asp His Asp Phe Gly Lys Val Thr Lys Gln
450 455 460
Glu Val Lys Asp Phe Phe Arg Trp Ala Lys Asp His Val Val Glu Val
465 470 475 480
Glu His Glu Phe Tyr Val Lys Lys Gly Gly Ala Lys Lys Arg Pro Ala
485 490 495
Pro Ser Asp Ala Asp Ile Ser Glu Pro Lys Arg Val Arg Glu Ser Val
500 505 510
Ala Gln Pro Ser Thr Ser Asp Ala Glu Ala Ser Ile Asn Tyr Ala Asp
515 520 525
Arg Tyr Gln Asn Lys Cys Ser Arg His Val Gly Met Asn Leu Met Leu
530 535 540
Phe Pro Cys Arg Gln Cys Glu Arg Met Asn Gln Asn Ser Asn Ile Cys
545 550 555 560
Phe Thr His Gly Gln Lys Asp Cys Leu Glu Cys Phe Pro Val Ser Glu
565 570 575
Ser Gln Pro Val Ser Val Val Lys Lys Ala Tyr Gln Lys Leu Cys Tyr
580 585 590
Ile His His Ile Met Gly Lys Val Pro Asp Ala Cys Thr Ala Cys Asp
595 600 605
Leu Val Asn Val Asp Leu Asp Asp Cys Ile Phe Glu Gln
610 615 620
<210> 22
<211> 1194
<212> DNA
<213> Adeno-associated virus 2
<400> 22
atggagctgg tcgggtggct cgtggacaag gggattacct cggagaagca gtggatccag 60
gaggaccagg cctcatacat ctccttcaat gcggcctcca actcgcggtc ccaaatcaag 120
gctgccttgg acaatgcggg aaagattatg agcctgacta aaaccgcccc cgactacctg 180
gtgggccagc agcccgtgga ggacatttcc agcaatcgga tttataaaat tttggaacta 240
aacgggtacg atccccaata tgcggcttcc gtctttctgg gatgggccac gaaaaagttc 300
ggcaagagga acaccatctg gctgtttggg cctgcaacta ccgggaagac caacatcgcg 360
gaggccatag cccacactgt gcccttctac gggtgcgtaa actggaccaa tgagaacttt 420
cccttcaacg actgtgtcga caagatggtg atctggtggg aggaggggaa gatgaccgcc 480
aaggtcgtgg agtcggccaa agccattctc ggaggaagca aggtgcgcgt ggaccagaaa 540
tgcaagtcct cggcccagat agacccgact cccgtgatcg tcacctccaa caccaacatg 600
tgcgccgtga ttgacgggaa ctcaacgacc ttcgaacacc agcagccgtt gcaagaccgg 660
atgttcaaat ttgaactcac ccgccgtctg gatcatgact ttgggaaggt caccaagcag 720
gaagtcaaag actttttccg gtgggcaaag gatcacgtgg ttgaggtgga gcatgaattc 780
tacgtcaaaa agggtggagc caagaaaaga cccgccccca gtgacgcaga tataagtgag 840
cccaaacggg tgcgcgagtc agttgcgcag ccatcgacgt cagacgcgga agcttcgatc 900
aactacgcag acaggtacca aaacaaatgt tctcgtcacg tgggcatgaa tctgatgctg 960
tttccctgca gacaatgcga gagaatgaat cagaattcaa atatctgctt cactcacgga 1020
cagaaagact gtttagagtg ctttcccgtg tcagaatctc aacccgtttc tgtcgtcaaa 1080
aaggcgtatc agaaactgtg ctacattcat catatcatgg gaaaggtgcc agacgcttgc 1140
actgcctgcg atctggtcaa tgtggatttg gatgactgca tctttgaaca ataa 1194
<210> 23
<211> 397
<212> PRT
<213> Adeno-associated virus 2
<400> 23
Met Glu Leu Val Gly Trp Leu Val Asp Lys Gly Ile Thr Ser Glu Lys
1 5 10 15
Gln Trp Ile Gln Glu Asp Gln Ala Ser Tyr Ile Ser Phe Asn Ala Ala
20 25 30
Ser Asn Ser Arg Ser Gln Ile Lys Ala Ala Leu Asp Asn Ala Gly Lys
35 40 45
Ile Met Ser Leu Thr Lys Thr Ala Pro Asp Tyr Leu Val Gly Gln Gln
50 55 60
Pro Val Glu Asp Ile Ser Ser Asn Arg Ile Tyr Lys Ile Leu Glu Leu
65 70 75 80
Asn Gly Tyr Asp Pro Gln Tyr Ala Ala Ser Val Phe Leu Gly Trp Ala
85 90 95
Thr Lys Lys Phe Gly Lys Arg Asn Thr Ile Trp Leu Phe Gly Pro Ala
100 105 110
Thr Thr Gly Lys Thr Asn Ile Ala Glu Ala Ile Ala His Thr Val Pro
115 120 125
Phe Tyr Gly Cys Val Asn Trp Thr Asn Glu Asn Phe Pro Phe Asn Asp
130 135 140
Cys Val Asp Lys Met Val Ile Trp Trp Glu Glu Gly Lys Met Thr Ala
145 150 155 160
Lys Val Val Glu Ser Ala Lys Ala Ile Leu Gly Gly Ser Lys Val Arg
165 170 175
Val Asp Gln Lys Cys Lys Ser Ser Ala Gln Ile Asp Pro Thr Pro Val
180 185 190
Ile Val Thr Ser Asn Thr Asn Met Cys Ala Val Ile Asp Gly Asn Ser
195 200 205
Thr Thr Phe Glu His Gln Gln Pro Leu Gln Asp Arg Met Phe Lys Phe
210 215 220
Glu Leu Thr Arg Arg Leu Asp His Asp Phe Gly Lys Val Thr Lys Gln
225 230 235 240
Glu Val Lys Asp Phe Phe Arg Trp Ala Lys Asp His Val Val Glu Val
245 250 255
Glu His Glu Phe Tyr Val Lys Lys Gly Gly Ala Lys Lys Arg Pro Ala
260 265 270
Pro Ser Asp Ala Asp Ile Ser Glu Pro Lys Arg Val Arg Glu Ser Val
275 280 285
Ala Gln Pro Ser Thr Ser Asp Ala Glu Ala Ser Ile Asn Tyr Ala Asp
290 295 300
Arg Tyr Gln Asn Lys Cys Ser Arg His Val Gly Met Asn Leu Met Leu
305 310 315 320
Phe Pro Cys Arg Gln Cys Glu Arg Met Asn Gln Asn Ser Asn Ile Cys
325 330 335
Phe Thr His Gly Gln Lys Asp Cys Leu Glu Cys Phe Pro Val Ser Glu
340 345 350
Ser Gln Pro Val Ser Val Val Lys Lys Ala Tyr Gln Lys Leu Cys Tyr
355 360 365
Ile His His Ile Met Gly Lys Val Pro Asp Ala Cys Thr Ala Cys Asp
370 375 380
Leu Val Asn Val Asp Leu Asp Asp Cys Ile Phe Glu Gln
385 390 395
<210> 24
<211> 736
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<400> 24
Thr 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 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 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 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 Val Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val 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 Glu 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 Glu 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 Phe Gln Ser Ser Ser Thr Asp Pro Ala
580 585 590
Thr Gly Asp Val His Ala 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 Asn 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> 25
<211> 735
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<400> 25
Thr 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 Val Ala Thr Gly Ser Gly
195 200 205
Ala Pro Val 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 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 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> 26
<211> 736
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<400> 26
Leu 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 Val Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Arg 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 Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Ile 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 Asp Gln Ser Pro Gln Glu Pro Asp Ser Ser Ser Gly Val Gly
145 150 155 160
Lys Ser Gly Lys Gln Pro Ala Arg 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 Ala Pro Thr Ser Leu Gly Ser Asn Thr Val Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn 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 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 Lys Leu Ser 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 Gln 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 Asn Arg Thr
435 440 445
Gln Gly Thr Thr Ser Gly Thr Thr Asn Gln Ser Arg Leu Leu Phe Ser
450 455 460
Gln Ala Gly Pro Gln Ser Met Ser Leu Gln Ala Arg Asn Trp Leu Pro
465 470 475 480
Gly Pro Cys Tyr Arg Gln Gln Arg Leu Ser Lys Thr Ala Asn Asp Asn
485 490 495
Asn Asn Ser Asn Phe Pro Trp Thr Ala Ala Ser Lys Tyr His Leu Asn
500 505 510
Gly Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Asp Asp Glu Glu Lys Phe Phe Pro Met His Gly Asn Leu Ile Phe Gly
530 535 540
Lys Glu Gly Thr Thr Ala Ser Asn Ala Glu Leu Asp Asn Val Met Ile
545 550 555 560
Thr Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln
565 570 575
Tyr Gly Thr Val Ala Asn Asn Leu Gln Ser Ser Asn Thr Ala Pro Thr
580 585 590
Thr Arg Thr Val Asn Asp Gln 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 Met Ile Lys Asn Thr Pro Val Pro Ala
645 650 655
Asn Pro Pro Thr Thr Phe Ser Pro Ala 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 Ile Gln Tyr Thr Ser Asn
690 695 700
Tyr Asn Lys Ser Val Asn Val Asp Phe Thr Val Asp Thr Asn 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> 27
<211> 736
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<400> 27
Leu 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 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 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 Val 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> 28
<211> 52
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<220>
<221> MOD_RES
<222> (15)..(15)
<223> Any amino acid
<220>
<221> MOD_RES
<222> (44)..(44)
<223> Any amino acid
<220>
<221> MOD_RES
<222> (47)..(47)
<223> Any amino acid
<400> 28
Asp Ser Ser Ser Gly Ile Gly Lys Ser Gly Gln Gln Pro Ala Xaa Lys
1 5 10 15
Arg Leu Asn Phe Gly Gln Thr Gly Asp Ser Glu Ser Val Pro Asp Pro
20 25 30
Gln Pro Leu Gly Glu Pro Pro Ala Ala Pro Ser Xaa Val Gly Xaa Asn
35 40 45
Thr Met Ala Ser
50
<210> 29
<211> 52
<212> PRT
<213> Adeno-associated virus 3B
<400> 29
Asp Ser Ser Ser Gly Val Gly Lys Ser Gly Lys Gln Pro Ala Arg Lys
1 5 10 15
Arg Leu Asn Phe Gly Gln Thr Gly Asp Ser Glu Ser Val Pro Asp Pro
20 25 30
Gln Pro Leu Gly Glu Pro Pro Ala Ala Pro Thr Ser Leu Gly Ser Asn
35 40 45
Thr Met Ala Ser
50
<210> 30
<211> 44
<212> PRT
<213> Adeno-associated virus 5
<400> 30
Lys Lys Ala Arg Thr Glu Glu Asp Ser Lys Pro Ser Thr Ser Ser Asp
1 5 10 15
Ala Glu Ala Gly Pro Ser Gly Ser Gln Gln Leu Gln Ile Pro Ala Gln
20 25 30
Pro Ala Ser Ser Leu Gly Ala Asp Thr Met Ser Ala
35 40
<210> 31
<211> 52
<212> PRT
<213> Adeno-associated virus 6
<400> 31
Asp Ser Ser Ser Gly Ile Gly Lys Thr Gly Gln Gln Pro Ala Lys Lys
1 5 10 15
Arg Leu Asn Phe Gly Gln Thr Gly Asp Ser Glu Ser Val Pro Asp Pro
20 25 30
Gln Pro Leu Gly Glu Pro Pro Ala Thr Pro Ala Ala Val Gly Pro Thr
35 40 45
Thr Met Ala Ser
50
<210> 32
<211> 52
<212> PRT
<213> Adeno-associated virus 8
<400> 32
Asp Ser Ser Thr Gly Ile Gly Lys Lys Gly Gln Gln Pro Ala Arg Lys
1 5 10 15
Arg Leu Asn Phe Gly Gln Thr Gly Asp Ser Glu Ser Val Pro Asp Pro
20 25 30
Gln Pro Leu Gly Glu Pro Pro Ala Ala Pro Ser Gly Val Gly Pro Asn
35 40 45
Thr Met Ala Ala
50
<210> 33
<211> 52
<212> PRT
<213> Adeno-associated virus 9
<400> 33
Asp Ser Ser Ala Gly Ile Gly Lys Ser Gly Ala Gln Pro Ala Lys Lys
1 5 10 15
Arg Leu Asn Phe Gly Gln Thr Gly Asp Thr Glu Ser Val Pro Asp Pro
20 25 30
Gln Pro Ile Gly Glu Pro Pro Ala Ala Pro Ser Gly Val Gly Ser Leu
35 40 45
Thr Met Ala Ser
50
<210> 34
<211> 51
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<220>
<221> MOD_RES
<222> (15)..(15)
<223> Any amino acid
<400> 34
Asp Ser Ser Ser Gly Ile Gly Lys Lys Gly Gln Gln Pro Ala Xaa Lys
1 5 10 15
Arg Leu Asn Phe Gly Gln Thr Gly Asp Ser Glu Ser Val Pro Asp Pro
20 25 30
Gln Pro Leu Gly Glu Pro Pro Ala Ala Pro Ser Gly Val Gly Ser Asn
35 40 45
Thr Met Ala
50
<210> 35
<211> 51
<212> PRT
<213> Adeno-associated virus 1
<400> 35
Asp Ser Ser Ser Gly Ile Gly Lys Thr Gly Gln Gln Pro Ala Lys Lys
1 5 10 15
Arg Leu Asn Phe Gly Gln Thr Gly Asp Ser Glu Ser Val Pro Asp Pro
20 25 30
Gln Pro Leu Gly Glu Pro Pro Ala Thr Pro Ala Ala Val Gly Pro Thr
35 40 45
Thr Met Ala
50
<210> 36
<211> 51
<212> PRT
<213> Adeno-associated virus 2
<400> 36
Asp Ser Ser Ser Gly Thr Gly Lys Ala Gly Gln Gln Pro Ala Arg Lys
1 5 10 15
Arg Leu Asn Phe Gly Gln Thr Gly Asp Ala Asp Ser Val Pro Asp Pro
20 25 30
Gln Pro Leu Gly Gln Pro Pro Ala Ala Pro Ser Gly Leu Gly Thr Asn
35 40 45
Thr Met Ala
50
<210> 37
<211> 51
<212> PRT
<213> Adeno-associated virus 3B
<400> 37
Asp Ser Ser Ser Gly Val Gly Lys Ser Gly Lys Gln Pro Ala Arg Lys
1 5 10 15
Arg Leu Asn Phe Gly Gln Thr Gly Asp Ser Glu Ser Val Pro Asp Pro
20 25 30
Gln Pro Leu Gly Glu Pro Pro Ala Ala Pro Thr Ser Leu Gly Ser Asn
35 40 45
Thr Met Ala
50
<210> 38
<211> 46
<212> PRT
<213> Adeno-associated virus 4
<400> 38
Asp Ser Ser Thr Gly Ile Gly Lys Lys Gly Lys Gln Pro Ala Lys Lys
1 5 10 15
Lys Leu Val Phe Glu Asp Glu Thr Gly Ala Gly Asp Gly Pro Pro Glu
20 25 30
Gly Ser Thr Ser Gly Ala Met Ser Asp Asp Ser Glu Met Arg
35 40 45
<210> 39
<211> 51
<212> PRT
<213> Adeno-associated virus 7
<400> 39
Asp Ser Ser Thr Gly Ile Gly Lys Lys Gly Gln Gln Pro Ala Arg Lys
1 5 10 15
Arg Leu Asn Phe Gly Gln Thr Gly Asp Ser Glu Ser Val Pro Asp Pro
20 25 30
Gln Pro Leu Gly Glu Pro Pro Ala Ala Pro Ser Ser Val Gly Ser Gly
35 40 45
Thr Val Ala
50
<210> 40
<211> 51
<212> PRT
<213> Adeno-associated virus 8
<400> 40
Asp Ser Ser Thr Gly Ile Gly Lys Lys Gly Gln Gln Pro Ala Arg Lys
1 5 10 15
Arg Leu Asn Phe Gly Gln Thr Gly Asp Ser Glu Ser Val Pro Asp Pro
20 25 30
Gln Pro Leu Gly Glu Pro Pro Ala Ala Pro Ser Gly Val Gly Pro Asn
35 40 45
Thr Met Ala
50
<210> 41
<211> 51
<212> PRT
<213> Adeno-associated virus 9
<400> 41
Asp Ser Ser Ala Gly Ile Gly Lys Ser Gly Ala Gln Pro Ala Lys Lys
1 5 10 15
Arg Leu Asn Phe Gly Gln Thr Gly Asp Thr Glu Ser Val Pro Asp Pro
20 25 30
Gln Pro Ile Gly Glu Pro Pro Ala Ala Pro Ser Gly Val Gly Ser Leu
35 40 45
Thr Met Ala
50
<210> 42
<211> 51
<212> PRT
<213> Adeno-associated virus 10
<400> 42
Asp Ser Ser Thr Gly Ile Gly Lys Lys Gly Gln Gln Pro Ala Lys Lys
1 5 10 15
Arg Leu Asn Phe Gly Gln Thr Gly Glu Ser Glu Ser Val Pro Asp Pro
20 25 30
Gln Pro Ile Gly Glu Pro Pro Ala Gly Pro Ser Gly Leu Gly Ser Gly
35 40 45
Thr Met Ala
50
<210> 43
<211> 46
<212> PRT
<213> Adeno-associated virus 11
<400> 43
Asp Ser Ser Ser Gly Ile Gly Lys Lys Gly Lys Gln Pro Ala Arg Lys
1 5 10 15
Arg Leu Asn Phe Glu Glu Asp Thr Gly Ala Gly Asp Gly Pro Pro Glu
20 25 30
Gly Ser Asp Thr Ser Ala Met Ser Ser Asp Ile Glu Met Arg
35 40 45
<210> 44
<211> 173
<212> DNA
<213> Adeno-associated virus 6
<400> 44
aagagccaga ctcctcctcg ggcattggca agacaggcca gcagcccgct aaaaagagac 60
tcaattttgg tcagactggc gagtccccga cccacaacct ctcggagaac ctccagcaac 120
ccccgctgct gtgggaccta ctacaatggc ttcaggcggt ggcgcaccaa tgg 173
<210> 45
<211> 183
<212> DNA
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polynucleotide"
<400> 45
aagagccaga ctcctccgcg ggtattggca aatcgggtgc acagcccgct aaaaagagac 60
tcaatttcgg tcagactggc gacacagagt cagtcccaga ccctcaacca atcggagaac 120
ctcccgcagc cccctcaggt gtgggatctc ttacaatggc ttcaggcggt ggcgcaccaa 180
tgg 183
<210> 46
<211> 57
<212> PRT
<213> Adeno-associated virus 6
<400> 46
Pro Gln Glu Pro Asp Ser Ser Ser Gly Ile Gly Lys Thr Gly Gln Gln
1 5 10 15
Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr Gly Asp Ser Glu Ser
20 25 30
Val Pro Asp Pro Gln Pro Leu Gly Glu Pro Pro Ala Thr Pro Ala Ala
35 40 45
Val Gly Pro Thr Thr Met Ala Ser Gly
50 55
<210> 47
<211> 57
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<400> 47
Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly Lys Ser Gly Ala Gln
1 5 10 15
Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr Gly Asp Thr Glu Ser
20 25 30
Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro Ala Ala Pro Ser Gly
35 40 45
Val Gly Ser Leu Thr Met Ala Ser Gly
50 55
<210> 48
<211> 57
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<400> 48
Pro Gln Glu Pro Asp Ser Ser Ser Gly Ile Gly Lys Thr Gly Gln Gln
1 5 10 15
Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr Gly Asp Thr Glu Ser
20 25 30
Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro Ala Ala Pro Ser Gly
35 40 45
Val Gly Ser Leu Thr Met Ala Ser Gly
50 55
<210> 49
<211> 57
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<400> 49
Pro Gln Glu Pro Asp Ser Ser Ser Gly Ile Gly Lys Thr Gly Gln Gln
1 5 10 15
Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr Gly Asp Thr Glu Ser
20 25 30
Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro Ala Ala Pro Ser Gly
35 40 45
Val Gly Pro Thr Thr Met Ala Ser Gly
50 55
<210> 50
<211> 57
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<400> 50
Pro Gln Glu Pro Asp Ser Ser Ser Gly Ile Gly Lys Thr Gly Gln Gln
1 5 10 15
Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr Gly Asp Ser Glu Ser
20 25 30
Val Pro Asp Pro Gln Pro Leu Gly Glu Pro Pro Ala Ala Pro Ser Gly
35 40 45
Val Gly Ser Leu Thr Met Ala Ser Gly
50 55
<210> 51
<211> 57
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<400> 51
Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly Lys Ser Gly Ala Gln
1 5 10 15
Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr Gly Asp Ser Glu Ser
20 25 30
Val Pro Asp Pro Gln Pro Leu Gly Glu Pro Pro Ala Thr Pro Ala Ala
35 40 45
Val Gly Pro Thr Thr Met Ala Ser Gly
50 55
<210> 52
<211> 150
<212> DNA
<213> Adeno-associated virus 6
<400> 52
gccagcagcc cgctaaaaag agactcaatt ttggtcagac tggcgactca gagtcagtcc 60
ccgacccaca acctctcgga gaacctccag caacccccgc tgctgtggga cctactacaa 120
tggcttcagg cggtggcgca ccaatggcag 150
<210> 53
<211> 150
<212> DNA
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polynucleotide"
<400> 53
gtgcacagcc cgctaaaaag agactcaatt tcggtcagac tggcgacaca gagtcagtcc 60
cagaccctca accaatcgga gaacctcccg cagccccctc aggtgtggga tctcttacaa 120
tggcttcagg cggtggcgca ccaatggcag 150
<210> 54
<211> 150
<212> DNA
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polynucleotide"
<400> 54
gccagcagcc cgctaaaaag agactcaatt ttggtcagac tggcgacaca gagtcagtcc 60
ccgacccaca acctatcgga gaacctccag cagccccctc aggtgtggga tctcttacaa 120
tggcttcagg cggtggcgca ccaatggcag 150
<210> 55
<211> 150
<212> DNA
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polynucleotide"
<400> 55
gccagcagcc cgctaaaaag agactcaatt ttggtcagac tggcgacaca gagtcagtcc 60
ccgacccaca acctatcgga gaacctccag cagccccctc aggtgtggga cctactacaa 120
tggcttcagg cggtggcgca ccaatggcag 150
<210> 56
<211> 150
<212> DNA
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polynucleotide"
<400> 56
gccagcagcc cgctaaaaag agactcaatt ttggtcagac tggcgactca gagtcagtcc 60
ccgacccaca acctctcgga gaacctccag cagccccctc aggtgtggga tctcttacaa 120
tggcttcagg cggtggcgca ccaatggcag 150
<210> 57
<211> 150
<212> DNA
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polynucleotide"
<400> 57
gcgcgcagcc cgctaaaaag agactcaatt ttggtcagac tggcgactca gagtcagtcc 60
ccgacccaca acctctcgga gaacctccag caacccccgc tgctgtggga cctactacaa 120
tggcttcagg cggtggcgca ccaatggcag 150
<210> 58
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<400> 58
Met Ala Thr Gln Ser Gln Ser Pro Thr Leu Asn Leu Ser Glu Asn Leu
1 5 10 15
Gln Gln Pro Pro Leu Val Trp Asp Leu Leu Gln Trp Leu Gln
20 25 30
<210> 59
<211> 30
<212> PRT
<213> Adeno-associated virus 1
<400> 59
Met Ala Thr Gln Ser Gln Ser Pro Ile His Asn Leu Ser Glu Asn Leu
1 5 10 15
Gln Gln Pro Pro Leu Leu Trp Asp Leu Leu Gln Trp Leu Gln
20 25 30
<210> 60
<211> 30
<212> PRT
<213> Adeno-associated virus 2
<400> 60
Met Glu Thr Gln Thr Gln Tyr Leu Thr Pro Ser Leu Ser Asp Ser His
1 5 10 15
Gln Gln Pro Pro Leu Val Trp Glu Leu Ile Arg Trp Leu Gln
20 25 30
<210> 61
<211> 30
<212> PRT
<213> Adeno-associated virus 3B
<400> 61
Met Ala Thr Gln Ser Gln Ser Gln Thr Leu Asn Leu Ser Glu Asn His
1 5 10 15
Gln Gln Pro Pro Gln Val Trp Asp Leu Ile Gln Trp Leu Gln
20 25 30
<210> 62
<211> 24
<212> PRT
<213> Adeno-associated virus 4
<400> 62
Met Glu Gln Ala Thr Asp Pro Leu Arg Asp Gln Leu Pro Glu Pro Cys
1 5 10 15
Leu Met Thr Val Arg Cys Val Gln
20
<210> 63
<211> 30
<212> PRT
<213> Adeno-associated virus 7
<400> 63
Met Ala Thr Gln Ser Gln Ser Pro Thr Leu Asn Leu Ser Glu Asn Leu
1 5 10 15
Gln Gln Arg Pro Leu Val Trp Asp Leu Val Gln Trp Leu Gln
20 25 30
<210> 64
<211> 30
<212> PRT
<213> Adeno-associated virus 8
<400> 64
Met Ala Thr Gln Ser Gln Phe Gln Thr Leu Asn Leu Ser Glu Asn Leu
1 5 10 15
Gln Gln Arg Pro Leu Val Trp Asp Leu Ile Gln Trp Leu Gln
20 25 30
<210> 65
<211> 30
<212> PRT
<213> Adeno-associated virus 10
<400> 65
Met Ala Ser Gln Ser Gln Ser Pro Thr Leu Asn Gln Ser Glu Asn His
1 5 10 15
Gln Gln Ala Pro Leu Val Trp Asp Leu Val Gln Trp Leu Gln
20 25 30
<210> 66
<211> 24
<212> PRT
<213> Adeno-associated virus 11
<400> 66
Met Glu Pro Glu Thr Asp Pro Leu Lys Asp Gln Ile Pro Ala Pro Cys
1 5 10 15
Leu Gln Thr Leu Lys Cys Val Gln
20
<210> 67
<211> 49
<212> PRT
<213> Adeno-associated virus 6
<220>
<221> VARIANT
<222> (14)..(14)
<223> /replace="Met"
<220>
<221> SITE
<222> (1)..(49)
<223> /note="Variant residues given in the sequence have no
preference with respect to those in the annotations
for variant positions"
<400> 67
Gly Gln Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Leu Ala Thr
1 5 10 15
Gln Ser Gln Ser Pro Thr His Asn Leu Ser Glu Asn Leu Gln Gln Pro
20 25 30
Pro Leu Leu Trp Asp Leu Leu Gln Trp Leu Gly Gly Gly Ala Pro Met
35 40 45
Ala
<210> 68
<211> 49
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<220>
<221> VARIANT
<222> (14)..(14)
<223> /replace="Met"
<220>
<221> SITE
<222> (1)..(49)
<223> /note="Variant residues given in the sequence have no
preference with respect to those in the annotations
for variant positions"
<400> 68
Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Leu Ala Thr
1 5 10 15
Gln Ser Gln Ser Gln Thr Leu Asn Gln Ser Glu Asn Leu Pro Gln Pro
20 25 30
Pro Gln Val Trp Asp Leu Leu Gln Trp Leu Gly Gly Gly Ala Pro Met
35 40 45
Ala
<210> 69
<211> 49
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<220>
<221> VARIANT
<222> (14)..(14)
<223> /replace="Met"
<220>
<221> SITE
<222> (1)..(49)
<223> /note="Variant residues given in the sequence have no
preference with respect to those in the annotations
for variant positions"
<400> 69
Gly Gln Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Leu Ala Thr
1 5 10 15
Gln Ser Gln Ser Pro Thr His Asn Leu Ser Glu Asn Leu Gln Gln Pro
20 25 30
Pro Gln Val Trp Asp Leu Leu Gln Trp Leu Gly Gly Gly Ala Pro Met
35 40 45
Ala
<210> 70
<211> 49
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<220>
<221> VARIANT
<222> (14)..(14)
<223> /replace="Met"
<220>
<221> SITE
<222> (1)..(49)
<223> /note="Variant residues given in the sequence have no
preference with respect to those in the annotations
for variant positions"
<400> 70
Gly Gln Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Leu Ala Thr
1 5 10 15
Gln Ser Gln Ser Pro Thr His Asn Leu Ser Glu Asn Leu Gln Gln Pro
20 25 30
Pro Gln Val Trp Asp Leu Leu Gln Trp Leu Gly Gly Gly Ala Pro Met
35 40 45
Ala
<210> 71
<211> 49
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<220>
<221> VARIANT
<222> (14)..(14)
<223> /replace="Met"
<220>
<221> SITE
<222> (1)..(49)
<223> /note="Variant residues given in the sequence have no
preference with respect to those in the annotations
for variant positions"
<400> 71
Gly Gln Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Leu Ala Thr
1 5 10 15
Gln Ser Gln Ser Pro Thr His Asn Leu Ser Glu Asn Leu Gln Gln Pro
20 25 30
Pro Gln Val Trp Asp Leu Leu Gln Trp Leu Gly Gly Gly Ala Pro Met
35 40 45
Ala
<210> 72
<211> 49
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<220>
<221> VARIANT
<222> (14)..(14)
<223> /replace="Met"
<220>
<221> SITE
<222> (1)..(49)
<223> /note="Variant residues given in the sequence have no
preference with respect to those in the annotations
for variant positions"
<400> 72
Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Leu Ala Thr
1 5 10 15
Gln Ser Gln Ser Pro Thr His Asn Leu Ser Glu Asn Leu Gln Gln Pro
20 25 30
Pro Leu Leu Trp Asp Leu Leu Gln Trp Leu Gly Gly Gly Ala Pro Met
35 40 45
Ala
<210> 73
<211> 51
<212> PRT
<213> Adeno-associated virus 6
<400> 73
Asp Ser Ser Ser Gly Ile Gly Lys Thr Gly Gln Gln Pro Ala Lys Lys
1 5 10 15
Arg Leu Asn Phe Gly Gln Thr Gly Asp Ser Glu Ser Val Pro Asp Pro
20 25 30
Gln Pro Leu Gly Glu Pro Pro Ala Thr Pro Ala Ala Val Gly Pro Thr
35 40 45
Thr Met Ala
50
Claims (20)
- Rep78에 대한 발현 카세트를 포함하는 제1 바큘로바이러스 벡터 및 Rep52에 대한 발현 카세트를 포함하는 제2 바큘로바이러스 벡터를 포함하며, 여기서 제1 벡터 및 제2 벡터는 (i) 각각 VP1에 대한 발현 카세트 및 VP2/VP3에 대한 발현 카세트; 또는 (ii) 각각 VP2/VP3에 대한 발현 카세트 및 VP1에 대한 발현 카세트를 추가로 포함하는 것인 곤충 세포.
- 제1항에 있어서, Rep78 발현 카세트 및 Rep52 발현 카세트가 동일한 곤충 프로모터를 포함하는 것인 곤충 세포.
- 제1항 또는 제2항에 있어서, Rep78 발현 카세트가 Rep78 코딩 서열에 대한 비-정규 개시 코돈을 포함하며, 여기서 코돈은 임의로 ACG, TTG, GTG 또는 CTG인 곤충 세포.
- 제1항 내지 제3항 중 어느 한 항에 있어서, VP1 발현 카세트 및 VP2/VP3 발현 카세트가 동일한 곤충 프로모터를 포함하는 것인 곤충 세포.
- 제1항 내지 제4항 중 어느 한 항에 있어서, VP1, VP2, 및 VP3 단백질이 동일한 AAV 혈청형으로부터의, 또는 1종 초과의 AAV 혈청형으로부터의 아미노산 서열을 포함하는 것인 곤충 세포.
- 제5항에 있어서, VP1, VP2, 및/또는 VP3 단백질이 AAV1, AAV2, AAV3 (임의로 AAV3B), AAV6, 및/또는 AAV9로부터의 아미노산 서열을 포함하는 것인 곤충 세포.
- 제1항 내지 제6항 중 어느 한 항에 있어서, Rep78 및 Rep52 단백질이 VP1, VP2, 및/또는 VP3 단백질과 상이한 AAV 혈청형으로부터 유래된 것인 곤충 세포.
- 제1항 내지 제7항 중 어느 한 항에 있어서,
(i) VP1이 제1 아미노산 잔기를 갖거나 갖지 않는 서열식별번호: 1, 7, 또는 16을 포함하고;
VP2가 서열식별번호: 1 또는 7의 아미노산 잔기 138-736 또는 139-736을 포함하거나, 또는 제1 아미노산 잔기를 갖거나 갖지 않는 서열식별번호: 18을 포함하고;
VP3이 서열식별번호: 1의 204-736 또는 205-736의 아미노산 잔기 또는 서열식별번호: 7의 아미노산 잔기 203-736 또는 204-736을 포함하거나, 또는 제1 아미노산 잔기를 갖거나 갖지 않는 서열식별번호: 19를 포함하거나; 또는
(ii) VP1이 제1 아미노산 잔기를 갖거나 갖지 않는 서열식별번호: 24를 포함하고;
VP2가 서열식별번호: 24의 아미노산 잔기 138-736 또는 139-736을 포함하고;
VP3이 서열식별번호: 24의 203-736 또는 204-736의 아미노산 잔기를 포함하거나; 또는
(iii) VP1이 제1 아미노산 잔기를 갖거나 갖지 않는 서열식별번호: 25를 포함하고;
VP2가 서열식별번호: 25의 아미노산 잔기 138-735 또는 139-735를 포함하고;
VP3이 서열식별번호: 25의 203-735 또는 204-735를 포함하거나; 또는
(iv) VP1이 제1 아미노산 잔기를 갖거나 갖지 않는 서열식별번호: 26을 포함하고;
VP2가 서열식별번호: 26의 아미노산 잔기 138-736 또는 139-736을 포함하고;
VP3이 서열식별번호: 26의 203-736 또는 204-736의 아미노산 잔기를 포함하거나; 또는
(v) VP1이 제1 아미노산 잔기를 갖거나 갖지 않는 서열식별번호: 27을 포함하고;
VP2가 서열식별번호: 27의 아미노산 잔기 138-736 또는 139-736을 포함하고;
VP3이 서열식별번호: 27의 203-736 또는 204-736의 아미노산 잔기를 포함하고;
임의로 여기서 Rep78이 제1 아미노산 잔기를 갖거나 갖지 않는 서열식별번호: 21을 포함하고/거나; Rep52가 제1 아미노산 잔기를 갖거나 갖지 않는 서열식별번호: 23을 포함하는 것인
곤충 세포. - 제1항 내지 제8항 중 어느 한 항에 있어서, Rep78, Rep52, VP1, 및 VP2/VP3 발현 카세트 각각이 폴리헤드론 프로모터, IE-1 프로모터, 및 p10 프로모터로부터 선택된 곤충 프로모터를 포함하는 것인 곤충 세포.
- 제1항 내지 제9항 중 어느 한 항에 있어서, 제1 바큘로바이러스 벡터가 VP2/VP3에 대한 발현 카세트를 포함하고, 제2 바큘로바이러스 벡터가 VP1에 대한 발현 카세트를 포함하는 것인 곤충 세포.
- 제1항 내지 제10항 중 어느 한 항에 있어서, 제1 및 제2 벡터 중 하나 또는 둘 다가 곤충 세포의 게놈 내로 안정하게 통합된 것인 곤충 세포.
- 제1항 내지 제11항 중 어느 한 항에 있어서, Sf9 또는 Sf21 세포인 곤충 세포.
- 제1항 내지 제12항 중 어느 한 항에 있어서, 재조합 AAV 게놈에 대한 코딩 서열을 추가로 포함하며, 여기서 재조합 AAV 게놈은
포유동물 프로모터의 전사 제어 하에 있는 관심 트랜스진에 대한 발현 카세트, 및
양쪽 말단 상의 AAV 역전된 말단 반복부 (ITR)
를 포함하는 것인 곤충 세포. - 제13항에 있어서, 재조합 AAV 게놈에 대한 코딩 서열이 제1 또는 제2 벡터 상에 위치하거나, 또는 제3 벡터 상에 위치하는 것인 곤충 세포.
- 제13항 또는 제14항에 있어서, 관심 트랜스진이, 임의로 아연 핑거 단백질 (ZFP) 전사 인자, 및 유전 질환에서 기능이 결여 또는 결핍된 단백질로부터 선택된, 치료 단백질을 코딩하는 것인 곤충 세포.
- 제13항 또는 제14항에 있어서, 관심 트랜스진이, 임의로 아연 핑거 뉴클레아제, ZFP 데아미나제, ZFP 레콤비나제, TALEN, CRISPR Cas 단백질 및 CRISPR Cpf 단백질로부터 선택된, 유전자 편집 단백질을 코딩하는 것인 곤충 세포.
- 제13항 내지 제16항 중 어느 한 항의 곤충 세포를 제공하는 단계,
재조합 AAV 게놈의 발현 및 VP1, VP2, 및 VP3 단백질을 포함하는 AAV 캡시드 내의 재조합 AAV 게놈의 패키징을 허용하는 조건 하에 곤충 세포를 배양하는 단계, 및
생산된 재조합 AAV 비리온을 배양물로부터 단리하는 단계
를 포함하는, 재조합 AAV 비리온을 생산하는 방법. - 제13항 내지 제16항 중 어느 한 항의 곤충 세포에서 또는 제17항의 방법에 의해 생산된 재조합 AAV 비리온.
- 제18항의 재조합 AAV 비리온 및 제약상 허용되는 담체를 포함하는 제약 조성물.
- 제1항 내지 제16항 중 어느 한 항의 발현 카세트의 조합물.
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