KR20200016988A - 변이체 캡시드를 지니는 아데노-관련 바이러스 및 이의 사용 방법 - Google Patents
변이체 캡시드를 지니는 아데노-관련 바이러스 및 이의 사용 방법 Download PDFInfo
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Abstract
본 개시내용은 변성된 캡시드 단백질을 지니는 아데노-관련 바이러스(AAV) 비리온을 제공하되, AAV 비리온은 유리체내 주사를 통해 투여될 때, 야생형 AAV에 비해 더 큰 감염성의 망막 세포를 나타낸다. 본 개시내용은 개체에서 망막 세포에 유전자 산물을 전달하는 방법 및 안질환을 치료하는 방법을 추가로 제공한다.
Description
관련참조
본 출원은 2011년 4월 22일 출원된 미국 가특허 출원 제61/478,355호의 우선권을 주장하며, 이 기초출원은 본 명세서에 전문이 참조로서 포함된다.
연방정부 지원된 연구에 대한 언급
본 발명은 미국 국립보건원의 국립안연구소에 의해 부여된 등록번호 EY016994-02호 및 EY1018241호 하에서 정부 지원에 의해 이루어졌다.
광수용체는 시각적 정보를 수용하고 처리하기 위한 망막 내 제1 뉴런인데, 이는 광전환(phototransduction)을 통해 시각적 전자기파 방사선을 과분극화된 반응으로 전환시킨다. 압도적인 대다수의 유전성 망막질병은 직접적으로, 예컨대 로돕신 단백질 폴딩에 영향을 미치는 우성 돌연변이에 또는 간접적으로, 예컨대 망막 색소 상피층(retinal pigment epithelium: RPE) 내 망막의 재사용 경로에 영향을 미치는 이들 세포의 손실을 초래한다.
AAV는 파보비리다에(Parvoviridae)과 및 데펜도바이러스(Dependovirus) 속에 속하는데, 이것의 구성원은 복제를 촉진하기 위해 아데노바이러스와 같은 헬퍼 바이러스와 공동-감염을 필요로 하며, AAV는 헬퍼 없이 잠재적 감염을 확립한다. 비리온은 2개의 오픈 리딩 프레임: rep 및 cap을 지니는 4.9 kb 단일 가닥 DNA 게놈을 포함하는 25㎚ 20면체 캡시드로 구성된다. 비구조적 rep 유전자는 바이러스 복제를 위해 필수적인 4개의 조절 단백질을 암호화하는 반면, cap은 60-량체 캡시드 껍질로 조립되는 3개의 구조적 단백질(VP1 내지 3)을 암호화할 수 있다. 이 바이러스 캡시드는 세포 표면 수용체 결합, 엔도사이토시스, 세포내 교환 및 핵 내 언패키징(unpackaging)을 포함하는 바이러스 형질도입의 다수의 생물학적 장벽을 극복하는 AAV 벡터의 능력을 매개한다.
Allocca et al. (2007) J. Virol. 81:11372
Boucas et al. (2009) J. Gene Med. 11:1103
본 개시내용은 변성된 캡시드 단백질을 지니는 아데노-관련 바이러스(adeno-associated virus: AAV)를 제공하되, 야생형 AAV에 비해 유리체내 주사를 통해 투여될 때, AAV 비리온은 망막 세포의 더 큰 감염성을 나타낸다. 본 발명의 개시내용은 추가로 개체의 망막 세포에 유전자 산물을 전달하는 방법 및 안질환의 치료방법을 제공한다.
도 1은 아미노산 587 다음에 무작위 헵타머를 함유하는 대표적인 AAV2의 3차원 모델을 도시한 도면;
도 2는 AAV2(좌)에 대해 AAV2 7M8 변이체(우)에 의한 유리체내 더 큰 수준의 형질도입을 도시한 도면;
도 3은 흔한 CAG 프로모터(좌) 또는 광수용체-특이적 Rho 프로모터(우)의 제어하에 GFP 유전자를 운반하는 7M8로부터 초래되는 녹색 형광 단백질(green fluorescent protein: GFP) 발현을 나타내는 망막 냉동슬라이스의 대표적인 형광 이미지를 도시한 도면;
도 4는 7M8에 의해 또는 4개의 티로신 돌연변이를 함유하는 7M8(7m8.4YF)에 의해 형질도입 후, 유세포 분석기에 의해 계측되는 바와 같은 백만 개의 망막세포 당 GFP+ 광수용체 세포를 도시한 도면;
도 5는 AAV2 VP1의 아미노산 서열(서열번호 1)을 도시한 도면;
도 6은 다양한 AAV 혈청형의 AAV 캡시드 단백질 VP1의 AAV2(도 5)의 아미노산 570 내지 610에 대응되는 아미노산 서열을 도시한 도면;
도 7a 내지 도 7i는 유전자 전달 후 Rs1h-/- 마우스 망막에서 구조적 개선을 도시한 도면;
도 8a 내지 도 8d는 RS1 유전자 전달 후 망막전도(electroretinogram) A 및 B 웨이브의 기능적 구제(functional rescue)를 도시한 도면;
도 9a 내지 도 9e는 7m8-rho-RS1 처리 후 10개월에 측정된 망막 두께에서 지속적인 개선을 도시한 도면;
도 10은 망막층간 단백질(retinoschisin)의 아미노산 서열을 도시한 도면;
도 11은 뇌 유래 신경영양 인자의 아미노산 서열을 도시한 도면;
도 12는 RPE65의 아미노산 서열을 도시한 도면;
도 13a 내지 도 13c는 7m8-rho-RS1 작제물의 뉴클레오타이드 서열을 도시한 도면;
도 14는 페리페린-2의 아미노산 서열을 도시한 도면;
도 15는 페리페린의 아미노산 서열을 도시한 도면;
도 16은 망막 색소 변성증 GTPase 조절자-상호작용 단백질-1의 아미노산 서열을 도시한 도면;
도 17a 내지 도 17c는 AAV 캡시드 단백질 루프 IV(GH 루프) 영역의 아미노산 서열의 정렬을 도시한 도면. 삽입 부위는 볼드체 및 밑줄로 나타낸다;
도 18a 내지 도 18c는 이종성 펩타이드 삽입을 지니는 AAV 캡시드 단백질 GH 루프 영역의 아미노산 서열의 정렬을 도시한 도면;
도 19는 커넥신36(connexin36) 프로모터의 제어 하에 7m8 운반 GFP의 투여 9주 후, 중추 영장류 망막에서 GFP 발현을 나타내는 형광 안저 영상을 도시한 도면.
도 2는 AAV2(좌)에 대해 AAV2 7M8 변이체(우)에 의한 유리체내 더 큰 수준의 형질도입을 도시한 도면;
도 3은 흔한 CAG 프로모터(좌) 또는 광수용체-특이적 Rho 프로모터(우)의 제어하에 GFP 유전자를 운반하는 7M8로부터 초래되는 녹색 형광 단백질(green fluorescent protein: GFP) 발현을 나타내는 망막 냉동슬라이스의 대표적인 형광 이미지를 도시한 도면;
도 4는 7M8에 의해 또는 4개의 티로신 돌연변이를 함유하는 7M8(7m8.4YF)에 의해 형질도입 후, 유세포 분석기에 의해 계측되는 바와 같은 백만 개의 망막세포 당 GFP+ 광수용체 세포를 도시한 도면;
도 5는 AAV2 VP1의 아미노산 서열(서열번호 1)을 도시한 도면;
도 6은 다양한 AAV 혈청형의 AAV 캡시드 단백질 VP1의 AAV2(도 5)의 아미노산 570 내지 610에 대응되는 아미노산 서열을 도시한 도면;
도 7a 내지 도 7i는 유전자 전달 후 Rs1h-/- 마우스 망막에서 구조적 개선을 도시한 도면;
도 8a 내지 도 8d는 RS1 유전자 전달 후 망막전도(electroretinogram) A 및 B 웨이브의 기능적 구제(functional rescue)를 도시한 도면;
도 9a 내지 도 9e는 7m8-rho-RS1 처리 후 10개월에 측정된 망막 두께에서 지속적인 개선을 도시한 도면;
도 10은 망막층간 단백질(retinoschisin)의 아미노산 서열을 도시한 도면;
도 11은 뇌 유래 신경영양 인자의 아미노산 서열을 도시한 도면;
도 12는 RPE65의 아미노산 서열을 도시한 도면;
도 13a 내지 도 13c는 7m8-rho-RS1 작제물의 뉴클레오타이드 서열을 도시한 도면;
도 14는 페리페린-2의 아미노산 서열을 도시한 도면;
도 15는 페리페린의 아미노산 서열을 도시한 도면;
도 16은 망막 색소 변성증 GTPase 조절자-상호작용 단백질-1의 아미노산 서열을 도시한 도면;
도 17a 내지 도 17c는 AAV 캡시드 단백질 루프 IV(GH 루프) 영역의 아미노산 서열의 정렬을 도시한 도면. 삽입 부위는 볼드체 및 밑줄로 나타낸다;
도 18a 내지 도 18c는 이종성 펩타이드 삽입을 지니는 AAV 캡시드 단백질 GH 루프 영역의 아미노산 서열의 정렬을 도시한 도면;
도 19는 커넥신36(connexin36) 프로모터의 제어 하에 7m8 운반 GFP의 투여 9주 후, 중추 영장류 망막에서 GFP 발현을 나타내는 형광 안저 영상을 도시한 도면.
정의
용어 "망막 세포"는 본 명세서에서 망막을 포함하는 임의의 세포 유형, 예컨대 망막 신경절세포, 아마크린 세포, 수평세포, 양극 세포 및 간체(rod) 및 추체(cone)를 포함하는 광수용체 세포, 뮐러 신경교세포(Muller glial cell) 및 망막 색소성 상피세포를 지칭할 수 있다.
"AAV"는 아데노-관련 바이러스에 대한 약어이며, 바이러스 그 자체 또는 이의 유도체를 지칭하기 위해 사용될 수 있다. 해당 용어는 그 밖에 필요한 경우를 제외하고, 모든 하위유형 및 자연적으로 발생하는 형태와 재조합 형태를 둘 다 다룬다. 약어 "rAAV"는 재조합 아데노-관련 바이러스를 지칭하며, 또한 재조합 AAV 벡터(또는 "rAAV 벡터")로서 지칭된다. 용어 "AAV"는 AAV 1형(AAV-1), AAV 2형(AAV-2), AAV 3형(AAV-3), AAV 4형(AAV-4), AAV 5형(AAV-5), AAV 6형(AAV-6), AAV 7형(AAV-7), AAV 8형(AAV-8), 조류 AAV, 소 AAV, 개 AAV, 말 AAV, 영장류 AAV, 비-영장류 AAV 및 양 AAV을 포함한다. "영장류 AAV"는 영장류를 감염시키는 AAV를 지칭하며, "비-영장류 AAV"는 비-영장류 포유류를 감염시키는 AAV를 지칭하고, "소 AAV"는 소 포유류 등을 감염시키는 AAV를 지칭한다.
AAV의 다양한 혈청형의 게놈 서열뿐만 아니라 천연 말단 반복체(terminal repeat: TR)의 서열, Rep 단백질 및 캡시드 서브유닛은 당업계에 공지되어 있다. 이러한 서열은 문헌에서 또는 젠뱅크(GenBank)와 같은 공용 데이터베이스에서 찾을 수 있다. 예를 들어, 젠뱅크(GenBank) 등록번호 NC_002077(AAV-1), AF063497(AAV-1), NC_001401(AAV-2), AF043303(AAV-2), NC_001729(AAV-3), NC_001829(AAV-4), U89790(AAV-4), NC_006152(AAV-5), AF513851(AAV-7), AF513852(AAV-8) 및 NC_006261(AAV-8)을 참조하며; 이것의 개시내용은 AAV 핵산 및 아미노산 서열을 교시하기 위해 본 명세서에 참조로서 포함된다. 또한 예를 들어 문헌[Srivistava et al. (1983) J. Virology 45:555; Chiorini et al. (1998) J. Virology 71:6823; Chiorini et al. (1999) J. Virology 73:1309; Bantel-Schaal et al. (1999) J. Virology 73:939; Xiao et al. (1999) J. Virology 73:3994; Muramatsu et al. (1996) Virology 221:208; Shade et al.,(1986) J. Virol. 58:921; Gao et al. (2002) Proc. Nat. Acad. Sci. USA 99:11854; Moris et al. (2004) Virology 33:375-383]; 국제특허 공개 WO 00/28061호, WO 99/61601호, WO 98/11244호; 및 미국 특허 제6,156,303호를 참조한다.
본 명세서에 사용되는 바와 같은 "rAAV 벡터"는 AAV 유래가 아닌 폴리뉴클레오타이드 서열(즉, AAV에 대해 이종성인 폴리뉴클레오타이드), 전형적으로는 세포의 유전적 형질전환을 위한 관심의 서열을 포함하는 AAV 벡터를 지칭한다. 일반적으로, 이종성 폴리뉴클레오타이드는 적어도 하나, 및 일반적으로는 2개의 AAV 역위 말단 반복 서열(inverted terminal repeat sequence: ITR)에 측접된다. 용어 rAAV 벡터는 rAAV 벡터 입자와 rAAV 벡터 플라스미드를 둘 다 포함한다. rAAV 벡터는 단일 가닥(single-stranded: ssAAV) 또는 자기-상보적(self-complementary: scAAV)일 수 있다.
"AAV 바이러스" 또는 "AAV 바이러스 입자" 또는 "rAAV 벡터 입자"는 적어도 하나의 AAV 캡시드 단백질(야생형 AAV의 모든 캡시드 단백질에 의함) 및 캡시드 내 이입된(encapsidated) 폴리뉴클레오타이드 rAAV 벡터로 구성되는 바이러스 입자를 지칭한다. 입자가 이종성 폴리뉴클레오타이드(즉, 야생형 AAV 게놈 이외의 폴리뉴클레오타이드, 예컨대 포유류 세포에 전달되는 이식유전자)를 포함한다면, 이는 전형적으로 "rAAV 벡터 입자" 또는 간단하게 "rAAV 벡터"로서 지칭된다. 따라서, rAAV 입자의 생성은 필연적으로 rAAV의 생성을 포함하는데, 이러한 벡터가 rAAV 입자 내에 함유되기 때문이다.
"패키징"은 AAV 입자의 조립체 및 캡시드 내 이입을 야기하는 일련의 세포내 사건을 지칭한다.
AAV "rep" 및 "cap" 유전자는 아데노-관련 바이러스의 복제 및 캡시드 내 이입 단백질을 암호화하는 폴리뉴클레오타이드 서열을 지칭한다. AAV rep 및 cap은 본 명세서에서 AAV "패키징 유전자"로서 지칭된다.
AAV에 대한 "헬퍼 바이러스"는 AAV(예를 들어, 야생형 AAV)가 포유류 세포에 의해 복제되고, 패키징되게 하는 바이러스를 지칭한다. 아데노바이러스, 헤르페스바이러스, 및 백시니아와 같은 폭스바이러스를 포함하는, AAV에 대한 다양한 이러한 헬퍼 바이러스는 당업계에 공지되어 있다. 서브그룹 C의 아데노바이러스 5형이 가장 흔히 사용되지만, 아데노바이러스는 다수의 상이한 서브그룹을 포함한다. 인간, 비인간 포유류 및 조류 유래의 수많은 아데노바이러스는 공지되어 있고, ATCC와 같은 기탁기관으로부터 입수가능하다. 헤르페스과의 바이러스는, 예를 들어 헤르페스 심플렉스 바이러스(herpes simplex viruses: HSV) 및 엡스타인-바르 바이러스(Epstein-Barr viruses: EBV)뿐만 아니라 사이토메칼로바이러스(cytomegaloviruses: CMV) 및 가성광견병 바이러스(pseudorabies viruses: PRV)를 포함하는데; 이들은 또한 ATCC와 같은 기탁기관으로부터 입수가능하다.
"헬퍼 바이러스 기능(들)"은 AAV 복제 및 패키징(본 명세서에 기재된 복제 및 패키징을 위한 다른 요구사항과 함께)을 허용하는 헬퍼 바이러스 게놈에서 암호화된 기능(들)을 지칭한다. 본 명세서에 기재된 바와 같이, "헬퍼 바이러스 기능"은 헬퍼 바이러스를 제공하거나 또는, 예를 들어 트랜스로 생산자 세포에 필수 기능(들)을 암호화하는 폴리뉴클레오타이드 서열을 제공함으로써 포함되는, 다양한 방법으로 제공될 수 있다. 예를 들어, 하나 이상의 아데노바이러스 단백질을 암호화하는 뉴클레오타이드 서열을 포함하는 플라스미드 또는 다른 발현 벡터는 rAAV 벡터와 함께 생산자 세포로 형질감염된다.
"감염성" 바이러스 또는 바이러스 입자는 적격성 있게(competently) 조립된 바이러스 캡시드를 포함하는 것이며, 바이러스 종이 열대성인 세포에 폴리뉴클레오타이드 성분을 전달할 수 있다. 용어는 바이러스의 임의의 복제 능력을 필연적으로 나타내지 않는다. 감염성 바이러스 입자를 계측하기 위한 분석은 본 개시내용 및 당업계 어디에서나 기재되어 있다. 바이러스 감염성은 감염성 바이러스 입자 대 전체 바이러스 감염의 비로서 표현될 수 있다. 감염성 바이러스 입자 대 전체 바이러스 입자 비의 결정 방법은 당업계에 공지되어 있다. 예를 들어, 문헌[Grainger et al. (2005) Mol. Ther. 11:S337(TCID50 감염성 역가 분석을 기재함); 및 Zolotukhin et al. (1999) Gene Ther. 6:973]을 참조한다. 또한 실시예를 참조한다.
"복제-적격(replication-competent)" 바이러스(예를 들어, 복제-적격 AAV)는 감염성이며, 또한 감염된 세포에서(즉, 헬퍼 바이러스 또는 헬퍼 바이러스 기능의 존재에서) 복제될 수 있는 표현형으로 야생형인 바이러스를 지칭한다. AAV의 경우에, 복제 적격성은 일반적으로 기능적 AAV 패키징 유전자의 존재를 필요로 한다. 일반적으로, 본 명세서에 기재된 rAAV 벡터는 하나 이상의 AAV 패키징 유전자의 결여 때문에 포유류 세포에서(특히, 인간 세포에서) 복제-부적격이다. 전형적으로는, 이러한 rAAV 벡터는 복제 적격 AAV가 AAV 패키징 유전자와 유입 rAAV 벡터 사이의 재조합에 의해 만들어지는 가능성을 최소화하기 위해 임의의 AAV 패키징 유전자 서열을 결여한다. 다수의 실시형태에서, 본 명세서에 기재된 바와 같은 rAAV 벡터 제제는 임의의 복제 적격 AAV(rcAAV, 또한 RCA로서 지칭됨)(예를 들어, 102 rAAV 입자 당 약 1 미만의 rcAAV, 104 rAAV 입자 당 약 1 미만의 rcAAV, 108 rAAV 입자 당 약 1 미만의 rcAAV, 1012 rAAV 입자 당 약 1 미만의 rcAAV 또는 rcAAV 없음)가 있다고 해도 거의 없는 것이다.
용어 "폴리뉴클레오타이드"는 데옥시리보뉴클레오타이드 또는 리보뉴클레오타이드 또는 이들의 유사체를 포함하는, 임의의 길이의 뉴클레오타이드의 중합체 형태를 지칭한다. 폴리뉴클레오타이드는 변형된 뉴클레오타이드, 예컨대 메틸화된 뉴클레오타이드 및 뉴클레오타이드 유사체를 포함할 수 있고, 비뉴클레오타이드 성분에 의해 방해될 수 있다. 존재한다면, 뉴클레오타이드 구조에 대한 변형은 중합체의 조립 전 또는 후에 전해질 수 있다. 본 명세서에서 사용되는 용어 폴리뉴클레오타이드는 상호호환적으로 이중- 및 단일-가닥 분자를 지칭한다. 달리 특정되거나 또는 필요로 되지 않는다면, 폴리뉴클레오타이드인 본 발명에 기재된 본 발명의 임의의 실시형태는 이중 가닥 형태를 구성하는 것으로 공지되거나 또는 예측된 이중-가닥 형태와 각각의 2개의 상보적 단일-가닥 형태를 포함한다.
핵산 혼성화 반응은 상이한 "엄격" 조건 하에 수행될 수 있다. 엄격한 혼성화 반응을 증가시키는 조건은 당업계에 널리 공지되고, 공개되어 있다. 예를 들어, 본 명세서에 참조로서 포함된 문헌[Sambrook et al. Molecular Cloning, A Laboratory Manual, 2nd Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989]을 참조한다. 예를 들어, 문헌[Sambrook et al]의 7.52 페이지를 참조한다. 적절한 조건의 예는(엄격함을 증가시키기 위해) 25℃, 37℃, 50℃ 및 68℃의 인큐베이션 온도; 10 × SSC, 6 × SSC, 1 × SSC, 0.1 × SSC의 완충제 농도(1 × SSC는 0.15 M NaCl 및 15mM 시트레이트 완충제임) 및 다른 완충제 시스템을 사용하는 이들의 등가물; 0%, 25%, 50% 및 75%의 포름아마이드 농도; 5분 내지 24시간의 인큐베이션 시간; 1, 2 이상의 세척 단계; 1, 2 또는 15분의 세척 인큐베이션 시간; 및 6 × SSC, 1 × SSC, 0.1 × SSC의 세척 용액 또는 탈이온수를 포함한다. 엄격한 혼성화 조건의 예는 50℃ 이상 및 0.1×SSC에서 혼성화이다(15mM 염화나트륨/1.5mM 시트르산나트륨). 엄격한 혼성화 조건의 다른 예는 42℃에서 용액: 50% 포름아마이드, 1 × SSC (150mM NaCl, 15mM 시트르산나트륨), 50mM 인산나트륨(pH 7.6), 5 × 덴하르트 용액(덴하르트 용액), 10% 덱스트란 설페이트 및 20㎍/㎖ 변성되고, 전단된 연어 정자 DNA 중에서 밤새 인큐베이션시킨 후, 약 65℃에서 0.1 × SSC 중에서 필터를 세척한다. 다른 예로서, 엄격한 혼성화 조건은 65℃에서 6X 착즙 그대로의 시트레이트(single strength citrate: SSC)(1X SSC는 0.15 M NaCl, 0.015 M Na 시트레이트임; pH 7.0), 5X 덴하르트 용액, 0.05% 파이로인산나트륨 및 100 ㎍/㎖ 청어 정자 DNA를 포함하는 용액 중에서 8시간 내지 밤새 예비혼성화 단계; 65℃에서 18시간 내지 20시간 동안 6X SSC, 1X 덴하르트 용액, 100 ㎍/㎖ 효모 tRNA 및 0.05% 파이로인산나트륨을 함유하는 용액 중에서 혼성화 단계; 및 0.2X SSC 및 0.1% SDS(도데실 황산 나트륨)을 함유하는 용액 중에서 65℃에서 1시간 동안 충전제의 세척 단계를 포함한다.
엄격한 혼성화 조건은 적어도 상기 대표적인 조건만큼 엄격한 혼성화 조건이다. 다른 엄격한 혼성화 조건은 당업계에 공지되어 있고, 본 발명의 이 특정 실시형태의 핵산을 확인하기 위해 사용될 수 있다.
"Tm"은 왓슨-크릭 염기쌍에 의해 역평행 방향으로 결합된 상보적 가닥 수소로 만들어진 폴리뉴클레오타이드 듀플렉스의 50%가 실험 조건 하에 단일 가닥으로 해리되는 섭씨의 온도이다. Tm은 하기와 같은 표준식에 따라 예측될 수 있다:
Tm = 81.5 + 16.6 log[X+] + 0.41 (%G/C) - 0.61 (%F) - 600/L
상기 식에서 [X+]는 ㏖/ℓ로 양이온 농도(보통 나트륨 이온, Na+)이고; (%G/C)는 듀플렉스 내 전체 잔기의 백분율로서 G 및 C 잔기의 수이며; (%F)는 용액 내 포름아마이드의 백분율(중량/용적)이고; L은 듀플렉스의 각 가닥에서 뉴클레오타이드의 수이다.
폴리뉴클레오타이드 또는 폴리펩타이드는 다른 폴리뉴클레오타이드 또는 폴리펩타이드에 대해 특정 백분율의 "서열 동일성"을 가지는데, 이는 정렬될 때 염기 또는 아미노산의 백분율이 두 서열을 비교할 때 동일하다는 것을 의미한다. 서열 유사성은 다수의 상이한 방법으로 결정될 수 있다. 서열 동일성을 결정하기 위해, 서열은 월드 와이드 웹 ncbi.nlm.nih.gov/BLAST/을 거쳐 입수가능한 BLAST를 포함하는 방법 및 컴퓨터 프로그램을 사용하여 정렬될 수 있다. 다른 정렬 알고리즘은 옥스포드 몰레큘러 그룹 인코포레이티드(Oxford Molecular Group, Inc.)의 전액 출자 자회사인 미국 위스콘신주 매디슨에 소재한 제네틱 컴퓨팅 그룹(Genetics Computing Group: GCG) 패키지에서 입수가능한 FASTA이다. 정렬을 위한 다른 기법은 문헌[Methods in Enzymology, vol. 266: Computer Methods for Macromolecular Sequence Analysis (1996), ed. Doolittle, Academic Press, Inc., a division of Harcourt Brace & Co., San Diego, California, USA]에 기재되어 있다. 서열에서 갭을 허용하는 정렬 프로그램에 특히 관심이 있다. 스미스-워터만(Smith-Waterman)은 서열 정렬에서 갭을 허용하는 일 유형의 알고리즘이다. 문헌[Meth. Mol. Biol. 70: 173-187 (1997)]을 참조한다. 또한, 서열을 정렬시키기 위해 니들만(Needleman) 및 분쉬(Wunsch)를 사용하는 GAP 프로그램이 이용될 수 있다. 문헌[J. Mol. Biol. 48: 443-453 (1970)]을 참조한다.
서열 동일성을 결정하기 위해 스미스 및 워터만의 국소 상동성 알고리즘(Advances in Applied Mathematics 2: 482-489 (1981))을 사용하는 베스트핏(BestFit) 프로그램에 특정 관심이 있다. 갭 발생 페널티는 일반적으로 1 내지 5, 보통 2 내지 4의 범위에 있을 것이고, 다수의 실시형태에서 3일 것이다. 갭 확장 페널티는 일반적으로 약 0.01 내지 0.20의 범위일 것이고, 다수의 예에서 0.10일 것이다. 프로그램은 비교되는 입력된 서열에 의해 결정된 디폴트 변수를 가진다. 바람직하게는, 서열 동일성은 프로그램에 의해 결정된 디폴트 변수를 사용하여 결정된다. 이 프로그램은 또한 미국 위스콘신주 매디슨에 소재한 제네틱 컴퓨팅 그룹(Genetics Computing Group: GCG) 패키지로부터 입수가능하다.
관심의 다른 프로그램은 FastDB 알고리즘이다. FastDB는 문헌[Current Methods in Sequence Comparison and Analysis, Macromolecule Sequencing and Synthesis, Selected Methods and Applications, pp. 127-149, 1988, Alan R. Liss, Inc]에 기재되어 있다. 서열 동일성 백분율은 다음의 변수를 기준으로 FastDB에 의해 계산된다:
미스매치 페널티:
1.00;
갭 페널티:
1.00;
갭 크기 페널티:
0.33; 및
결합 페널티:
30.0.
"유전자"는 전사되고 번역된 후 특정 단백질을 암호화할 수 있는 적어도 하나의 오픈 리딩 프레임을 함유하는 폴리뉴클레오타이드를 지칭한다.
"유전자 산물"은 특정 유전자의 발현으로부터 초래되는 분자이다. 유전자 산물은, 예를 들어 폴리펩타이드, 앱타머, 간섭 RNA, mRNA 등을 포함한다.
"짧은 간섭" 또는 "짧은 간섭 RNA" 또는 siRNA는 관심의 유전자("표적 유전자")에 표적화된 뉴클레오타이드의 RNA 듀플렉스이다. "RNA 듀플렉스"는 RNA 분자의 두 영역 사이의 상보적 쌍에 의해 형성된 구조를 지칭한다. siRNA는 siRNA의 듀플렉스 부분의 뉴클레오타이드 서열이 표적화된 유전자의 뉴클레오타이드 서열에 상보적인 유전자에 "표적화된다". 일부 실시형태에서, siRNA의 듀플렉스 길이는 30개 미만의 뉴클레오타이드이다. 일부 실시형태에서, 듀플렉스는 길이로 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11 또는 10개 뉴클레오타이드일 수 있다. 일부 실시형태에서, 듀플렉스의 길이는 길이로 19 내지 25개의 뉴클레오타이드이다. siRNA의 RNA 듀플렉스 부분은 헤어핀 구조의 부분일 수 있다. 듀플렉스 부분에 추가로, 헤어핀 구조는 듀플렉스를 형성하는 두 서열 사이에 위치된 루프 부분을 함유할 수 있다. 루프는 길이가 다를 수 있다. 일부 실시형태에서, 루프는 길이로 5, 6, 7, 8, 9, 10, 11, 12 또는 13개 뉴클레오타이드이다. 헤어핀 구조는 또한 3' 또는 5' 돌출부 부분을 함유할 수 있다. 일부 실시형태에서, 돌출부는 길이로 0, 1, 2, 3, 4 또는 5개 뉴클레오타이드의 3' 또는 5' 돌출부이다.
"짧은 헤어핀 RNA" 또는 shRNA는 siRNA와 같은 간섭 RNA를 발현시키기 위해 만들어질 수 있는 폴리뉴클레오타이드 작제물이다.
폴리뉴클레오타이드에 적용되는 "재조합체"는 클로닝, 제한 또는 결찰 단계 및 천연에서 발견되는 폴리뉴클레오타이드와 별개인 작제물을 만드는 다른 과정의 다양한 조합의 산물이다. 재조합 바이러스는 재조합 폴리뉴클레오타이드를 포함하는 바이러스 입자이다. 해당 용어는 각각 본래의 폴리뉴클레오타이드 작제물의 복제물 및 바이러스 작제물의 후손을 포함한다.
"제어 구성요소" 또는 "제어 서열"은 폴리뉴클레오타이드의 복제, 중복, 전사, 스플라이싱, 번역 또는 분해를 포함하는, 폴리뉴클레오타이드의 기능 조절에 기여하는 분자의 상호작용에 수반되는 뉴클레오타이드 서열이다. 조절은 처리의 빈도, 속도 또는 특이성에 영향을 미칠 수 있고, 사실상 향상성이거나 또는 억제성일 수 있다. 당업계에 공지된 제어 구성요소는, 예를 들어 프로모터 및 인핸서와 같은 전사 조절 서열을 포함한다. 프로모터는 RNA 중합효소에 결합되고, 프로모터로부터 보통 하류에 위치된(3' 방향으로) 암호 영역의 전사를 개시하는 특정 조건 하에서 가능한 DNA 영역이다.
"작동가능하게(operatively) 연결된" 또는 "조작가능하게(operably) 연결된"은 유전자 구성요소의 병치를 지칭하되, 구성요소는 그것을 예상된 방식으로 작동되게 하는 관계에 있다. 예를 들어, 프로모터는 프로모터가 암호 서열의 전사를 개시하게 한다면, 암호 영역에 작동가능하게 연결된다. 이 작용 관계가 유지되는 한, 프로모터와 암호 영역 사이에 잔기가 개입될 수 있다.
"발현 벡터"는 관심의 폴리펩타이드를 암호화하는 영역을 포함하는 벡터이며, 의도된 표적 세포에서 단백질의 발현을 달성하기 위해 사용된다. 발현 벡터는 또한 표적에서 단백질의 발현을 가능하게 하는 암호화 영역에 작동가능하게 연결된 제어 구성요소를 포함한다. 발현을 위해 조작가능하게 연결된 제어 구성요소 및 유전자 또는 유전자들의 조합은 때때로 "발현 카세트"로서 지칭되는데, 이중 대다수는 당업계에 공지되어 있고, 입수가능하거나, 또는 당업계에서 입수가능한 성분으로부터 용이하게 구성될 수 있다.
"이종성"은 비교되는 나머지 독립체와 기하학적으로 별개인 독립체로부터 유래되었음을 의미한다. 예를 들어, 상이한 종으로부터 유래된 플라스미드 또는 벡터 내로 유전자 조작 기법에 의해 도입된 폴리뉴클레오타이드는 이종성 폴리뉴클레오타이드이다. 본래의 암호 서열로부터 제거되고 연결이 자연적으로 발견되지 않은 암호 서열에 작동가능하게 연결된 프로모터는 이종성 프로모터이다. 따라서, 예를 들어, 이종성 유전자 산물을 암호화하는 이종성 핵산을 포함하는 rAAV는 자연적으로-발생되는 야생형 AAV에 보통 포함되지 않는 핵산을 포함하는 rAAV이며, 암호화된 이종성 유전자 산물은 보통 자연적으로-발생되는 야생형 AAV에 의해 암호화되지 않는 유전자 산물이다.
용어 "유전자 변성(alteration)" 및 "유전자 변형"(및 이들의 문법적 변형)은 유전적 구성요소(예를 들어, 폴리뉴클레오타이드)가 유사분열 또는 감수분열 이외의 세포에 도입되는 방법을 지칭하기 위해 본 명세서에서 상호호환적으로 사용된다. 구성요소는 세포에 대해 이종성일 수 있거나, 또는 세포에 이미 존재하는 구성요소의 추가적인 복제물 또는 개선된 형태일 수 있다. 유전적 변성은, 당업계에 공지된 임의의 방법, 예컨대 전기천공법, 인산칼슘 침전법 또는 폴리뉴클레오타이드-리포좀 복합체와 접촉을 통해 재조합 플라스미드 또는 다른 폴리뉴클레오타이드로 세포를 형질감염시킴으로써 달성될 수 있다. 유전적 변성은 또한, 예를 들어 DNA 또는 RNA 바이러스 또는 바이러스 벡터에 의한 형질도입 또는 감염에 의해 달성될 수 있다. 일반적으로, 유전적 구성요소는 세포 내 염색체 또는 미니-염색체 내로 도입되지만; 세포 및 그것의 자손의 표현형 및/또는 유전자형을 변화시키는 임의의 변성이 이 용어에 포함된다.
시험관내 세포의 장기간 배양 동안 서열이 그것의 기능을 수행하도록 이용가능하다면, 세포는 "안정하게" 변성되고, 형질도입되며, 유전적으로 변형되거나 또는 형질전환되는 것으로 언급된다. 일반적으로, 이러한 세포는 "유전가능하게" 변성되며(유전적으로 변형됨), 즉, 유전적 변성은 또한 변성된 세포의 후손에 의해 유전가능하게 도입된다.
용어 "폴리펩타이드", "펩타이드" 및 "단백질"은 임의의 길이의 아미노산의 중합체를 지칭하기 위해 본 명세서에서 상호호환적으로 사용된다. 해당 용어는 또한 변형된, 예를 들어 이황화 결합 형성, 글라이코실화, 지질화, 포스포릴화 또는 표지 성분과 컨쥬게이션된 아미노산 중합체를 포함한다. 포유류 대상에 유전자 산물 및 그에 대한 조성물을 전달하기 위한 내용으로 논의될 때, 항혈관신생 폴리펩타이드, 신경보호작용 폴리펩타이드 등과 같은 폴리펩타이드는 무결함 단백질의 원하는 생화학적 기능 보유하는 각각의 무결함 폴리펩타이드 또는 이것의 임의의 단편 또는 이들의 유전적으로 조작된 유도체를 지칭한다. 유사하게, 항혈관신생 폴리펩타이드를 암호화하는 핵산, 신경보호작용 폴리펩타이드를 암호화하는 핵산, 및 포유류 피험체에 유전자 산물의 전달에서 사용을 위한 다른 이러한 핵산(이는 수용 세포에 전달되는 "이식유전자"로서 지칭될 수 있음)에 대한 언급은 무결함 폴리펩타이드를 암호화하는 폴리뉴클레오타이드 또는 원하는 생화학적 작용을 소유하는 임의의 단편 또는 유전적으로 유전자 조작된 유도체를 포함한다.
"단리된" 플라스미드, 핵산, 벡터, 바이러스, 비리온, 숙주 세포, 또는 다른 물질은, 물질 또는 유사한 물질이 자연적으로 생기거나 또는 이들로부터 처음에 제조된 경우, 또한 존재할 수 있는 적어도 일부의 다른 성분이 없는 물질의 제조를 지칭한다. 따라서, 예를 들어, 단리된 물질은 공급 혼합물로부터 그것을 풍부하게 하는 정제 기법을 사용하여 제조될 수 있다. 풍부도는 절대적 기준, 예컨대 용액의 용적 당 중량에 대해 측정될 수 있거나, 또는 공급 혼합물에 존재하는 제2의, 잠재적 간섭 물질에 대해 측정될 수 있다. 본 개시내용의 실시형태의 풍부도가 증가되면, 단리물도 더 증가된다. 단리된 플라스미드, 핵산, 벡터, 바이러스, 숙주 세포, 또는 다른 물질은 일부 실시형태에서, 예를 들어 약 80% 내지 약 90% 순도, 적어도 약 90% 순도, 적어도 약 95% 순도, 적어도 약 98% 순도, 또는 적어도 약 99% 이상의 순도로 정제된다.
본 명세서에 사용된 바와 같이, 용어 "치료", "치료하는" 등은 원하는 약학적 및/또는 생리적 효과를 얻는 것을 지칭한다. 효과는 질병 또는 이것의 증상을 완전히 또는 부분적으로 예방하는 면에서 예방적일 수 있고/있거나 질병 및/또는 질병에 기인하는 부작용에 대한 부분적 또는 완전한 치료의 면에서 치료적일 수 있다. 본 명세서에 사용된 바와 같은 "치료"는 포유류, 특히 인간에서 질병의 어떤 치료를 포괄하며, (a) 질병을 획득할 위험에 있거나 또는 질병의 성향이 있지만 아직 질병이 있는 것으로 진단되지 않은 피험체에서 질병이 생기는 것을 예방하는 것; (b) 질병을 억제하는 것, 즉, 그것의 발생을 막는 것; 및 (c) 질병을 완화시키는 것, 즉 질병의 퇴보를 야기하는 것을 포함한다.
용어 "개체", "숙주", "피험체" 및 "환자"는 본 명세서에서 상호 호환적으로 사용되며, 인간 및 유인원을 포함하는 비인간 영장류 및 인간들을 포함하지만, 이들에 제한되지 않는 포유류; 포유류 스포츠 동물(예를 들어, 말); 포유류 농장 동물(예를 들어, 양, 염소 등); 포유류 애완동물(개, 고양이 등); 및 설치류(예를 들어, 마우스, 래트 등)를 지칭한다.
본 발명을 추가로 기재하기 전, 본 발명은 기재되는 특정 실시형태로 제한되지 않으며, 물론 다를 수 있다는 것이 이해되어야 한다. 또한 본 명세서에 사용된 전문용어는 단지 특정 실시형태를 설명하는 목적을 위한 것이며, 제한하는 것으로 의도되지 않는다는 것이 이해되어야 하는데, 본 발명의 범주는 단지 첨부되는 특허청구범위에 의해서만 제한될 것이기 때문이다.
값의 범위가 제공되는 경우, 달리 명확하게 지시되지 않는다면, 해당 범위 및 어떤 다른 언급되거나 또는 그 언급된 범위에서 사이에 있는 값 사이의 상한과 하한 사이에서 하한 단위의 10분의 1까지의 각각의 사이에 있는 값은 본 발명 내에 포함되는 것으로 이해된다. 이들 더 작은 범위의 상한 및 하한은 더 작은 범위에 독립적으로 포함될 수 있으며, 또한 언급된 범위에서 어떤 구체적으로 제외된 경계의 대상으로 본 발명 내에 포함될 수 있다. 언급된 범위가 경계 중 하나 또는 둘 다를 포함하는 경우, 이들 포함된 경계 중 하나 또는 둘 다를 제외하는 범위는 또한 본 발명에 포함된다.
달리 정의되지 않는다면, 본 명세서에서 사용된 모든 기술적 및 과학적 용어는 본 발명이 속하는 당업자에 의해 보통 이해되는 것과 동일한 의미를 가진다. 본 명세서에 기재된 것과 유사하거나 또는 동일한 임의의 방법 및 물질이 또한 본 발명의 실행 또는 시험에서 사용될 수 있지만, 바람직한 방법 및 물질이 이제 기재된다. 본 명세서에서 언급된 모든 간행물은 간행물이 인용되는 것과 관련하여 방법 및/또는 물질을 개시하고 기재하기 위해 본 명세서에 참조로서 포함된다.
본 명세서 및 첨부되는 특허청구범위에서 사용되는 바와 같은 단수 형태는 달리 명확하게 지시되지 않는다면 복수의 대상을 포함하는 것으로 이해되어야 한다. 따라서, 예를 들어, "재조합 AAV 비리온"에 대한 언급은 복수의 이러한 비리온을 포함하며, "광수용체 세포"에 대한 언급은 하나 이상의 광수용체 세포 및 당업자에게 공지된 이것의 동등물 등을 포함한다. 추가로 특허청구범위는 임의의 선택적 구성요소를 제외하도록 초안이 작성될 수 있다는 것을 주의한다. 이와 같이, 이런 언급은 특허청구범위 구성요소의 인용 또는 "부정적" 제한의 사용과 함께 "단독으로", "단지" 등으로서 이러한 제외 용어의 사용을 위한 선행 근거의 역할을 하는 것으로 의도된다.
명확성을 위해 별개의 실시형태의 내용으로 기재된 본 발명의 어떤 특징은 단일 실시형태와 조합으로 제공될 수 있다는 것이 인식된다. 반대로, 간결성을 위해 단일 실시형태의 내용으로 기재된 본 발명의 다양한 특징은 또한 별개로 또는 임의의 적합한 하위-조합으로 제공될 수 있다. 본 발명에 속하는 실시형태의 모든 조합은 본 발명에 의해 구체적으로 포함되며, 각각 및 모든 조합이 개별적이고 명확하게 개시되는 것과 같이 본 명세서에 개시된다. 추가로, 다양한 실시형태 및 이들의 구성요소의 모든 하위-조합은 본 발명에 의해 구체적으로 포함되며, 각각 및 모든 이러한 하위-조합은 본 명세서에서 개별적이고 명확하게 개시되는 것과 같이 본 명세서에 개시된다.
본 명세서에 논의된 간행물은 본 출원의 출원일 전에 그것의 개시내용에 대해서만 제공된다. 본 명세서의 어떤 것도 본 발명이 이러한 간행물을 선행 발명이라는 이유로 선행하는 것으로 자격을 부여하지 않는다는 용인으로서 해석되어서는 안 된다. 추가로, 제공된 공개일은 독립적으로 확인될 필요가 있을 수 있는 실제 공개일과 상이할 수 있다.
상세한 설명
본 개시내용은 변성된 캡시드 단백질을 지니는 아데노-관련 바이러스(AAV) 비리온을 제공하며, 여기서 야생형 AAV가 유리체내 주사를 통해 투여될 때에 비해 AAV 비리온이 유리체내 주사를 통해 투여될 때 망막 세포의 더 큰 감염성을 나타낸다. 본 개시내용은 개체에서 망막 세포에 유전자 산물을 전달하는 방법 및 안질환을 치료하는 방법을 추가로 제공한다.
망막 세포는 광수용체(예를 들어, 간체; 추체)일 수 있고, 망막 신경절 세포(retinal ganglion cell: RGC), 뮐러 세포(뮐러 신경교세포), 양극 세포, 아마크린 세포, 수평 세포 또는 망막 색소성 상피(RPE) 세포일 수 있다.
변이체 AAV 캡시드 폴리펩타이드
본 개시내용은 변이체 AAV 캡시드 단백질을 제공하며, 변이체 AAV 캡시드 단백질은 대응되는 모(parental) AAV 캡시드 단백질에 대해 캡시드 단백질 GH 루프 또는 루프 IV 내 삽입 부위에서 약 5개 아미노산 내지 약 11개 아미노산의 삽입을 포함하고, AAV 비리온에 존재할 때, 변이체 캡시드 단백질은 대응되는 모 AAV 캡시드 단백질을 포함하는 AAV 비리온에 의한 망막 세포의 감염성에 비해 망막 세포의 증가된 감염성을 부여한다. 일부 경우에, 망막 세포는 광수용체 세포(예를 들어, 간체; 추체)이다. 다른 경우에, 망막 세포는 RGC이다. 다른 경우에, 망막 세포는 RPE 세포이다. 다른 경우에, 망막 세포는 뮐러 세포이다. 다른 망막 세포는 아마크린 세포, 양극 세포 및 수평 세포를 포함한다. "약 5개 아미노산 내지 약 11개 아미노산의 삽입"은 또한 본 명세서에서 "펩타이드 삽입"(예를 들어, 이종성 펩타이드 삽입)으로서 지칭된다. "대응되는 모 AAV 캡시드 단백질"은 펩타이드 삽입이 없는 동일한 AAV 혈청형의 AAV 캡시드 단백질을 지칭한다.
삽입 부위는 AAV 캡시드 단백질의 AAV 캡시드 단백질에, 예를 들어 AAV 캡시드 단백질의 GH 루프 또는 루프 IV의 용매-접근가능 부분에 있다. AAV 캡시드의 GH 루프/루프 IV에 대해, 예를 들어, 문헌[van Vliet et al. (2006) Mol. Ther. 14:809; Padron et al. (2005) J. Virol. 79:5047; 및 Shen et al. (2007) Mol. Ther. 15:1955]을 참조한다. 예를 들어, 삽입 부위는 도 17a 및 17b에 도시된 바와 같은 AAV 캡시드 단백질의 아미노산 411 내지 650 내에 있을 수 있다. 예를 들어, 삽입 부위는 도 6에서 도시하는 바와 같이 AAV2의 아미노산 570 내지 611 내에, AAV1의 아미노산 571 내지 612 내에, AAV5의 아미노산 560 내지 601 내에, AAV6의 아미노산 571 내지 612 내에, AAV7의 아미노산 572 내지 613 내에, AAV8의 아미노산 573 내지 614 내에, AAV9의 아미노산 571 내지 612 내에, 또는 AAV10의 아미노산 573 내지 614 내에 있을 수 있다.
일부 경우에, 약 5개 아미노산 내지 약 11개 아미노산이 대응되는 모 AAV 캡시드 단백질에 대해 캡시드 단백질의 GH 루프 또는 루프 IV 내 삽입 부위에 삽입된다. 예를 들어, 삽입 부위는 AAV2의 아미노산 587솨 588 사이 또는 다른 AAV 혈청형의 캡시드 서브유닛의 대응되는 위치에 있을 수 있다. 삽입 부위 587/588은 AAV2 캡시드 단백질에 기반한다는 것을 주목하여야 한다. 약 5개 아미노산 내지 약 11개 아미노산이 AAV2 이외의 AAV 혈청형(예를 들어, AAV8, AAV9 등) 내 대응되는 부위에 삽입될 수 있다. 당업자는 다양한 AAV 혈청형의 캡시드 단백질의 아미노산 서열의 비교를 기반으로, "AAV2의 아미노산 587 내지 588에 대응되는" 삽입 부위가 임의의 주어진 AAV 혈청형의 캡시드 단백질에 있다는 것을 알 것이다. 다양한 AAV 혈청형 내 AAV2의 캡시드 단백질 VP1(도 5 참조)의 아미노산 570 내지 611에 대응되는 서열은 도 6에 나타낸다. 예를 들어 AV1에 대해 젠뱅크(GenBank) 등록번호 NP_049542; AAV5에 대해 젠뱅크(GenBank) 등록번호 AAD13756; AAV6에 대해 젠뱅크(GenBank) 등록번호 AAB95459; AAV7에 대해 젠뱅크(GenBank) 등록번호 YP_077178; AAV8에 대해 젠뱅크(GenBank) 등록번호 YP_077180; AAV9에 대해 젠뱅크(GenBank) 등록번호 AAS99264 및 AAV10에 대해 젠뱅크(GenBank) 등록번호 AAT46337을 참조한다.
일부 실시형태에서, 삽입 부위는 임의의 AAV 혈청형의 VP1의 아미노산 570 내지 614 사이에 위치된 두 인접한 아미노산 사이의 단일 삽입 부위이며, 예를 들어 삽입 부위는 어떤 AAV 혈청형 또는 변이체의 VP1의 아미노산 570 내지 610, 아미노산 580 내지 600, 아미노산 570 내지 575, 아미노산 575 내지 580, 아미노산 580 내지 585, 아미노산 585 내지 590, 아미노산 590 내지 600 또는 아미노산 600 내지 614에 위치된 두 인접한 아미노산 사이에 있다. 예를 들어, 삽입 부위는 아미노산 580 내지 581, 아미노산 581 내지 582, 아미노산 583 내지 584, 아미노산 584 내지 585, 아미노산 585 내지 586, 아미노산 586 내지 587, 아미노산 587 내지 588, 아미노산 588 내지 589 또는 아미노산 589 내지 590 사이에 있을 수 있다. 삽입 부위는 아미노산 575 내지 576, 아미노산 576 내지 577, 아미노산 577 내지 578, 아미노산 578 내지 579 또는 아미노산 579 내지 580 사이에 있을 수 있다. 삽입 부위는 아미노산 590과 591 사이, 아미노산 591과 592 사이, 아미노산 592와 593 사이, 아미노산 593과 594 사이, 아미노산 594와 595 사이, 아미노산 595와 596 사이, 아미노산 596 내지 597 사이, 아미노산 597과 598 사이, 아미노산 598과 599 사이 또는 아미노산 599와 600 사이에 있을 수 있다.
예를 들어, 삽입 부위는 AAV2의 아미노산 587과 588 사이, AAV1의 아미노산 590과 591 사이, AAV5의 아미노산 575와 576 사이, AAV6의 아미노산 590과 591 사이, AAV7의 아미노산 589와 590 사이, AAV8의 아미노산 590과 591 사이, AAV9의 아미노산 588과 589 사이 또는 AAV10의 아미노산 588과 589 사이일 수 있다.
다른 예로서, 삽입 부위는 도 17a에서 나타내는 바와 같이 AAV 캡시드 단백질의 아미노산 450 내지 460에 있을 수 있다. 예를 들어, 삽입 부위는 도 17a에서 나타내는 바와 같이 AAV2의 아미노산 453에(예를 들어 바로 N-말단), AAV1의 아미노산 454에, AAV6의 아미노산 454에, AAV7의 아미노산 456에, AAV8의 아미노산 456에, AAV9의 아미노산 454에 또는 AAV10의 아미노산 456에 있을 수 있다.
일부 실시형태에서, 대상 캡시드 단백질은 도 18a 내지 c에 제시된 아미노산에 대해 적어도 약 85%, 적어도 약 90%, 적어도 약 95%, 적어도 약 98%, 적어도 약 99% 또는 100%의 아미노산 서열 동일성을 갖는 아미노산 서열을 포함하는 GH 루프를 포함한다.
삽입 펩타이드
상기 논의한 바와 같이, 길이로 약 5개 아미노산 내지 약 11개 아미노산의 펩타이드는 AAV 캡시드의 GH 루프 내로 삽입된다. 삽입 펩타이드는 5개 아미노산, 6개 아미노산, 7개 아미노산, 8개 아미노산, 9개 아미노산, 10개 아미노산 또는 11개 아미노산의 길이를 가진다.
삽입 펩타이드는 이하에 제시되는 식 중 어느 하나의 아미노산 서열을 포함할 수 있다.
예를 들어, 삽입 펩타이드는 길이로 5 내지 11개의 아미노산의 펩타이드일 수 있으며, 여기서 삽입 펩타이드는 하기 식 I을 갖는다:
[식 I]
Y1Y2X1X2X3X4X5X6X7Y3Y4
상기 식에서:
각각의 Y1 내지 Y4는, 존재한다면 Ala, Leu, Gly, Ser 및 Thr으로부터 독립적으로 선택되고;
X1은, 존재한다면, Leu, Asn 및 Lys으로부터 선택되며;
X2는 Gly, Glu, Ala 및 Asp으로부터 선택되고;
X3은 Glu, Thr, Gly 및 Pro으로부터 선택되며;
X4는 Thr, Ile, Gln 및 Lys으로부터 선택되고;
X5는 Thr 및 Ala으로부터 선택되며;
X6은 Arg, Asn 및 Thr으로부터 선택되고;
X7은, 존재한다면, Pro 및 Asn으로부터 선택된다.
다른 예로서, 삽입 펩타이드는 길이로 5 내지 11개의 아미노산의 펩타이드일 수 있으며, 여기서 삽입 펩타이드는 하기 식 IIa를 갖는다:
[식 IIa]
Y1Y2X1X2X3X4X5X6X7Y3Y4
상기 식에서:
각각의 Y1 내지 Y4는, 존재한다면, Ala, Leu, Gly, Ser 및 Thr으로부터 독립적으로 선택되고;
각각의 X1 내지 X4는 임의의 아미노산이며;
X5는 Thr이고;
X6은 Arg이며;
X7은 Pro이다.
다른 예로서, 삽입 펩타이드는 길이로 5 내지 11개의 아미노산의 펩타이드일 수 있으며, 여기서 삽입 펩타이드는 식 IIb를 갖는다:
[식 IIb]
Y1Y2X1X2X3X4X5X6X7Y3Y4
상기 식에서:
각각의 Y1 내지 Y4는, 존재한다면, Ala, Leu, Gly, Ser 및 Thr으로부터 독립적으로 선택되고;
X1는, 존재한다면, Leu 및 Asn으로부터 선택되며;
X2는, 존재한다면, Gly 및 Glu으로부터 선택되고;
X3은 Glu 및 Thr으로부터 선택되며;
X4는 Thr 및 Ile으로부터 선택되고;
X5는 Thr이며;
X6은 Arg이고;
X7은 Pro이다.
다른 예로서, 삽입 펩타이드는 길이로 5 내지 11개 아미노산의 펩타이드이며, 여기서 삽입 펩타이드는 하기 식 III을 갖는다:
[식 III]
Y1Y2X1X2X3X4X5X6X7Y3Y4
상기 식에서:
각각의 Y1 내지 Y4는, 존재한다면, Ala, Leu, Gly, Ser 및 Thr으로부터 독립적으로 선택되고;
X1은, 존재한다면, Lys이며;
X2는 Ala 및 Asp으로부터 선택되며;
X3은 Gly 및 Pro으로부터 선택되고;
X4는 Gln 및 Lys으로부터 선택되며;
X5는 Thr 및 Ala로부터 선택되고;
X6은 Asn 및 Thr으로부터 선택되며;
X7은, 존재한다면, Asn이다.
다른 예로서, 삽입 펩타이드는 길이로 5 내지 11개 아미노산의 펩타이드 일 수 있으며, 여기서 삽입 펩타이드는 하기 식 IV를 갖는다:
[식 IV]
Y1Y2X1X2X3X4X5X6X7Y3Y4
상기 식에서:
각각의 Y1 내지 Y4는, 존재한다면, Ala, Leu, Gly, Ser 및 Thr으로부터 독립적으로 선택되고;
X1은, 존재한다면, 양으로 하전된 아미노산 또는 비하전된 아미노산이거나; 또는 Leu, Asn, Arg, Ala, Ser 및 Lys으로부터 선택되고;
X2는 음으로 하전된 아미노산 또는 비하전된 아미노산이거나; 또는 Gly, Glu, Ala, Val, Thr 및 Asp로부터 선택되며;
X3은 음으로 하전된 아미노산 또는 비하전된 아미노산이거나; 또는 Glu, Thr, Gly, Asp 또는 Pro로부터 선택되고;
X4는 Thr, Ile, Gly, Lys, Asp 및 Gln로부터 선택되며;
X5는 극성 아미노산, 알코올(유리 하이드록실 기를 갖는 아미노산) 또는 소수성 아미노산이거나; 또는 Thr, Ser, Val 및 Ala로부터 선택되고;
X6은 양으로 하전된 아미노산 또는 비하전된 아미노산이거나; 또는 Arg, Val, Lys, Pro, Thr 및 Asn으로부터 선택되며;
X7은, 존재한다면, 양으로 하전된 아미노산 또는 비하전된 아미노산이거나; 또는 Pro, Gly, Phe, Asn 및 Arg으로부터 선택된다.
비제한적인 예로서, 삽입 펩타이드는 LGETTRP(서열번호 13), NETITRP(서열번호 14), KAGQANN(서열번호 15), KDPKTTN(서열번호 16), KDTDTTR(서열번호 57), RAGGSVG(서열번호 58), AVDTTKF(서열번호 59) 및 STGKVPN(서열번호 60)으로부터 선택된 아미노산 서열을 포함할 수 있다.
일부 경우에, 삽입 펩타이드는 LGETTRP(서열번호 13), NETITRP(서열번호 14), KAGQANN(서열번호 15), KDPKTTN(서열번호 16), KDTDTTR(서열번호 57), RAGGSVG(서열번호 58), AVDTTKF(서열번호 59) 및 STGKVPN(서열번호 60) 중 어느 하나의 아미노 말단 및/또는 카복시 말단에서 1 내지 4개의 스페이서 아미노산(Y1 내지 Y4)를 가진다. 적합한 스페이서 아미노산은 류신, 알기닌, 글라이신 및 세린을 포함하지만, 이들로 제한되지 않는다.
예를 들어, 일부 경우에, 삽입 펩타이드는 다음의 아미노산 서열: LALGETTRPA(서열번호 45); LANETITRPA(서열번호 46), LAKAGQANNA(서열번호 47), LAKDPKTTNA(서열번호 48), LAKDTDTTRA(서열번호 61), LARAGGSVGA(서열번호 62), LAAVDTTKFA(서열번호 63) 및 LASTGKVPNA(서열번호 64) 중 하나를 가진다. 다른 예로서, 일부 경우에, 삽입 펩타이드는 다음의 아미노산 서열: AALGETTRPA(서열번호 49); AANETITRPA(서열번호 50), AAKAGQANNA(서열번호 51) 및 AAKDPKTTNA(서열번호 52) 중 하나를 가진다. 또한 다른 예로서, 일부 경우에, 삽입 펩타이드는 다음의 아미노산 서열: GLGETTRPA(서열번호 53); GNETITRPA(서열번호 54), GKAGQANNA(서열번호 55) 및 GKDPKTTNA(서열번호 56) 중 하나를 가진다. 다른 예로서, 일부 경우에, 삽입 펩타이드는 AA에 의해 C-말단에 그리고 A에 의해 N-말단에 측접한 KDTDTTR(서열번호 57), RAGGSVG(서열번호 58), AVDTTKF(서열번호 59) 및 STGKVPN(서열번호 60) 중 하나를 포함하거나; 또는 G에 의해 C-말단에 그리고 A에 의해 N-말단에 측접한 KDTDTTR(서열번호 57), RAGGSVG(서열번호 58), AVDTTKF(서열번호 59) 및 STGKVPN(서열번호 60) 중 하나를 포함한다.
일부 실시형태에서, 대상 변이체 AAV 캡시드는 대응되는 모 AAV 캡시드 단백질에 대해 GH 루프 또는 루프 IV에서 약 5개 아미노산 내지 약 11개 아미노산의 삽입 이외의 임의의 다른 아미노산 치환, 삽입 또는 결실을 포함하지 않는다. 다른 실시형태에서, 대상 변이체 AAV 캡시드는 대응되는 모 AAV 캡시드 단백질에 대해 GH 루프 또는 루프 IV 내 약 5개 아미노산 내지 약 11개 아미노산의 삽입에 추가로, 모 AAV 캡시드 단백질에 비해 1 내지 약 25개 아미노산의 삽입, 결실 또는 치환을 포함한다. 예를 들어, 일부 실시형태에서, 대상 변이체 AAV 캡시드는 대응되는 모 AAV 캡시드 단백질에 대해 GH 루프 또는 루프 IV에서 약 5개 아미노산 내지 약 11개 아미노산의 삽입에 추가로, 모 AAV 캡시드 단백질에 비해 1 내지 약 5, 약 5 내지 약 10, 약 10 내지 약 15, 약 15 내지 약 20, 또는 약 20 내지 약 25개 아미노산 삽입, 결실 또는 치환을 포함한다.
일부 실시형태에서, 대상 변이체 캡시드 폴리펩타이드는 다음의 아미노산 치환: Y273F, Y444F, Y500F 및 Y730F 중 1, 2, 3 또는 4가지를 포함하지 않는다.
일부 실시형태에서, 대상 변이체 캡시드 폴리펩타이드는 상기 기재한 바와 같이 삽입 펩타이드에 추가로 다음의 아미노산 치환: Y273F, Y444F, Y500F 및 Y730F 중 1, 2, 3 또는 4가지를 포함한다.
일부 실시형태에서, 변이체 AAV 캡시드 폴리펩타이드는 키메라 캡시드이며, 예를 들어, 캡시드는 제1 AAV 혈청형의 AAV 캡시드 부분 및 제2 혈청형의 AAV 캡시드 부분을 포함하고; 대응되는 모 AAV 캡시드 단백질에 대해 GH 루프 또는 루프 IV에서 약 5개 아미노산 내지 약 11개 아미노산의 삽입을 포함한다.
일부 실시형태에서, 대상 변이체 캡시드 단백질은 도 5에 제공된 아미노산 서열에 대해 적어도 약 85%, 적어도 약 90%, 적어도 약 95%, 적어도 약 98% 또는 적어도 약 99%, 아미노산 서열 동일성; 및 대응되는 모 AAV 캡시드 단백질에 대해 GH 루프 또는 루프 IV에서 약 5개 아미노산 내지 약 11개 아미노산의 삽입을 갖는 아미노산 서열을 포함한다.
일부 실시형태에서, 대상 변이체 캡시드 단백질은 단리, 예를 들어 정제된다. 일부 경우에, 대상 변이체 캡시드 단백질은 또한 제공되는 AAV 벡터에 포함된다. 이하에 상세하게 기재되는 바와 같이, 대상 변이체 캡시드 단백질은 재조합 AAV 비리온에 포함될 수 있다.
재조합 AAV 비리온
본 개시내용은 a) 변이체 AAV 캡시드 단백질; 및 b) 유전자 산물을 암호화하는 뉴클레오타이드 서열을 포함하는 이종성 핵산을 포함하는 재조합 아데노-관련 바이러스(rAAV) 비리온을 제공하되, 변이체 AAV 캡시드 단백질은 대응되는 모 AAV 캡시드 단백질에 대해 캡시드 단백질 GH 루프 또는 루프 IV 내 삽입 부위에서 약 5개 아미노산 내지 약 11개 아미노산의 삽입을 포함하고, 변이체 캡시드 단백질은 대응되는 모 AAV 캡시드 단백질을 포함하는 AAV 비리온에 의한 망막 세포의 감염성에 비해 망막 세포의 증가된 감염성을 부여한다. 일부 경우에, 망막 세포는 광수용체 세포(예를 들어, 간체 및/또는 추체)이다. 다른 경우에, 망막 세포는 RGC 세포이다. 다른 경우에, 망막 세포는 RPE 세포이다. 다른 경우에, 망막 세포는 뮐러 세포이다. 다른 경우에, 망막 세포는 아마크린 세포, 양극 세포 및 수평 세포를 포함할 수 있다. "약 5개 아미노산 내지 약 11개 아미노산의 삽입"은 또한 본 명세서에서 "펩타이드 삽입"(예를 들어, 이종성 펩타이드 삽입)으로서 지칭된다. "대응되는 모 AAV 캡시드 단백질"은 펩타이드 삽입 없이 동일 AAV 혈청형의 AAV 캡시드 단백질을 지칭한다.
삽입 부위는 AAV 캡시드 단백질의 GH 루프, 또는 루프 IV에, 예를 들어 AAV 캡시드 단백질의 GH 루프, 또는 루프 IV의 용매-접근가능 부분에 있다. GH 루프에 대해, 예를 들어, 문헌[van Vliet et al. (2006) Mol. Ther. 14:809; Padron et al. (2005) J. Virol. 79:5047; 및 Shen et al. (2007) Mol. Ther. 15:1955]을 참조한다. 예를 들어, 삽입 부위는 AAV2의 아미노산 570 내지 611 내에, AAV1의 아미노산 571 내지 612 내에, AAV5의 아미노산 560 내지 601 내에, AAV6의 아미노산 571 내지 612 내에, AAV7의 아미노산 572 내지 613 내에, AAV8의 아미노산 573 내지 614 내에, AAV9의 아미노산 571 내지 612 내에 또는 AAV10의 아미노산 573 내지 614 내에 있다.
약 5개 아미노산 내지 약 11개 아미노산은 대응되는 모 AAV 캡시드 단백질에 대해 캡시드 단백질의 GH 루프 또는 루프 IV 내 삽입 부위에 삽입된다. 예를 들어, 삽입 부위는 AAV2의 아미노산 587과 588 사이, 또는 다른 AAV 혈청형의 캡시드 서브유닛의 대응되는 위치일 수 있다. 삽입 부위 587/588은 AAV2 캡시드 단백질에 기반한다는 것을 주의하여야 한다. 약 5개 아미노산 내지 약 11개 아미노산은 AAV2 이외의 AAV 혈청형(예를 들어, AAV8, AAV9 등)에서 대응되는 부위에 삽입될 수 있다. 당업자는 다양한 AAV 혈청형의 캡시드 단백질의 아미노산 서열과 비교에 기반하여, "AAV2의 아미노산 587 내지 588에 대응되는" 삽입 부위가 어떤 주어진 AAV 혈청형의 캡시드 단백질에 있다는 것을 알 것이다. 다양한 AAV 혈청형에서 AAV2의 캡시드 단백질 VP1(도 5)의 아미노산 570 내지 611에 대응되는 서열은 도 6에 나타낸다.
일부 실시형태에서, 삽입 부위는 어떤 AAV 혈청형의 VP1의 아미노산 570 내지 614 사이에 위치된 두 인접한 아미노산 사이의 단일 삽입 부위이며, 예를 들어 삽입 부위는 어떤 AAV 혈청형 또는 변이체의 VP1의 아미노산 570 내지 614, 아미노산 580 내지 600, 아미노산 570 내지 575, 아미노산 575 내지 580, 아미노산 580 내지 585, 아미노산 585 내지 590, 아미노산 590 내지 600 또는 아미노산 600 내지 610에 위치된 두 인접한 아미노산 사이에 있다. 예를 들어, 삽입 부위는 아미노산 580 내지 581, 아미노산 581 내지 582, 아미노산 583 내지 584, 아미노산 584 내지 585, 아미노산 585 내지 586, 아미노산 586 내지 587, 아미노산 587 내지 588, 아미노산 588 내지 589 또는 아미노산 589 내지 590에 있을 수 있다. 삽입 부위는 아미노산 575 내지 576, 아미노산 576 내지 577, 아미노산 577 내지 578, 아미노산 578 내지 579 또는 아미노산 579 내지 580에 있을 수 있다. 삽입 부위는 아미노산 590과 591 사이, 아미노산 591과 592 사이, 아미노산 592와 593 사이, 아미노산 593과 594 사이, 아미노산 594와 595 사이, 아미노산 595와 596 사이, 아미노산 596과 597 사이, 아미노산 597과 598 사이, 아미노산 598과 599 사이 또는 아미노산 599와 600 사이에 있을 수 있다.
예를 들어, 삽입 부위는 AAV2의 아미노산 587과 588 사이, AAV1의 아미노산 590과 591 사이, AAV5의 아미노산 575와 576 사이, AAV6의 아미노산 590과 591 사이, AAV7의 아미노산 589와 590 사이, AAV8의 아미노산 590과 591 사이, AAV9의 아미노산 588과 589 사이 또는 AAV10의 아미노산 589 내지 590 사이에 있을 수 있다.
삽입 펩타이드
상기 논의한 바와 같이, 대상 rAAV 비리온은 AAV 캡시드의 GH 루프 내로 삽입된 길이로 약 5개 아미노산 내지 약 11개 아미노산의 펩타이드를 포함한다. 삽입 펩타이드는 5개 아미노산, 6 아미노산, 7 아미노산, 8 아미노산, 9 아미노산, 10 아미노산 또는 11 아미노산의 길이를 가진다.
삽입 펩타이드는 이하에 제시된 식 중 어느 하나의 아미노산 서열을 포함할 수 있다.
예를 들어, 삽입 펩타이드는 길이로 5 내지 11개 아미노산의 펩타이드일 수 있으며, 여기서 삽입 펩타이드는 식 I을 갖는다:
[식 I]
Y1Y2X1X2X3X4X5X6X7Y3Y4
상기 식에서:
각각의 Y1 내지 Y4는, 존재한다면 Ala, Leu, Gly, Ser 및 Thr으로부터 독립적으로 선택되고;
X1은, 존재한다면, Leu, Asn 및 Lys으로부터 선택되며;
X2는 Gly, Glu, Ala 및 Asp으로부터 선택되고;
X3은 Glu, Thr, Gly 및 Pro으로부터 선택되며;
X4는 Thr, Ile, Gln 및 Lys으로부터 선택되고;
X5는 Thr 및 Ala으로부터 선택되며;
X6은 Arg, Asn 및 Thr으로부터 선택되고;
X7은, 존재한다면, Pro 및 Asn으로부터 선택된다.
다른 예로서, 삽입 펩타이드는 길이로 5 내지 11개의 아미노산의 펩타이드일 수 있으며, 여기서 삽입 펩타이드는 하기 식 IIa를 갖는다:
[식 IIa]
Y1Y2X1X2X3X4X5X6X7Y3Y4
상기 식에서:
각각의 Y1 내지 Y4는, 존재한다면, Ala, Leu, Gly, Ser 및 Thr으로부터 독립적으로 선택되고;
각각의 X1 내지 X4는 임의의 아미노산이며;
X5는 Thr이고;
X6은 Arg이며;
X7은 Pro이다.
다른 예로서, 삽입 펩타이드는 길이로 5 내지 11개의 아미노산의 펩타이드일 수 있으며, 여기서 삽입 펩타이드는 식 IIb를 갖는다:
[식 IIb]
Y1Y2X1X2X3X4X5X6X7Y3Y4
상기 식에서:
각각의 Y1 내지 Y4는, 존재한다면, Ala, Leu, Gly, Ser 및 Thr으로부터 독립적으로 선택되고;
X1는, 존재한다면, Leu 및 Asn으로부터 선택되며;
X2는, 존재한다면, Gly 및 Glu으로부터 선택되고;
X3은 Glu 및 Thr으로부터 선택되며;
X4는 Thr 및 Ile으로부터 선택되고;
X5는 Thr이며;
X6은 Arg이고;
X7은 Pro이다.
다른 예로서, 삽입 펩타이드는 길이로 5 내지 11개 아미노산의 펩타이드이며, 여기서 삽입 펩타이드는 하기 식 III을 갖는다:
[식 III]
Y1Y2X1X2X3X4X5X6X7Y3Y4
상기 식에서:
각각의 Y1 내지 Y4는, 존재한다면, Ala, Leu, Gly, Ser 및 Thr으로부터 독립적으로 선택되고;
X1은, 존재한다면, Lys이며;
X2는 Ala 및 Asp으로부터 선택되며;
X3은 Gly 및 Pro으로부터 선택되고;
X4는 Gln 및 Lys으로부터 선택되며;
X5는 Thr 및 Ala로부터 선택되고;
X6은 Asn 및 Thr으로부터 선택되며;
X7은, 존재한다면, Asn이다.
다른 예로서, 삽입 펩타이드는 길이로 5 내지 11개 아미노산의 펩타이드 일 수 있으며, 여기서 삽입 펩타이드는 하기 식 IV를 갖는다:
[식 IV]
Y1Y2X1X2X3X4X5X6X7Y3Y4
상기 식에서:
각각의 Y1 내지 Y4는, 존재한다면, Ala, Leu, Gly, Ser 및 Thr으로부터 독립적으로 선택되고;
X1은, 존재한다면, 양으로 하전된 아미노산 또는 비하전된 아미노산이거나; 또는 Leu, Asn, Arg, Ala, Ser 및 Lys으로부터 선택되고;
X2는 음으로 하전된 아미노산 또는 비하전된 아미노산이거나; 또는 Gly, Glu, Ala, Val, Thr 및 Asp로부터 선택되며;
X3은 음으로 하전된 아미노산 또는 비하전된 아미노산이거나; 또는 Glu, Thr, Gly, Asp 또는 Pro로부터 선택되고;
X4는 Thr, Ile, Gly, Lys, Asp 및 Gln로부터 선택되며;
X5는 극성 아미노산, 알코올(유리 하이드록실 기를 갖는 아미노산) 또는 소수성 아미노산이거나; 또는 Thr, Ser, Val 및 Ala로부터 선택되고;
X6은 양으로 하전된 아미노산 또는 비하전된 아미노산이거나; 또는 Arg, Val, Lys, Pro, Thr 및 Asn으로부터 선택되며;
X7은, 존재한다면, 양으로 하전된 아미노산 또는 비하전된 아미노산이거나; 또는 Pro, Gly, Phe, Asn 및 Arg으로부터 선택된다.
비제한적인 예로서, 삽입 펩타이드는 LGETTRP(서열번호 13), NETITRP(서열번호 14), KAGQANN(서열번호 15), KDPKTTN(서열번호 16), KDTDTTR(서열번호 57), RAGGSVG(서열번호 58), AVDTTKF(서열번호 59) 및 STGKVPN(서열번호 60)으로부터 선택된 아미노산 서열을 포함할 수 있다.
일부 경우에, 삽입 펩타이드는 LGETTRP(서열번호 13), NETITRP(서열번호 14), KAGQANN(서열번호 15), KDPKTTN(서열번호 16), KDTDTTR(서열번호 57), RAGGSVG(서열번호 58), AVDTTKF(서열번호 59) 및 STGKVPN(서열번호 60) 중 어느 하나의 아미노 말단 및/또는 카복시 말단에서 1 내지 4개의 스페이서 아미노산(Y1 내지 Y4)를 가진다. 적합한 스페이서 아미노산은 류신, 알기닌, 글라이신 및 세린을 포함하지만, 이들로 제한되지 않는다.
예를 들어, 일부 경우에, 삽입 펩타이드는 다음의 아미노산 서열: LALGETTRPA(서열번호 45); LANETITRPA(서열번호 46), LAKAGQANNA(서열번호 47), LAKDPKTTNA(서열번호 48), LAKDTDTTRA(서열번호 61), LARAGGSVGA(서열번호 62), LAAVDTTKFA(서열번호 63) 및 LASTGKVPNA(서열번호 64) 중 하나를 가진다. 다른 예로서, 일부 경우에, 삽입 펩타이드는 다음의 아미노산 서열: AALGETTRPA(서열번호 49); AANETITRPA(서열번호 50), AAKAGQANNA(서열번호 51) 및 AAKDPKTTNA(서열번호 52) 중 하나를 가진다. 또한 다른 예로서, 일부 경우에, 삽입 펩타이드는 다음의 아미노산 서열: GLGETTRPA(서열번호 53); GNETITRPA(서열번호 54), GKAGQANNA(서열번호 55) 및 GKDPKTTNA(서열번호 56) 중 하나를 가진다. 다른 예로서, 일부 경우에, 삽입 펩타이드는 AA에 의해 C-말단에 그리고 A에 의해 N-말단에 측접한 KDTDTTR(서열번호 57), RAGGSVG(서열번호 58), AVDTTKF(서열번호 59) 및 STGKVPN(서열번호 60) 중 하나를 포함하거나; 또는 G에 의해 C-말단에 그리고 A에 의해 N-말단에 측접한 KDTDTTR(서열번호 57), RAGGSVG(서열번호 58), AVDTTKF(서열번호 59) 및 STGKVPN(서열번호 60) 중 하나를 포함한다.
일부 실시형태에서, 대상 rAAV 비리온은 대응되는 모 AAV 캡시드 단백질에 대해 GH 루프 또는 루프 IV에서 약 7개 아미노산 내지 약 10개 아미노산의 삽입 이외의 임의의 다른 아미노산 치환, 삽입 또는 결실을 포함하지 않는다. 다른 실시형태에서, 대상 rAAV 비리온 캡시드는 대응되는 모 AAV 캡시드 단백질에 대해 GH 루프 또는 루프 IV 내 약 7개 아미노산 내지 약 10개 아미노산의 삽입에 추가로, 모 AAV 캡시드 단백질에 비해 1 내지 약 25개 아미노산의 삽입, 결실 또는 치환을 포함한다. 예를 들어, 일부 실시형태에서, 대상 변이체 rAAV 캡시드는 대응되는 모 AAV 캡시드 단백질에 대해 GH 루프 또는 루프 IV에서 약 7개 아미노산 내지 약 10개 아미노산의 삽입에 추가로, 모 AAV 캡시드 단백질에 비해 1 내지 약 5, 약 5 내지 약 10, 약 10 내지 약 15, 약 15 내지 약 20, 또는 약 20 내지 약 25개 아미노산 삽입, 결실 또는 치환을 포함한다.
일부 실시형태에서, 대상 rAAV 비리온 캡시드는 다음의 아미노산 치환: Y273F, Y444F, Y500F 및 Y730F 중 1, 2, 3 또는 4가지를 포함하지 않는다.
일부 실시형태에서, 대상 변이체 캡시드 폴리펩타이드는 상기 기재한 바와 같이 삽입 펩타이드에 추가로 다음의 아미노산 치환: Y273F, Y444F, Y500F 및 Y730F 중 1, 2, 3 또는 4가지를 포함한다.
일부 실시형태에서, 대상 rAAV 비리온 캡시드는 키메라 캡시드이며, 예를 들어, 캡시드는 제1 AAV 혈청형의 AAV 캡시드 부분 및 제2 혈청형의 AAV 캡시드 부분을 포함하고; 대응되는 모 AAV 캡시드 단백질에 대해 GH 루프 또는 루프 IV에서 약 5개 아미노산 내지 약 11개 아미노산의 삽입을 포함한다.
일부 실시형태에서, 대상 rAAV 비리온은 도 5에 제공된 아미노산 서열에 대해 적어도 약 85%, 적어도 약 90%, 적어도 약 95%, 적어도 약 98% 또는 적어도 약 99%, 아미노산 서열 동일성; 및 대응되는 모 AAV 캡시드 단백질에 대해 GH 루프 또는 루프 IV에서 약 5개 아미노산 내지 약 11개 아미노산의 삽입을 갖는 아미노산 서열을 포함한다.
일부 실시형태에서, 대상 rAAV 비리온은 도 18a 내지 c에 제시된 아미노산 서열에 대해 적어도 약 85%, 적어도 약 90%, 적어도 약 95%, 적어도 약 98%, 적어도 약 99% 또는 100%, 아미노산 서열 동일성을 갖는 아미노산 서열을 포함하는 GH 루프를 포함하는 캡시드 단백질을 포함한다.
대상 rAAV 비리온은 대응되는 모 AAV 캡시드 단백질을 포함하는 AAV 비리온에 의한 망막 세포의 감염성에 비해 망막 세포의 적어도 10배, 적어도 15배, 적어도 20배, 적어도 25배, 적어도 50배, 또는 50배 초과의 증가된 감염성을 나타낸다.
일부 경우에, 대상 rAAV 비리온은 유리체내 주사를 통해 투여될 때 대응되는 모 AAV 캡시드 단백질을 포함하는 AAV 비리온에 의한 망막 세포의 감염성에 비해, 유리체내 주사를 통해 투여될 때, 망막세포의 적어도 10배, 적어도 15배, 적어도 20배, 적어도 25배, 적어도 50배, 또는 50배 초과의 증가된 감염성을 나타낸다.
일부 실시형태에서, 대상 rAAV 비리온은 대응되는 모 AAV 캡시드 단백질을 포함하는 AAV 비리온에 의한 광수용체 세포의 감염성에 비해 광수용체(간체 또는 추체) 세포의 적어도 10배, 적어도 15배, 적어도 20배, 적어도 25배, 적어도 50배, 또는 50배 이상의 증가된 감염성을 나타낸다.
일부 실시형태에서, 대상 rAAV 비리온은 유리체내 주사를 통해 투여될 때, 대응되는 모 AAV 캡시드 단백질을 포함하는 AAV 비리온에 의한 광수용체 세포의 감염성에 비해, 유리체내 주사를 통해 투여될 때, 적어도 10배, 적어도 15배, 적어도 20배, 적어도 25배, 적어도 50배 또는 50배 이상의 증가된 광수용체(간체 또는 추체) 세포의 감염성을 나타낸다.
일부 실시형태에서, 대상 rAAV 비리온은 대응되는 모 AAV 캡시드 단백질을 포함하는 AAV 비리온에 의한 RGC의 감염성에 비해, RGC의 적어도 10배, 적어도 15배, 적어도 20배, 적어도 25배, 적어도 50배 또는 50배 초과의 증가된 감염성을 나타낸다.
일부 실시형태에서, 대상 rAAV 비리온은 유리체내 주사를 통해 투여될 때, 대응되는 모 AAV 캡시드 단백질을 포함하는 AAV 비리온에 의한 RGC의 감염성에 비해, 유리체내 주사를 통해 투여될 때, RGC의 적어도 10배, 적어도 15배, 적어도 20배, 적어도 25배, 적어도 50배 또는 50배 초과의 증가된 감염성을 나타낸다.
일부 실시형태에서, 대상 rAAV 비리온은 대응되는 모 AAV 캡시드 단백질을 포함하는 AAV 비리온에 의한 RPE 세포의 감염성에 비해 RPE 세포의 적어도 10배, 적어도 15배, 적어도 20배, 적어도 25배, 적어도 50배 또는 50배 초과의 증가된 감염성을 나타낸다.
일부 실시형태에서, 대상 rAAV 비리온은 유리체내 주사를 통해 투여될 때, 대응되는 모 AAV 캡시드 단백질을 포함하는 AAV 비리온에 의한 RPE 세포의 감염성에 비해 유리체내 주사를 통해 투여될 때, RPE 세포의 적어도 10배, 적어도 15배, 적어도 20배, 적어도 25배, 적어도 50배, 또는 50배 초과의 증가된 감염성을 나타낸다.
일부 실시형태에서, 대상 rAAV 비리온은 대응되는 모 AAV 캡시드 단백질을 포함하는 AAV 비리온에 의한 뮐러 세포의 감염성에 비해 뮐러 세포의 적어도 10배, 적어도 15배, 적어도 20배, 적어도 25배, 적어도 50배 또는 50배 초과의 증가된 감염성을 나타낸다.
일부 실시형태에서, 대상 rAAV 비리온은 유리체내 주사를 통해 투여될 때, 대응되는 모 AAV 캡시드 단백질을 포함하는 AAV 비리온에 의한 뮐러 세포의 감염성에 비해 유리체내 주사를 통해 투여될 때, 뮐러 세포의 적어도 10배, 적어도 15배, 적어도 20배, 적어도 25배, 적어도 50배, 또는 50배 초과의 증가된 감염성을 나타낸다.
일부 실시형태에서, 대상 rAAV 비리온은 대응되는 모 AAV 캡시드 단백질을 포함하는 AAV 비리온에 의한 양극 세포의 감염성에 비해, 양극 세포의 적어도 10배, 적어도 15배, 적어도 20배, 적어도 25배, 적어도 50배, 또는 50배 초과의 증가된 감염성을 나타낸다.
일부 실시형태에서, 대상 rAAV 비리온은 유리체내 주사를 통해 투여될 때, 대응되는 모 AAV 캡시드 단백질을 포함하는 AAV 비리온에 의한 양극 세포의 감염성에 비해 유리체내 주사를 통해 투여될 때, 양극 세포의 적어도 10배, 적어도 15배, 적어도 20배, 적어도 25배, 적어도 50배, 또는 50배 초과의 증가된 감염성을 나타낸다.
일부 실시형태에서, 대상 rAAV 비리온은 대응되는 모 AAV 캡시드 단백질을 포함하는 AAV 비리온에 의한 아마크린 세포의 감염성에 비해 아마크린 세포의 적어도 10배, 적어도 15배, 적어도 20배, 적어도 25배, 적어도 50배, 또는 50배 초과의 증가된 감염성을 나타낸다.
일부 실시형태에서, 대상 rAAV 비리온은 유리체내 주사를 통해 투여될 때, 대응되는 모 AAV 캡시드 단백질을 포함하는 AAV 비리온에 의한 아마크린 세포의 감염성에 비해 유리체내 주사를 통해 투여될 때, 아마크린 세포의 적어도 10배, 적어도 15배, 적어도 20배, 적어도 25배, 적어도 50배, 또는 50배 초과의 증가된 감염성을 나타낸다.
일부 실시형태에서, 대상 rAAV 비리온은 대응되는 모 AAV 캡시드 단백질을 포함하는 AAV 비리온에 의한 수평 세포의 감염성에 비해 수평 세포의 적어도 10배, 적어도 15배, 적어도 20배, 적어도 25배, 적어도 50배, 또는 50배 초과의 증가된 감염성을 나타낸다.
일부 실시형태에서, 대상 rAAV 비리온은 유리체내 주사를 통해 투여될 때, 대응되는 모 AAV 캡시드 단백질을 포함하는 AAV 비리온에 의한 수평 세포의 감염성에 비해 유리체내 주사를 통해 투여될 때, 수평 세포의 적어도 10배, 적어도 15배, 적어도 20배, 적어도 25배, 적어도 50배, 또는 50배 초과의 증가된 감염성을 나타낸다.
일부 경우에, 대상 rAAV 비리온은 ILM을 가로지르는 대응되는 모 AAV 캡시드 단백질을 포함하는 AAV 비리온의 능력에 비해 내경계막(internal limiting membrane: ILM)을 가로지르는 적어도 10배, 적어도 15배, 적어도 20배, 적어도 25배, 적어도 50배, 또는 50배 초과의 증가된 능력을 나타낸다.
일부 경우에, 대상 rAAV 비리온은 유리체내 주사를 통해 투여될 때 ILM을 가로지르는 대응되는 모 AAV 캡시드 단백질을 포함하는 AAV 비리온의 능력에 비해 유리체내 주사를 통해 투여될 때 내경계막(ILM)을 가로지르는 적어도 10배, 적어도 15배, 적어도 20배, 적어도 25배, 적어도 50배, 또는 50배 초과의 증가된 능력을 나타낸다.
대상 rAAV 비리온은 ILM을 가로지를 수 있고, 또한 뮐러 세포, 아마크린 세포 등을 포함하는 세포층을 횡단하여 광수용체 세포 또는 RPE 세포에 도달될 수 있다. 예를 들어, 유리체내 주사를 통해 투여될 때, 대상 rAAV 비리온은 ILM을 가로지를 수 있고, 또한 뮐러 세포, 아마크린 세포 등을 포함하는 세포층을 횡단하여 광수용체 세포 및 또는 RPE 세포에 도달될 수 있다.
일부 실시형태에서, 대상 rAAV 비리온은 망막세포를 선택적으로 감염시키며, 예를 들어, 대상 rAAV 비리온은 비망막 세포, 예를 들어 눈 바깥쪽의 세포보다 10배, 15배, 20배, 25배, 50배 또는 50배 초과의 특이성으로 망막 세포를 감염시킨다. 예를 들어, 일부 실시형태에서, 대상 rAAV 비리온은 망막 세포를 선택적으로 감염시키며, 예를 들어 대상 rAAV 비리온은 비망막 세포, 예를 들어 눈 바깥쪽의 세포보다 10배, 15배, 20배, 25배, 50배 또는 50배 초과의 특이성으로 광수용체 세포를 감염시킨다.
일부 실시형태에서, 대상 rAAV 비리온은 광수용체 세포를 선택적으로 감염시키며, 예를 들어, 대상 rAAV 비리온은 눈에 존재하는 비광수용체 세포, 예를 들어 망막 신경절 세포, 뮐러 세포 등보다 10배, 15배, 20배, 25배, 50배 또는 50배 초과의 특이성으로 광수용체 세포를 감염시킨다.
일부 실시형태에서, 대상 rAAV 비리온은 유리체내 주사를 통해 투여될 때 대응되는 모 AAV 캡시드 단백질을 포함하는 AAV 비리온에 의한 광수용체 세포의 감염성에 비해 유리체내 주사를 통해 투여될 때, 광수용체 세포의 적어도 10배, 적어도 15배, 적어도 20배, 적어도 25배, 적어도 50배, 또는 50배 초과의 증가된 감염성을 나타낸다.
유전자 산물
대상 rAAV 비리온은 유전자 산물을 암호화하는 뉴클레오타이드 서열을 포함하는 이종성 핵산을 포함한다. 일부 실시형태에서, 유전자 산물은 간섭 RNA이다. 일부 실시형태에서, 유전자 산물은 앱타머이다. 일부 실시형태에서, 유전자 산물은 폴리펩타이드이다. 일부 실시형태에서, 유전자 산물은 유전자 기능의 부위-특이적 녹다운을 제공하는 부위-특이적 뉴클레아제이다.
간섭 RNA
유전자 산물이 간섭 RNA(RNAi)인 경우, 적합한 RNAi는 세포에서 아포토시스(apoptosis) 또는 혈관형성 수준을 감소시키는 RNAi를 포함한다. 예를 들어, RNAi는 세포에서 아포토시스를 유발하거나 또는 촉진하는 유전자 산물의 수준을 감소시키는 shRNA 또는 siRNA일 수 있다. 유전자 산물이 아포토시스를 유발하거나 또는 촉진하는 유전자는 본 명세서에서 "프로-아포토시스 유전자"로서 지칭되며, 해당 유전자의 산물(mRNA; 단백질)은 "프로-아포토시스 유전자 산물"로서 지칭된다. 프로-아포토시스 유전자 산물은, 예를 들어, Bax, Bid, Bak 및 Bad 유전자 산물을 포함한다. 예를 들어, 미국 특허 제7,846,730호를 참조한다.
간섭 RNA는 또한 혈관형성 산물, 예를 들어 VEGF(예를 들어, Cand5; 예를 들어, 미국 특허 공개 제2011/0143400호; 미국 특허 공개 제2008/0188437호; 및 문헌[Reich et al. (2003) Mol. Vis. 9:210] 참조), VEGFR1 (예를 들어, Sirna-027; 예를 들어, 문헌[Kaiser et al. (2010) Am. J. Ophthalmol. 150:33; 및 Shen et al. (2006) Gene Ther. 13:225] 참조), 또는 VEGFR2(Kou et al. (2005) Biochem. 44:15064)에 대한 것일 수 있다. 또한, 미국 특허 제6,649,596호, 제6,399,586호, 제5,661,135호, 제5,639,872호 및 제5,639,736호; 및 미국 특허 제7,947,659호 및 제7,919,473호를 참조한다.
앱타머
유전자 산물이 앱타머인 경우, 관심의 대표적인 앱타머는 혈관내피세포 성장인자(vascular endothelial growth factor: VEGF)에 대해 앱타머를 포함한다. 예를 들어, 문헌[Ng et al. (2006) Nat. Rev. Drug Discovery 5:123; 및 Lee et al. (2005) Proc. Natl. Acad. Sci. USA 102:18902]을 포함한다. 예를 들어, VEGF 앱타머는 뉴클레오타이드 서열 5'-cgcaaucagugaaugcuuauacauccg-3'(서열번호 17)을 포함할 수 있다. 또한 PDGF-특이적 앱타머, 예를 들어, E10030가 사용에 적합하며; 예를 들어, 문헌[Ni and Hui (2009) Ophthalmologica 223:401; 및 Akiyama et al. (2006) J. Cell Physiol. 207:407)]을 참조한다.
폴리펩타이드
유전자 산물이 폴리펩타이드인 경우, 폴리펩타이드는 일반적으로 망막 세포의 기능, 예를 들어 간체 또는 추체 광수용체 세포, 망막 신경절 세포, 뮐러 세포, 양극 세포, 아마크린 세포, 수평 세포 또는 망막 색소성 상피 세포의 기능을 향상시키는 폴리펩타이드이다. 대표적인 폴리펩타이드는 신경보호 폴리펩타이드(예를 들어, GDNF, CNTF, NT4, NGF 및 NTN); 항혈관신생 폴리펩타이드(예를 들어, 가용성 혈관내피세포 성장인자 (VEGF) 수용체; VEGF-결합 항체; VEGF-결합 항체 단편(예를 들어, 단일 쇄 항-VEGF 항체); 엔도스타틴; 툼스타틴(tumstatin); 앤지오스타틴; 가용성 Flt 폴리펩타이드(Lai et al. (2005) Mol. Ther. 12:659); 가용성 Flt 폴리펩타이드를 포함하는 Fc 융합 단백질(예를 들어, 문헌[Pechan et al. (2009) Gene Ther. 16:10] 참조); 안료 상피세포-유래 인자(pigment epithelium-derived factor: PEDF); 가용성 Tie-2 수용체 등); 메탈로프로테이나제-3(metalloproteinases-3: TIMP-3)의 조직 억제제; 광-반응성 옵신, 예를 들어, 로돕신; 항-아포토시스 폴리펩타이드(예를 들어, Bcl-2, Bcl-Xl) 등을 포함한다. 적합한 폴리펩타이드는, 신경교 유래 신경영양 인자(glial derived neurotrophic factor: GDNF); 섬유아세포 성장인자 2; 뉴투린(neurturin: NTN); 섬모 신경영양 인자(ciliary neurotrophic factor:CNTF); 신경 성장 인자(nerve growth factor: NGF); 뉴로트로핀-4(neurotrophin-4: NT4); 뇌 유래 신경영양 인자(brain derived neurotrophic factor: BDNF; 예를 들어, 도 11에 도시된 아미노산 서열(서열번호 11)의 약 200 아미노산으로부터 247 아미노산까지의 연속적 신축에 대해 적어도 약 90%, 적어도 약 95%, 적어도 약 98%, 적어도 약 99% 또는 100%의 아미노산 서열 동일성을 갖는 아미노산 서열을 포함하는 폴리펩타이드; 표피성장인자; 로돕신; 아포토시스의 X-연결된 억제제; 및 소닉 헤지호그(Sonic hedgehog)를 포함하지만, 이들로 제한되지 않는다.
적합한 광-반응성 옵신은, 예를 들어 미국 특허 공개 제2007/0261127호(예를 들어, ChR2; Chop2); 미국 특허 공개 제2001/0086421호; 미국 특허 공개 제2010/0015095호; 및 문헌[Diester et al. (2011) Nat. Neurosci. 14:387]에 기재된 바와 같은 광-반응성 옵신을 포함한다
적합한 폴리펩타이드는 또한 망막층간 단백질(예를 들어, 도 10에 도시된 아미노산 서열(서열번호 10)의 약 200 아미노산 내지 224 아미노산의 연속적 신장에 대해 적어도 약 90%, 적어도 약 95%, 적어도 약 98%, 적어도 약 99% 또는 100%, 아미노산 서열 동일성을 갖는 아미노산 서열을 포함하는 폴리펩타이드)을 포함한다. 적합한 폴리펩타이드는, 예를 들어 망막 색소 변성증(retinitis pigmentosa GTPase regulator: RGPR)-상호작용 단백질-1(예를 들어, 젠뱅크(GenBank) 등록번호 Q96KN7, Q9EPQ2, 및 Q9GLM3을 참조)(예를 들어, 도 16에 도시된 아미노산 서열(서열번호 21)의 약 1150 아미노산 내지 약 1200 아미노산, 또는 약 1200 아미노산 내지 1286 아미노산의 연속적 신장에 대해 적어도 약 90%, 적어도 약 95%, 적어도 약 98%, 적어도 약 99% 또는 100%, 아미노산 서열 동일성을 갖는 아미노산 서열을 포함하는 폴리펩타이드; 페리페린-2(Prph2)(예를 들어, 젠뱅크(GenBank) 등록번호 NP_000313(예를 들어, 도 14에 도시된 아미노산 서열(서열번호 19)의 약 300 아미노산 내지 346 아미노산의 연속적 신장에 대해 적어도 약 90%, 적어도 약 95%, 적어도 약 98%, 적어도 약 99% 또는 100%, 아미노산 서열 동일성을 갖는 아미노산 서열을 포함하는 폴리펩타이드; 및 문헌[Travis et al. (1991) Genomics 10:733] 참조); 페리페린(예를 들어, 도 15에 도시된 아미노산 서열(서열번호 20)의 약 400 아미노산 내지 약 470 아미노산의 연속적 신장에 대해 적어도 약 90%, 적어도 약 95%, 적어도 약 98%, 적어도 약 99% 또는 100% 아미노산 서열 동일성을 갖는 아미노산 서열을 포함하는 폴리펩타이드; 망막 색소 상피세포-특이적 단백질(RPE65), (예를 들어, 도 12에 도시된 아미노산 서열(서열번호 12)의 약 200 아미노산 내지 247 아미노산의 연속적 신장에 대해 적어도 약 90%, 적어도 약 95%, 적어도 약 98%, 적어도 약 99% 또는 100%, 아미노산 서열 동일성을 갖는 아미노산 서열을 포함하는 폴리펩타이드)(예를 들어, 젠뱅크(GenBank) AAC39660; 및 문헌[Morimura et al. (1998) Proc. Natl. Acad. Sci. USA 95:3088] 참조) 등을 포함한다.
적합한 폴리펩타이드는 또한 CHM(맥락막 결여(Rab 에스코트 단백질 1)), 결함이 있거나 또는 빠져있을 때, 맥락막 결여를 야기하는 폴리펩타이드(예를 들어, 문헌[Donnelly et al. (1994) Hum. Mol. Genet. 3:1017; 및 van Bokhoven et al. (1994) Hum. Mol. Genet. 3:1041] 참조); 및 크럼스(Crumbs) 상동체 1(CRB1), 결함이 있거나 또는 빠져있을 때, 레베르 선천성 흑암시(Leber congenital amaurosis) 및 망막 색소 변성증을 야기하는 폴리펩타이드(예를 들어, 문헌[den Hollander et al. (1999) Nat. Genet. 23:217]; 및 젠뱅크(GenBank) 등록번호 CAM23328)를 포함한다.
적합한 폴리펩타이드는 결함이 있거나 또는 빠져있을 때, 이러한 폴리펩타이드가, 예를 들어 추체 광수용체 cGMP-개폐형 통로 서브유닛 알파(CNGA3)(예를 들어, 젠뱅크(GenBank) 등록번호 NP_001289; 및 문헌[Booij et al. (2011) Ophthalmology 118:160-167)]; 추체 광수용체 cGMP-개폐형 양이온 통로 베타-서브유닛(CNGB3)(예를 들어, 문헌[Kohl et al.(2005) Eur J Hum Genet. 13(3):302] 참조); 구아닌 뉴클레오타이드 결합 단백질(G 단백질), 알파 형질도입 활성 폴리펩타이드 2(GNAT2)(ACHM4); 및 ACHM5를 포함하는 경우 색맹을 유발하는 폴리펩타이드; 및 결함이 있거나 결여되었을 때, 다양한 형태의 색각이상을 야기하는 폴리펩타이드(예를 들어, L-옵신, M-옵신 및 S-옵신)를 포함한다. 문헌[Mancuso et al. (2009) Nature 461(7265):784-787]을 참조한다.
부위-특이적 엔도뉴클레아제
일부 경우에, 관심의 유전자 산물은, 예를 들어 엔도뉴클레아제가 망막질병과 관련된 대립유전자를 녹아웃하는 경우, 유전자 기능의 부위-특이적 녹다운을 제공하는 부위-특이적 엔도뉴클레아제이다. 예를 들어, 야생형일 때 대립유전자가 망막 구조 단백질이고/이거나 정상 망막 기능을 제공하는 유전자의 결함있는 복제물을 암호화하는 경우, 부위-특이적 엔도뉴클레아제는 결함있는 대립유전자에 대해 표적화될 수 있고, 결함있는 대립유전자를 녹아웃시킬 수 있다.
결함있는 대립유전자를 녹아웃시키는 것에 추가로, 부위-특이적 뉴클레아제는 또한 결함있는 대립유전자에 의해 암호화된 단백질의 기능적 복제물을 암호화하는 공여체 DNA에 의한 상동성 재조합을 자극하기 위해 사용될 수 있다. 따라서, 예를 들어, 대상 rAAV 비리온은 결함있는 대립유전자를 녹아웃시키고, 결함있는 대립유전자의 기능적 복제물을 전달하기 위해 사용될 수 있는 부위-특이적 엔도뉴클레아제를 둘 다 전달하기 위해 사용될 수 있는데, 이는 결함있는 대립유전자의 복구를 초래하고, 이에 의해 기능성 망막 단백질(예를 들어, 기능성 망막층간 단백질, 기능성 RPE65, 기능성 페리페린 등)의 생성을 제공한다. 예를 들어, 문헌[Li et al. (2011) Nature 475:217]을 참조한다. 일부 실시형태에서, 대상 rAAV 비리온은 기능성 복제물이 기능성 망막 단백질을 암호화하는 경우, 부위-특이적 엔도뉴클레아제를 암호화하는 이종성 뉴클레오타이드 서열; 및 결함있는 대립유전자의 기능적 복제물을 암호화하는 이종성 뉴클레오타이드 서열을 포함한다. 기능성 망막 단백질은, 예를 들어 망막층간 단백질, RPE65, 망막 색소 변성증 GTPase 조절제(RGPR)-상호작용 단백질-1, 페리페린, 페리페린-2 등을 포함한다.
사용에 적합한 부위-특이적 엔도뉴클레아제는, 이러한 부위-특이적 엔도뉴클레아제가 비자연적으로 생기고, 특이적 유전자를 표적화하도록 변형되는 경우, 예를 들어, 아연 핑거 뉴클레아제(zinc finger nucleases: ZFN); 및 전사 활성제-유사 효과기 뉴클레아제(transcription activator-like effector nucleases: TALEN)를 포함한다. 이러한 부위-특이적 뉴클레아제는 게놈 내 특이적 위치를 절단하도록 유전자조작될 수 있고, 그 다음에 비-상동성 말단 결합은 몇몇 뉴클레오타이드가 삽입되거나 또는 결실되는 동안 파손을 복구할 수 있다. 그 다음에 이러한 부위-특이적 엔도뉴클레아제(또한 "INDEL"로서 지칭됨)는 프레임 바깥으로 단백질을 던지며, 유전자를 효과적으로 녹아웃시킨다. 예를 들어, 미국 특허 공개 제2011/0301073호를 참조한다.
조절 서열
일부 실시형태에서, 관심의 유전자 산물을 암호화하는 뉴클레오타이드 서열은 구성 프로모터에 조작가능하게 연결된다. 다른 실시형태에서, 관심의 유전자 산물을 암호화하는 뉴클레오타이드 서열은 유도성 프로모터에 조작가능하게 연결된다. 일부 예에서, 관심의 유전자 산물을 암호화하는 뉴클레오타이드 서열은 조직-특이적 또는 세포 유형-특이적 조절 구성요소에 조작가능하게 연결된다. 예를 들어, 일부 예에서, 관심의 유전자 산물을 암호화하는 뉴클레오타이드 서열은 광수용체-특이적 조절 구성요소(예를 들어, 광수용체-특이적 프로모터), 예를 들어, 광수용체 세포에서 조작가능하게 연결된 유전자의 선택적 발현을 부여하는 조절 구성요소에 조작가능하게 연결된다. 적합한 광수용체-특이적 조절 구성요소는, 예를 들어 로돕신 프로모터; 로돕신 키나제 프로모터(Young et al. (2003) Ophthalmol. Vis. Sci. 44:4076); 베타 포스포다이에스터라제 유전자 프로모터(Nicoud et al. (2007) J. Gene Med. 9:1015); 망막 색소 변성증 유전자 프로모터(Nicoud et al. (2007) 상기 참조); 광수용체간 레티노이드-결합 단백질(interphotoreceptor retinoid-binding protein: IRBP) 유전자 인핸서(Nicoud et al. (2007) 상기 참조); IRBP 유전자 프로모터(Yokoyama et al. (1992) Exp Eye Res. 55:225)를 포함한다.
약제학적 조성물
본 발명은 a) 상기 기재한 바와 같은 대상 rAAV 비리온; 및 b) 약제학적으로 허용가능한 담체, 희석제, 부형제 또는 완충제를 포함하는 약제학적 조성물을 제공한다. 일부 실시형태에서, 약제학적으로 허용가능한 담체, 희석제, 부형제 또는 완충제는 인간에서 사용에 적합하다.
이러한 부형제, 담체, 희석제 및 완충제는 과도한 독성 없이 투여될 수 있는 임의의 약제학적 작용제를 포함한다. 약제학적으로 허용가능한 부형제는, 물, 식염수, 글라이세롤 및 에탄올과 같은 액체를 포함하지만, 이들로 제한되지는 않는다. 약제학적으로 허용가능한 염은 그것에, 예를 들어 무기산염, 예컨대 하이드로클로라이드, 하이드로브로마이드, 포스페이트, 설페이트 등; 및 유기산의 염, 예컨대 아세테이트, 프로피오네이트, 말로네이트, 벤조에이트 등이 포함될 수 있다. 추가적으로, 보조 물질, 예컨대 습윤제 또는 에멀젼화제, pH 완충 물질 등이 이러한 비히클에 존재할 수 있다. 매우 다양한 약제학적으로 허용가능한 부형제는 당업계에 공지되어 있고, 본 명세서에서 상세하게 논의될 필요가 없다. 약제학적으로 허용가능한 부형제는, 예를 들어 문헌[A. Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 20th edition, Lippincott, Williams, & Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C. Ansel et al., eds., 7th ed., Lippincott, Williams, & Wilkins; 및 Handbook of Pharmaceutical Excipients (2000) A.H. Kibbe et al., eds., 3rd ed. Amer. Pharmaceutical Assoc]을 포함하는 다양한 간행물에 상세하게 기재되어있다.
망막 세포에의 유전자 산물의 전달 방법 및 치료 방법
본 개시내용은 개체에서 망막 세포에 유전자 산물을 전달하는 방법을 제공하며, 해당 방법은 상기 기재한 바와 같은 대상 rAAV 비리온을 개체에 투여하는 단계를 포함한다. 유전자 산물은 상기 기재한 바와 같은 폴리펩타이드 또는 간섭 RNA(예를 들어, shRNA, siRNA 등), 앱타머 또는 부위-특이적 엔도뉴클레아제일 수 있다. 망막 세포에 유전자 산물을 전달하는 것은 망막질병의 치료를 제공할 수 있다. 망막 세포는 광수용체, 망막 신경절 세포, 뮐러 세포, 양극 세포, 아마크린 세포, 수평 세포 또는 망막 색소성 상피 세포일 수 있다. 일부 경우에, 망막 세포는 광수용체 세포, 예를 들어 간체 또는 추체 세포이다.
본 개시내용은 망막 질병의 치료방법을 제공하며, 해당 방법은 상기 기재한 바와 같은 대상 rAAV 비리온의 유효량을 치료가 필요한 개체에게 투여하는 단계를 포함한다. 대상 rAAV 비리온은 안구내 주사를 통해, 유리체내 주사에 의해 또는 임의의 다른 편리한 투여 방식 또는 경로에 의해 투여될 수 있다. 다른 편리한 투여 방식 또는 경로는, 예를 들어 정맥내, 비강내 등을 포함한다.
"치료적 유효량"은 실험 및/또는 임상 시험을 통해 결정될 수 있는 상대적으로 넓은 범위에 속할 것이다. 예를 들어, 생체내 주사, 즉, 눈에 직접적으로 주사를 위해, 치료적 유효량은 rAAV 비리온의 약 106 내지 약 1015, 예를 들어 약 108 내지 1012 rAAV 비리온의 규모일 것이다. 시험관내 형질도입을 위해, 세포에 전달되는 rAAV 비리온의 유효량은 rAAV 비리온의 약 108 내지 약 1013의 규모일 것이다. 다른 효과적인 투약량은 용량 반응 곡선을 확립하는 일상적인 시도를 통해 당업자에 의해 용이하게 확립될 수 있다.
일부 실시형태에서, 다양한 간격의 기간, 예를 들어 매일, 매주, 매달, 매년 등에 걸쳐 유전자 발현의 원하는 수준을 달성하기 위해 1회 이상의 투여(예를 들어, 2, 3, 4회 이상의 투여)가 사용될 수 있다.
대상 방법을 사용하여 치료될 수 있는 안질환은 급성 황반 신경망막병증; 베체트병; 맥락막 혈관신생; 당뇨병성 포도막염; 히스토플라즈마증; 황반변성, 예컨대 급성 황반변성, 비삼출성 노인성 황반변성 및 삼출성 노인성 황반변성; 부종, 예컨대 황반 부종, 낭포 황반 부종 및 당뇨병성 황반 부종; 다소성 맥락막염; 안후부 부위 또는 위치에 영향을 미치는 안구 외상; 안구 종양; 망막 장애, 예컨대 중심성 망막 정맥 폐색, 당뇨 망막병증(증식성 당뇨 망막병증을 포함), 증식 유리체 망막병증(proliferative vitreoretinopathy: PVR), 망막 동맥 폐쇄증, 망막 박리, 포도막 망막질병; 교감성 안염; 보그트 코야나기-하라다(Vogt Koyanagi-Harada: VKH) 증후군; 포도막 확산; 눈의 레이처 치료에 의해 야기되거나 또는 영향받는 안후부 질환; 광역동요법에 의해 야기되거나 또는 영향받는 안후부 질환; 광응고법, 방사선 망막증; 망막전막 장애; 분지 망막 정맥 폐쇄; 앞허혈 시신경병증; 비망막병증 당뇨병증성 망막 기능장애; 망막층간분리; 망막 색소 변성증; 녹내장; 어셔 증후군, 추체-간체 이영양증; 스타가르트병(노란점 안저); 유전성 황반변성; 맥락망막 변성; 레버 선천성 흑암시; 선천성 정지형 야맹증; 맥락막 결여; 바르데-비들 증후군; 황반 모세혈관확장증; 레버 시신경위축증; 미숙아망막증; 및 색맹, 제1색맹, 제2색맹 및 제3색맹을 포함하는 색각 장애를 포함하지만, 이들로 제한되지는 않는다.
핵산 및 숙주 세포
본 개시내용은 상기 기재한 바와 같이 대상 변이체 아데노-관련 바이러스(AAV) 캡시드 단백질을 암호화하는 뉴클레오타이드 서열을 포함하는 단리된 핵산을 제공하되, 변이체 AAV 캡시드 단백질은 대응되는 모 AAV 캡시드 단백질에 대해 GH 루프 또는 루프 IV 내 약 5개 아미노산 내지 약 11개 아미노산의 삽입을 포함하며, AAV 비리온에 존재할 때, 변이체 캡시드 단백질은 대응되는 모 AAV 캡시드 단백질을 포함하는 AAV 비리온에 의한 망막 세포의 감염성에 비해 망막 세포의 증가된 감염성을 제공한다. 대상의 단리된 핵산은 AAV 벡터, 예를 들어 재조합 AAV 벡터일 수 있다.
삽입 펩타이드
대상 핵산에 의해 암호화된 변이체 AAV 캡시드 단백질은 길이로 약 5개 아미노산 내지 약 11개 아미노산의 삽입 펩타이드를 가지며, AAV 캡시드의 GH 루프 내로 삽입된다. 삽입 펩타이드는 5개 아미노산, 6개 아미노산, 7개 아미노산, 8개 아미노산, 9개 아미노산, 10개 아미노산 또는 11개 아미노산의 길이를 가진다.
삽입 펩타이드는 이하에 제시되는 식 중 어느 하나의 아미노산 서열을 포함할 수 있다.
예를 들어, 삽입 펩타이드는 길이로 5 내지 11개의 아미노산의 펩타이드일 수 있으며, 여기서 삽입 펩타이드는 하기 식 I을 갖는다:
[식 I]
Y1Y2X1X2X3X4X5X6X7Y3Y4
상기 식에서:
각각의 Y1 내지 Y4는, 존재한다면 Ala, Leu, Gly, Ser 및 Thr으로부터 독립적으로 선택되고;
X1은, 존재한다면, Leu, Asn 및 Lys으로부터 선택되며;
X2는 Gly, Glu, Ala 및 Asp으로부터 선택되고;
X3은 Glu, Thr, Gly 및 Pro으로부터 선택되며;
X4는 Thr, Ile, Gln 및 Lys으로부터 선택되고;
X5는 Thr 및 Ala으로부터 선택되며;
X6은 Arg, Asn 및 Thr으로부터 선택되고;
X7은, 존재한다면, Pro 및 Asn으로부터 선택된다.
다른 예로서, 삽입 펩타이드는 길이로 5 내지 11개의 아미노산의 펩타이드일 수 있으며, 여기서 삽입 펩타이드는 하기 식 IIa를 갖는다:
[식 IIa]
Y1Y2X1X2X3X4X5X6X7Y3Y4
상기 식에서:
각각의 Y1 내지 Y4는, 존재한다면, Ala, Leu, Gly, Ser 및 Thr으로부터 독립적으로 선택되고;
각각의 X1 내지 X4는 임의의 아미노산이며;
X5는 Thr이고;
X6은 Arg이며;
X7은 Pro이다.
다른 예로서, 삽입 펩타이드는 길이로 5 내지 11개의 아미노산의 펩타이드일 수 있으며, 여기서 삽입 펩타이드는 식 IIb를 갖는다:
[식 IIb]
Y1Y2X1X2X3X4X5X6X7Y3Y4
상기 식에서:
각각의 Y1 내지 Y4는, 존재한다면, Ala, Leu, Gly, Ser 및 Thr으로부터 독립적으로 선택되고;
X1는, 존재한다면, Leu 및 Asn으로부터 선택되며;
X2는, 존재한다면, Gly 및 Glu으로부터 선택되고;
X3은 Glu 및 Thr으로부터 선택되며;
X4는 Thr 및 Ile으로부터 선택되고;
X5는 Thr이며;
X6은 Arg이고;
X7은 Pro이다.
다른 예로서, 삽입 펩타이드는 길이로 5 내지 11개 아미노산의 펩타이드이며, 여기서 삽입 펩타이드는 하기 식 III을 갖는다:
[식 III]
Y1Y2X1X2X3X4X5X6X7Y3Y4
상기 식에서:
각각의 Y1 내지 Y4는, 존재한다면, Ala, Leu, Gly, Ser 및 Thr으로부터 독립적으로 선택되고;
X1은, 존재한다면, Lys이며;
X2는 Ala 및 Asp으로부터 선택되며;
X3은 Gly 및 Pro으로부터 선택되고;
X4는 Gln 및 Lys으로부터 선택되며;
X5는 Thr 및 Ala로부터 선택되고;
X6은 Asn 및 Thr으로부터 선택되며;
X7은, 존재한다면, Asn이다.
다른 예로서, 삽입 펩타이드는 길이로 5 내지 11개 아미노산의 펩타이드 일 수 있으며, 여기서 삽입 펩타이드는 하기 식 IV를 갖는다:
[식 IV]
Y1Y2X1X2X3X4X5X6X7Y3Y4
상기 식에서:
각각의 Y1 내지 Y4는, 존재한다면, Ala, Leu, Gly, Ser 및 Thr으로부터 독립적으로 선택되고;
X1은, 존재한다면, 양으로 하전된 아미노산 또는 비하전된 아미노산이거나; 또는 Leu, Asn, Arg, Ala, Ser 및 Lys으로부터 선택되고;
X2는 음으로 하전된 아미노산 또는 비하전된 아미노산이거나; 또는 Gly, Glu, Ala, Val, Thr 및 Asp로부터 선택되며;
X3은 음으로 하전된 아미노산 또는 비하전된 아미노산이거나; 또는 Glu, Thr, Gly, Asp 또는 Pro로부터 선택되고;
X4는 Thr, Ile, Gly, Lys, Asp 및 Gln로부터 선택되며;
X5는 극성 아미노산, 알코올(유리 하이드록실 기를 갖는 아미노산) 또는 소수성 아미노산이거나; 또는 Thr, Ser, Val 및 Ala로부터 선택되고;
X6은 양으로 하전된 아미노산 또는 비하전된 아미노산이거나; 또는 Arg, Val, Lys, Pro, Thr 및 Asn으로부터 선택되며;
X7은, 존재한다면, 양으로 하전된 아미노산 또는 비하전된 아미노산이거나; 또는 Pro, Gly, Phe, Asn 및 Arg으로부터 선택된다.
비제한적인 예로서, 삽입 펩타이드는 LGETTRP(서열번호 13), NETITRP(서열번호 14), KAGQANN(서열번호 15), KDPKTTN(서열번호 16), KDTDTTR(서열번호 57), RAGGSVG(서열번호 58), AVDTTKF(서열번호 59) 및 STGKVPN(서열번호 60)으로부터 선택된 아미노산 서열을 포함할 수 있다.
일부 경우에, 삽입 펩타이드는 LGETTRP(서열번호 13), NETITRP(서열번호 14), KAGQANN(서열번호 15), KDPKTTN(서열번호 16), KDTDTTR(서열번호 57), RAGGSVG(서열번호 58), AVDTTKF(서열번호 59) 및 STGKVPN(서열번호 60) 중 어느 하나의 아미노 말단 및/또는 카복시 말단에서 1 내지 4개의 스페이서 아미노산(Y1 내지 Y4)를 가진다. 적합한 스페이서 아미노산은 류신, 알기닌, 글라이신 및 세린을 포함하지만, 이들로 제한되지 않는다.
예를 들어, 일부 경우에, 삽입 펩타이드는 다음의 아미노산 서열: LALGETTRPA(서열번호 45); LANETITRPA(서열번호 46), LAKAGQANNA(서열번호 47), LAKDPKTTNA(서열번호 48), LAKDTDTTRA(서열번호 61), LARAGGSVGA(서열번호 62), LAAVDTTKFA(서열번호 63) 및 LASTGKVPNA(서열번호 64) 중 하나를 가진다. 다른 예로서, 일부 경우에, 삽입 펩타이드는 다음의 아미노산 서열: AALGETTRPA(서열번호 49); AANETITRPA(서열번호 50), AAKAGQANNA(서열번호 51) 및 AAKDPKTTNA(서열번호 52) 중 하나를 가진다. 또한 다른 예로서, 일부 경우에, 삽입 펩타이드는 다음의 아미노산 서열: GLGETTRPA(서열번호 53); GNETITRPA(서열번호 54), GKAGQANNA(서열번호 55) 및 GKDPKTTNA(서열번호 56) 중 하나를 가진다. 다른 예로서, 일부 경우에, 삽입 펩타이드는 AA에 의해 C-말단에 그리고 A에 의해 N-말단에 측접한 KDTDTTR(서열번호 57), RAGGSVG(서열번호 58), AVDTTKF(서열번호 59) 및 STGKVPN(서열번호 60) 중 하나를 포함하거나; 또는 G에 의해 C-말단에 그리고 A에 의해 N-말단에 측접한 KDTDTTR(서열번호 57), RAGGSVG(서열번호 58), AVDTTKF(서열번호 59) 및 STGKVPN(서열번호 60) 중 하나를 포함한다.
대상 재조합 AAV 벡터는 상기 기재한 바와 같이 대상 재조합 AAV 비리온을 만들기 위해 사용될 수 있다. 따라서, 본 개시내용은, 적합한 세포 내로 도입되었을 때, 대상 재조합 AAV 비리온의 생성을 제공할 수 있는 재조합 AAV 벡터를 제공한다.
본 발명은 대상 핵산을 포함하는 숙주 세포, 예를 들어, 단리된(유전적으로 변형된) 숙주 세포를 추가로 제공한다. 대상 숙주 세포는 단리된 세포, 예를 들어 시험관내 배양물 내 세포일 수 있다. 대상 숙주 세포는 이하에 기재되는 바와 같이 대상 rAAV 비리온을 생성하는데 유용하다. 대상 rAAV 비리온을 생성하기 위해 대상 숙주 세포가 사용되는 경우, 이는 "패키징 세포"로서 지칭된다. 일부 실시형태에서, 대상 숙주 세포는 대상 핵산으로 안정하게 유전적으로 변형된다. 다른 실시형태에서, 대상 숙주 세포는 대상 핵산으로 일시적으로 유전적으로 변형된다.
대상 핵산은 전기천공법, 인산칼슘 침전법, 리포좀-매개 형질감염 등을 포함하지만, 이들로 제한되지 않는 확립된 기법을 사용하여 안정하게 또는 일시적으로 숙주 세포 내로 도입된다. 안정한 형질전환을 위해, 대상 핵산은 일반적으로 선별가능한 마커, 예를 들어 네오마이신 저항 등과 같은 몇몇 잘-공지된 선별가능하 마커 중 어떤 것을 추가로 포함할 것이다.
대상 숙주 세포는 임의의 다양한 세포, 예를 들어 뮤린 세포 및 영장류 세포(예를 들어, 인간 세포)를 포함하는, 예를 들어 포유류 세포 내로 대상 핵산을 도입함으로써 만들어진다. 적합한 세포주가, 이하에 제한되는 것은 아니지만, 293 세포, COS 세포, HeLa 세포, Vero 세포, 3T3 마우스 섬유아세포, C3H10T1/2 섬유아세포, CHO 세포 등을 포함하는 경우, 적합한 포유류 세포는 1차 세포 및 세포주를 포함하지만, 이들로 제한되는 것은 아니다. 적합한 숙주 세포의 비제한적인 예는, 예를 들어 HeLa 세포(예를 들어, American Type Culture Collection (ATCC) No. CCL-2), CHO 세포(예를 들어, ATCC No. CRL9618, CCL61, CRL9096), 293 세포(예를 들어, ATCC No. CRL-1573), Vero 세포, NIH 3T3 세포(예를 들어, ATCC No. CRL-1658), Huh-7 세포, BHK 세포(예를 들어, ATCC No. CCL10), PC12 세포(ATCC No. CRL1721), COS 세포, COS-7 세포(ATCC No. CRL1651), RAT1 세포, 마우스 L 세포(ATCC No. CCLI.3), 인간 배아 신장(human embryonic kidney: HEK) 세포(ATCC No. CRL1573), HLHepG2 세포 등을 포함한다. 대상 숙주 세포는 AAV를 생성하는 Sf9 세포와 같은 곤충 세포를 감염시키기 위해 바큘로바이러스를 사용하여 만들어질 수 있다(예를 들어, 미국 특허 제7,271,002호; 미국 특허 출원 제12/297,958호)
일부 실시형태에서, 대상인 유전적으로 변형된 숙주 세포는 상기 기재된 바와 같은 변이체 AAV 캡시드 단백질을 암호화하는 뉴클레오타이드 서열을 포함하는 핵산에 추가적으로 하나 이상의 AAV rep 단백질을 암호화하는 뉴클레오타이드 서열을 포함하는 핵산을 포함한다. 다른 실시형태에서, 대상 숙주 세포는 rAAV 벡터를 추가로 포함한다. rAAV 비리온은 대상 숙주 세포를 사용하여 만들어질 수 있다. rAAV 비리온의 생성 방법은, 예를 들어 미국 특허 공개 제2005/0053922호 및 미국 특허 공개 제2009/0202490호에 기재된다.
실시예
다음의 실시예는 본 발명의 제조 및 사용 방법의 완전한 개시 및 설명을 당업자에게 제공하기 위해 제공되며, 본 발명자들이 그들의 발명으로 간주하는 것의 범위를 제한하는 것으로 의도되지 않으며, 이하의 실험이 모든 또는 유일한 수행되는 실험이라는 것을 나타내는 것으로 의도되지 않는다. 사용한 숫자(예를 들어, 양, 온도 등)에 대한 정확성을 보장하기 위한 노력을 하였지만, 일부 실험적 오차 및 편차를 고려하여야 한다. 달리 표시되지 않는다면, 부분은 중량부이며, 분자량은 평균분자량이고, 온도는 섭씨 온도이며, 압력은 대기압이거나 대기압 근처이다. 표준 약어, 예를 들어 bp, 염기쌍(들); kb, 킬로베이스(들); pl, 피코리터(들); s 또는 sec, 초(들); 분, 분(들); h 또는 hr, 시간(들); aa, 아미노산(들); kb, 킬로베이스(들); bp, 염기쌍(들); nt, 뉴클레오타이드(들); i.m., 근육내(로); i.p., 복강내(로); s.c., 피하(로); 등을 사용할 수 있다.
실시예 1: 망막 세포의 향상된 형질도입을 지니는 AAV 변이체
중합효소 연쇄 반응(polymerase chain reaction: PCR) 돌연변이유발에 의해 아미노산 587 내지 588의 야생형 AAV2 게놈 내로 독특한 AvrII 부위를 도입함으로써 펩타이드 디스플레이 라이브러리를 만드는 접근을 사용하였다. 무작위 21 뉴클레오타이드 삽입물인 7량체 For을 사용하여 안티센스 프라이머 7량체 Rev와 함께 dsDNA 삽입물을 합성하였다. 얻어진 dsDNA 삽입물을 NheI로 분해 후 게놈의 AvrII 부위 내로 클로닝시켰고, 그 다음에 패키징된 다양한 7량체 디스플레이 라이브러리를 생성하였다(Perabo et al., 2003; Muller et al., 2003). 해당 게놈이 암호화된 캡시드 단백질 내에서 각 바이러스 게놈이 패키징되거나 캡시드 내에 이입되도록 바이러스를 만들었다. 이에 대해, 선별을 통해 확인한 추가적인 개선은 바이러스 캡시드 내에 함유된 이런 개선된 기능을 암호화하는 게놈 서열과 연관될 수 있다.
이 라이브러리에 rho-GFP 마우스 내 양성 선별을 실시하였다(Wensel et al. (2005) Vision Res. 45:3445). 간단하게, 선별의 1 라운드에서, 성체 rho-GFP 마우스를 대략 1x1012 바이러스 게놈(vg)/㎖의 게놈 역가에 의해 2㎕의 인산염 완충 식염수(phosphate buffered saline: PBS)-투석되고, 이오딕사놀-정제된 라이브러리로 유리체내로 주사하였다. 초미세 30 1/2-게이지 일회용 바늘을 유리체강 내로 적도에서 그리고 가장자리 옆에서 동물 눈의 공막을 통해 통과시켰다. 유리체강의 중심에서 바늘의 직접 관찰에 의해 2㎕의 바이러스를 주사하였다. 주사 1주 후, 눈에서 세포핵을 제거하였고, 빛, 파파인 프로테아제 처리를 사용하여 망막을 해리시킨 다음, 광수용체 집단을 형광 활성화 세포 분리기(fluorescence activated cell sorter: FACS)로 단리시켰다. 그 다음에 후속 게놈 추출물로부터 성공적인 비리온을 PCR 증폭시켰고, 추가로 클로닝시켰으며, 주사를 위해 재패키징하였다.
이 선별의 추가 반복을 수행하였고, 가장 허용되는 돌연변이를 지니는 서브세트로 변이체의 풀(pool)을 좁혔다. 3회 반복한 후, 실수유발 PCR의 라운드를 수행하여 선별을 위한 변이체의 추가 산물을 만들었다. 전체적으로, 2회 발생을 위해 이 과정을 반복하였다. 이에 대해, 관련 진화의 이런 과정은 천연 진화 과정과 유사한 양성 선별 및 유도된 돌연변이유발의 적용을 통해 광수용체-허용성 AAV 변이체를 만들었다.
후속적으로, 대부분의 우세하고 성공적인 변이체가 유리체내 광수용체 형질도입에 대해 허용적인 돌연변이를 갖는지를 결정하기 위해 50개 변이체의 캡(cap) 유전자를 시퀀싱하였다. 50개의 클론 중에서, 46개에 7량체 삽입물의 판독가능한 서열을 제공하였다. 현저하게, 클론의 거의 2/3는 동일한 별개의 7량체 모티프를 함유하였다(~588LGETTRP~; 서열번호 13). 흥미롭게도, 다음의 대부분의 우세한 변이체(~588NETITRP~; 서열번호 14)는 또한 극성 트레오닌과 비극성 프롤린 잔기(TRP) 사이의 양으로-하전된 아르기닌으로 이루어진 유사한 측접 모티프를 함유하였다.
표 1 관련된 진화로부터 단리된 변이체의 시퀀싱은 바이러스 라이브러리에서 높은 수렴도를 나타낸다. 모든 변이체는 AAV2 7량체로부터 유래되었고, 대략 64%의 변이체는 동일한 7량체 모티프(~588LGETTRP~ (서열번호 13))를 함유하였다.
7량체 삽입 서열 중에서, 특정 위치에서 보통의 선호도, 예를 들어 위치 1에서 양으로 하전된 아미노산; 위치 2에서 음으로 하전된 아미노산; 위치 5에서 알코올(예를 들어, 알코올 기를 갖는 아미노산(유리 하이드록실 기), 예컨대 Thr 또는 Ser)이 있었다.
7량체 삽입물은 표 2에 나타내는 바와 같이 스페이서에 측접하였다:
도 1. 아미노산 587 다음에 무작위 헵타머(오렌지 색으로 나타냄)를 함유하는 AAV2의 대표적인 3차원 캡시드 모델. AAV2 캡시드의 이런 영역은 세포-표면 수용체 결합에 참여할 가능성이 있다.
상기-기재한 선별로부터 높은 라이브러리 수렴도에 비추어, AAV2 ~588LGETTRP~(서열번호 13; 별칭 7M8)의 재조합 형태를 클로닝하였고, scCAG-GFP 이식유전자와 함께 벡터를 패키징하여 그것의 형질도입 프로파일을 시각화하였다. 성체 마우스에서 유리체내 주사의 3주 후, 망막 신경절 세포(RGC) 및 뮐러 세포를 포함하는 수많은 세포 유형에서 강한 발현을 관찰하였다. 중요하게는, 외곽 핵층(outer nuclear layer: ONL) 핵(적색 화살표)에서 및 외곽 절편(도 2, 청색 화살표)에서 GFP 발현에 의해 알 수 있는 바와 같이 7M8을 주사한 망막 내 광수용체의 형질도입을 관찰한 반면, AAV2는 인식가능한 광수용체 발현을 나타내지 않았다.
도 2 AAV2 7M8 변이체(우)는 AAV2(좌)에 비해 더 큰 수준의 유리체내 광수용체 형질도입을 증명한다. 성체 마우스에서 1x1012 vg/㎖의 AAV2 7M8 및 AAV2 scCAG GFP의 2㎕의 유리체내 주사 3주 후 횡단 망막 부분의 공초점 현미경 관찰. 적색 화살표(상부)는 광수용체 핵을 의미하며, 청색 화살표(상부)는 광수용체 외곽 절편을 의미한다.
망막 세포 형질도입에서 이런 이득에 비추어, 구체적으로는 광수용체에서 형질도입 효율을 더 양호하게 결정하기 위해 광수용체-특이적 로돕신 프로모터를 함유하는 ssRho-eGFP 이식유전자의 사용을 통한 발현에서 특이성을 증가시키는 시도를 하였다(도 3). 사실, 광수용체 특이적 Rho 프로모터의 사용은 광수용체에 대한 GFP 발현을 제한하였다. 이전의 관련된 진화 접근에 대한 합리적 설계와 조합에 의해 7M8 형질도입 효율을 개선시키는 시도를 하였다. 따라서, 티로신 잔기가 노출된 4개의 표면을 앞서 광수용체 감염성이 증가된 것으로 나타난 7M8 캡시드 상의 페닐알라닌으로 돌연변이유발시켰다(Y273F, Y444F, Y500F 및 Y730F)(Petrs-Silva et al., 2009). 흥미롭게도, 돌연변이의 첨가는 7m8 또는 7m8-4YF 감염된 망막으로부터 GFP(+) 광수용체의 FAC 분류에 의해 나타나는 바와 같이 본래 바이러스에 비해 형질도입된 광수용체의 수를 감소시켰다(도 4).
도 3. 흔한 CAG 프로모터(좌) 또는 광수용체 특이적 Rho 프로모터(우)의 제어 하에서 GFP 유전자를 운반하는 7m8로부터 초래된 GFP 발현을 나타내는 망막 냉동 슬라이스의 대표적인 형광 이미지.
도 4. 유세포분석기에 의해 계측되는 바와 같은 백만개의 망막 세포 당 GFP(+) 광수용체 세포. 7m8은 4개의 티로신 돌연변이를 함유하는 7m8(상부)에 비해 광수용체의 양을 2x 초과로 형질도입한다.
실시예 2: 망막층간분리의 처리
발현 작제물 7m8-rho-RS1을 사용하여, 기능성 망막층간분리(RS1) 단백질을 망막층간분리-결함 마우스(Rs1h-결함 마우스; Rs1h는 인간 RS1의 마우스 상동체임)에 전달하였다. 벡터는 로돕신 프로모터의 전사 제어 하에 기능성 망막층간분리 단백질을 암호화하는 뉴클레오타이드 서열을 포함한다. 도 13a 내지 c에서, 볼드체 및 밑줄친 뉴클레오타이드 서열(뉴클레오타이드 4013 내지 4851)는 로돕신 프로모터이며; 뉴클레오타이드 4866 내지 5540(볼드체로 나타낸 시작 atg 및 정지 tga 서열을 지님)은 인간 RS1 단백질을 암호화한다.
7m8-rho-RS1 작제물을 P15에서 Rs1h-/- 마우스에 유리체내로 투여하였다. (Weber et al. (2002) Proc. Natl. Acad. Sci. USA 99:6222)에 기재된 바와 같이 Rs1h 유전자의 엑손 3의 표적화된 파괴를 통해 Rs1h-/- 마우스를 만들었다. Rs1h-/- 마우스는 Rs1h 단백질 산물이 결여되어 있고, 음전성 ERG(예를 들어 a-웨이브의 상대적 보존에 의해 감소된 b-웨이브)를 가지며, 인간 망막층간분리 환자에서 보이는 것과 유사한 망막층의 분할이 있다. Rs1h-/- 내로 7m8-rho-RS1 벡터의 주사는 망막 내 광수용체로부터 고수준의 범망막성(panretinal) RS1 발현을 야기하였다. RS1 발현은 스펙트럼-도메인 빛 간섭 단층촬영(spectral-domain optical coherence tomography: SD-OCT) 영상(도 7A 내지 I), ERG b-웨이브의 구제(도 8A 내지 D) 및 망막의 장기간 구조적 보존(도 9A 내지 E)에서 알 수 있는 바와 같이 망막 내 구멍의 수 및 크기의 감소와 함께 개선된 망막 형태를 야기하였다.
도 7A 내지 I. 7m8-rho-GFP(왼쪽 컬럼), 7m8-rho-RS1(중간 컬럼)으로 주사하거나, 또는 주사하지 않은 WT 동물(오른쪽 컬럼)의 망막의 대표적인 고해상도 SD-OCT 영상. 상부 망막의 내부 핵층을 통해 안저 영상을 촬영하였고, 다른 층(a 내지 c)을 제외한다. 망막의 상부(d 내지 f) 및 하부(g 내지 i)의 횡단 이미지를 표지점으로서 시신경두(optic nerve head)를 사용하여 촬영하였다.
내부 망막의 층간 분리에 기인하여 병리가 진행됨에 따라, 미처리 RS1 망막은 내경계막(inner limiting membrane: ILM)으로부터 광수용체까지 측정될 때 전반적인 두께를 증가시켰다. 이 과정은 층간분리를 형성하지 않지만, INL에서 진행성 광수용체 세포 사멸 및 부수적인 망막의 얇아짐 및 ERG 진폭의 손실을 나타내는, 대부분의 망막 퇴행 질환(retinal degenerative diseases: RDD)에서 관찰된 것과 완전히 다르다. RS1에서, 광수용체가 질병으로 사멸됨에 따라 ONL은 얇아지지만, 이는 전반적인 망막 두께 변화와는 완전히 다르다. 이는 일반적으로 RS1에 대한 성공적인 요법이 전반적인 망막 두께를 야생형으로 되돌리고, ONL에서 광수용체 손실을 개선시키는 것으로 생각된다. Rs1 이외의 대부분의 RDD에서, ONL 얇아짐에 의해 표시되는 광수용체의 손실은 ERG 진폭에 의해 측정되는 바와 같이 망막의 생리적 출력의 감소와 유사하다. RS1은 병적 측면이 망막 두께를 증가시키며 부수적인 erg 진폭이 손실되는 매우 소수의 망막질병의 예 중 하나이다. 요약하면, RS1 유전자 산물을 회복하면, 세포밖 망막의 "신경교"는 망막을 다시 야생형 두께로 얇아지게 하며, erg 진폭은 층간분리가 해결된다면, 거의 정상 수준으로 되돌아온다.
도 8a는 주사 후 1개월(좌)과 4개월(우) 둘 다에서 AAV2-rho-RS1, 7m8-rho-GFP 및 7m8-rho-RS1이 주사된 눈에 대해 미처리 Rs1-/- 눈의 기능적 구제의 비교를 나타낸다. 주사 1개월 후, 7m8-rho-RS1은 ERG b-웨이브 진폭의 상당한 구제를 야기한 반면, AAV2-rho.RS1은 미처리 눈과 통계적으로 구별가능하지 않았다.
4개월 후, 7m8-rho-RS1 진폭은 야생형 진폭(우)에 대해 추가로 증가된다. 도 8b는 7m8-rho-RS1-주사된 눈으로부터 대표적인 ERG 추적을 나타내며, 7m8-rho-GFP-주사된 눈에 비해 a-웨이브 및 b-웨이브 및 야생형 눈에 대해 더 가까운 웨이브형태의 개선된 진폭을 나타낸다. 도 8c는 고강도(1 log cd x s/m2)로부터 초래된 전계 암소시(full-field scotopi) b-웨이브의 진폭을 나타내며, 각 조건에 대해 P15에서 주사 1개월 후 시작된 매달의 기준에 대해 기록하였다. 3회 반응을 기록하였고, 각 시점에 각 눈에 대해 평균을 내었다.
평균 ERG b-웨이브 진폭을 주사 후 시간의 함수로서 플롯팅하였다. 조건 둘 다에 대해 n=7을 사용하였다. 도 8d는 암소시(-3 내지 1 log cd x s/m2 범위의 상부 추적, 자국) 및 주간시(-0.9 내지 1.4 log cd x s/m2 범위의 하부 자국) 조건 하에서 ERG 반응의 분석을 나타내며, 자극 강도의 범위에 걸쳐 개선된 간체 및 추체 함수를 표시한다.
도 9A 내지 E. 7m8-rho-RS1 처리 후 10개월에 측정한 망막 두께의 지속적인 개선. 시신경두에 집중된 주사 10개월 후 a) 7m8-rho-RS1 또는 b) 7m8-rho-GFP 처리된 망막의 대표적인 횡단 SD-OCT 영상. c) 망막 두께, d) ONL 두께, 및 e) 내부 및 외부 절편 두께의 측정을 시신경두로부터의 거리의 함수로서 플롯팅한다.
실시예 3: 마카크(macaque)에서 망막 세포에 단백질을 전달하기 위해 사용한 AAV 변이체
재조합 AAV2 비리온(커넥신36 프로모터의 제어 하에 GFP를 운반하는 7m8)을 만들었다. 재조합 AAV2 비리온은 AAV2 캡시드의 아미노산 587과 588 사이에 LALGETTRPA 펩타이드의 삽입을 지니는 AAV2 캡시드 변이체 및 개재뉴런(interneuron)에서 발현되는 커넥신36 프로모터의 전사 제어 하에 GFP를 포함하였다. rAAV2 비리온을 마카크의 눈에 유리체내로 주사하였다. 데이터를 도 18에 나타낸다.
도 18은 커넥신36 프로모터의 제어 하에 GFP를 운반하는 7m8의 투여 9주 후 망막위 뒤쪽에서 GFP 발현을 나타내는 형광 안저 영상을 제공한다. 모 AAV2 혈청형에 비해(Yin et al, IOVS 52(5); 2775), 중심와 고리(fovea ring)에서 고수준의 발현이 보였고, 중심와 바깥의 중심 망막에서 가시적인 형광이 보였다.
참고문헌
본 발명을 그의 구체적 실시형태를 참조하여 기재하였지만, 당업자라면 본 발명의 진정한 정신과 범주로부터 벗어나는 일 없이 다양한 변화가 이루어질 수 있고 동등물로 치환될 수 있다는 것을 이해하여야 한다. 추가로, 본 발명의 객관적인 정신과 범주에 대해 사안, 처리, 처리 단계 또는 단계들의 특별한 상황, 물질, 조성물을 적용하기 위해 다수의 변형이 이루어질 수 있다. 모든 이러한 변형은 본 명세서에 첨부된 특허청구범위의 범주 내인 것으로 의도된다.
SEQUENCE LISTING
<110> THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
<120> Adeno-Associated Virus Virions with Variant Capsid and Methods of
Use Thereof
<130> WO/2012/145601
<140> PCT/US2012/034413
<141> 2012-04-20
<150> 61/478,355
<151> 2011-04-22
<160> 64
<170> PatentIn version 2.0
<210> 1
<211> 733
<212> PRT
<213> Adeno-associated virus-2
<400> 1
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Arg Gln Ala Ala Thr
580 585 590
Ala Asp Val Asn Thr Gln Gly Val Leu Pro Gly Met Val Trp Gln Asp
595 600 605
Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr
610 615 620
Asp Gly His Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu Lys
625 630 635 640
His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala Asn
645 650 655
Pro Ser Thr Thr Phe Ser Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln
660 665 670
Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln Lys
675 680 685
Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr
690 695 700
Asn Lys Ser Val Asn Val Asp Phe Thr Val Asp Thr Asn Gly Val Tyr
705 710 715 720
Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
725 730
<210> 2
<211> 42
<212> PRT
<213> Adeno-associated virus-2
<400> 2
Pro Val Ala Thr Glu Gln Tyr Gly Ser Val Ser Thr Asn Leu Gln Arg
1 5 10 15
Gly Asn Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln Gly Val Leu
20 25 30
Pro Gly Met Val Trp Gln Asp Arg Asp Val
35 40
<210> 3
<211> 42
<212> PRT
<213> Adeno-associated virus-AAV-1
<400> 3
Pro Val Ala Thr Glu Arg Phe Gly Thr Val Ala Val Asn Phe Gln Ser
1 5 10 15
Ser Ser Thr Asp Pro Ala Thr Gly Asp Val His Ala Met Gly Ala Leu
20 25 30
Pro Gly Met Val Trp Gln Asp Arg Asp Val
35 40
<210> 4
<211> 42
<212> PRT
<213> Adeno-associated virus-5
<400> 4
Arg Val Ala Tyr Asn Val Gly Gly Gln Met Ala Thr Asn Asn Gln Ser
1 5 10 15
Ser Thr Thr Ala Pro Ala Thr Gly Thr Tyr Asn Leu Gln Glu Ile Val
20 25 30
Pro Gly Ser Val Trp Met Glu Arg Asp Val
35 40
<210> 5
<211> 42
<212> PRT
<213> Adeno-associated virus-AAV-6
<400> 5
Pro Val Ala Thr Glu Arg Phe Gly Thr Val Ala Val Asn Leu Gln Ser
1 5 10 15
Ser Ser Thr Asp Pro Ala Thr Gly Asp Val His Val Met Gly Ala Leu
20 25 30
Pro Gly Met Val Trp Gln Asp Arg Asp Val
35 40
<210> 6
<211> 42
<212> PRT
<213> Adeno-associated virus-AAV-
<400> 6
Pro Val Ala Thr Glu Glu Tyr Gly Ile Val Ser Ser Asn Leu Gln Ala
1 5 10 15
Ala Asn Thr Ala Ala Gln Thr Gln Val Val Asn Asn Gln Gly Ala Leu
20 25 30
Pro Gly Met Val Trp Gln Asn Arg Asp Val
35 40
<210> 7
<211> 42
<212> PRT
<213> Adeno-associated virus-AAV-8
<400> 7
Pro Val Ala Thr Glu Glu Tyr Gly Ile Val Ala Asp Asn Leu Gln Gln
1 5 10 15
Gln Asn Thr Ala Pro Gln Ile Gly Thr Val Asn Ser Gln Gly Ala Leu
20 25 30
Pro Gly Met Val Trp Gln Asn Arg Asp Val
35 40
<210> 8
<211> 42
<212> PRT
<213> Adeno-associated virus-AAV-9
<400> 8
Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln Ser
1 5 10 15
Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile Leu
20 25 30
Pro Gly Met Val Trp Gln Asp Arg Asp Val
35 40
<210> 9
<211> 42
<212> PRT
<213> Adeno-associated virus-AAV-10
<400> 9
Pro Val Ala Thr Glu Gln Tyr Gly Val Val Ala Asp Asn Leu Gln Gln
1 5 10 15
Ala Asn Thr Gly Pro Ile Val Gly Asn Val Asn Ser Gln Gly Ala Leu
20 25 30
Pro Gly Met Val Trp Gln Asn Arg Asp Val
35 40
<210> 10
<211> 224
<212> PRT
<213> Homo sapiens
<400> 10
Met Ser Arg Lys Ile Glu Gly Phe Leu Leu Leu Leu Leu Phe Gly Tyr
1 5 10 15
Glu Ala Thr Leu Gly Leu Ser Ser Thr Glu Asp Glu Gly Glu Asp Pro
20 25 30
Trp Tyr Gln Lys Ala Cys Lys Cys Asp Cys Gln Gly Gly Pro Asn Ala
35 40 45
Leu Trp Ser Ala Gly Ala Thr Ser Leu Asp Cys Ile Pro Glu Cys Pro
50 55 60
Tyr His Lys Pro Leu Gly Phe Glu Ser Gly Glu Val Thr Pro Asp Gln
65 70 75 80
Ile Thr Cys Ser Asn Pro Glu Gln Tyr Val Gly Trp Tyr Ser Ser Trp
85 90 95
Thr Ala Asn Lys Ala Arg Leu Asn Ser Gln Gly Phe Gly Cys Ala Trp
100 105 110
Leu Ser Lys Phe Gln Asp Ser Ser Gln Trp Leu Gln Ile Asp Leu Lys
115 120 125
Glu Ile Lys Val Ile Ser Gly Ile Leu Thr Gln Gly Arg Cys Asp Ile
130 135 140
Asp Glu Trp Met Thr Lys Tyr Ser Val Gln Tyr Arg Thr Asp Glu Arg
145 150 155 160
Leu Asn Trp Ile Tyr Tyr Lys Asp Gln Thr Gly Asn Asn Arg Val Phe
165 170 175
Tyr Gly Asn Ser Asp Arg Thr Ser Thr Val Gln Asn Leu Leu Arg Pro
180 185 190
Pro Ile Ile Ser Arg Phe Ile Arg Leu Ile Pro Leu Gly Trp His Val
195 200 205
Arg Ile Ala Ile Arg Met Glu Leu Leu Glu Cys Val Ser Lys Cys Ala
210 215 220
<210> 11
<211> 247
<212> PRT
<213> Homo sapiens
<400> 11
Met Thr Ile Leu Phe Leu Thr Met Val Ile Ser Tyr Phe Gly Cys Met
1 5 10 15
Lys Ala Ala Pro Met Lys Glu Ala Asn Ile Arg Gly Gln Gly Gly Leu
20 25 30
Ala Tyr Pro Gly Val Arg Thr His Gly Thr Leu Glu Ser Val Asn Gly
35 40 45
Pro Lys Ala Gly Ser Arg Gly Leu Thr Ser Leu Ala Asp Thr Phe Glu
50 55 60
His Val Ile Glu Glu Leu Leu Asp Glu Asp His Lys Val Arg Pro Asn
65 70 75 80
Glu Glu Asn Asn Lys Asp Ala Asp Leu Tyr Thr Ser Arg Val Met Leu
85 90 95
Ser Ser Gln Val Pro Leu Glu Pro Pro Leu Leu Phe Leu Leu Glu Glu
100 105 110
Tyr Lys Asn Tyr Leu Asp Ala Ala Asn Met Ser Met Met Val Leu Arg
115 120 125
His Ser Asp Pro Ala Arg Arg Gly Glu Leu Ser Val Cys Asp Ser Ile
130 135 140
Ser Glu Trp Val Thr Ala Ala Asp Lys Lys Thr Ala Val Asp Met Ser
145 150 155 160
Gly Gly Thr Val Thr Val Leu Glu Lys Val Pro Val Ser Lys Gly Gln
165 170 175
Leu Lys Gln Tyr Phe Tyr Glu Thr Lys Cys Asn Pro Met Gly Tyr Thr
180 185 190
Lys Glu Gly Cys Arg Gly Ile Asp Lys Arg His Trp Asn Ser Gln Cys
195 200 205
Arg Thr Thr Gln Ser Tyr Val Arg Ala Leu Thr Met Asp Ser Lys Lys
210 215 220
Arg Ile Gly Trp Arg Phe Ile Arg Ile Asp Thr Ser Cys Val Cys Thr
225 230 235 240
Leu Thr Ile Lys Arg Gly Arg
245
<210> 12
<211> 533
<212> PRT
<213> Homo sapiens
<400> 12
Met Ser Ile Gln Val Glu His Pro Ala Gly Gly Tyr Lys Lys Leu Phe
1 5 10 15
Glu Thr Val Glu Glu Leu Ser Ser Pro Leu Thr Ala His Val Thr Gly
20 25 30
Arg Ile Pro Leu Trp Leu Thr Gly Ser Leu Leu Arg Cys Gly Pro Gly
35 40 45
Leu Phe Glu Val Gly Ser Glu Pro Phe Tyr His Leu Phe Asp Gly Gln
50 55 60
Ala Leu Leu His Lys Phe Asp Phe Lys Glu Gly His Val Thr Tyr His
65 70 75 80
Arg Arg Phe Ile Arg Thr Asp Ala Tyr Val Arg Ala Met Thr Glu Lys
85 90 95
Arg Ile Val Ile Thr Glu Phe Gly Thr Cys Ala Phe Pro Asp Pro Cys
100 105 110
Lys Asn Ile Phe Ser Arg Phe Phe Ser Tyr Phe Arg Gly Val Glu Val
115 120 125
Thr Asp Asn Ala Leu Val Asn Val Tyr Pro Val Gly Glu Asp Tyr Tyr
130 135 140
Ala Cys Thr Glu Thr Asn Phe Ile Thr Lys Ile Asn Pro Glu Thr Leu
145 150 155 160
Glu Thr Ile Lys Gln Val Asp Leu Cys Asn Tyr Val Ser Val Asn Gly
165 170 175
Ala Thr Ala His Pro His Ile Glu Asn Asp Gly Thr Val Tyr Asn Ile
180 185 190
Gly Asn Cys Phe Gly Lys Asn Phe Ser Ile Ala Tyr Asn Ile Val Lys
195 200 205
Ile Pro Pro Leu Gln Ala Asp Lys Glu Asp Pro Ile Ser Lys Ser Glu
210 215 220
Ile Val Val Gln Phe Pro Cys Ser Asp Arg Phe Lys Pro Ser Tyr Val
225 230 235 240
His Ser Phe Gly Leu Thr Pro Asn Tyr Ile Val Phe Val Glu Thr Pro
245 250 255
Val Lys Ile Asn Leu Phe Lys Phe Leu Ser Ser Trp Ser Leu Trp Gly
260 265 270
Ala Asn Tyr Met Asp Cys Phe Glu Ser Asn Glu Thr Met Gly Val Trp
275 280 285
Leu His Ile Ala Asp Lys Lys Arg Lys Lys Tyr Leu Asn Asn Lys Tyr
290 295 300
Arg Thr Ser Pro Phe Asn Leu Phe His His Ile Asn Thr Tyr Glu Asp
305 310 315 320
Asn Gly Phe Leu Ile Val Asp Leu Cys Cys Trp Lys Gly Phe Glu Phe
325 330 335
Val Tyr Asn Tyr Leu Tyr Leu Ala Asn Leu Arg Glu Asn Trp Glu Glu
340 345 350
Val Lys Lys Asn Ala Arg Lys Ala Pro Gln Pro Glu Val Arg Arg Tyr
355 360 365
Val Leu Pro Leu Asn Ile Asp Lys Ala Asp Thr Gly Lys Asn Leu Val
370 375 380
Thr Leu Pro Asn Thr Thr Ala Thr Ala Ile Leu Cys Ser Asp Glu Thr
385 390 395 400
Ile Trp Leu Glu Pro Glu Val Leu Phe Ser Gly Pro Arg Gln Ala Phe
405 410 415
Glu Phe Pro Gln Ile Asn Tyr Gln Lys Tyr Cys Gly Lys Pro Tyr Thr
420 425 430
Tyr Ala Tyr Gly Leu Gly Leu Asn His Phe Val Pro Asp Arg Leu Cys
435 440 445
Lys Leu Asn Val Lys Thr Lys Glu Thr Trp Val Trp Gln Glu Pro Asp
450 455 460
Ser Tyr Pro Ser Glu Pro Ile Phe Val Ser His Pro Asp Ala Leu Glu
465 470 475 480
Glu Asp Asp Gly Val Val Leu Ser Val Val Val Ser Pro Gly Ala Gly
485 490 495
Gln Lys Pro Ala Tyr Leu Leu Ile Leu Asn Ala Lys Asp Leu Ser Glu
500 505 510
Val Ala Arg Ala Glu Val Glu Ile Asn Ile Pro Val Thr Phe His Gly
515 520 525
Leu Phe Lys Lys Ser
530
<210> 13
<211> 7
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic peptide
<400> 13
Leu Gly Glu Thr Thr Arg Pro
1 5
<210> 14
<211> 7
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic peptide
<400> 14
Asn Glu Thr Ile Thr Arg Pro
1 5
<210> 15
<211> 7
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic peptide
<400> 15
Lys Ala Gly Gln Ala Asn Asn
1 5
<210> 16
<211> 7
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic peptide
<400> 16
Lys Asp Pro Lys Thr Thr Asn
1 5
<210> 17
<211> 27
<212> RNA
<213> Artificial sequence
<220>
<223> Synthetic oligonucleotide
<400> 17
cgcaaucagu gaaugcuuau acauccg 27
<210> 18
<211> 5541
<212> DNA
<213> Artificial sequence
<220>
<223> Synthetic construct
<400> 18
agcttggatc caatcaacct ctggattaca aaatttgtga aagattgact ggtattctta 60
actatgttgc tccttttacg ctatgtggat acgctgcttt aatgcctttg tatcatgcta 120
ttgcttcccg tatggctttc attttctcct ccttgtataa atcctggttg ctgtctcttt 180
atgaggagtt gtggcccgtt gtcaggcaac gtggcgtggt gtgcactgtg tttgctgacg 240
caacccccac tggttggggc attgccacca cctgtcagct cctttccggg actttcgctt 300
tccccctccc tattgccacg gcggaactca tcgccgcctg ccttgcccgc tgctggacag 360
gggctcggct gttgggcact gacaattccg tggtgttgtc ggggaagctg acgtcctttc 420
catggctgct cgcctgtgtt gccacctgga ttctgcgcgg gacgtccttc tgctacgtcc 480
cttcggccct caatccagcg gaccttcctt cccgcggcct gctgccggct ctgcggcctc 540
ttccgcgtct tcgagatctg cctcgactgt gccttctagt tgccagccat ctgttgtttg 600
cccctccccc gtgccttcct tgaccctgga aggtgccact cccactgtcc tttcctaata 660
aaatgaggaa attgcatcgc attgtctgag taggtgtcat tctattctgg ggggtggggt 720
ggggcaggac agcaaggggg aggattggga agacaatagc aggcatgctg gggactcgag 780
ttaagggcga attcccgatt aggatcttcc tagagcatgg ctacgtagat aagtagcatg 840
gcgggttaat cattaactac aaggaacccc tagtgatgga gttggccact ccctctctgc 900
gcgctcgctc gctcactgag gccgggcgac caaaggtcgc ccgacgcccg ggctttgccc 960
gggcggcctc agtgagcgag cgagcgcgca gccttaatta acctaattca ctggccgtcg 1020
ttttacaacg tcgtgactgg gaaaaccctg gcgttaccca acttaatcgc cttgcagcac 1080
atcccccttt cgccagctgg cgtaatagcg aagaggcccg caccgatcgc ccttcccaac 1140
agttgcgcag cctgaatggc gaatgggacg cgccctgtag cggcgcatta agcgcggcgg 1200
gtgtggtggt tacgcgcagc gtgaccgcta cacttgccag cgccctagcg cccgctcctt 1260
tcgctttctt cccttccttt ctcgccacgt tcgccggctt tccccgtcaa gctctaaatc 1320
gggggctccc tttagggttc cgatttagtg ctttacggca cctcgacccc aaaaaacttg 1380
attagggtga tggttcacgt agtgggccat cgccccgata gacggttttt cgccctttga 1440
cgctggagtt cacgttcctc aatagtggac tcttgttcca aactggaaca acactcaacc 1500
ctatctcggt ctattctttt gatttataag ggatttttcc gatttcggcc tattggttaa 1560
aaaatgagct gatttaacaa aaatttaacg cgaattttaa caaaatatta acgtttataa 1620
tttcaggtgg catctttcgg ggaaatgtgc gcggaacccc tatttgttta tttttctaaa 1680
tacattcaaa tatgtatccg ctcatgagac aataaccctg ataaatgctt caataatatt 1740
gaaaaaggaa gagtatgagt attcaacatt tccgtgtcgc ccttattccc ttttttgcgg 1800
cattttgcct tcctgttttt gctcacccag aaacgctggt gaaagtaaaa gatgctgaag 1860
atcagttggg tgcacgagtg ggttacatcg aactggatct caatagtggt aagatccttg 1920
agagttttcg ccccgaagaa cgttttccaa tgatgagcac ttttaaagtt ctgctatgtg 1980
gcgcggtatt atcccgtatt gacgccgggc aagagcaact cggtcgccgc atacactatt 2040
ctcagaatga cttggttgag tactcaccag tcacagaaaa gcatcttacg gatggcatga 2100
cagtaagaga attatgcagt gctgccataa ccatgagtga taacactgcg gccaacttac 2160
ttctgacaac gatcggagga ccgaaggagc taaccgcttt tttgcacaac atgggggatc 2220
atgtaactcg ccttgatcgt tgggaaccgg agctgaatga agccatacca aacgacgagc 2280
gtgacaccac gatgcctgta gtaatggtaa caacgttgcg caaactatta actggcgaac 2340
tacttactct agcttcccgg caacaattaa tagactggat ggaggcggat aaagttgcag 2400
gaccacttct gcgctcggcc cttccggctg gctggtttat tgctgataaa tctggagccg 2460
gtgagcgtgg gtctcgcggt atcattgcag cactggggcc agatggtaag ccctcccgta 2520
tcgtagttat ctacacgacg gggagtcagg caactatgga tgaacgaaat agacagatcg 2580
ctgagatagg tgcctcactg attaagcatt ggtaactgtc agaccaagtt tactcatata 2640
tactttagat tgatttaaaa cttcattttt aatttaaaag gatctaggtg aagatccttt 2700
ttgataatct catgaccaaa atcccttaac gtgagttttc gttccactga gcgtcagacc 2760
ccgtagaaaa gatcaaagga tcttcttgag atcctttttt tctgcgcgta atctgctgct 2820
tgcaaacaaa aaaaccaccg ctaccagcgg tggtttgttt gccggatcaa gagctaccaa 2880
ctctttttcc gaaggtaact ggcttcagca gagcgcagat accaaatact gtccttctag 2940
tgtagccgta gttaggccac cacttcaaga actctgtagc accgcctaca tacctcgctc 3000
tgctaatcct gttaccagtg gctgctgcca gtggcgataa gtcgtgtctt accgggttgg 3060
actcaagacg atagttaccg gataaggcgc agcggtcggg ctgaacgggg ggttcgtgca 3120
cacagcccag cttggagcga acgacctaca ccgaactgag atacctacag cgtgagctat 3180
gagaaagcgc cacgcttccc gaagggagaa aggcggacag gtatccggta agcggcaggg 3240
tcggaacagg agagcgcacg agggagcttc cagggggaaa cgcctggtat ctttatagtc 3300
ctgtcgggtt tcgccacctc tgacttgagc gtcgattttt gtgatgctcg tcaggggggc 3360
ggagcctatg gaaaaacgcc agcaacgcgg cctttttacg gttcctggcc ttttgctgcg 3420
gttttgctca catgttcttt cctgcgttat cccctgattc tgtggataac cgtattaccg 3480
cctttgagtg agctgatacc gctcgccgca gccgaacgac cgagcgcagc gagtcagtga 3540
gcgaggaagc ggaagagcgc ccaatacgca aaccgcctct ccccgcgcgt tggccgattc 3600
attaatgcag ctggcacgac aggtttcccg actggaaagc gggcagtgag cgcaacgcaa 3660
ttaatgtgag ttagctcact cattaggcac cccaggcttt acactttatg cttccggctc 3720
gtatgttgtg tggaattgtg agcggataac aatttcacac aggaaacagc tatgaccatg 3780
attacgccag atttaattaa ggctgcgcgc tcgctcgctc actgaggccg cccgggcaaa 3840
gcccgggcgt cgggcgacct ttggtcgccc ggcctcagtg agcgagcgag cgcgcagaga 3900
gggagtggcc aactccatca ctaggggttc cttgtagtta atgattaacc cgccatgcta 3960
cttatctacg tagccatgct ctaggaagat cggaattcgc ccttaagcta gcagatcttc 4020
cccacctagc cacctggcaa actgctcctt ctctcaaagg cccaaacatg gcctcccaga 4080
ctgcaacccc caggcagtca ggccctgtct ccacaacctc acagccaccc tggacggaat 4140
ctgcttcttc ccacatttga gtcctcctca gcccctgagc tcctctgggc agggctgttt 4200
ctttccatct ttgtattccc aggggcctgc aaataaatgt ttaatgaacg aacaagagag 4260
tgaattccaa ttccatgcaa caaggattgg gctcctgggc cctaggctat gtgtctggca 4320
ccagaaacgg aagctgcagg ttgcagcccc tgccctcatg gagctcctcc tgtcagagga 4380
gtgtggggac tggatgactc cagaggtaac ttgtggggga acgaacaggt aaggggctgt 4440
gtgacgagat gagagactgg gagaataaac cagaaagtct ctagctgtcc agaggacata 4500
gcacagaggc ccatggtccc tatttcaaac ccaggccacc agactgagct gggaccttgg 4560
gacagacaag tcatgcagaa gttaggggac cttctcctcc cttttcctgg atggatcctg 4620
agtaccttct cctccctgac ctcaggcttc ctcctagtgt caccttggcc cctcttagaa 4680
gccaattagg ccctcagttt ctgcagcggg gattaatatg attatgaaca cccccaatct 4740
cccagatgct gattcagcca ggagcttagg agggggaggt cactttataa gggtctgggg 4800
gggtcagaac ccagagtcat cccctgaatt ctgcagatat ccatcacact ggcggccgcg 4860
ccaccatgtc acgcaagata gaaggctttt tgttattact tctctttggc tatgaagcca 4920
cattgggatt atcgtctacc gaggatgaag gcgaggaccc ctggtaccaa aaagcatgca 4980
agtgcgattg ccaaggagga cccaatgctc tgtggtctgc aggtgccacc tccttggact 5040
gtataccaga atgcccatat cacaagcctc tgggtttcga gtcaggggag gtcacaccgg 5100
accagatcac ctgctctaac ccggagcagt atgtgggctg gtattcttcg tggactgcaa 5160
acaaggcccg gctcaacagt caaggctttg ggtgtgcctg gctctccaag ttccaggaca 5220
gtagccagtg gttacagata gatctgaagg agatcaaagt gatttcaggg atcctcaccc 5280
aggggcgctg tgacatcgat gagtggatga ccaagtacag cgtgcagtac aggaccgatg 5340
agcgcctgaa ctggatttac tacaaggacc agactggaaa caaccgggtc ttctatggca 5400
actcggaccg cacctccacg gttcagaacc tgctgcggcc ccccatcatc tcccgcttca 5460
tccgcctcat cccgctgggc tggcacgtcc gcattgccat ccggatggag ctgctggagt 5520
gcgtcagcaa gtgtgcctga a 5541
<210> 19
<211> 346
<212> PRT
<213> Homo sapiens
<400> 19
Met Ala Leu Leu Lys Val Lys Phe Asp Gln Lys Lys Arg Val Lys Leu
1 5 10 15
Ala Gln Gly Leu Trp Leu Met Asn Trp Phe Ser Val Leu Ala Gly Ile
20 25 30
Ile Ile Phe Ser Leu Gly Leu Phe Leu Lys Ile Glu Leu Arg Lys Arg
35 40 45
Ser Asp Val Met Asn Asn Ser Glu Ser His Phe Val Pro Asn Ser Leu
50 55 60
Ile Gly Met Gly Val Leu Ser Cys Val Phe Asn Ser Leu Ala Gly Lys
65 70 75 80
Ile Cys Tyr Asp Ala Leu Asp Pro Ala Lys Tyr Ala Arg Trp Lys Pro
85 90 95
Trp Leu Lys Pro Tyr Leu Ala Ile Cys Val Leu Phe Asn Ile Ile Leu
100 105 110
Phe Leu Val Ala Leu Cys Cys Phe Leu Leu Arg Gly Ser Leu Glu Asn
115 120 125
Thr Leu Gly Gln Gly Leu Lys Asn Gly Met Lys Tyr Tyr Arg Asp Thr
130 135 140
Asp Thr Pro Gly Arg Cys Phe Met Lys Lys Thr Ile Asp Met Leu Gln
145 150 155 160
Ile Glu Phe Lys Cys Cys Gly Asn Asn Gly Phe Arg Asp Trp Phe Glu
165 170 175
Ile Gln Trp Ile Ser Asn Arg Tyr Leu Asp Phe Ser Ser Lys Glu Val
180 185 190
Lys Asp Arg Ile Lys Ser Asn Val Asp Gly Arg Tyr Leu Val Asp Gly
195 200 205
Val Pro Phe Ser Cys Cys Asn Pro Ser Ser Pro Arg Pro Cys Ile Gln
210 215 220
Tyr Gln Ile Thr Asn Asn Ser Ala His Tyr Ser Tyr Asp His Gln Thr
225 230 235 240
Glu Glu Leu Asn Leu Trp Val Arg Gly Cys Arg Ala Ala Leu Leu Ser
245 250 255
Tyr Tyr Ser Ser Leu Met Asn Ser Met Gly Val Val Thr Leu Leu Ile
260 265 270
Trp Leu Phe Glu Val Thr Ile Thr Ile Gly Leu Arg Tyr Leu Gln Thr
275 280 285
Ser Leu Asp Gly Val Ser Asn Pro Glu Glu Ser Glu Ser Glu Ser Gln
290 295 300
Gly Trp Leu Leu Glu Arg Ser Val Pro Glu Thr Trp Lys Ala Phe Leu
305 310 315 320
Glu Ser Val Lys Lys Leu Gly Lys Gly Asn Gln Val Glu Ala Glu Gly
325 330 335
Ala Asp Ala Gly Gln Ala Pro Glu Ala Gly
340 345
<210> 20
<211> 470
<212> PRT
<213> Homo sapiens
<400> 20
Met Ser His His Pro Ser Gly Leu Arg Ala Gly Phe Ser Ser Thr Ser
1 5 10 15
Tyr Arg Arg Thr Phe Gly Pro Pro Pro Ser Leu Ser Pro Gly Ala Phe
20 25 30
Ser Tyr Ser Ser Ser Ser Arg Phe Ser Ser Ser Arg Leu Leu Gly Ser
35 40 45
Ala Ser Pro Ser Ser Ser Val Arg Leu Gly Ser Phe Arg Ser Pro Arg
50 55 60
Ala Gly Ala Gly Ala Leu Leu Arg Leu Pro Ser Glu Arg Leu Asp Phe
65 70 75 80
Ser Met Ala Glu Ala Leu Asn Gln Glu Phe Leu Ala Thr Arg Ser Asn
85 90 95
Glu Lys Gln Glu Leu Gln Glu Leu Asn Asp Arg Phe Ala Asn Phe Ile
100 105 110
Glu Lys Val Arg Phe Leu Glu Gln Gln Asn Ala Ala Leu Arg Gly Glu
115 120 125
Leu Ser Gln Ala Arg Gly Gln Glu Pro Ala Arg Ala Asp Gln Leu Cys
130 135 140
Gln Gln Glu Leu Arg Glu Leu Arg Arg Glu Leu Glu Leu Leu Gly Arg
145 150 155 160
Glu Arg Asp Arg Val Gln Val Glu Arg Asp Gly Leu Ala Glu Asp Leu
165 170 175
Ala Ala Leu Lys Gln Arg Leu Glu Glu Glu Thr Arg Lys Arg Glu Asp
180 185 190
Ala Glu His Asn Leu Val Leu Phe Arg Lys Asp Val Asp Asp Ala Thr
195 200 205
Leu Ser Arg Leu Glu Leu Glu Arg Lys Ile Glu Ser Leu Met Asp Glu
210 215 220
Ile Glu Phe Leu Lys Lys Leu His Glu Glu Glu Leu Arg Asp Leu Gln
225 230 235 240
Val Ser Val Glu Ser Gln Gln Val Gln Gln Val Glu Val Glu Ala Thr
245 250 255
Val Lys Pro Glu Leu Thr Ala Ala Leu Arg Asp Ile Arg Ala Gln Tyr
260 265 270
Glu Ser Ile Ala Ala Lys Asn Leu Gln Glu Ala Glu Glu Trp Tyr Lys
275 280 285
Ser Lys Tyr Ala Asp Leu Ser Asp Ala Ala Asn Arg Asn His Glu Ala
290 295 300
Leu Arg Gln Ala Lys Gln Glu Met Asn Glu Ser Arg Arg Gln Ile Gln
305 310 315 320
Ser Leu Thr Cys Glu Val Asp Gly Leu Arg Gly Thr Asn Glu Ala Leu
325 330 335
Leu Arg Gln Leu Arg Glu Leu Glu Glu Gln Phe Ala Leu Glu Ala Gly
340 345 350
Gly Tyr Gln Ala Gly Ala Ala Arg Leu Glu Glu Glu Leu Arg Gln Leu
355 360 365
Lys Glu Glu Met Ala Arg His Leu Arg Glu Tyr Gln Glu Leu Leu Asn
370 375 380
Val Lys Met Ala Leu Asp Ile Glu Ile Ala Thr Tyr Arg Lys Leu Leu
385 390 395 400
Glu Gly Glu Glu Ser Arg Ile Ser Val Pro Val His Ser Phe Ala Ser
405 410 415
Leu Asn Ile Lys Thr Thr Val Pro Glu Val Glu Pro Pro Gln Asp Ser
420 425 430
His Ser Arg Lys Thr Val Leu Ile Lys Thr Ile Glu Thr Arg Asn Gly
435 440 445
Glu Val Val Thr Glu Ser Gln Lys Glu Gln Arg Ser Glu Leu Asp Lys
450 455 460
Ser Ser Ala His Ser Tyr
465 470
<210> 21
<211> 1286
<212> PRT
<213> Homo sapiens
<400> 21
Met Ser His Leu Val Asp Pro Thr Ser Gly Asp Leu Pro Val Arg Asp
1 5 10 15
Ile Asp Ala Ile Pro Leu Val Leu Pro Ala Ser Lys Gly Lys Asn Met
20 25 30
Lys Thr Gln Pro Pro Leu Ser Arg Met Asn Arg Glu Glu Leu Glu Asp
35 40 45
Ser Phe Phe Arg Leu Arg Glu Asp His Met Leu Val Lys Glu Leu Ser
50 55 60
Trp Lys Gln Gln Asp Glu Ile Lys Arg Leu Arg Thr Thr Leu Leu Arg
65 70 75 80
Leu Thr Ala Ala Gly Arg Asp Leu Arg Val Ala Glu Glu Ala Ala Pro
85 90 95
Leu Ser Glu Thr Ala Arg Arg Gly Gln Lys Ala Gly Trp Arg Gln Arg
100 105 110
Leu Ser Met His Gln Arg Pro Gln Met His Arg Leu Gln Gly His Phe
115 120 125
His Cys Val Gly Pro Ala Ser Pro Arg Arg Ala Gln Pro Arg Val Gln
130 135 140
Val Gly His Arg Gln Leu His Thr Ala Gly Ala Pro Val Pro Glu Lys
145 150 155 160
Pro Lys Arg Gly Pro Arg Asp Arg Leu Ser Tyr Thr Ala Pro Pro Ser
165 170 175
Phe Lys Glu His Ala Thr Asn Glu Asn Arg Gly Glu Val Ala Ser Lys
180 185 190
Pro Ser Glu Leu Val Ser Gly Ser Asn Ser Ile Ile Ser Phe Ser Ser
195 200 205
Val Ile Ser Met Ala Lys Pro Ile Gly Leu Cys Met Pro Asn Ser Ala
210 215 220
His Ile Met Ala Ser Asn Thr Met Gln Val Glu Glu Pro Pro Lys Ser
225 230 235 240
Pro Glu Lys Met Trp Pro Lys Asp Glu Asn Phe Glu Gln Arg Ser Ser
245 250 255
Leu Glu Cys Ala Gln Lys Ala Ala Glu Leu Arg Ala Ser Ile Lys Glu
260 265 270
Lys Val Glu Leu Ile Arg Leu Lys Lys Leu Leu His Glu Arg Asn Ala
275 280 285
Ser Leu Val Met Thr Lys Ala Gln Leu Thr Glu Val Gln Glu Ala Tyr
290 295 300
Glu Thr Leu Leu Gln Lys Asn Gln Gly Ile Leu Ser Ala Ala His Glu
305 310 315 320
Ala Leu Leu Lys Gln Val Asn Glu Leu Arg Ala Glu Leu Lys Glu Glu
325 330 335
Ser Lys Lys Ala Val Ser Leu Lys Ser Gln Leu Glu Asp Val Ser Ile
340 345 350
Leu Gln Met Thr Leu Lys Glu Phe Gln Glu Arg Val Glu Asp Leu Glu
355 360 365
Lys Glu Arg Lys Leu Leu Asn Asp Asn Tyr Asp Lys Leu Leu Glu Ser
370 375 380
Met Leu Asp Ser Ser Asp Ser Ser Ser Gln Pro His Trp Ser Asn Glu
385 390 395 400
Leu Ile Ala Glu Gln Leu Gln Gln Gln Val Ser Gln Leu Gln Asp Gln
405 410 415
Leu Asp Ala Glu Leu Glu Asp Lys Arg Lys Val Leu Leu Glu Leu Ser
420 425 430
Arg Glu Lys Ala Gln Asn Glu Asp Leu Lys Leu Glu Val Thr Asn Ile
435 440 445
Leu Gln Lys His Lys Gln Glu Val Glu Leu Leu Gln Asn Ala Ala Thr
450 455 460
Ile Ser Gln Pro Pro Asp Arg Gln Ser Glu Pro Ala Thr His Pro Ala
465 470 475 480
Val Leu Gln Glu Asn Thr Gln Ile Glu Pro Ser Glu Pro Lys Asn Gln
485 490 495
Glu Glu Lys Lys Leu Ser Gln Val Leu Asn Glu Leu Gln Val Ser His
500 505 510
Ala Glu Thr Thr Leu Glu Leu Glu Lys Thr Arg Asp Met Leu Ile Leu
515 520 525
Gln Arg Lys Ile Asn Val Cys Tyr Gln Glu Glu Leu Glu Ala Met Met
530 535 540
Thr Lys Ala Asp Asn Asp Asn Arg Asp His Lys Glu Lys Leu Glu Arg
545 550 555 560
Leu Thr Arg Leu Leu Asp Leu Lys Asn Asn Arg Ile Lys Gln Leu Glu
565 570 575
Gly Ile Leu Arg Ser His Asp Leu Pro Thr Ser Glu Gln Leu Lys Asp
580 585 590
Val Ala Tyr Gly Thr Arg Pro Leu Ser Leu Cys Leu Glu Thr Leu Pro
595 600 605
Ala His Gly Asp Glu Asp Lys Val Asp Ile Ser Leu Leu His Gln Gly
610 615 620
Glu Asn Leu Phe Glu Leu His Ile His Gln Ala Phe Leu Thr Ser Ala
625 630 635 640
Ala Leu Ala Gln Ala Gly Asp Thr Gln Pro Thr Thr Phe Cys Thr Tyr
645 650 655
Ser Phe Tyr Asp Phe Glu Thr His Cys Thr Pro Leu Ser Val Gly Pro
660 665 670
Gln Pro Leu Tyr Asp Phe Thr Ser Gln Tyr Val Met Glu Thr Asp Ser
675 680 685
Leu Phe Leu His Tyr Leu Gln Glu Ala Ser Ala Arg Leu Asp Ile His
690 695 700
Gln Ala Met Ala Ser Glu His Ser Thr Leu Ala Ala Gly Trp Ile Cys
705 710 715 720
Phe Asp Arg Val Leu Glu Thr Val Glu Lys Val His Gly Leu Ala Thr
725 730 735
Leu Ile Gly Ala Gly Gly Glu Glu Phe Gly Val Leu Glu Tyr Trp Met
740 745 750
Arg Leu Arg Phe Pro Ile Lys Pro Ser Leu Gln Ala Cys Asn Lys Arg
755 760 765
Lys Lys Ala Gln Val Tyr Leu Ser Thr Asp Val Leu Gly Gly Arg Lys
770 775 780
Ala Gln Glu Glu Glu Phe Arg Ser Glu Ser Trp Glu Pro Gln Asn Glu
785 790 795 800
Leu Trp Ile Glu Ile Thr Lys Cys Cys Gly Leu Arg Ser Arg Trp Leu
805 810 815
Gly Thr Gln Pro Ser Pro Tyr Ala Val Tyr Arg Phe Phe Thr Phe Ser
820 825 830
Asp His Asp Thr Ala Ile Ile Pro Ala Ser Asn Asn Pro Tyr Phe Arg
835 840 845
Asp Gln Ala Arg Phe Pro Val Leu Val Thr Ser Asp Leu Asp His Tyr
850 855 860
Leu Arg Arg Glu Ala Leu Ser Ile His Val Phe Asp Asp Glu Asp Leu
865 870 875 880
Glu Pro Gly Ser Tyr Leu Gly Arg Ala Arg Val Pro Leu Leu Pro Leu
885 890 895
Ala Lys Asn Glu Ser Ile Lys Gly Asp Phe Asn Leu Thr Asp Pro Ala
900 905 910
Glu Lys Pro Asn Gly Ser Ile Gln Val Gln Leu Asp Trp Lys Phe Pro
915 920 925
Tyr Ile Pro Pro Glu Ser Phe Leu Lys Pro Glu Ala Gln Thr Lys Gly
930 935 940
Lys Asp Thr Lys Asp Ser Ser Lys Ile Ser Ser Glu Glu Glu Lys Ala
945 950 955 960
Ser Phe Pro Ser Gln Asp Gln Met Ala Ser Pro Glu Val Pro Ile Glu
965 970 975
Ala Gly Gln Tyr Arg Ser Lys Arg Lys Pro Pro His Gly Gly Glu Arg
980 985 990
Lys Glu Lys Glu His Gln Val Val Ser Tyr Ser Arg Arg Lys His Gly
995 1000 1005
Lys Arg Ile Gly Val Gln Gly Lys Asn Arg Met Glu Tyr Leu Ser
1010 1015 1020
Leu Asn Ile Leu Asn Gly Asn Thr Pro Glu Gln Val Asn Tyr Thr
1025 1030 1035
Glu Trp Lys Phe Ser Glu Thr Asn Ser Phe Ile Gly Asp Gly Phe
1040 1045 1050
Lys Asn Gln His Glu Glu Glu Glu Met Thr Leu Ser His Ser Ala
1055 1060 1065
Leu Lys Gln Lys Glu Pro Leu His Pro Val Asn Asp Lys Glu Ser
1070 1075 1080
Ser Glu Gln Gly Ser Glu Val Ser Glu Ala Gln Thr Thr Asp Ser
1085 1090 1095
Asp Asp Val Ile Val Pro Pro Met Ser Gln Lys Tyr Pro Lys Ala
1100 1105 1110
Asp Ser Glu Lys Met Cys Ile Glu Ile Val Ser Leu Ala Phe Tyr
1115 1120 1125
Pro Glu Ala Glu Val Met Ser Asp Glu Asn Ile Lys Gln Val Tyr
1130 1135 1140
Val Glu Tyr Lys Phe Tyr Asp Leu Pro Leu Ser Glu Thr Glu Thr
1145 1150 1155
Pro Val Ser Leu Arg Lys Pro Arg Ala Gly Glu Glu Ile His Phe
1160 1165 1170
His Phe Ser Lys Val Ile Asp Leu Asp Pro Gln Glu Gln Gln Gly
1175 1180 1185
Arg Arg Arg Phe Leu Phe Asp Met Leu Asn Gly Gln Asp Pro Asp
1190 1195 1200
Gln Gly His Leu Lys Phe Thr Val Val Ser Asp Pro Leu Asp Glu
1205 1210 1215
Glu Lys Lys Glu Cys Glu Glu Val Gly Tyr Ala Tyr Leu Gln Leu
1220 1225 1230
Trp Gln Ile Leu Glu Ser Gly Arg Asp Ile Leu Glu Gln Glu Leu
1235 1240 1245
Asp Ile Val Ser Pro Glu Asp Leu Ala Thr Pro Ile Gly Arg Leu
1250 1255 1260
Lys Val Ser Leu Gln Ala Ala Ala Val Leu His Ala Ile Tyr Lys
1265 1270 1275
Glu Met Thr Glu Asp Leu Phe Ser
1280 1285
<210> 22
<211> 240
<212> PRT
<213> Adeno-associated virus-1
<400> 22
Thr Phe Ser Tyr Thr Phe Glu Glu Val Pro Phe His Ser Ser Tyr Ala
1 5 10 15
His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr
20 25 30
Leu Tyr Tyr Leu Asn Arg Thr Gln Asn Gln Ser Gly Ser Ala Gln Asn
35 40 45
Lys Asp Leu Leu Phe Ser Arg Gly Ser Pro Ala Gly Met Ser Val Gln
50 55 60
Pro Lys Asn Trp Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser
65 70 75 80
Lys Thr Lys Thr Asp Asn Asn Asn Ser Asn Phe Thr Trp Thr Gly Ala
85 90 95
Ser Lys Tyr Asn Leu Asn Gly Arg Glu Ser Ile Ile Asn Pro Gly Thr
100 105 110
Ala Met Ala Ser His Lys Asp Asp Glu Asp Lys Phe Phe Pro Met Ser
115 120 125
Gly Val Met Ile Phe Gly Lys Glu Ser Ala Gly Ala Ser Asn Thr Ala
130 135 140
Leu Asp Asn Val Met Ile Thr Asp Glu Glu Glu Ile Lys Ala Thr Asn
145 150 155 160
Pro Val Ala Thr Glu Arg Phe Gly Thr Val Ala Val Asn Phe Gln Ser
165 170 175
Ser Ser Thr Asp Pro Ala Thr Gly Asp Val His Ala Met Gly Ala Leu
180 185 190
Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile
195 200 205
Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro Ser Pro Leu
210 215 220
Met Gly Gly Phe Gly Leu Lys Asn Pro Pro Pro Gln Ile Leu Ile Lys
225 230 235 240
<210> 23
<211> 240
<212> PRT
<213> Adeno-associated virus-6
<400> 23
Thr Phe Ser Tyr Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala
1 5 10 15
His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr
20 25 30
Leu Tyr Tyr Leu Asn Arg Thr Gln Asn Gln Ser Gly Ser Ala Gln Asn
35 40 45
Lys Asp Leu Leu Phe Ser Arg Gly Ser Pro Ala Gly Met Ser Val Gln
50 55 60
Pro Lys Asn Trp Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser
65 70 75 80
Lys Thr Lys Thr Asp Asn Asn Asn Ser Asn Phe Thr Trp Thr Gly Ala
85 90 95
Ser Lys Tyr Asn Leu Asn Gly Arg Glu Ser Ile Ile Asn Pro Gly Thr
100 105 110
Ala Met Ala Ser His Lys Asp Asp Lys Asp Lys Phe Phe Pro Met Ser
115 120 125
Gly Val Met Ile Phe Gly Lys Glu Ser Ala Gly Ala Ser Asn Thr Ala
130 135 140
Leu Asp Asn Val Met Ile Thr Asp Glu Glu Glu Ile Lys Ala Thr Asn
145 150 155 160
Pro Val Ala Thr Glu Arg Phe Gly Thr Val Ala Val Asn Leu Gln Ser
165 170 175
Ser Ser Thr Asp Pro Ala Thr Gly Asp Val His Val Met Gly Ala Leu
180 185 190
Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile
195 200 205
Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro Ser Pro Leu
210 215 220
Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys
225 230 235 240
<210> 24
<211> 240
<212> PRT
<213> Adeno-associated virus-3
<400> 24
Phe Ser Tyr Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His
1 5 10 15
Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu
20 25 30
Tyr Tyr Leu Asn Arg Thr Gln Gly Thr Thr Ser Gly Thr Thr Asn Gln
35 40 45
Ser Arg Leu Leu Phe Ser Gln Ala Gly Pro Gln Ser Met Ser Leu Gln
50 55 60
Ala Arg Asn Trp Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Leu Ser
65 70 75 80
Lys Thr Ala Asn Asp Asn Asn Asn Ser Asn Phe Pro Trp Thr Ala Ala
85 90 95
Ser Lys Tyr His Leu Asn Gly Arg Asp Ser Leu Val Asn Pro Gly Pro
100 105 110
Ala Met Ala Ser His Lys Asp Asp Glu Glu Lys Phe Phe Pro Met His
115 120 125
Gly Asn Leu Ile Phe Gly Lys Glu Gly Thr Thr Ala Ser Asn Ala Glu
130 135 140
Leu Asp Asn Val Met Ile Thr Asp Glu Glu Glu Ile Arg Thr Thr Asn
145 150 155 160
Pro Val Ala Thr Glu Gln Tyr Gly Thr Val Ala Asn Asn Leu Gln Ser
165 170 175
Ser Asn Thr Ala Pro Thr Thr Gly Thr Val Asn His Gln Gly Ala Leu
180 185 190
Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile
195 200 205
Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro Ser Pro Leu
210 215 220
Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile Met Ile Lys
225 230 235 240
<210> 25
<211> 240
<212> PRT
<213> Adeno-associated virus-2
<400> 25
Phe Ser Tyr Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His
1 5 10 15
Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu
20 25 30
Tyr Tyr Leu Ser Arg Thr Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser
35 40 45
Arg Leu Gln Phe Ser Gln Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser
50 55 60
Arg Asn Trp Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys
65 70 75 80
Thr Ser Ala Asp Asn Asn Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr
85 90 95
Lys Tyr His Leu Asn Gly Arg Asp Ser Leu Val Asn Pro Gly Pro Ala
100 105 110
Met Ala Ser His Lys Asp Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly
115 120 125
Val Leu Ile Phe Gly Lys Gln Gly Ser Glu Lys Thr Asn Val Asp Ile
130 135 140
Glu Lys Val Met Ile Thr Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro
145 150 155 160
Val Ala Thr Glu Gln Tyr Gly Ser Val Ser Thr Asn Leu Gln Arg Gly
165 170 175
Asn Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln Gly Val Leu Pro
180 185 190
Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp
195 200 205
Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro Ser Pro Leu Met
210 215 220
Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn
225 230 235 240
<210> 26
<211> 243
<212> PRT
<213> Adeno-associated virus-8
<400> 26
Asn Phe Gln Phe Thr Tyr Thr Phe Glu Asp Val Pro Phe His Ser Ser
1 5 10 15
Tyr Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp
20 25 30
Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr Gln Thr Thr Gly Gly Thr Ala
35 40 45
Asn Thr Gln Thr Leu Gly Phe Ser Gln Gly Gly Pro Asn Thr Met Ala
50 55 60
Asn Gln Ala Lys Asn Trp Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg
65 70 75 80
Val Ser Thr Thr Thr Gly Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr
85 90 95
Ala Gly Thr Lys Tyr His Leu Asn Gly Arg Asn Ser Leu Ala Asn Pro
100 105 110
Gly Ile Ala Met Ala Thr His Lys Asp Asp Glu Glu Arg Phe Phe Pro
115 120 125
Ser Asn Gly Ile Leu Ile Phe Gly Lys Gln Asn Ala Ala Arg Asp Asn
130 135 140
Ala Asp Tyr Ser Asp Val Met Leu Thr Ser Glu Glu Glu Ile Lys Thr
145 150 155 160
Thr Asn Pro Val Ala Thr Glu Glu Tyr Gly Ile Val Ala Asp Asn Leu
165 170 175
Gln Gln Gln Asn Thr Ala Pro Gln Ile Gly Thr Val Asn Ser Gln Gly
180 185 190
Ala Leu Pro Gly Met Val Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly
195 200 205
Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser
210 215 220
Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile Leu
225 230 235 240
Ile Lys Asn
<210> 27
<211> 243
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic polypeptide
<400> 27
Asn Phe Gln Phe Thr Tyr Thr Phe Glu Asp Val Pro Phe His Ser Ser
1 5 10 15
Tyr Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp
20 25 30
Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr Gln Thr Thr Gly Gly Thr Ala
35 40 45
Asn Thr Gln Thr Leu Gly Phe Ser Gln Gly Gly Pro Asn Thr Met Ala
50 55 60
Asn Gln Ala Lys Asn Trp Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg
65 70 75 80
Val Ser Thr Thr Thr Gly Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr
85 90 95
Ala Gly Thr Lys Tyr His Leu Asn Gly Arg Asn Ser Leu Ala Asn Pro
100 105 110
Gly Ile Ala Met Ala Thr His Lys Asp Asp Glu Glu Arg Phe Phe Pro
115 120 125
Ser Asn Gly Ile Leu Ile Phe Gly Lys Gln Asn Ala Ala Arg Asp Asn
130 135 140
Ala Asp Tyr Ser Asp Val Met Leu Thr Ser Glu Glu Glu Ile Lys Thr
145 150 155 160
Thr Asn Pro Val Ala Thr Glu Glu Tyr Gly Ile Val Ala Asp Asn Leu
165 170 175
Gln Gly Gln Arg Gln Ala Ala Gln Ile Gly Thr Val Asn Ser Gln Gly
180 185 190
Ala Leu Pro Gly Met Val Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly
195 200 205
Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser
210 215 220
Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile Leu
225 230 235 240
Ile Lys Asn
<210> 28
<211> 241
<212> PRT
<213> Adeno-associated virus-rh8
<400> 28
Phe Gln Phe Ser Tyr Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr
1 5 10 15
Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln
20 25 30
Tyr Leu Tyr Tyr Leu Val Arg Thr Gln Thr Thr Gly Thr Gly Gly Thr
35 40 45
Gln Thr Leu Ala Phe Ser Gln Ala Gly Pro Ser Ser Met Ala Asn Gln
50 55 60
Ala Arg Asn Trp Val Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser
65 70 75 80
Thr Thr Thr Asn Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Gly Ala
85 90 95
Ala Lys Phe Lys Leu Asn Gly Arg Asp Ser Leu Met Asn Pro Gly Val
100 105 110
Ala Met Ala Ser His Lys Asp Asp Asp Asp Arg Phe Phe Pro Ser Ser
115 120 125
Gly Val Leu Ile Phe Gly Lys Gln Gly Ala Gly Asn Asp Gly Val Asp
130 135 140
Tyr Ser Gln Val Leu Ile Thr Asp Glu Glu Glu Ile Lys Ala Thr Asn
145 150 155 160
Pro Val Ala Thr Glu Glu Tyr Gly Ala Val Ala Ile Asn Asn Gln Ala
165 170 175
Ala Asn Thr Gln Ala Gln Thr Gly Leu Val His Asn Gln Gly Val Ile
180 185 190
Pro Gly Met Val Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile
195 200 205
Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu
210 215 220
Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys
225 230 235 240
Asn
<210> 29
<211> 243
<212> PRT
<213> Adeno-associated virus-10
<400> 29
Asn Phe Glu Phe Ser Tyr Thr Phe Glu Asp Val Pro Phe His Ser Ser
1 5 10 15
Tyr Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp
20 25 30
Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr Gln Ser Thr Gly Gly Thr Gln
35 40 45
Gly Thr Gln Gln Leu Leu Phe Ser Gln Ala Gly Pro Ala Asn Met Ser
50 55 60
Ala Gln Ala Lys Asn Trp Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg
65 70 75 80
Val Ser Thr Thr Leu Ser Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr
85 90 95
Gly Ala Thr Lys Tyr His Leu Asn Gly Arg Asp Ser Leu Val Asn Pro
100 105 110
Gly Val Ala Met Ala Thr His Lys Asp Asp Glu Glu Arg Phe Phe Pro
115 120 125
Ser Ser Gly Val Leu Met Phe Gly Lys Gln Gly Ala Gly Arg Asp Asn
130 135 140
Val Asp Tyr Ser Ser Val Met Leu Thr Ser Glu Glu Glu Ile Lys Thr
145 150 155 160
Thr Asn Pro Val Ala Thr Glu Gln Tyr Gly Val Val Ala Asp Asn Leu
165 170 175
Gln Gln Ala Asn Thr Gly Pro Ile Val Gly Asn Val Asn Ser Gln Gly
180 185 190
Ala Leu Pro Gly Met Val Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly
195 200 205
Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser
210 215 220
Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile Leu
225 230 235 240
Ile Lys Asn
<210> 30
<211> 242
<212> PRT
<213> Adeno-associated virus-7
<400> 30
Phe Glu Phe Ser Tyr Ser Phe Glu Asp Val Pro Phe His Ser Ser Tyr
1 5 10 15
Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln
20 25 30
Tyr Leu Tyr Tyr Leu Ala Arg Thr Gln Ser Asn Pro Gly Gly Thr Ala
35 40 45
Gly Asn Arg Glu Leu Gln Phe Tyr Gln Gly Gly Pro Ser Thr Met Ala
50 55 60
Glu Gln Ala Lys Asn Trp Leu Pro Gly Pro Cys Phe Arg Gln Gln Arg
65 70 75 80
Val Ser Lys Thr Leu Asp Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr
85 90 95
Gly Ala Thr Lys Tyr His Leu Asn Gly Arg Asn Ser Leu Val Asn Pro
100 105 110
Gly Val Ala Met Ala Thr His Lys Asp Asp Glu Asp Arg Phe Phe Pro
115 120 125
Ser Ser Gly Val Leu Ile Phe Gly Lys Thr Gly Ala Thr Asn Lys Thr
130 135 140
Thr Leu Glu Asn Val Leu Met Thr Asn Glu Glu Glu Ile Arg Pro Thr
145 150 155 160
Asn Pro Val Ala Thr Glu Glu Tyr Gly Ile Val Ser Ser Asn Leu Gln
165 170 175
Ala Ala Asn Thr Ala Ala Gln Thr Gln Val Val Asn Asn Gln Gly Ala
180 185 190
Leu Pro Gly Met Val Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro
195 200 205
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
210 215 220
Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile
225 230 235 240
Lys Asn
<210> 31
<211> 240
<212> PRT
<213> Adeno-associated virus-9
<400> 31
Phe Gln Phe Ser Tyr Glu Phe Glu Asn Val Pro Phe His Ser Ser Tyr
1 5 10 15
Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln
20 25 30
Tyr Leu Tyr Tyr Leu Ser Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln
35 40 45
Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val Gln
50 55 60
Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser
65 70 75 80
Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala
85 90 95
Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro Gly Pro
100 105 110
Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser
115 120 125
Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn Val Asp
130 135 140
Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn
145 150 155 160
Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln Ser
165 170 175
Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile Leu
180 185 190
Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile
195 200 205
Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu
210 215 220
Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile Lys
225 230 235 240
<210> 32
<211> 239
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic polypeptide
<400> 32
Gln Phe Ser Tyr Glu Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala
1 5 10 15
His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr
20 25 30
Leu Tyr Tyr Leu Ser Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln
35 40 45
Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly
50 55 60
Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr
65 70 75 80
Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser
85 90 95
Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala
100 105 110
Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly
115 120 125
Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala
130 135 140
Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro
145 150 155 160
Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln Ser Gly
165 170 175
Gln Ala Gln Ala Ala Thr Gly Trp Val Gln Asn Gln Gly Ile Leu Pro
180 185 190
Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp
195 200 205
Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met
210 215 220
Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile Lys
225 230 235
<210> 33
<211> 240
<212> PRT
<213> Adeno-associated virus-5
<400> 33
Asn Phe Glu Phe Thr Tyr Asn Phe Glu Glu Val Pro Phe His Ser Ser
1 5 10 15
Phe Ala Pro Ser Gln Asn Leu Phe Lys Leu Ala Asn Pro Leu Val Asp
20 25 30
Gln Tyr Leu Tyr Arg Phe Val Ser Thr Asn Asn Thr Gly Gly Val Gln
35 40 45
Phe Asn Lys Asn Leu Ala Gly Arg Tyr Ala Asn Thr Tyr Lys Asn Trp
50 55 60
Phe Pro Gly Pro Met Gly Arg Thr Gln Gly Trp Asn Leu Gly Ser Gly
65 70 75 80
Val Asn Arg Ala Ser Val Ser Ala Phe Ala Thr Thr Asn Arg Met Glu
85 90 95
Leu Glu Gly Ala Ser Tyr Gln Val Pro Pro Gln Pro Asn Gly Met Thr
100 105 110
Asn Asn Leu Gln Gly Ser Asn Thr Tyr Ala Leu Glu Asn Thr Met Ile
115 120 125
Phe Asn Ser Gln Pro Ala Asn Pro Gly Thr Thr Ala Thr Tyr Leu Glu
130 135 140
Gly Asn Met Leu Ile Thr Ser Glu Ser Glu Thr Gln Pro Val Asn Arg
145 150 155 160
Val Ala Tyr Asn Val Gly Gly Gln Met Ala Thr Asn Asn Gln Ser Ser
165 170 175
Thr Thr Ala Pro Ala Thr Gly Thr Tyr Asn Leu Gln Glu Ile Val Pro
180 185 190
Gly Ser Val Trp Met Glu Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp
195 200 205
Ala Lys Ile Pro Glu Thr Gly Ala His Phe His Pro Ser Pro Ala Met
210 215 220
Gly Gly Phe Gly Leu Lys His Pro Pro Pro Met Met Leu Ile Lys Asn
225 230 235 240
<210> 34
<211> 250
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic polypeptide
<400> 34
Thr Phe Ser Tyr Thr Phe Glu Glu Val Pro Phe His Ser Ser Tyr Ala
1 5 10 15
His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr
20 25 30
Leu Tyr Tyr Leu Asn Arg Thr Gln Asn Gln Ser Gly Ser Ala Gln Asn
35 40 45
Lys Asp Leu Leu Phe Ser Arg Gly Ser Pro Ala Gly Met Ser Val Gln
50 55 60
Pro Lys Asn Trp Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser
65 70 75 80
Lys Thr Lys Thr Asp Asn Asn Asn Ser Asn Phe Thr Trp Thr Gly Ala
85 90 95
Ser Lys Tyr Asn Leu Asn Gly Arg Glu Ser Ile Ile Asn Pro Gly Thr
100 105 110
Ala Met Ala Ser His Lys Asp Asp Glu Asp Lys Phe Phe Pro Met Ser
115 120 125
Gly Val Met Ile Phe Gly Lys Glu Ser Ala Gly Ala Ser Asn Thr Ala
130 135 140
Leu Asp Asn Val Met Ile Thr Asp Glu Glu Glu Ile Lys Ala Thr Asn
145 150 155 160
Pro Val Ala Thr Glu Arg Phe Gly Thr Val Ala Val Asn Phe Gln Ser
165 170 175
Ser Ser Thr Asp Leu Ala Leu Gly Glu Thr Thr Arg Pro Ala Pro Ala
180 185 190
Thr Gly Asp Val His Ala Met Gly Ala Leu Pro Gly Met Val Trp Gln
195 200 205
Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His
210 215 220
Thr Asp Gly His Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu
225 230 235 240
Lys Asn Pro Pro Pro Gln Ile Leu Ile Lys
245 250
<210> 35
<211> 250
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic polypeptide
<400> 35
Thr Phe Ser Tyr Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala
1 5 10 15
His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr
20 25 30
Leu Tyr Tyr Leu Asn Arg Thr Gln Asn Gln Ser Gly Ser Ala Gln Asn
35 40 45
Lys Asp Leu Leu Phe Ser Arg Gly Ser Pro Ala Gly Met Ser Val Gln
50 55 60
Pro Lys Asn Trp Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser
65 70 75 80
Lys Thr Lys Thr Asp Asn Asn Asn Ser Asn Phe Thr Trp Thr Gly Ala
85 90 95
Ser Lys Tyr Asn Leu Asn Gly Arg Glu Ser Ile Ile Asn Pro Gly Thr
100 105 110
Ala Met Ala Ser His Lys Asp Asp Lys Asp Lys Phe Phe Pro Met Ser
115 120 125
Gly Val Met Ile Phe Gly Lys Glu Ser Ala Gly Ala Ser Asn Thr Ala
130 135 140
Leu Asp Asn Val Met Ile Thr Asp Glu Glu Glu Ile Lys Ala Thr Asn
145 150 155 160
Pro Val Ala Thr Glu Arg Phe Gly Thr Val Ala Val Asn Leu Gln Ser
165 170 175
Ser Ser Thr Asp Leu Ala Leu Gly Glu Thr Thr Arg Pro Ala Pro Ala
180 185 190
Thr Gly Asp Val His Val Met Gly Ala Leu Pro Gly Met Val Trp Gln
195 200 205
Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His
210 215 220
Thr Asp Gly His Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu
225 230 235 240
Lys His Pro Pro Pro Gln Ile Leu Ile Lys
245 250
<210> 36
<211> 250
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic polypeptide
<400> 36
Phe Ser Tyr Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His
1 5 10 15
Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu
20 25 30
Tyr Tyr Leu Ser Arg Thr Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser
35 40 45
Arg Leu Gln Phe Ser Gln Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser
50 55 60
Arg Asn Trp Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys
65 70 75 80
Thr Ser Ala Asp Asn Asn Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr
85 90 95
Lys Tyr His Leu Asn Gly Arg Asp Ser Leu Val Asn Pro Gly Pro Ala
100 105 110
Met Ala Ser His Lys Asp Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly
115 120 125
Val Leu Ile Phe Gly Lys Gln Gly Ser Glu Lys Thr Asn Val Asp Ile
130 135 140
Glu Lys Val Met Ile Thr Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro
145 150 155 160
Val Ala Thr Glu Gln Tyr Gly Ser Val Ser Thr Asn Leu Gln Arg Gly
165 170 175
Asn Leu Ala Leu Gly Glu Thr Thr Arg Pro Ala Arg Gln Ala Ala Thr
180 185 190
Ala Asp Val Asn Thr Gln Gly Val Leu Pro Gly Met Val Trp Gln Asp
195 200 205
Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr
210 215 220
Asp Gly His Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu Lys
225 230 235 240
His Pro Pro Pro Gln Ile Leu Ile Lys Asn
245 250
<210> 37
<211> 253
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic polypeptide
<400> 37
Asn Phe Gln Phe Thr Tyr Thr Phe Glu Asp Val Pro Phe His Ser Ser
1 5 10 15
Tyr Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp
20 25 30
Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr Gln Thr Thr Gly Gly Thr Ala
35 40 45
Asn Thr Gln Thr Leu Gly Phe Ser Gln Gly Gly Pro Asn Thr Met Ala
50 55 60
Asn Gln Ala Lys Asn Trp Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg
65 70 75 80
Val Ser Thr Thr Thr Gly Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr
85 90 95
Ala Gly Thr Lys Tyr His Leu Asn Gly Arg Asn Ser Leu Ala Asn Pro
100 105 110
Gly Ile Ala Met Ala Thr His Lys Asp Asp Glu Glu Arg Phe Phe Pro
115 120 125
Ser Asn Gly Ile Leu Ile Phe Gly Lys Gln Asn Ala Ala Arg Asp Asn
130 135 140
Ala Asp Tyr Ser Asp Val Met Leu Thr Ser Glu Glu Glu Ile Lys Thr
145 150 155 160
Thr Asn Pro Val Ala Thr Glu Glu Tyr Gly Ile Val Ala Asp Asn Leu
165 170 175
Gln Gln Gln Asn Leu Ala Leu Gly Glu Thr Thr Arg Pro Ala Thr Ala
180 185 190
Pro Gln Ile Gly Thr Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val
195 200 205
Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
210 215 220
Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
225 230 235 240
Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn
245 250
<210> 38
<211> 252
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic polypeptide
<400> 38
Asn Phe Gln Phe Thr Tyr Thr Phe Glu Asp Val Pro Phe His Ser Ser
1 5 10 15
Tyr Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp
20 25 30
Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr Gln Thr Thr Gly Gly Thr Ala
35 40 45
Asn Thr Gln Thr Leu Gly Phe Ser Gln Gly Gly Pro Asn Thr Met Ala
50 55 60
Asn Gln Ala Lys Asn Trp Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg
65 70 75 80
Val Ser Thr Thr Thr Gly Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr
85 90 95
Ala Gly Thr Lys Tyr His Leu Asn Gly Arg Asn Ser Leu Ala Asn Pro
100 105 110
Gly Ile Ala Met Ala Thr His Lys Asp Asp Glu Glu Arg Phe Phe Pro
115 120 125
Ser Asn Gly Ile Leu Ile Phe Gly Lys Gln Asn Ala Ala Arg Asp Asn
130 135 140
Ala Asp Tyr Ser Asp Val Met Leu Thr Ser Glu Glu Glu Ile Lys Thr
145 150 155 160
Thr Asn Pro Val Ala Thr Glu Glu Tyr Gly Ile Val Ala Asp Asn Leu
165 170 175
Gln Gly Gln Arg Gly Leu Gly Glu Thr Thr Arg Pro Ala Gln Ala Ala
180 185 190
Gln Ile Gly Thr Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val Trp
195 200 205
Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro
210 215 220
His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly
225 230 235 240
Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn
245 250
<210> 39
<211> 251
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic polypeptide
<400> 39
Phe Gln Phe Ser Tyr Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr
1 5 10 15
Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln
20 25 30
Tyr Leu Tyr Tyr Leu Val Arg Thr Gln Thr Thr Gly Thr Gly Gly Thr
35 40 45
Gln Thr Leu Ala Phe Ser Gln Ala Gly Pro Ser Ser Met Ala Asn Gln
50 55 60
Ala Arg Asn Trp Val Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser
65 70 75 80
Thr Thr Thr Asn Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Gly Ala
85 90 95
Ala Lys Phe Lys Leu Asn Gly Arg Asp Ser Leu Met Asn Pro Gly Val
100 105 110
Ala Met Ala Ser His Lys Asp Asp Asp Asp Arg Phe Phe Pro Ser Ser
115 120 125
Gly Val Leu Ile Phe Gly Lys Gln Gly Ala Gly Asn Asp Gly Val Asp
130 135 140
Tyr Ser Gln Val Leu Ile Thr Asp Glu Glu Glu Ile Lys Ala Thr Asn
145 150 155 160
Pro Val Ala Thr Glu Glu Tyr Gly Ala Val Ala Ile Asn Asn Gln Ala
165 170 175
Ala Asn Leu Ala Leu Gly Glu Thr Thr Arg Pro Ala Thr Gln Ala Gln
180 185 190
Thr Gly Leu Val His Asn Gln Gly Val Ile Pro Gly Met Val Trp Gln
195 200 205
Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His
210 215 220
Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu
225 230 235 240
Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn
245 250
<210> 40
<211> 253
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic polypeptide
<400> 40
Asn Phe Glu Phe Ser Tyr Thr Phe Glu Asp Val Pro Phe His Ser Ser
1 5 10 15
Tyr Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp
20 25 30
Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr Gln Ser Thr Gly Gly Thr Gln
35 40 45
Gly Thr Gln Gln Leu Leu Phe Ser Gln Ala Gly Pro Ala Asn Met Ser
50 55 60
Ala Gln Ala Lys Asn Trp Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg
65 70 75 80
Val Ser Thr Thr Leu Ser Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr
85 90 95
Gly Ala Thr Lys Tyr His Leu Asn Gly Arg Asp Ser Leu Val Asn Pro
100 105 110
Gly Val Ala Met Ala Thr His Lys Asp Asp Glu Glu Arg Phe Phe Pro
115 120 125
Ser Ser Gly Val Leu Met Phe Gly Lys Gln Gly Ala Gly Arg Asp Asn
130 135 140
Val Asp Tyr Ser Ser Val Met Leu Thr Ser Glu Glu Glu Ile Lys Thr
145 150 155 160
Thr Asn Pro Val Ala Thr Glu Gln Tyr Gly Val Val Ala Asp Asn Leu
165 170 175
Gln Gln Leu Ala Leu Gly Glu Thr Thr Arg Pro Ala Ala Asn Thr Gly
180 185 190
Pro Ile Val Gly Asn Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val
195 200 205
Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
210 215 220
Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
225 230 235 240
Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn
245 250
<210> 41
<211> 252
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic polypeptide
<400> 41
Phe Glu Phe Ser Tyr Ser Phe Glu Asp Val Pro Phe His Ser Ser Tyr
1 5 10 15
Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln
20 25 30
Tyr Leu Tyr Tyr Leu Ala Arg Thr Gln Ser Asn Pro Gly Gly Thr Ala
35 40 45
Gly Asn Arg Glu Leu Gln Phe Tyr Gln Gly Gly Pro Ser Thr Met Ala
50 55 60
Glu Gln Ala Lys Asn Trp Leu Pro Gly Pro Cys Phe Arg Gln Gln Arg
65 70 75 80
Val Ser Lys Thr Leu Asp Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr
85 90 95
Gly Ala Thr Lys Tyr His Leu Asn Gly Arg Asn Ser Leu Val Asn Pro
100 105 110
Gly Val Ala Met Ala Thr His Lys Asp Asp Glu Asp Arg Phe Phe Pro
115 120 125
Ser Ser Gly Val Leu Ile Phe Gly Lys Thr Gly Ala Thr Asn Lys Thr
130 135 140
Thr Leu Glu Asn Val Leu Met Thr Asn Glu Glu Glu Ile Arg Pro Thr
145 150 155 160
Asn Pro Val Ala Thr Glu Glu Tyr Gly Ile Val Ser Ser Asn Leu Gln
165 170 175
Ala Ala Asn Leu Ala Leu Gly Glu Thr Thr Arg Pro Ala Thr Ala Ala
180 185 190
Gln Thr Gln Val Val Asn Asn Gln Gly Ala Leu Pro Gly Met Val Trp
195 200 205
Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro
210 215 220
His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly
225 230 235 240
Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn
245 250
<210> 42
<211> 249
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic polypeptide
<400> 42
Phe Gln Phe Ser Tyr Glu Phe Glu Asn Val Pro Phe His Ser Ser Tyr
1 5 10 15
Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln
20 25 30
Tyr Leu Tyr Tyr Leu Ser Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln
35 40 45
Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val Gln
50 55 60
Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser
65 70 75 80
Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala
85 90 95
Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro Gly Pro
100 105 110
Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser
115 120 125
Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn Val Asp
130 135 140
Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn
145 150 155 160
Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln Ser
165 170 175
Ala Gln Leu Ala Leu Gly Glu Thr Thr Arg Pro Ala Gln Ala Gln Thr
180 185 190
Gly Trp Val Gln Asn Gln Gly Ile Leu Pro Gly Met Val Trp Gln Asp
195 200 205
Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr
210 215 220
Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Met Lys
225 230 235 240
His Pro Pro Pro Gln Ile Leu Ile Lys
245
<210> 43
<211> 248
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic polypeptide
<400> 43
Gln Phe Ser Tyr Glu Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala
1 5 10 15
His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr
20 25 30
Leu Tyr Tyr Leu Ser Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln
35 40 45
Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly
50 55 60
Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr
65 70 75 80
Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser
85 90 95
Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala
100 105 110
Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly
115 120 125
Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala
130 135 140
Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro
145 150 155 160
Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln Ser Gly
165 170 175
Gln Ala Ala Leu Gly Glu Thr Thr Arg Pro Ala Gln Ala Ala Thr Gly
180 185 190
Trp Val Gln Asn Gln Gly Ile Leu Pro Gly Met Val Trp Gln Asp Arg
195 200 205
Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp
210 215 220
Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Met Lys His
225 230 235 240
Pro Pro Pro Gln Ile Leu Ile Lys
245
<210> 44
<211> 250
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic peptide
<400> 44
Asn Phe Glu Phe Thr Tyr Asn Phe Glu Glu Val Pro Phe His Ser Ser
1 5 10 15
Phe Ala Pro Ser Gln Asn Leu Phe Lys Leu Ala Asn Pro Leu Val Asp
20 25 30
Gln Tyr Leu Tyr Arg Phe Val Ser Thr Asn Asn Thr Gly Gly Val Gln
35 40 45
Phe Asn Lys Asn Leu Ala Gly Arg Tyr Ala Asn Thr Tyr Lys Asn Trp
50 55 60
Phe Pro Gly Pro Met Gly Arg Thr Gln Gly Trp Asn Leu Gly Ser Gly
65 70 75 80
Val Asn Arg Ala Ser Val Ser Ala Phe Ala Thr Thr Asn Arg Met Glu
85 90 95
Leu Glu Gly Ala Ser Tyr Gln Val Pro Pro Gln Pro Asn Gly Met Thr
100 105 110
Asn Asn Leu Gln Gly Ser Asn Thr Tyr Ala Leu Glu Asn Thr Met Ile
115 120 125
Phe Asn Ser Gln Pro Ala Asn Pro Gly Thr Thr Ala Thr Tyr Leu Glu
130 135 140
Gly Asn Met Leu Ile Thr Ser Glu Ser Glu Thr Gln Pro Val Asn Arg
145 150 155 160
Val Ala Tyr Asn Val Gly Gly Gln Met Ala Thr Asn Asn Gln Ser Leu
165 170 175
Ala Leu Gly Glu Thr Thr Arg Pro Ala Ser Thr Thr Ala Pro Ala Thr
180 185 190
Gly Thr Tyr Asn Leu Gln Glu Ile Val Pro Gly Ser Val Trp Met Glu
195 200 205
Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro Glu Thr
210 215 220
Gly Ala His Phe His Pro Ser Pro Ala Met Gly Gly Phe Gly Leu Lys
225 230 235 240
His Pro Pro Pro Met Met Leu Ile Lys Asn
245 250
<210> 45
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 45
Leu Ala Leu Gly Glu Thr Thr Arg Pro Ala
1 5 10
<210> 46
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 46
Leu Ala Asn Glu Thr Ile Thr Arg Pro Ala
1 5 10
<210> 47
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 47
Leu Ala Lys Ala Gly Gln Ala Asn Asn Ala
1 5 10
<210> 48
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 48
Leu Ala Lys Asp Pro Lys Thr Thr Asn Ala
1 5 10
<210> 49
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 49
Ala Ala Leu Gly Glu Thr Thr Arg Pro Ala
1 5 10
<210> 50
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide
<400> 50
Ala Ala Asn Glu Thr Ile Thr Arg Pro Ala
1 5 10
<210> 51
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 51
Ala Ala Lys Ala Gly Gln Ala Asn Asn Ala
1 5 10
<210> 52
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 52
Ala Ala Lys Asp Pro Lys Thr Thr Asn Ala
1 5 10
<210> 53
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 53
Gly Leu Gly Glu Thr Thr Arg Pro Ala
1 5
<210> 54
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 54
Gly Asn Glu Thr Ile Thr Arg Pro Ala
1 5
<210> 55
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 55
Gly Lys Ala Gly Gln Ala Asn Asn Ala
1 5
<210> 56
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic peptide
<400> 56
Gly Lys Asp Pro Lys Thr Thr Asn Ala
1 5
<210> 57
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 57
Lys Asp Thr Asp Thr Thr Arg
1 5
<210> 58
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 58
Arg Ala Gly Gly Ser Val Gly
1 5
<210> 59
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 59
Ala Val Asp Thr Thr Lys Phe
1 5
<210> 60
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 60
Ser Thr Gly Lys Val Pro Asn
1 5
<210> 61
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 61
Leu Ala Lys Asp Thr Asp Thr Thr Arg Ala
1 5 10
<210> 62
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 62
Leu Ala Arg Ala Gly Gly Ser Val Gly Ala
1 5 10
<210> 63
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 63
Leu Ala Ala Val Asp Thr Thr Lys Phe Ala
1 5 10
<210> 64
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 64
Leu Ala Ser Thr Gly Lys Val Pro Asn Ala
1 5 10
Claims (27)
- 재조합 아데노-관련 바이러스(adeno-associated virus: rAAV) 비리온으로서,
a) 변이체 AAV 캡시드 단백질; 및
b) 유전자 산물을 암호화하는 뉴클레오타이드 서열을 포함하는 이종성 핵산을 포함하되,
상기 변이체 AAV 캡시드 단백질은 대응되는 모(parental) AAV 캡시드 단백질에 대해 캡시드 단백질 GH 루프에서 약 5개 아미노산 내지 약 11개 아미노산의 삽입물 포함하며, 상기 변이체 캡시드 단백질은 상기 대응되는 모 AAV 캡시드 단백질을 포함하는 AAV 비리온에 의한 망막 세포의 감염성에 비해 증가된 망막 세포의 감염성을 부여하는 것인 재조합 아데노-관련 바이러스(rAAV) 비리온. - 제1항에 있어서, 상기 삽입물은 식 I, 식 IIa, 식 III 또는 식 IV의 펩타이드인 것인, rAAV 비리온.
- 제2항에 있어서, 상기 삽입물은 LGETTRP(서열번호 13), NETITRP(서열번호 14), KAGQANN(서열번호 15), KDPKTTN(서열번호 16), KDTDTTR(서열번호 57), RAGGSVG(서열번호 58), AVDTTKF(서열번호 59) 및 STGKVPN(서열번호 60)으로부터 선택된 아미노산 서열을 포함하는 것인, rAAV 비리온.
- 제1항에 있어서, 상기 망막 세포는 광수용체, 망막 신경절 세포, 뮐러 세포, 양극 세포, 아마크린 세포, 수평 세포 또는 망막 색소성 상피세포인 것인, rAAV 비리온.
- 제1항에 있어서, 상기 삽입 부위는 AAV2의 아미노산 587과 588 사이, AAV1의 아미노산 590과 591 사이, AAV5의 아미노산 575와 576 사이, AAV6의 아미노산 590과 591 사이, AAV7의 아미노산 589와 590 사이, AAV8의 아미노산 590과 591 사이, AAV9의 아미노산 588과 589 사이 또는 AAV10의 아미노산 588과 589 사이인 것인, rAAV 비리온.
- 제1항에 있어서, 상기 rAAV 비리온은 상기 대응되는 모 AAV 캡시드 단백질을 포함하는 AAV 비리온에 의한 상기 망막 세포의 상기 감염성에 비해 적어도 10배 증가된 망막 세포의 감염성을 나타내는 것인, rAAV 비리온.
- 제1항에 있어서, 상기 rAAV 비리온은 상기 대응되는 모 AAV 캡시드 단백질을 포함하는 AAV 비리온에 의한 상기 망막 세포의 감염성에 비해 적어도 50배 증가된 망막 세포의 감염성을 나타내는 것인, rAAV 비리온.
- 제1항에 있어서, 유전자 산물은 간섭 RNA 또는 앱타머인 것인, rAAV 비리온.
- 제1항에 있어서, 상기 유전자 산물은 폴리펩타이드인 것인, rAAV 비리온.
- 제7항에 있어서, 상기 폴리펩타이드는 신경보호 폴리펩타이드, 항혈관신생 폴리펩타이드, 또는 망막 세포의 기능을 향상시키는 폴리펩타이드인 것인 rAAV 비리온.
- 약제학적 조성물로서,
a) 제1항의 재조합 아데노-관련 바이러스 비리온; 및
b) 약제학적으로 허용가능한 부형제를 포함하는 약제학적 조성물. - 개체에서 망막 세포에 유전자 산물을 전달하는 방법으로서, 상기 방법은 제1항에 따른 재조합 아데노-관련 바이러스(rAAV) 비리온을 개체에 투여하는 단계를 포함하는, 망막 세포에의 유전자 산물의 전달방법.
- 제11항에 있어서, 상기 유전자 산물은 폴리펩타이드인 것인, 망막 세포에의 유전자 산물의 전달방법.
- 제11항에 있어서, 상기 유전자 산물은 짧은 간섭 RNA 또는 앱타머인 것인, 망막 세포에의 유전자 산물의 전달방법.
- 제13항에 있어서, 상기 폴리펩타이드는 신경보호 인자, 항혈관신생 폴리펩타이드, 항-아포토시스 인자, 또는 망막 세포의 기능을 향상시키는 폴리펩타이드인 것인, 망막 세포에의 유전자 산물의 전달방법.
- 제13항에 있어서, 상기 폴리펩타이드는 신경교 유래 신경영양 인자, 섬유아세포 성장인자 2, 뉴투린(neurturin), 섬모 신경영양 인자, 신경 성장 인자, 뇌 유래 신경영양 인자, 표피성장인자, 로돕신, 아포토시스의 X-연결된 억제제, 망막층간 단백질, RPE65, 망막 색소 변성증 GTPase-상호작용 단백질-1, 페리페린, 페리페린-2, 로돕신 또는 소닉 헤지호그(Sonic hedgehog)인 것인, 망막 세포에의 유전자 산물의 전달방법.
- 망막질병을 치료하는 방법으로서, 상기 방법은 제1항에 따른 재조합 아데노-관련 바이러스(rAAV)의 유효량을 치료가 필요한 개체에게 투여하는 단계를 포함하는, 망막질병의 치료방법.
- 제17항에 있어서, 상기 투여는 안구내 주사에 의한 것인, 망막질병의 치료방법.
- 제17항에 있어서, 상기 투여는 유리체 내 주사에 의한 것인, 망막질병의 치료방법.
- 제17항에 있어서, 상기 안질환은 녹내장, 망막 색소 변성증, 황반변성, 망막층간분리, 레버 선천성 흑암시, 당뇨 망막병증, 색맹 또는 색각이상인 것인, 망막질병의 치료방법.
- 변이체 아데노-관련 바이러스(AAV) 캡시드 단백질을 암호화하는 뉴클레오타이드 서열을 포함하는 단리된 핵산으로서, 상기 변이체 AAV 캡시드 단백질은 대응되는 모 AAV 캡시드 단백질에 대해 캡시드 단백질 GH 루프에서 약 5개 아미노산 내지 약 11개 아미노산의 삽입을 포함하며, 상기 변이체 캡시드 단백질은, AAV 비리온에 존재할 때, 망막 세포의 상기 AAV 비리온의 증가된 감염성을 제공하는 것인, 단리된 핵산.
- 제21항에 있어서, 상기 삽입 부위는 AAV2의 아미노산 587과 588 사이, AAV1의 아미노산 590과 591 사이, AAV5의 아미노산 575와 576 사이, AAV6의 아미노산 590과 591 사이, AAV7의 아미노산 589와 590 사이, AAV8의 아미노산 590과 591 사이, AAV9의 아미노산 588과 589 사이 또는 AAV10의 아미노산 588과 589 사이인 것인, 단리된 핵산.
- 제21항의 핵산을 포함하는 단리되고, 유전적으로 변형된 숙주 세포.
- 변이체 아데노-관련 바이러스(AAV) 캡시드 단백질로서, 상기 변이체 AAV 캡시드 단백질은 약 5개 아미노산 내지 약 11개 아미노산의 삽입물을 포함하되, 상기 아미노산 삽입물은 천연 AAV 캡시드의 GH 루프이며, 상기 삽입물은 식 I, 식 IIa, 식 III 또는 식 IV의 펩타이드인 것인, 변이체 아데노-관련 바이러스(AAV) 캡시드 단백질.
- 제24항에 있어서, 상기 삽입물은 LGETTRP(서열번호 13), NETITRP(서열번호 14), KAGQANN(서열번호 15), KDPKTTN(서열번호 16), KDTDTTR(서열번호 57), RAGGSVG(서열번호 58), AVDTTKF(서열번호 59) 및 STGKVPN(서열번호 60)으로부터 선택된 아미노산 서열을 포함하는 것인, 변이체 AAV 캡시드 단백질.
- 제24항에 있어서, 상기 삽입 부위는 AAV2의 아미노산 587과 588 사이, AAV1의 아미노산 590과 591 사이, AAV5의 아미노산 575와 576 사이, AAV6의 아미노산 590과 591 사이, AAV7의 아미노산 589와 590 사이, AAV8의 아미노산 590과 591 사이, AAV9의 아미노산 588과 589 사이 또는 AAV10의 아미노산 588과 589 사이인 것인, 변이체 AAV 캡시드 단백질.
- 제24항의 변이체 AAV 캡시드 단백질을 암호화하는 뉴클레오타이드 서열을 포함하는 핵산.
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