KR20160049015A - 아데노-관련된 바이러스 인자 viii 벡터 - Google Patents

아데노-관련된 바이러스 인자 viii 벡터 Download PDF

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KR20160049015A
KR20160049015A KR1020167009492A KR20167009492A KR20160049015A KR 20160049015 A KR20160049015 A KR 20160049015A KR 1020167009492 A KR1020167009492 A KR 1020167009492A KR 20167009492 A KR20167009492 A KR 20167009492A KR 20160049015 A KR20160049015 A KR 20160049015A
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피터 카메론 콜로시
아밋 나트와니
제니 매킨토시
에드워드 터드넘
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바이오마린 파머수티컬 인크.
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Abstract

본 발명은 기능적 인자 VIII 폴리펩타이드를 생산하는 AAV FVIII 벡터를 포함하는 향상된 아데노-관련된 바이러스 (AAV) 인자 VIII (FVIII) 벡터 및 고발현 활성을 갖는 AAV FVIII 벡터를 제공한다.

Description

아데노-관련된 바이러스 인자 VIII 벡터{ADENO-ASSOCIATED VIRUS FACTOR VIII VECTORS}
본원은 미국 가출원 제61/877,042호(2013년 9월 12일 출원)에 대해 우선권을 주장하며, 이것은 그 전체가 참고로 본원에 편입되어 있다.
본 발명은 높은 발현 활성을 갖는 AAV FVIII 벡터 및 전장 (full-length)의 또는 말단이 절단된 기능적 FVIII을 발현하는 AAV FVIII 벡터를 포함하는, 아데노-관련된 바이러스 (AAV) 인자 VIII (FVIII) 벡터에 관한 것이다. 본 발명은 또한 본원에 기재된 AAV FVIII 벡터를 제조하는 방법 및 이의 관련된 치료 용도에 관한 것이다.
아데노-관련된 바이러스 (AAV)는 작은, 복제 불능, 외피가 없는 동물 바이러스로서, 인간 및 일부 다른 영장류 종을 감염시킨다. AAV의 몇 가지 특징들로 인해 이 바이러스는 유전자 치료요법에 의해 치료 단백질을 전달하기 위한 매력적인 운반체가 되었으며, 이러한 특징은, 예를 들면 AAV가 인간 질환을 유발하는 것으로 알려져 있지 않고 약한 면역 반응을 유도한다는 점과 AAV 벡터가 숙주세포 게놈 내로 통합되지 않으면서 분열 및 정지 세포 모두를 감염시킬 수 있다는 점을 포함한다. AAV를 이용하는 유전자 요법 벡터들은, 일부 임상 시험에서, 예를 들면, 혈우병 B의 치료를 위해 인간 인자 IX (FIX)를 간으로 전달하는데 성공적으로 사용되어 왔다 (Nathwani 등, New Engl. J. Med. 365:2357-2365, 2011).
그러나, AAV 유전자 요법 벡터는 몇 가지 단점이 있다. 특히, AAV 벡터의 클로닝 능력은 상기 바이러스의 DNA 패키징 능력의 결과로서 제한된다. 야생형 AAV의 단일가닥 DNA 게놈은 약 4.7 킬로베이스 (kb)이다. 실제로, 최대 약 5.0 kb의 AAV 게놈이 AAV 바이러스 입자 내로 완전히 패키징되는 것 (즉, 전장임)으로 보인다. AAV 벡터 내의 상기 핵산 게놈은 2개의 약 145개 염기의 AAV 역전된 말단 반복 (ITR)을 가져야 한다는 요건 때문에, AAV 벡터의 DNA 패키징 능력은 최대 약 4.4 kb의 단백질-코딩 서열이 캡시드화될 수 있는 정도이다.
이러한 크기 제약으로 인해, 큰 치료 유전자, 즉, 약 4.4 kb 길이보다 더 큰 유전자들은 일반적으로 AAV 벡터에 사용하는데 적합하지 않다. 그러한 한 가지 치료 유전자는 인자 VIII (FVIII) 유전자이며, 이는 N-말단에서 C-말단까지, 19개의 아미노산 신호 펩타이드, 및 3개의 거대 도메인 (즉, 중쇄 또는 A 도메인, 중심 또는 B 도메인, 및 경쇄 또는 C 도메인)을 포함하는, 2332개의 아미노산의 폴리펩타이드를 인코딩하는 약 7.0 kb의 mRNA를 갖는다. FVIII에 대한 AAV 벡터 크기 제한을 극복하기 위해 이용되어 온 한 가지 전략은 2개의 AAV 벡터, 즉 중쇄 또는 A 도메인을 인코딩하는 벡터, 및 경쇄 또는 C 도메인을 인코딩하는 벡터를 사용하는 것이었다 (예를 들면, Coutu 등, US 특허 제6,221349호, 제6,200,560호 및 제7,351,577호 참고). 이 크기 제약을 회피하는 또 다른 전략은 상기 단백질의 중심 부위 또는 B 도메인이 결실되고 SQ 서열로서 알려진 14개의 아미노산 링커로 치환된 FVIII를 인코딩하는 AAV 벡터를 생성하는 것이었다 (Ward 등, Blood, 117:798-807, 2011, 및 McIntosh 등, Blood 121:3335-3344, 2013).
> 5.0 kb의 AAV 게놈을 갖는 AAV 벡터들이 문헌에서 보고되었지만, 많은 경우 인코딩된 유전자의 5' 또는 3' 말단이 절단된 것으로 보인다 (Hirsch 등, Molec. Ther. 18-6-8, 2010, 및 Ghosh 등, Biotech. Genet. Engin. Rev. 24:165-178, 2007 참고). 그러나, AAV 감염된 세포에서 5' 말단 절단 및 3' 말단 절단을 갖는 핵산 사이에서 중첩하는 상동 재조합이 일어나 상기 거대 단백질을 인코딩하는 "완전 (complete)" 핵산이 생성되고, 그렇게 함으로써 기능적, 전장 유전자를 재구축하는 것으로 나타났다.
혈우병 A의 치료를 위한 유전자 요법 접근법에서 유용한 기능적 인자 VIII 단백질을 인코딩하는 신규 AAV 벡터가 요구된다. 이와 같이, 본 발명은 기능적 활성 FVIII을 인코딩하는 AAV 벡터에 관한 것이며, 그 결과 AAV 비리온이 치료적 단백질을 인코딩하는 전체 핵산을 감쌈으로써 (즉, 완전히 포장된 AAV FVIII 벡터) 대형 게놈의 상기 언급된 문제를 피하거나, 또는 말단이 절단되거나 절단되지 않을 수 있는 기능적 활성 인자 VIII 단백질을 최소한 생산한다. 게다가, 캡시드 유도된 면역 반응을 피하기 위해, AAV 벡터는 캡시드 입자당 상기 표적 단백질의 가능한 가장 높은 형질도입/발현 활성을 가져야 한다. 본 발명은 또한 높은 발현 활성을 갖는 완전한 AAV FVIII 벡터의 생산에 관한 것이다. 마지막으로, 본 발명은 본원에 기재된 AAV 인자 VIII 벡터를 생산하는 방법 및 이를 이용하기 위한 관련된 방법에 관한 것이다.
발명의 요약
본 발명은 기능적 활성 FVIII을 인코딩하는 AAV 벡터 (본원에서 "AAV FVIII 벡터"로 지칭됨)를 제공한다. 상기 기능적 활성 FVIII을 인코딩하는 게놈은 바람직하게는 최대 7.0 kb 길이, 더 바람직하게는 최대 6.5 kb 길이, 더욱 더 바람직하게는 최대 6.0 kb 길이, 더욱 더 바람직하게는 최대 5.5 kb 길이, 더욱 더 바람직하게는 최대 5.0 kb 길이이며, 향상된 프로모터 기능을 갖는다.
본원에서 사용된 바와 같이, "기능적 활성 FVIII"는 시험관내에서, 배양된 세포에서 발현될 때, 또는 생체내에서, 세포 또는 체 조직에서 발현될 때, 야생형 FVIII 단백질의 기능성을 갖는 FVIII 단백질이다. 이것은, 예를 들면, 혈우병 A를 겪고 있는 대상체에서 혈액 응고가 일어나게 하는 것 및 혈액이 응고하는데 걸리는 시간을 줄이는 것을 포함한다. 야생형 FVIII은 응고 캐스케이드를 통해 혈액 응고에 관여하며, 칼슘 이온 및 인지질의 존재하에 인자 X (FX)를 활성화된 FX (FXa)로 전환시키는 복합체를 형성하는 활성화된 FIX (FIXa)에 대한 보조인자로서 작용한다. 따라서, 기능적 활성 FVIII는 FIXa와 복합체를 형성할 수 있고, 이는 FX를 FXa로 전환시킬 수 있다.
본원에서 사용된 바와 같이, "AAV 벡터"는 전사 조절 요소, 즉, 하나 이상의 프로모터 및/또는 인핸서에 작동가능하게 연결된 단백질-코딩 서열의 측면에 있는 (flanking) AAV 5' 역전된 말단 반복 (ITR) 서열 및 AAV 3' ITR, 및 폴리아데닐화 서열, 및, 임의로, 상기 단백질-코딩 서열의 엑손 사이에 삽입된 하나 이상의 인트론을 갖는, 단일가닥 또는 이중-가닥의 핵산을 지칭한다. 단일가닥 AAV 벡터는 AAV 바이러스 입자의 게놈 내에 존재하는 핵산을 지칭하며, 이는 본원에서 개시된 핵산 서열의 센스 가닥 또는 안티-센스 가닥 중 하나일 수 있다. 그와 같은 단일가닥 핵산의 크기는 염기 (base)로 제공된다. 이중-가닥 AAV 벡터는, AAV 벡터 핵산을 발현하거나 전달하는데 사용되는, 플라스미드, 예를 들면, pUC19의 DNA, 또는 이중-가닥 바이러스, 예를 들면, 배큘로바이러스의 게놈 내에 존재하는 핵산을 지칭한다. 그와 같은 이중-가닥 핵산의 크기는 염기쌍 (bp)으로 제공된다.
본원에서 사용된 바와 같이 용어 "역전된 말단 반복 (ITR)"은 AAV 게놈의 5' 및 3' 말단에서 발견되는 본 기술분야에서 인식된 영역을 지칭하며, 이는 DNA 복제의 원점으로서 그리고 및 바이러스 게놈을 위한 패키징 신호로서 cis로 기능한다. AAV ITR은, AAV rep 코딩 영역과 함께, 숙주세포 게놈 내로 2개의 측접 (flanking) ITR 사이에 삽입된 뉴클레오타이드 서열의 효율적인 절제 (excision) 및 구조 (rescue), 및 통합을 제공한다. 어떤 AAV-관련된 ITR의 서열은 문헌[Yan 등, J. Virol. 79(1):364-379 (2005)]에 개시되어 있으며, 이는 그 전체가 참고로 본원에 편입되어 있다.
"전사 조절 인자"는 RNA 폴리머라제 결합을 돕고 발현을 촉진하는 전사 인자의 결합을 위한 프로모터 뿐만 아니라 반응 요소, 활성자 및 인핸서 서열, 및 RNA 폴리머라제 부착을 차단하고 발현을 방지하기 위해 억제인자 단백질이 결합하는 작동자 또는 사일런서 서열을 포함하는, 유전적 전사의 조절에 관여하는 유전자의 뉴클레오타이드 서열을 지칭한다. 용어 "간 특이적 전사 조절 요소"는 간 조직에서 특이적으로 유전자 발현을 조절하는 조절 요소를 지칭한다. 간 특이적 조절 요소의 예는, 비제한적으로, 마우스 티레틴 프로모터 (mTTR), 내인성 인간 인자 VIII 프로모터 (F8), 인간 알파-1-항트립신 프로모터 (hAAT) 및 이의 활성 단편, 인간 알부민 최소 프로모터, 및 마우스 알부민 프로모터를 포함한다. 간 특이적 전사 인자 결합 부위로부터 유래된 인핸서, 예컨대 Enh1과 함께, EBP, DBP, HNF1, HNF3, HNF4, HNF6이 또한 고려된다.
일 구현예에서, 본 발명의 AAV 벡터는 14개의 아미노산 SQ 서열, 즉, FVIII SQ를 인코딩하는 14개의 아미노산 SQ 서열로 치환된 B 도메인을 갖는 기능적 활성 FVIII을 인코딩하는 핵산을 포함한다. 상기 SQ 서열은 문헌[Ward 등, Blood, 117:798-807, 2011, 및 McIntosh 등, Blood 121:3335-3344, 2013]에 개시되어 있다. FVIII 코딩 영역 서열은 코돈-최적화된 서열이다 (본원에 그 전체가 참고로 편입되어 있는, 2013년 1월 24일에 공개된 Nathwani 등, US 특허 출원 공개 제2013/0024960A1호, 및 McIntosh 등, Blood 121:3335-3344, 2013 참고). 이 서열은 본원에서 "UCL SQ FVIII"로 지칭된다.
제1 측면에서, 본 발명의 AAV 벡터는 프로토 1을 포함하고, 이것은 도 2A에서 도식적으로 묘사되고, 서열번호 1에서 제시된 핵산 서열을 포함한다.
제2 측면에서, 본 발명의 AAV 벡터는 프로토 1S를 포함하고, 이것은 도 2B 에서 도식적으로 묘사되고, 서열번호 2에서 제시된 핵산 서열을 포함한다.
제3 측면에서, 본 발명의 AAV 벡터는 프로토 2S를 포함하고, 이것은 도 2C 에서 도식적으로 묘사되고, 서열번호 3에서 제시된 핵산 서열을 포함한다.
제4 측면에서, 본 발명의 AAV 벡터는 프로토 3S를 포함하고, 이것은 도 2D 에서 도식적으로 묘사되고, 서열번호 4에서 제시된 핵산 서열을 포함한다.
또 하나의 구현예에서, 본 발명의 AAV 벡터는 SQ 서열을 포함하는 전체 B 도메인, 및 경쇄 또는 C 도메인에 대해 바로 N-말단에 위치한 a3 도메인이 없는 FVIII을 인코딩히는 핵산을 포함한다. FVIII 코딩 영역 서열은 코돈-최적화된 서열이다 (참고 Nathwani 등, US 특허 출원 공개 번호 2013/0024960A1, 2013년, 1월 24일 공개, 이것은 본원에 그 전체가 참고로 편입되어 있음), 및 McIntosh 등, Blood 121:3335-3344, 2013).
제1 측면에서, 본 발명의 AAV 벡터는 프로토 4를 포함하고, 이것은 도 3A 에서 도식적으로 묘사되고, 서열번호 5에서 제시된 핵산 서열을 포함한다.
제2 측면에서, 본 발명의 AAV 벡터는 프로토 5를 포함하고, 이것은 도 3B 에서 도식적으로 묘사되고, 서열번호 6에서 제시된 핵산 서열을 포함한다.
제3 측면에서, 본 발명의 AAV 벡터는 프로토 6을 포함하고, 이것은 도 3C 에서 도식적으로 묘사되고, 서열번호 7에서 제시된 핵산 서열을 포함한다.
제4 측면에서, 본 발명의 AAV 벡터는 프로토 7을 포함하고, 이것은 도 3D 에서 도식적으로 묘사되고, 서열번호 8에서 제시된 핵산 서열을 포함한다.
또 하나의 구현예에서, 본 발명의 AAV 벡터는 AAV2 5' 역전된 말단 반복 (ITR), 간(liver)-특이적 전사 조절 영역, 코돈-최적화된 기능적 활성 FVIII 코딩 영역, 임의로 하나 이상의 인트론, 폴리아데닐화 서열, 및 AAV2 3' ITR을 포함하는 핵산을 포함한다. 바람직한 구현예에서, 간(liver)-특이적 전사 조절 영역은 단축된 ApoE 인핸서 서열, 5' 미번역된 영역 (UTR)의 42개의 염기를 포함하는 186개의 염기 인간 알파 항-트립신 (hAAT) 근위 프로모터, 및 (i) 34개의 염기 인간 ApoE/C1 인핸서, (ii) 32개의 염기 인간 AAT 프로모터 원위 X 영역 및 (iii) 인간 AAT 근위 프로모터의 원위 요소의 80개의 추가의 염기로 이루어진 군으로부터 선택된 하나 이상의 인핸서; 및 FVIII SQ 변종을 인코딩하는 코돈-최적화된 기능적 활성 FVIII 코딩 영역을 포함한다. 또 하나의 바람직한 구현예에서, 간 특이적 전사 조절 영역은 a1 마이크로-글로불린 인핸서 서열 및 186개의 염기 인간 알파 항-트립신 (AAT) 근위 프로모터를 포함한다.
제1 측면에서, 본 발명의 AAV 벡터는 서열번호 9에서 제시된 핵산 서열을 포함하는 작제물 100ATG을 포함한다.
제2 측면에서, 본 발명의 AAV 벡터는 서열번호 10에서 제시된 핵산 서열을 포함하는 작제물 100ATG bGH poly A을 포함한다.
제3 측면에서, 본 발명의 AAV 벡터는 서열번호 11에서 제시된 작제물 100ATG 짧은 bGH polyA 서열을 포함한다.
제4 측면에서, 본 발명의 AAV 벡터는 서열번호 12에서 제시된 핵산 서열을 포함하는 작제물 103ATG을 포함한다.
제 5 측면에서, 본 발명의 AAV 벡터는 서열번호 13에서 제시된 핵산 서열을 포함하는 작제물 103ATG 짧은 bGH poly A을 포함한다.
제6 측면에서, 본 발명의 AAV 벡터는 서열번호 14에서 제시된 핵산 서열을 포함하는 작제물 105ATG bGH poly A을 포함한다.
제7 측면에서, 본 발명의 AAV 벡터는 서열번호 15에서 제시된 핵산 서열을 포함하는 작제물 DC172ATG FVIII을 포함한다.
제8 측면에서, 본 발명의 AAV 벡터는 서열번호 16에서 제시된 핵산 서열을 포함하는 작제물 DC172ATG FVIII hAAT를 포함한다.
제9 측면에서, 본 발명의 AAV 벡터는 서열번호 17에서 제시된 핵산 서열을 포함하는 작제물 DC172 2xHCR ATG FVIII을 포함한다.
제10 측면에서, 본 발명의 AAV 벡터는 서열번호 18에서 제시된 핵산 서열을 포함하는 작제물 DC172 2xHCR ATG FVIII hAAT를 포함한다.
제11 측면에서, 본 발명의 AAV 벡터는 서열번호 19에서 제시된 핵산 서열을 포함하는 작제물 2x 세르핀A hAAT ATG FVIII을 포함한다.
제12 측면에서, 본 발명의 AAV 벡터는 서열번호 20에서 제시된 핵산 서열을 포함하는 작제물 2x 세르핀A hAAT ATG FVIII 2x μ-글로불린 인핸서을 포함한다.
제13 측면에서, 본 발명의 AAV 벡터는 서열번호 21에서 제시된 핵산 서열을 포함하는 작제물 100ATG 짧은 polyA 2x μ-글로불린 인핸서을 포함한다.
제14 측면에서, 본 발명의 AAV 벡터는 서열번호 22에서 제시된 핵산 서열을 포함하는 작제물 인자 VIII-BMN001을 포함한다.
제15 측면에서, 본 발명의 AAV 벡터는 서열번호 23에서 제시된 핵산 서열을 포함하는 작제물 인자 VIII-BMN002 서열을 포함한다.
제16 측면에서, 본 발명의 AAV 벡터는 서열번호 24에서 제시된 핵산 서열을 포함하는 작제물 99을 포함한다.
제17 측면에서, 본 발명의 AAV 벡터는 서열번호 25에서 제시된 핵산 서열을 포함하는 작제물 100을 포함한다.
제18 측면에서, 본 발명의 AAV 벡터는 서열번호 26에서 제시된 핵산 서열을 포함하는 작제물 100 역방향을 포함한다.
제19 측면, 본 발명의 AAV 벡터는 서열번호 27에서 제시된 핵산 서열을 포함하는 작제물 100AT를 포함한다.
제20 측면, 본 발명의 AAV 벡터는 서열번호 28에서 제시된 핵산 서열을 포함하는 작제물 100AT 2x MG을 포함한다.
제21 측면에서, 본 발명의 AAV 벡터는 서열번호 29에서 제시된 핵산 서열을 포함하는 작제물 100AT 2x MG bGH polyA을 포함한다.
제22 측면에서, 본 발명의 AAV 벡터는 서열번호 30에서 제시된 핵산 서열을 포함하는 작제물 100AT 2x MG (역) bGH polyA을 포함한다.
제23 측면에서, 본 발명의 AAV 벡터는 서열번호 31에서 제시된 핵산 서열을 포함하는 작제물 100 bGH polyA을 포함한다.
제24 측면에서, 본 발명의 AAV 벡터는 서열번호 32에서 제시된 핵산 서열을 포함하는 작제물 100-400을 포함한다.
제25측면에서, 본 발명의 AAV 벡터는 서열번호 33에서 제시된 핵산 서열을 포함하는 작제물 101을 포함한다.
제26 측면에서, 본 발명의 AAV 벡터는 서열번호 34에서 제시된 핵산 서열을 포함하는 작제물 102 서열을 포함한다.
제27 측면에서, 본 발명의 AAV 벡터는 서열번호 35에서 제시된 핵산 서열을 포함하는 작제물 103을 포함한다.
제29 측면에서, 본 발명의 AAV 벡터는 서열번호 36에서 제시된 핵산 서열을 포함하는 작제물 103 역방향을 포함한다.
제30 측면에서, 본 발명의 AAV 벡터는 서열번호 37에서 제시된 핵산 서열을 포함하는 작제물 103AT를 포함한다.
제31 측면에서, 본 발명의 AAV 벡터는 서열번호 38에서 제시된 핵산 서열을 포함하는 작제물 103AT 2xMG을 포함한다.
제32 측면에서, 본 발명의 AAV 벡터는 서열번호 39에서 제시된 핵산 서열을 포함하는 작제물 103AT 2xMG bGH polyA을 포함한다.
제33 측면에서, 본 발명의 AAV 벡터는 서열번호 40에서 제시된 핵산 서열을 포함하는 작제물 103 bGH polyA을 포함한다.
제34 측면에서, 본 발명의 AAV 벡터는 서열번호 41에서 제시된 핵산 서열을 포함하는 작제물 104를 포함한다.
제35 측면에서, 본 발명의 AAV 벡터는 서열번호 42에서 제시된 핵산 서열을 포함하는 작제물 105를 포함한다.
제36 측면에서, 본 발명의 AAV 벡터는 서열번호 43에서 제시된 핵산 서열을 포함하는 작제물 106을 포함한다.
제37 측면에서, 본 발명의 AAV 벡터는 서열번호 44에서 제시된 핵산 서열을 포함하는 작제물 106AT를 포함한다.
제38 측면에서, 본 발명의 AAV 벡터는 서열번호 45에서 제시된 핵산 서열을 포함하는 작제물 2x 세르핀A hAAT를 포함한다.
또 다른 구현예에서, 본 발명은 기능적 인자 VIII 폴리펩타이드를 인코딩하는 벡터 작제물에 관한 것이고, 여기서 상기 작제물은 상기 기재된 작제물의 개별 요소 중 하나 이상 및 이들의 조합을, 하나 이상의 상이한 방향(들)으로 포함한다. 본 발명은 또한, 반대의 방향의 상기 기재된 작제물에 관한 것이다.
단일 가닥 중 본 발명의 AAV 벡터는 약 7.0 kb 미만이거나, 또는 그 길이가 6.5kb 미만이거나, 또는 그 길이가 6.4 kb 미만이거나, 또는 그 길이가 6.3 kb 미만이거나, 또는 그 길이가 6.2 kb 미만이거나, 또는 그 길이가 6.0 kb 미만이거나, 또는 그 길이가 5.8 kb 미만이거나, 또는 그 길이가 5.6 kb 미만이거나, 또는 그 길이가 5.5 kb 미만이거나, 또는 그 길이가 5.4 kb 미만이거나, 또는 그 길이가 5.4 kb 미만이거나, 또는 그 길이가 5.2 kb 미만이거나, 그 길이가 5.0 kb 미만이다. 단일 가닥 중 본 발명의 AAV 벡터는 그 길이가 약 5.0 kb 내지 약 6.5 kb의 범위이거나, 또는 그 길이가 약 4.8 kb 내지 약 5.2 k의 범위이거나, 또는 4.8 kb 내지 5.3 kb의 범위이거나, 또는 그 길이가 약 4.9 kb 내지 약 5.5 kb의 범위이거나, 또는 약 4.8 kb 내지 약 6.0 kb의 범위이거나, 또는 약 5.0 kb 내지 6.2 kb의 범위이고 또는 약 5.1 kb 내지 약 6.3 kb의 범위이거나, 또는 약 5.2 kb 내지 약 6.4 kb의 범위이거나, 또는 약 5.5 kb 내지 약 6.5 kb의 범위이다.
또 하나의 구현예에서, 본 발명은 본 발명의 AAV 벡터 중 임의의 것을 포함하는 재조합 아데노-관련된 바이러스 (AAV) 입자를 생산하는 방법을 제공한다. 상기 방법은 본 발명의 AAV 벡터 중 임의의 것으로 형질감염된 세포를 배양하는 단계 및 재조합 AAV를 상기 형질감염된 세포의 상청액으로부터 회수하는 단계를 포함한다.
본 발명의 세포는 하기를 포함하는 바큘로바이러스 감염에 민감한 임의의 세포형이다: 곤충 세포 예컨대 High 5, Sf9, Se301, SeIZD2109, SeUCR1, Sf9, Sf900+, Sf21, BTI-TN-5B1-4, MG-1, Tn368, HzAm1, BM-N, Ha2302, Hz2E5 및 Ao38. 사용된 바람직한 포유동물 세포는 HEK293, HeLa, CHO, NS0, SP2/0, PER.C6, Vero, RD, BHK, HT 1080, A549, Cos-7, ARPE-19 및 MRC-5 세포일 수 있고, 그리고 포유동물 세포 예컨대 HEK293, HeLa, CHO, NS0, SP2/0, PER.C6, Vero, RD, BHK, HT 1080, A549, Cos-7, ARPE-19 및 MRC-5 세포를 포함한다.
본 발명은 또한, 본 발명의 AAV 벡터 중 임의의 것을 포함하는 바이러스 입자 또는 본 발명의 상기 방법에 의해 생산된 임의의 바이러스 입자를 제공한다.
"AAV 비리온" 또는 "AAV 바이러스 입자" 또는 "AAV 벡터 입자"는 적어도 하나의 AAV 캡시드 단백질 및 캡시드화된 폴리뉴클레오타이드 AAV 벡터로 구성된 바이러스 입자를 의미한다. 입자가 이종성 폴리뉴클레오타이드 (즉 야생형 AAV 게놈 예컨대 포유동물 세포에 전달될 이식유전자 이외의 폴리뉴클레오타이드)를 포함하면, 전형적으로 "AAV 벡터 입자" 또는 간단히 "AAV 벡터"로 불린다. 따라서, AAV 벡터 입자의 생산은 필연적으로, 그와 같은 벡터가 AAV 벡터 입자 내에 함유된 것처럼 AAV 벡터의 생산을 포함한다.
본 발명은 또한, 본 발명의 AAV 벡터 중 임의의 것를 포함하는 세포, 및 본 발명의 이들 세포에 의해 생산된 바이러스 입자를 제공한다.
또 하나의 구현예에서, 본 발명은 혈우병 A를 앓고 있는 환자를 치료하는 방법을 제공하고, 이 방법은 상기 환자에게 유효량의 본 발명의 AAV 벡터 중 임의의 것, 또는 본 발명의 바이러스 입자 또는 본 발명의 방법으로 생산된 바이러스 입자를 투여하는 것을 포함한다.
추가 구현예에서, 본 발명은 혈우병 A의 치료용 약제의 제조를 위한, 본 발명의 AAV 벡터 중 임의의 것의 용도를 제공한다. 일 측면에서, 상기 약제는 혈우병 A를 치료하는데 효과적인 양으로 인간 FVIII를 발현시키는 AAV 벡터의 양을 포함한다.
또 하나의 구현예에서, 본 발명은 혈우병 A의 치료를 위해 본 발명의 AAV 벡터 중 임의의 것을 포함하는 조성물을 제공한다. 일 측면에서, 본 조성물은 혈우병 A를 치료하는데 효과적인 양으로 인간 FVIII을 발현시키는 AAV 벡터의 양을 포함한다.
또 하나의 구현예에서, 본 발명의 AAV 벡터는 혈우병 A를 앓고 있는 환자를 치료하는데 유용한 AAV 바이러스 입자를 생산하기 위해 사용된다.
도 1은 UCL SQ 벡터의 도식을 제공한다. 좌측에서 우측으로, UCL SQ 벡터는 AAV2 5' ITR, 야생형 AAV2 바이러스 서열, 34개 염기의 인간 ApoE/C1 인핸서, 32개 염기의 인간 AAT 프로모터 원위 X 영역, 5' UTR 서열의 42개의 염기를 포함하는 186개 염기의 인간 AAT 프로모터, 코돈-최적화된 인간 FVIII SQ 서열 (본원에 그 전체가 참고로 편입되어 있는, 2013년 1월 24일에 공개된 Nathwani 등, US 특허 출원 공개 제2013/0024960A1호, 및 McIntosh 등, Blood 121:3335-3344, 2013 참고), 49개 염기의 합성 폴리아데닐화 서열, 야생형 AAV2 바이러스 서열, 및 AAV2 3'ITR을 포함한다. UCL SQ 벡터는 5081개의 염기 길이를 갖는다.
도 2는 프로토 1, 프로토 1S, 프로토 2S 및 프로토 3S 벡터의 도식 및 서열을 제공한다. (A) 프로토 1 벡터의 도식. UCL SQ 벡터 (도 1 참고)로부터 시작하여, 외부 야생형 AAV2 바이러스 서열이 결실되었고, 인간 AAT 5' UTR 및 인간 FVIII 코딩 영역 사이의 제한 부위, 및 인간 FVIII 종료 코돈 및 합성 폴리아데닐화 서열 사이의 제한 부위에 상응하는 서열들이 제거되었다. (B) 프로토 1S 벡터의 도식. 프로토 1 벡터로부터 시작하여, AAV2 5'ITR의 3' 말단에 있는 10개의 염기 및 3' ITR의 5' 말단에 있는 10개의 염기가 결실되었다. (C) 프로토 2S 벡터의 도식. 프로토 1S 벡터로부터 시작하여, 인간 ApoE/C1 인핸서 및 인간 AAT 프로모터 원위 X 영역이 인간 FVIII 서열의 엑손 1 및 2 사이에 삽입된 100개 염기의 합성 인트론 내로 이동되었다. 화살표로 표시된 바와 같이, 인간 ApoE/C1 인핸서 및 인간 AAT 프로모터 원위 X 영역의 방향은 프로토 1S에서의 방향과 비교하여 역전되어 있다. (D) 프로토 3S 벡터의 도식. 프로토 2S로부터 시작하여, 인간 AAT 프로모터 원위 X 영역이 역방향으로 인간 ApoE/C1 인핸서의 제2 카피에 의해 치환되어 있다.
도 3은 프로토 4, 프로토 5, 프로토 6 및 프로토 7 벡터의 도식을 제공한다. (A) 프로토 4 벡터의 도식. 프로토 1 벡터로부터 시작하여, SQ 서열 및 a3 도메인이 결실되어 있다. (B) 프로토 5 벡터의 도식. 프로토 4 벡터로부터 시작하여, 129개의 염기 FVIII 인트론이 인간 인자 VIII 서열의 엑손 1 및 2 사이에 삽입되었다. (C) 프로토 6 벡터의 도식. 프로토 5 벡터로부터 시작하여, 인간 ApoE/C1 인핸서의 제2 카피가 순방향으로 FVIII 인트론 내로 삽입되었다. (D) 프로토 7 벡터의 도식. 프로토 5 벡터로부터 시작하여, 인간 ApoE/C1 인핸서의 제2 카피가 역방향으로 FVIII 인트론 내로 삽입되었다.
도 4A-도 4KK는 개선된 프로모터/인핸서 서열을 갖는 AAV FVIII 벡터의 도식을 제공한다. (A) 작제물 100ATG의 도식. (B) 작제물 100ATG bGH polyA의 도식. (C) 작제물 100ATG 짧은 bGH poly A의 도식. (D) 작제물 103ATG의 도식. (E) 작제물 103ATG 짧은 bGH poly A의 도식. (F) 작제물 105ATG bGH polyA의 도식. (G) 작제물 DC172ATG FVIII의 도식. (H) 작제물 DC172ATG FVIII hAAT의 도식. (I) 작제물 DC172 2xHCR ATG FVIII의 도식. (J) 작제물 DC172 2xHCR ATG FVIII hAAT의 도식. (K) 작제물 2x 세르핀A hAAT ATG FVIII의 도식. (L) 작제물 2x 세르핀A hAAT ATG FVIII 2x μ-글로불린 인핸서의 도식. (M) 작제물 100ATG 짧은 bGH poly A 2x μ-글로불린 인핸서의 도식. (N) 작제물 인자 VIII-BMN001의 도식. (O) 작제물 FVIII-BMN002의 도식. (P) 작제물 99의 도식. (Q) 작제물 100의 도식. (R) 작제물 100 역방향의 도식. (S) 작제물 100AT의 도식. (T) 작제물 100AT 2x MG의 도식. (U) 작제물 100AT 2x MG bGH polyA의 도식. (V) 작제물 100AT 2x MG (역) bGH poly A의 도식. (W) 작제물 100 bGH poly A의 도식. (X) 작제물 100-400의 도식. (Y) 작제물 101의 도식. (Z) 작제물 102의 도식. (AA) 작제물 103의 도식. (BB) 작제물 103 역방향의 도식 (CC) 작제물 103AT의 도식. (DD) 작제물 103AT 2x MG의 도식. (EE) 작제물 103AT 2x MG bGH poly A의 도식. (FF) 103 sbGH poly A의 도식. (GG) 작제물 104의 도식. (HH) 작제물 105의 도식. (II) 작제물 106의 도식. (JJ) 작제물 106AT의 도식. (KK) 작제물 2x 세르핀A hAAT의 도식.
도 5는 Rag2 마우스에서 프로토 작제물의 결과를 제공하며, 프로토 1은 야생형과 유사하게 FVIII을 전달함을 입증한다.
도 6 및 7은 프로토 1, 프로토 1S, 프로토 2S 및 프로토 3S가 VP1, VP2 및 VP3 단백질을 발현하고 (도 5), VP1, VP2 및 VP3 DNA를 발현하는 것 (도 6)을 입증한다.
도 8-10은 개선된 프로모터 작제물이 FVIII의 발현을 증가시킨다는 것을 입증한다.
대형 AAV 벡터는 5' 말단이 무작위로 절단되고 5' AAV ITR이 결실되어 있다. AAV는 단일가닥 DNA 바이러스이며, 센스 또는 안티센스 가닥 중 하나를 패키징하기 때문에, 대형 AAV 벡터 내의 센스 가닥은 5' AAV ITR 및 가능하게는 표적 단백질-코딩 유전자의 5' 말단 부분이 결실되어 있고, 대형 AAV 벡터 내의 안티센스 가닥은 3' ITR 및 가능하게는 표적 단백질-코딩 유전자의 3' 말단 부분이 결실되어 있다. 기능적 이식유전자는 표적 세포 내에서 센스 및 안티센스 말단이 절단된 (truncated) 게놈의 어닐링에 의해 대형 AAV 벡터 감염된 세포에서 생산된다.
본 발명은 기능적 활성 FVIII을 인코딩하는 AAV 벡터, 즉, 완전히 패키징된 AAV FVIII 벡터 또는 높은 발현 활성을 갖는 AAV FVIII 벡터를 제공한다. 본 발명의 AAV FVIII 벡터는 개선된 발현/입자, 뿐만 아니라 개선된 AAV 바이러스 생산 수율 및 간소화한 정제를 갖는다. 하나 이상의 인트론을 FVIII 단백질-코딩 영역 내로 도입하는 것은 발현을 향상시킨다. 인핸서의 수 및 위치를 변경하는 것 역시 발현을 향상시킨다.
UCL SQ 벡터
문헌[Nathwani 등, US 특허 출원 공개 제2013/0024960A1호(2013년 1월 24일에 공개됨, 이는 본원에 그 전체가 참고로 편입되어 있음), 및 McIntosh 등, Blood 121:3335-3344, 2013]에 상세히 기재된 UCL SQ 벡터는 대형, 즉, 5.0 kb보다 큰, AAV 벡터이다. 도 1에 나타난 바와 같이, UCL SQ 벡터는 좌측에서 우측으로 AAV 혈청형 2 (AAV2) 5' ITR, 야생형 AAV2 바이러스 서열, 34개 염기의 인간 아포지질단백질 E (ApoE)/C1 인핸서, 32개 염기의 인간 알파 항-트립신 (AAT) 프로모터 원위 X 영역, 5' 미번역된 영역 (UTR) 서열의 42개의 염기를 포함하는 186개 염기의 인간 AAT 프로모터, B 도메인이 14개 아미노산 SQ 서열로 치환된 코돈-최적화된 인간 FVIII 서열, 49개 염기의 합성 폴리아데닐화 서열, 야생형 AAV2 바이러스 서열, 및 AAV2 3'ITR을 포함한다. UCL SQ 벡터는 5081개의 염기의 길이를 갖는다.
문헌[Nathwani 등, US 특허 출원 공개 제2013/0024960A1호(2013년 1월 24일에 공개됨), 및 McIntosh 등, Blood 121:3335-3344, 2013]에서 나타나 바와 같이, UCL SQ 벡터는 시험관내 및 생체내에서 기능적 활성 FVIII을 발현한다.
프로토 1, 프로토 1S, 프로토 2S 및 프로토 3S 벡터
대형의 AAV 벡터의 문제를 피하고/거나 AAV 벡터의 발현을 증가시키기 위해, 본 발명은 완전히 포장된, 더 작은, 즉, 5.0 kb 미만의, FVIII SQ 변종을 인코딩하는 AAV 벡터를 제공한다. 프로토 1의 서열의4970 bp 뉴클레오타이드 서열은 서열번호 1에서 제시되어 있다.
AAV 벡터 프로토 1을 산출하기 위해, 기능적 활성 FVIII의 생산에 불필요한 것으로 보이는 서열은 UCL SQ 벡터와 비교하여 결실되었다. 실시예 1에서 보여진 바와 같이, 이질적인 DNA의110개의 염기는 제거되었고, 이 염기는 AAV2 바이러스 서열 3'에서 AAV2 5'ITR로의 53개의 염기, AAV2 바이러스 서열 5'에서 AAV2 3'ITR로의 46개의 염기, 및 코돈-최적화된 FVIII SQ 코딩 영역에 인접한 11개의 염기를 포함한다. 그 결과로 생긴 프로토 1 벡터는 4970개의 염기의 길이를 갖는다. 설계될 때, 프로토 1 벡터가 시험관내 또는 생체내에서 기능적 FVIII 폴리펩타이드를 발현시킬 수 있는 지는 미공지되어 있다.
AAV 벡터 프로토 1S을 산출하기 위해, AAV2 5’ITR의 3’ 말단에 있는 10개의 염기, 및 AAV32 3’ITR의 5’ 말단에 있는 10개의 염기는, 프로토 1 벡터로부터 제거되었다. 그 결과로 생긴 프로토 1S 벡터는 4950개의 염기의 길이를 갖는다. 프로토 1S의 서열의 뉴클레오타이드 서열은 서열번호 2에서 제시되어 있다.
AAV 벡터 프로토 2S를 산출하기 위해, 100개의 염기 합성 인트론은 프로토 1S 벡터에서 코돈-최적화된 FVIII SQ 서열의 엑손 1과 2 사이에서 삽입되었다. 34개의 염기 ApoE/C1 인핸서 및 32개의 염기 인간 AAT 프로모터 원위 X 영역은 인간 AAT 프로모터의 업스트림으로부터 제거되었고 (이들 요소가 인간 AAT 프로모터의 업스트림에서 위치한 방향과 비교할 때) 역방향에서 합성 인트론에 삽입되었다. 그 결과로 생긴 프로토 2S 벡터는 4983개의 염기의 길이를 갖는다. 프로토 2S의 서열의 뉴클레오타이드 서열은 서열번호 3에서 제시되어 있다.
AAV 벡터 프로토 3S를 산출하기 위해, 인간 AAT 프로모터 원위 X 영역은 프로토 2S 벡터로부터 제거되었고, 역방향에서 34개의 염기 ApoE/C1 인핸서의 제2 복제물로 대체되었다. 그 결과로 생긴 프로토 3S 벡터는 4984개의 염기의 길이를 갖는다. 프로토 3S의 서열의 뉴클레오타이드 서열은 서열번호 4에서 제시되어 있다.
프로토 4, 프로토 S, 프로토 6 및 프로토 7 벡터
AAV 벡터의 크기를 감소시키고/거나 AAV 벡터의 발현을 증가시키기 위해, 본 발명은 또한, 완전히 포장된, 더 작은, 즉, 5.0 kb 미만의, B 도메인을 인코딩하는 AAV 벡터 및 a3 도메인 결실된 FVIII을 제공한다.
AAV 벡터 프로토 4를 산출하기 위해, 14 아미노산 SQ 서열 및 C 도메인에 인접하여 위치한 a3 도메인은 프로토 1 벡터로부터 제거되었다. 결실된 FVIII 서열의 총량은 55 아미노산 또는 165개의 염기이다. 그 결과로 생긴 프로토 4 벡터는 4805개의 염기의 길이를 갖는다. 프로토 4의 서열의 뉴클레오타이드 서열은 서열번호 5에서 제시되어 있다.
AAV 벡터 프로토 5를 산출하기 위해, 129개의 염기 말단이 절단된 FVIII 인트론은 프로토 4 벡터에서 코돈-최적화된 FVIII 서열의 엑손 1와 2 사이에 삽입되었다. 그 결과로 생긴 프로토 5 벡터는 4934개의 염기의 길이를 갖는다. 프로토 5의 서열의 뉴클레오타이드 서열은 서열번호 6에서 제시되어 있다.
AAV 프로토 6 벡터를 산출하기 위해, FVIII 인트론의 34개의 염기는 프로토 5 벡터의 순방향에서 34개의 염기 인간 ApoE/C1 인핸서의 제2 복제물로 대체되었다. 그 결과로 생긴 프로토 6 벡터는 4934개의 염기의 길이를 갖는다. 프로토 6의 서열의 뉴클레오타이드 서열은 서열번호 7에서 제시되어 있다.
AAV 프로토 7 벡터를 산출하기 위해, FVIII 인트론의 34개의 염기는 프로토 5 벡터의 역방향에서 34개의 염기 인간 ApoE/C1 인핸서의 제2 복제물로 대체되었다. 그 결과로 생긴 프로토 7 벡터는 4934개의 염기의 길이를 갖는다. 프로토 7의 서열의 뉴클레오타이드 서열은 서열번호 8에서 제시되어 있다.
향상된 프로모터/ 인핸서 서열을 갖는 추가의 AAV FVIII 벡터
강한 프로모터를 갖는 대형 AAV 벡터는 B 도메인 및 a3 도메인 결실된 FVIII의 발현을 증가시키기 위해 산출되었고, 이들 작제물은 변형된 인핸서 및/또는 프로모터 서열로 산출되었다. 일부 구현예에서, AAV FVIII 벡터는 말단이 절단된 기능적 FVIII을 발현시킨다. 이들 작제물은 하기를 포함했다: 하나 이상의 프로모터 및 인핸서 서열 예컨대 ApoE HCR 또는 그것의 단편, μ-글로불린 인핸서 또는 그것의 단편, 인간 알파 1 항트립신 프로모터 (hAAT) 또는 그것의 단편, 세르핀 A 인핸서 또는 그것의 단편, LP1 프로모터 인핸서 또는 그것의 단편 또는 매크로글로불린 인핸서 또는 그것의 단편. 이들 작제물은 폴리아데닐화 서열 예컨대 bGH poly A 서열 또는 합성 토끼 β-글로빈 poly A 서열을 포함한다. 일부 구현예에서, 작제물은 인트론 또는 인트론 예컨대 hAAT 인트론 또는 인간 β-글로빈 인트론의 단편을 포함한다.
작제물 100ATG는 5511개의 염기의 길이를 갖는다. 이 작제물은 서열번호 9에서 제시되고, 여기서 염기 1-145는 5'AAV2 ITR이고, 염기 160-502는 ApoE HCR이고, 염기 509-726은 hAAT 프로모터이고, 염기 727-910은 변형된 인간 β-글로빈 제2 인트론이고, 염기 923-5296은 코돈 최적화된 SQ FVIII이고, 염기 5305-5352는 합성 토끼 β-글로빈 poly A이고, 그리고 염기 5367-5511은 3' AAV2 ITR이다.
작제물 100ATG bGH poly A는 5688개의 염기의 길이를 갖는다. 이 작제물은 서열번호 10에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 160-502는 ApoE HCR이고, 염기 509-726은 hAAT 프로모터이고, 염기 727-910은 변형된 인간 β-글로빈 제2 인트론이고, 염기 923-5296은 코돈 최적화된 SQ FVIII이고, 염기 5305-5529는 bGH poly A이고, 그리고 염기 5544-5688은 3' AAV2 ITR이다.
작제물 100ATG 짧은 bGH poly A는 5613개의 염기의 길이를 갖는다. 이 작제물은 서열번호 11에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 160-502는 ApoE HCR이고, 염기 509-726은 hAAT 프로모터이고, 염기 727-910은 변형된 인간 β-글로빈 제2 인트론이고, 염기 923-5296은 코돈 최적화된 SQ FVIII이고, 염기 5305-5454는 짧은 bGH poly A이고, 그리고 염기 5469-5613은 3' AAV2 ITR이다.
작제물 103ATG는 5362개의 염기의 길이를 갖는다. 이 작제물은 서열번호 12에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 169-344는 44bp ApoE 반복체의 4개의 복제물(4x)이고, 염기 360-577은 hAAT 프로모터이고, 염기 578-761은 변형된 인간 β-글로빈 제2 인트론이고, 염기 774-5147은 코돈 최적화된 SQ FVIII이고, 염기 5156-5203는 합성 토끼 β-글로빈 poly A이고, 그리고 염기 5218-5362은 3' AAV2 ITR이다.
작제물 103ATG 짧은 bGH poly A는 5464개의 염기의 길이를 갖는다. 이 작제물은 서열번호 13에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 169-344는 44bp ApoE 반복체의 4개의 복제물(4x)이고, 염기 360-577은 hAAT 프로모터이고, 염기 578-761은 변형된 인간 β-글로빈 제2 인트론이고, 염기 774-5147은 코돈 최적화된 SQ FVIII이고, 염기 5156-5305는 bGH 짧은 poly A 및 염기 5320-5464은 3' AAV2 ITR이다.
작제물 105ATG bGH polyA은 6354개의 염기의 길이를 갖는다. 이 작제물은 서열번호 14에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 173-512는 170 bp 마이크로글로불린 인핸서의 2개의 복제물(2x)이고, 염기 519-736은 hAAT 프로모터이고, 염기 737-920은 변형된 인간 β-글로빈 제2 인트론이고, 염기 933-5306은 코돈 최적화된 SQ FVIII이고, 염기 5315-5539는 bGH poly A이고, 염기 5546-6195는 325 bp ApoE HCR의 2개의 복제물(2x)이고, 그리고 염기 6210-6354은 3' AAV2 ITR이다.
작제물 DC172ATG FVIII은 6308개의 염기의 길이를 갖는다. 이 작제물은 서열번호 15에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 160-449는 145 bp 매크로글로불린 인핸서의 2개의 복제물 (2x)이고, 염기 450-1347은 898 bp hAAT 프로모터이고, 염기 1348-1531은 변형된 인간 β-글로빈 제2 인트론이고, 염기 1544-5917은 코돈 최적화된 SQ FVIII이고, 염기 5926-6149는 bGH poly A이고, 그리고 염기 6164-6308은 3' AAV2 ITR이다.
작제물 DC172ATG FVIII hAAT는 5635개의 염기의 길이를 가지며, 이 작제물은 서열번호 16에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 160-449는 145 bp 매크로글로불린 인핸서의 2개의 복제물 (2x)이고, 염기 457-674은 hAAT 프로모터이고, 염기 675-858은 변형된 인간 β-글로빈 제2 인트론이고, 염기 871-5244은 코돈 최적화된 SQ FVIII이고, 염기 5253-5476는 bGH poly A이고, 그리고 염기 5490-5635은 3' AAV2 ITR이다.
작제물 DC172 2xHCR ATG FVIII은 6962개의 염기의 길이를 갖는다. 이 작제물은 서열번호 17에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 160-807는 321 bp ApoE HCR의 2개의 복제물 (2x)이고, 염기 814-1103는 145 bp 매크로글로불린 인핸서의 2개의 복제물 (2x)이고, 염기 1104-2001는 898 bp hAAT 프로모터이고, 염기 2002-2185는 변형된 인간 β -글로빈 제2 인트론이고, 염기 2198-6571은 코돈 최적화된 SQ FVIII이고, 염기 6580-6803는 bGH poly A이고, 그리고 염기 6818-6962은 3' AAV2 ITR이다.
작제물 DC172 2xHCR ATG FVIII hAAT는 6289개의 염기의 길이를 갖는다. 이 작제물은 서열번호 18에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 160-807는 321 bp ApoE HCR의 2개의 복제물 (2x)이고, 염기 814-1103는 145 bp 매크로글로불린 인핸서의 2개의 복제물 (2x)이고, 염기 1111-1328은 hAAT 프로모터이고, 염기 1329-1512는 변형된 인간 β -글로빈 제2 인트론이고, 염기 1525-5898은 코돈 최적화된 SQ FVIII이고, 염기 5907-6130는 bGH poly A이고, 그리고 염기 6245-6289은 3' AAV2 ITR이다.
작제물 2x 세르핀A hAAT ATG FVIII은 5430개의 염기의 길이를 갖는다. 이 작제물은 서열번호 19에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 168-309는 71 bp 세르핀A 인핸서의 2개의 복제물 (2x)이고, 염기 326-543은 hAAT 프로모터이고, 염기 544-727은 변형된 인간 β-글로빈 제2 인트론이고, 염기 740-5113은 코돈 최적화된 SQ FVIII이고, 염기 5122-5271는 짧은 bGH poly A이고, 그리고 염기 5286-5430은 3'AAV2 ITR이다.
작제물 2x 세르핀A hAAT ATG FVIII 2x μ-글로불린 인핸서은 5779개의 염기의 길이를 갖는다. 이 작제물은 서열번호 20에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 168-309는 71 bp 세르핀A 인핸서의 2개의 복제물 (2x)이고, 염기 326-543은 hAAT 프로모터이고, 염기 544-727는 변형된 인간 β -글로빈 제2 인트론이고, 염기 740-5113은 코돈 최적화된 SQ FVIII이고, 염기 5122-5271는 짧은 bGH poly A이고, 염기 5279-5618은 170 bp μ-글로불린 인핸서의 2개의 복제물 (2x)이고, 그리고 염기 5635-5779은 3' AAV2 ITR이다.
작제물 100ATG 짧은 bGH poly A 2x μ-글로불린 인핸서은 5962개의 염기의 길이를 갖는다. 이 작제물은 서열번호 21에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 160-502는 ApoE HCR이고, 염기 509-726은 hAAT 프로모터이고, 염기 727-910은 변형된 인간 β-글로빈 제2 인트론이고, 염기 923-5296은 코돈 최적화된 SQ FVIII이고, 염기 5305-5454는 짧은 bGH poly A이고, 염기 5462-5801은 170 bp 마이크로글로불린 인핸서의 2개의 복제물 (2x)이고, 그리고 염기 5818-5962은 3' AAV2 ITR이다.
작제물 인자 VIII-BMN001은 5919개의 염기의 길이를 갖는다. 이 작제물은 서열번호 22에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 160-480는 ApoE HCR이고, 염기 487-884는 398bp hAAT 프로모터이고, 염기 885-1145는 끝이 잘린 hAAT 인트론이고, 염기 1155-5528은 코돈 최적화된 SQ FVIII이고, 염기 5537-5760는 bGH poly A이고, 그리고 염기 5775-5919은 3' AAV2 ITR이다.
작제물 FVIII-BMN002는 5306개의 염기의 길이를 갖는다. 이 작제물은 서열번호 23에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 175-705는 LP1 프로모터/인핸서이고, 염기 718-5091은 코돈 최적화된 SQ FVIII이고, 염기 5100-5147는 합성 토끼 β-글로빈 poly A이고, 그리고 염기 5162-5306은 3' AAV2 ITR이다.
작제물 99는 5461개의 염기의 길이를 갖는다. 이 작제물은 서열번호 24에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 169-627는 ApoE HCR/MAR, 염기 634-866은 hAAT 프로모터이고, 염기 873-5246은 코돈 최적화된 SQ FVIII이고, 염기 5255-5302는 합성 토끼 β-글로빈 poly A이고, 그리고 염기 5317-5461은 3' AAV2 ITR이다.
작제물 100은 5327개의 염기의 길이를 갖는다. 이 작제물은 서열번호 25에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 169-493는 ApoE HCR이고, 염기 509-726은 hAAT 프로모터이고, 염기 739-5112은 코돈 최적화된 SQ FVIII이고, 염기 5121-5168는 합성 토끼 β-글로빈 poly A이고, 그리고 염기 5183-5327은 3' AAV2 ITR이다.
작제물 100 역방향은 5309개의 염기의 길이를 갖는다. 이 작제물은 서열번호 26에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 160-484는 역방향의 ApoE HCR이고, 염기 491-708은 hAAT 프로모터이고, 염기 721-5094은 코돈 최적화된 SQ FVIII이고, 염기 5103-5150는 합성 토끼 β-글로빈 poly A이고, 그리고 염기 5165-5309은 3' AAV2 ITR이다.
작제물 100AT는 5532개의 염기의 길이를 갖는다. 이 작제물은 서열번호 27에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 169-493는 ApoE HCR이고, 염기 509-726은 hAAT 프로모터이고, 염기 727-931는 hAAT 인트론이고, 염기 944-5317은 코돈 최적화된 SQ FVIII이고, 염기 5326-5373는 합성 토끼 β-글로빈 poly A이고, 그리고 염기 5388-5532은 3' AAV2 ITR이다.
작제물 100AT 2x MG는 5877개의 염기의 길이를 갖는다. 이 작제물은 서열번호 28에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 169-493는 ApoE HCR이고, 염기 508-847은 170 bp μ-글로불린 인핸서의 2개의 복제물 (2x)이고, 염기 854-1071은 hAAT 프로모터이고, 염기 1072-1276는 hAAT 인트론이고, 염기 1289-5662은 코돈 최적화된 SQ FVIII이고, 염기 5671-5718는 합성 토끼 β-글로빈 poly A이고, 그리고 염기 5733-5877은 3' AAV2 ITR이다.
작제물 100AT 2x MG bGH poly A는 6054개의 염기의 길이를 갖는다. 이 작제물은 서열번호 29에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 169-493는 ApoE HCR이고, 염기 508-847은 170 bp μ-글로불린 인핸서의 2개의 복제물 (2x)이고, 염기 854-1071은 hAAT 프로모터이고, 염기 1072-1276는 hAAT 인트론이고, 염기 1289-5662은 코돈 최적화된 SQ FVIII이고, 염기 5671-5895는 bGH poly A이고, 그리고 염기 5910-6054은 3' AAV2 ITR이다.
작제물 100AT 2x MG (역) bGH poly A는 6054개의 염기의 길이를 갖는다. 이 작제물은 서열번호 30에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 169-493는 ApoE HCR이고, 염기 508-847은 역방향의 170 bp μ-글로불린 인핸서의 2개의 복제물 (2x)이고, 염기 854-1071은 hAAT 프로모터이고, 염기 1072-1276는 hAAT 인트론이고, 염기 1289-5662은 코돈 최적화된 SQ FVIII이고, 염기 5671-5895는 bGH poly A이고, 그리고 염기 5910-6054은 3' AAV2 ITR이다.
작제물 100 bGH poly A는 5504개의 염기의 길이를 갖는다. 이 작제물은 서열번호 31에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 169-493는 ApoE HCR이고, 염기 509-726은 hAAT 프로모터이고, 염기 739-5112은 코돈 최적화된 SQ FVIII이고, 염기쌍 5121-5345는 bGH poly A이고, 그리고 염기 5360-5504은 3' AAV2 ITR이다.
작제물 100-400은 5507개의 염기의 길이를 갖는다. 이 작제물은 서열번호 32에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 169-493는 ApoE HCR이고, 염기 512-906는 398 bp hAAT 프로모터이고, 염기 919-5292은 코돈 최적화된 SQ FVIII이고, 염기 5301-5348는 합성 토끼 β-글로빈 poly A이고, 그리고 염기 5363-5507은 3' AAV2 ITR이다.
작제물 101은 5311개의 염기의 길이를 갖는다. 이 작제물은 서열번호 33에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 170-477은 154bp ApoE HCR의 2개의 복제물 (2x)이고, 염기 493-710은 hAAT 프로모터이고, 염기 723-5096은 코돈 최적화된 SQ FVIII이고, 염기 5105-5152는 합성 토끼 β-글로빈 poly A이고, 그리고 염기 5167-5311은 3' AAV2 ITR이다.
작제물 102는 5156개의 염기의 길이를 갖는다. 이 작제물은 서열번호 34에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 169-322는 154bp ApoE HCR이고, 염기 338-555은 hAAT 프로모터이고, 염기 568-4941은 코돈 최적화된 SQ FVIII이고, 염기 4950-4997는 합성 토끼 β-글로빈 poly A이고, 그리고 염기 5012-5156은 3' AAV2 ITR이다.
작제물 103은 5178개의 염기의 길이를 갖는다. 이 작제물은 서열번호 35에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 169-344는 44 bp ApoE HCR의 4개의 복제물(4x)이고, 염기 360-577은 hAAT 프로모터이고, 염기 590-4963은 코돈 최적화된 SQ FVIII이고, 염기 4972-5019는 합성 토끼 β-글로빈 poly A이고, 그리고 염기 5034-5178은 3' AAV2 ITR이다.
작제물 103 역방향은 5160개의 염기의 길이를 갖는다. 이 작제물은 서열번호 36에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 160-335는 44 bp 역방향의 ApoE HCR의 4개의 복제물(4x)이고, 염기 342-559는 hAAT 프로모터이고, 염기 572-4945은 코돈 최적화된 SQ FVIII이고, 염기 4954-5001는 합성 토끼 β-글로빈 poly A이고, 그리고 염기 5016-5160은 3' AAV2 ITR이다.
작제물 103AT는 5383개의 염기의 길이를 갖는다. 이 작제물은 서열번호 37에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 169-344는 44 bp ApoE HCR의 4개의 복제물(4x)이고, 염기 360-577은 hAAT 프로모터이고, 염기 578-782는 hAAT 인트론이고, 염기 795-4374은 코돈 최적화된 SQ FVIII이고, 염기 5177-5224는 합성 토끼 β-글로빈 poly A이고, 그리고 염기 5239-5383은 3' AAV2 ITR이다.
작제물 103AT 2x MG는 5728개의 염기의 길이를 갖는다. 이 작제물은 서열번호 38에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 169-344는 44 bp ApoE HCR의 4개의 복제물(4x)이고, 염기 359-698은 170bp μ-글로불린 인핸서의 2개의 복제물 (2x)이고, 염기 705-922은 hAAT 프로모터이고, 염기 923-1127는 hAAT 인트론이고, 염기 1140-5513은 코돈 최적화된 SQ FVIII이고, 염기 5522-5569는 합성 토끼 β-글로빈 poly A이고, 그리고 염기 5584-5728은 3' AAV2 ITR이다.
작제물 103AT 2x MG bGH poly A는 5905개의 염기의 길이를 갖는다. 이 작제물은 서열번호 39에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 169-344는 44 bp ApoE HCR의 4개의 복제물(4x)이고, 염기 359-698은 170bp μ-글로불린 인핸서의 2개의 복제물 (2x)이고, 염기 705-922은 hAAT 프로모터이고, 염기 923-1127는 hAAT 인트론이고, 염기 1140-5513은 코돈 최적화된 SQ FVIII이고, 염기 5522-5746는 합성 토끼 β-글로빈 poly A이고, 그리고 염기 5761-5905는 5' AAV2 ITR이다.
작제물 103 bGH poly A는 5355개의 염기의 길이를 갖는다. 이 작제물은 서열번호 40에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 169-344는 44 bp ApoE HCR의 4개의 복제물(4x)이고, 염기 360-577은 hAAT 프로모터이고, 염기 590-4963은 코돈 최적화된 SQ FVIII이고, 염기 4972-5196는 합성 토끼 β-글로빈 poly A이고, 그리고 염기 5211-5355은 3' AAV2 ITR이다.
작제물 104은 5618개의 염기의 길이를 갖는다. 이 작제물은 서열번호 41에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 169-784는 154bp ApoE HCR의 4개의 복제물 (4x)이고, 염기 800-1017은 hAAT 프로모터이고, 염기 1030-5403은 코돈 최적화된 SQ FVIII이고, 염기 5412-5459는 합성 토끼 β-글로빈 poly A이고, 그리고 염기 5474-5618은 3' AAV2 ITR이다.
작제물 105은 5993개의 염기의 길이를 갖는다. 이 작제물은 서열번호 42에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 173-512은 170 bp μ-글로불린 인핸서의 2개의 복제물 (2x)이고, 염기 519-736은 hAAT 프로모터이고, 염기 749-5122은 코돈 최적화된 SQ FVIII이고, 염기 5131-5178는 합성 토끼 β-글로빈 poly A, 염기 5185-5834는 ApoE HCR의 2개의 복제물 (2x)이고, 그리고 염기 5849-5993은 3' AAV2 ITR이다.
작제물 106은 5337개의 염기의 길이를 갖는다. 이 작제물은 서열번호 43에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 173-512은 170 bp μ-글로불린 인핸서의 2개의 복제물 (2x)이고, 염기 519-736은 hAAT 프로모터이고, 염기 749-5122은 코돈 최적화된 SQ FVIII이고, 염기 5131-5178는 합성 토끼 β-글로빈 poly A이고, 그리고 염기 5193-5337은 3' AAV2 ITR이다.
작제물 106AT는 5542개의 염기의 길이를 갖는다. 이 작제물은 서열번호 44에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 173-512은 170 bp μ-글로불린 인핸서의 2개의 복제물 (2x)이고, 염기 519-736은 hAAT 프로모터이고, 염기 737-941는 hAAT 인트론이고, 염기 954-5327은 코돈 최적화된 SQ FVIII이고, 염기 5336-5383는 합성 토끼 β-글로빈 poly A이고, 그리고 염기 5398-5542은 3' AAV2 ITR이다.
작제물 2x 세르핀A hAAT는 5126개의 염기이다. 이 작제물은 서열번호 45에서 제시되고, 여기서 염기 1-145는 5' AAV2 ITR이고, 염기 160-301는 ApoE HCR이고, 염기 308-525은 hAAT 프로모터이고, 염기 538-4911은 코돈 최적화된 SQ FVIII이고, 염기 4920-4967는 합성 토끼 β-글로빈 poly A이고, 그리고 염기 4982-5126은 3' AAV2 ITR이다.
AAV 벡터
본원에서 사용된 바와 같이, 용어 "AAV"는 아데노-관련된 바이러스에 대한 표준 약어이다. 아데노-관련된 바이러스는 세포에서만 성장하는 단일가닥 DNA 파보바이러스이며, 소정의 기능들이 헬퍼 바이러스를 공동감염시킴으로써 제공된다. 하기 표 1에서 보는 바와 같이, 현재 AAV의 13개의 혈청형이 규명되었다. AAV의 일반적인 정보 및 검토는, 예를 들면, 문헌[Carter, 1989, Handbook of Parvoviruses, Vol. 1, pp. 169-228, 및 Berns, 1990, Virology, pp. 1743-1764, Raven Press, (New York)]에서 발견될 수 있다. 그러나, 다양한 혈청형이 구조적으로 및 기능적으로 모두, 심지어 유전적 수준으로 상당히 밀접히 관련되어 있음이 잘 알려져 있으므로, 이들 동일한 원리는 추가의 AAV 혈청형에 적용가능할 것으로 충분히 기대된다. (예를 들면, Blacklowe, 1988, pp. 165-174 of Parvoviruses and Human Disease, J. R. Pattison, ed.; 및 Rose, Comprehensive Virology 3:1-61 (1974) 참고). 예를 들면, 모든 AAV 혈청형은 상동성 rep 유전자에 의해 매개되는 매우 유사한 복제 특성을 분명하게 나타내고; 모두 AAV 6에서 발현된 것과 같은 3개의 관련된 캡시드 단백질을 갖는다. 상기 관련성의 정도는 게놈의 길이를 따라 혈청형 사이에 광범위한 교차-하이브리드화를 밝히는 헤테로듀플렉스 분석 및 "역전된 말단 반복 서열" (ITR)에 해당하는 말단에 있는 비슷한 자가-어닐링 세그먼트의 존재에 의해 추가로 제안된다. 유사한 감염성 패턴은 또한 각 혈청형에서의 복제 기능이 유사한 조절 제어하에 있음을 제시한다.
본원에서 사용된 바와 같이 "AAV 벡터"는 AAV 말단 반복 서열 (ITR)의 측면에 있는 하나 이상의 관심 폴리뉴클레오타이드(또는 이식유전자)를 포함하는 벡터를 지칭한다. 그와 같은 AAV 벡터는 rep 및 cap 유전자 생성물을 인코딩하고 발현하는 벡터로 형질감염된 숙주세포 내에 존재할 때 복제되고 감염성 바이러스 입자 내로 패키징될 수 있다.
"AAV 비리온" 또는 "AAV 바이러스 입자" 또는 "AAV 벡터 입자"는 적어도 하나의 AAV 캡시드 단백질 및 캡시드화된 폴리뉴클레오타이드 AAV 벡터를 포함하는 바이러스 입자를 지칭한다. 만약 상기 입자가 이종성 폴리뉴클레오타이드 (즉 포유동물 세포로 전달될 이식 유전자와 같은 야생형 AAV 게놈 이외의 폴리뉴클레오타이드)를 포함하면, 그것은 전형적으로 "AAV 벡터 입자" 또는 간단하게는 "AAV 벡터"로 불린다. 따라서, 상기 벡터가 AAV 벡터 입자 내에 함유되므로, AAV 벡터 입자의 생산은 필연적으로 AAV 벡터의 생산을 포함한다.
AAV "rep" 및 "cap" 유전자는 복제 및 캡시드화 단백질을 각각 인코딩하는 유전자이다. AAV rep 및 cap 유전자는 현재까지 조사된 모든 AAV 혈청형에서 발견되었고, 본원에 그리고 언급된 참조문헌에 기재되어 있다. 야생형 AAV에서, rep 및 cap 유전자는 일반적으로 바이러스 게놈에서 서로 인접한 것으로 확인되며 (즉, 이들은 인접 또는 중첩 전사 단위로서 함께 "커플링됨"), 이들은 일반적으로 AAV 혈청형 사이에서 보존되어 있다. AAV rep 및 cap 유전자는 또한 개별적으로 및 총괄적으로 "AAV 패키징 유전자"로 불린다. 본 발명에 따른 AAV cap 유전자는 rep 및 아데노 헬퍼 기능의 존재하에 AAV 벡터를 패키징할 수 있고 표적 세포 수용체에 결합할 수 있는 Cap 단백질을 인코딩한다. 일부 구현예에서, 상기 AAV cap 유전자는 특정한 AAV 혈청형, 예를 들면 표 1에 나타난 혈청형으로부터 유래된 아미노산 서열을 갖는 캡시드 단백질을 인코딩한다.
표 1. AAV 혈청형
Figure pct00001
AAV의 생산을 위해 이용되는 AAV 서열은 임의의 AAV 혈청형의 게놈으로부터 유래될 수 있다. 일반적으로, AAV 혈청형은 아미노산 및 핵산 수준에서 유의미한 상동성의 게놈 서열을 갖고, 유사한 유전적 기능들을 제공하며, 본질적으로 물리적으로 그리고 기능적으로 동등한 비리온을 생산하고, 실제로 동일한 기전에 의해 복제하고 조립한다. AAV 혈청형의 유전자 서열 및 게놈 유사성의 논의를 위해, 예를 들면, 유전자은행 수납 번호 U89790; 유전자은행 수납 번호 J01901; 유전자은행 수납 번호 AF043303; 유전자은행 수납 번호 AF085716; Chlorini 등, J. Vir. 71: 6823-33(1997); Srivastava 등, J. Vir. 45:555-64 (1983); Chlorini 등, J. Vir. 73:1309-1319 (1999); Rutledge 등, J. Vir. 72:309-319 (1998); 및 Wu 등, J. Vir. 74: 8635-47 (2000)을 참고한다.
공지된 모든 AAV 혈청형의 게놈 조직은 매우 유사하다. AAV의 게놈은 약 5,000 뉴클레오타이드 (nt) 미만의 길이의 선형, 단일가닥 DNA 분자이다. 역전된 말단 반복 (ITR)은 비-구조적 복제 (Rep) 단백질 및 구조적 (VP) 단백질에 대한 독특한 코딩 뉴클레오타이드 서열의 측면에 있다. 상기 VP 단백질은 캡시드를 형성한다. 말단 145 nt는 자가-상보적이며, T-모양의 헤어핀을 형성하는 에너지적으로 안정한 분자내 듀플렉스가 형성될 수 있도록 조직화된다. 이들 헤어핀 구조는 바이러스 DNA 복제를 위한 원점으로서 기능하며, 세포성 DNA 폴리머라제 복합체에 대한 프라이머로서 역할을 한다. Rep 유전자는 Rep 단백질, Rep78, Rep68, Rep52, 및 Rep40을 인코딩한다. Rep78 및 Rep68은 p5 프로모터로부터 전사되고, Rep 52 및 Rep40은 p19 프로모터로부터 전사된다. 상기 cap 유전자는 VP 단백질, VP1, VP2, 및 VP3을 인코딩한다. 상기 cap 유전자는 p40 프로모터로부터 전사된다.
일부 구현예에서, AAV 캡시드 단백질을 인코딩하는 핵산 서열은 특정 세포 유형, 예컨대 Sf9 또는 HEK 세포에서 발현하기 위한 발현 조절 서열에 작동가능하게 연결된다. 곤충 숙주세포 또는 포유동물 숙주세포에서 외부 유전자를 발현하기 위해 당해분야의 숙련가에게 공지된 기술들이 본 발명을 실시하는데 사용될 수 있다. 곤충 세포에서 폴리펩타이드의 분자 공학 및 발현을 위한 방법은, 예를 들면, 문헌[Summers 및 Smith. 1986. A Manual of Methods for Baculovirus Vectors and Insect Culture Procedures, Texas Agricultural Experimental Station Bull. No. 7555, College Station, Tex.; Luckow. 1991. In Prokop 등, Cloning and Expression of Heterologous Genes in Insect Cells with Baculovirus Vectors' Recombinant DNA Technology and Applications, 97-152; King, L. A. 및 R. D. Possee, 1992, The baculovirus expression system, Chapman 및 Hall, United Kingdom; O'Reilly, D. R., L. K. Miller, V. A. Luckow, 1992, Baculovirus Expression Vectors: A Laboratory Manual, New York; W.H. Freeman 및 Richardson, C. D., 1995, Baculovirus Expression Protocols, Methods in Molecular Biology, volume 39; U.S. Pat. No. 4,745,051; US2003148506; 및 WO 03/074714]에 기재되어 있다. AAV 캡시드 단백질을 인코딩하는 뉴클레오타이드 서열의 전사를 위한 특히 적합한 프로모터는 예를 들면 폴리히드론 (polyhedron promoter) 프로모터이다. 그러나, 곤충 세포에서 활성인 다른 프로모터, 예를 들면 p10, p35 또는 IE-1 프로모터가 당해기술에 공지되어 있고, 상기 참조문헌에 기재된 추가 프로모터가 또한 고려된다.
이종성 단백질의 발현을 위한 곤충 세포의 사용은 핵산, 예컨대 벡터, 예를 들면, 곤충-세포 양립가능한 벡터를 그와 같은 세포 내로 도입하는 방법 및 상기 세포를 배양에서 유지하는 방법과 마찬가지로, 문서에 잘 기재되어 있다. 예를 들면, 문헌[METHODS IN MOLECULAR BIOLOGY, ed. Richard, Humana Press, NJ (1995); O'Reilly 등, BACULOVIRUS EXPRESSION VECTORS, A LABORATORY MANUAL, Oxford Univ. Press (1994); Samulski 등, J. Vir. 63:3822-8 (1989); Kajigaya 등, Proc. Nat'l. Acad. Sci. USA 88: 4646-50 (1991); Ruffing 등, J. Vir. 66:6922-30 (1992); Kirnbauer 등, Vir. 219:37-44 (1996); Zhao 등, Vir. 272:382-93 (2000); 및 Samulski 등, U.S. Pat. No. 6,204,059]을 참고한다. 일부 구현예에서, 곤충 세포에서 AAV를 인코딩하는 핵산 작제물은 곤충 세포-양립가능한 벡터이다. 본원에서 사용된 바와 같이 "곤충 세포-양립가능한 벡터" 또는 "벡터"는 곤충 또는 곤충 세포의 생산적인 형질전환 또는 형질감염을 할 수 있는 핵산 분자를 지칭한다. 예시적인 생물학적 벡터는 플라스미드, 선형 핵산 분자, 및 재조합 바이러스를 포함한다. 곤충 세포-양립가능한 한, 임의의 벡터가 이용될 수 있다. 상기 벡터는 곤충 세포 게놈 내로 통합될 수 있지만 곤충 세포 내에서의 벡터의 존재는 영구적일 필요는 없고 일시적 에피솜 벡터가 또한 포함된다. 상기 벡터는 공지된 임의의 수단, 예를 들면 세포의 화학적 처리, 전기천공, 또는 감염에 의해 도입될 수 있다. 일부 구현예에서, 상기 벡터는 배큘로바이러스, 바이러스 벡터, 또는 플라스미드이다. 더 바람직한 구현예에서, 상기 벡터는 배큘로바이러스이며, 즉 작제물은 배큘로바이러스 벡터이다. 배큘로바이러스 벡터 및 그것의 사용 방법은 곤충 세포의 분자공학에 대한 상기 언급된 참조문헌에 기재되어 있다.
배큘로바이러스는 절지동물의 외피가 있는 DNA 바이러스로서, 이의 두 멤버는 세포 배양에서 재조합 단백질을 생산하기 위한 잘 알려진 발현 벡터이다. 배큘로바이러스는 거대 게놈 내용물을 특정 세포에 전달하도록 조작될 수 있는 원형 이중-가닥 게놈 (80-200 kbp)을 갖는다. 벡터로서 사용되는 바이러스는 일반적으로 오토그라파 칼리포르니카 멀티캡시드 뉴클레오폴리헤드로바이러스 (AcMNPV) 또는 봄빅스 모리 (Bm-NPV)이다 (Kato 등, 2010).
배큘로바이러스는 통상적으로 재조합 단백질의 발현을 위해 곤충 세포의 감염을 위해 사용된다. 특히, 곤충에서 이종성 유전자의 발현은, 예를 들면 미국 특허 4,745,051; Friesen 등 (1986); EP 127,839; EP 155,476; Vlak 등 (1988); Miller 등 (1988); Carbonell 등 (1988); Maeda 등 (1985); Lebacq-Verheyden 등 (1988); Smith 등 (1985); Miyajima 등 (1987); 및 Martin 등 (1988)에 기재된 바와 같이 달성될 수 있다. 단백질 생산을 위해 사용될 수 있는 많은 배큘로바이러스 균주와 변이체 및 상응하는 허용된 곤충 숙주세포가 Luckow 등 (1988), Miller 등 (1986); Maeda 등 (1985) 및 McKenna (1989)에 기재되어 있다.
재조합 AAV를 생산하는 방법
본 개시내용은 곤충 또는 포유동물 세포에서 재조합 AAV를 생산하기 위한 물질 및 방법을 제공한다. 일부 구현예에서, 상기 바이러스 작제물은 프로모터 및 하나 이상의 관심 단백질을 인코딩하는 폴리뉴클레오타이드의 삽입을 가능하게 하는 프로모터의 다운스트림에 있는 제한 부위를 추가로 포함하고, 상기 프로모터 및 제한 부위는 5' AAV ITR의 다운스트림 및 3' AAV ITR의 업스트림에 위치한다. 일부 구현예에서, 상기 바이러스 작제물은 제한 부위의 다운스트림 및 3' AAV ITR의 업스트림에 있는 후전사 조절 요소를 추가로 포함한다. 일부 구현예에서, 상기 바이러스 작제물은 상기 제한 부위에 삽입되고 프로모터와 작동가능하게 연결된 폴리뉴클레오타이드를 추가로 포함하고, 상기 폴리뉴클레오타이드는 관심 단백질의 코딩 영역을 포함한다. 숙련가는 본원에 개시된 AAV 벡터 중 어느 하나가 재조합 AAV를 생산하는 바이러스 작제물로서 상기 방법에 사용될 수 있음을 인식할 것이다.
일부 구현예에서, 헬퍼 기능은 아데노바이러스 또는 배큘로바이러스 헬퍼 유전자를 포함하는 하나 이상의 헬퍼 플라스미드 또는 헬퍼 바이러스에 의해 제공된다. 아데노바이러스 또는 배큘로바이러스 헬퍼 유전자의 비-제한적인 예는, 비제한적으로, E1A, E1B, E2A, E4 및 VA를 포함하고, 이는 AAV 패키징에 헬퍼 기능을 제공할 수 있다.
AAV의 헬퍼 바이러스는 당해기술에 공지되어 있고, 예를 들면, 패밀리 아데노비리다에 및 패밀리 헤르레스비리다에로부터의 바이러스를 포함한다. AAV의 헬퍼 바이러스의 예는, 비제한적으로, US 공개 제20110201088호 (이의 개시내용이 본원에 참고로 편입되어 있음)에 기재된 SAdV-13 헬퍼 바이러스 및 SAdV-13-유사 헬퍼 바이러스, 헬퍼 벡터 pHELP (Applied Viromics)를 포함한다. 숙련가는 AAV에 충분한 헬퍼 기능을 제공할 수 있는 AAV의 임의의 헬퍼 바이러스 또는 헬퍼 플라스미드가 본원에서 사용될 수 있음을 인식할 것이다.
일부 구현예에서, AAV cap 유전자는 플라스미드 내에 존재한다. 상기 플라스미드는 AAV rep 유전자를 추가로 포함할 수 있다. 임의의 AAV 혈청형 (비제한적으로, AAV1, AAV2, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV13 및 이의 임의의 변이체를 포함함)으로부터의 cap 유전자 및/또는 rep 유전자가 재조합 AAV를 생산하기 위해 본원에서 사용될 수 있다. 일부 구현예에서, 상기 AAV cap 유전자는 혈청형 1, 혈청형 2, 혈청형 4, 혈청형 5, 혈청형 6, 혈청형 7, 혈청형 8, 혈청형 9, 혈청형 10, 혈청형 11, 혈청형 12, 혈청형 13 또는 그것의 변이체로부터의 캡시드를 인코딩한다.
일부 구현예에서, 곤충 또는 포유동물 세포는 헬퍼 플라스미드 또는 헬퍼 바이러스, AAV cap 유전자를 인코딩하는 바이러스 작제물 및 플라스미드로 형질감염될 수 있고; 상기 재조합 AAV 바이러스는 공동-형질감염 후 다양한 시점에 수집될 수 있다. 예를 들면, 상기 재조합 AAV 바이러스는 공동-형질감염 후 약 12시간, 약 24시간, 약 36시간, 약 48시간, 약 72시간, 약 96시간, 약 120시간, 또는 이들 어느 두 시점 사이의 시간에 수집될 수 있다.
재조합 AAV는 또한 감염성 재조합 AAV를 생산하는데 적합한 본 기술분야에 알려진 임의의 종래 방법을 이용하여 생산될 수 있다. 일부 경우, 재조합 AAV는 AAV 입자 생산에 필요한 성분 중 일부를 안정적으로 발현하는 곤충 또는 포유동물 세포를 이용하여 생산될 수 있다. 예를 들면, AAV rep 및 cap 유전자, 및 선별 마커, 예컨대 네오마이신 내성 유전자를 포함하는 플라스미드 (또는 다수의 플라스미드)가 세포의 게놈 내로 통합될 수 있다. 그리고 나서, 상기 곤충 또는 포유동물 세포는 헬퍼 바이러스 (예를 들면, 헬퍼 기능을 제공하는 아데노바이러스 또는 배큘로바이러스) 및 5' 및 3' AAV ITR (및 원한다면, 이종성 단백질을 인코딩하는 뉴클레오타이드 서열)을 포함하는 바이러스 벡터로 공동-감염될 수 있다. 이 방법의 이점은 상기 세포가 재조합 AAV의 대규모 생산을 위해 선택될 수 있고 적합하다는 점이다. 또 다른 비-제한적인 예로서, 플라스미드보다 아데노바이러스 또는 배큘로바이러스가 rep 및 cap 유전자를 패키징 세포 내로 도입하는데 사용될 수 있다. 또 하나의 비-제한적인 예로서, 5' 및 3' AAV LTR 및 rep-cap 유전자를 함유하는 바이러스 벡터가 생산자 세포의 DNA 내로 안정적으로 통합될 수 있고, 재조합 AAV를 생산하기 위해 헬퍼 기능이 야생형 아데노바이러스에 제공될 수 있다.
AAV 생산에 사용되는 세포 유형
본 발명의 AAV 벡터를 포함하는 바이러스 입자는 AAV 또는 생물학적 생성물의 생산을 가능하게 하고 배양 중에 유지될 수 있는 임의의 무척추동물 세포 유형을 이용하여 생산될 수 있다. 예를 들면, 사용되는 곤충 세포주는 스포도프테라 프루지페르다 (Spodoptera frugiperda), 예컨대 SF9, SF21, SF900+, 드로소필라 세포주, 모기 세포주, 예를 들면, 아에데스 알보픽투스 (Aedes albopictus) 유래 세포주, 사육되는 누에 세포주, 예를 들면 봄빅스모리 (Bombyxmori) 세포주, 트리코플러시아 니 (Trichoplusia ni) 세포주, 예컨대 하이 파이브(High Five) 세포 또는 레피돕테라 (Lepidoptera) 세포주, 예컨대 아스칼라파 오도라타 (Ascalapha odorata) 세포주로부터일 수 있다. 바람직한 곤충 세포는 배큘로바이러스 감염에 민감한 곤충 종 유래의 세포이며, 이는 하이 파이브, Sf9, Se301, SeIZD2109, SeUCR1, Sf9, Sf900+, Sf21, BTI-TN-5B1-4, MG-1, Tn368, HzAm1, BM-N, Ha2302, Hz2E5 및 Ao38을 포함한다.
배큘로바이러스는 절지동물의 외피가 있는 DNA 바이러스로서, 이의 두 멤버는 세포 배양에서 재조합 단백질을 생산하기 위한 잘 알려진 발현 벡터이다. 배큘로바이러스는 거대 게놈 내용물을 특이적 세포로 전달하도록 조작될 수 있는 원형 이중-가닥 게놈 (80-200 kbp)을 갖는다. 벡터로서 사용되는 상기 바이러스는 일반적으로 오토그라파 칼리포르니카 멀티캡시드 뉴클레오폴리헤드로바이러스 (AcMNPV) 또는 봄빅스 모리 (Bm-NPV) (Kato 등, 2010)이다.
배큘로바이러스는 통상적으로 재조합 단백질의 발현을 위한 곤충 세포의 감염을 위해 사용된다. 특히, 곤충에서의 이종성 유전자의 발현은 예를 들면 미국 특허 4,745,051; Friesen 등 (1986); EP 127,839; EP 155,476; Vlak 등 (1988); Miller 등 (1988); Carbonell 등 (1988); Maeda 등 (1985); Lebacq-Verheyden 등 (1988); Smith 등 (1985); Miyajima 등 (1987); 및 Martin 등 (1988)에 기재된 바와 같이 달성될 수 있다. 단백질 생산을 위해 사용될 수 있는 많은 배큘로바이러스 균주와 변이체 및 상응하는 허용된 곤충 숙주 세포는 문헌[Luckow 등 (1988), Miller 등 (1986); Maeda 등 (1985) 및 McKenna (1989)]에 기재되어 있다.
본 발명의 또 다른 측면에서, 본 발명의 방법은 또한 AAV의 복제 또는 생물학적 생성물의 생산을 가능하게 하며, 배양에서 유지될 수 있는 임의의 포유동물 세포 유형을 이용하여 수행된다. 사용된 바람직한 포유동물 세포는 HEK293, HeLa, CHO, NS0, SP2/0, PER.C6, Vero, RD, BHK, HT 1080, A549, Cos-7, ARPE-19 및 MRC-5 세포일 수 있다.
AAV FVIII 벡터의 시험
본 발명의 완전히 패키징된 AAV FVIII 벡터를 시험하는 분석은, 예를 들면, (1) 간-특이적 mRNA 발현 및 스플라이싱, 및 시험관내에서 FVIII 단백질 생산 및 분비를 확인하기 위한 인간 간으로부터 유래된 세포주인 HepG2 세포에서 AAV 벡터 핵산을 포함하는 이중-가닥 DNA 플라스미드의 일시적 형질감염; (2) 293 세포 및 배큘로바이러스-감염된 곤충 세포에서 AAV FVIII 벡터를 포함하는 AAV 비리온의 생산; (3) 알칼리성 겔 분석 및 복제 분석에 의한 AAV 벡터 핵산의 평가; 및 (4) Rag2 마우스에서 FVIII 발현, FVIII 활성, 및 FVIII 특이적 활성의 평가. 이들 분석은 실시예에 더 상세히 기재되어 있다.
본 발명의 완전히 포장된 AAV FVIII 벡터는 UCL SQ 벡터와 적어도 동일한 발현 및/또는 활성을 나타내며, 바람직하게는 UCL SQ 벡터와 비교하여 1.5-배, 2-배, 3-배, 4-배, 또는 5-배 또는 그 이상의 발현 및/또는 활성을 나타낸다.
본 발명의 완전히 포장된 AAV FVIII 벡터는 단편적인 게놈 오염물질이 거의 또는 전혀 없이 높은 벡터 수율을 가지며, 바람직하게는 UCL SQ 벡터와 비교하여 1.5-배, 2-배, 3-배, 4-배, 또는 5-배 더 큰 벡터 수율을 갖는다.
본 발명의 다른 측면 및 이점은 하기 예시적인 실시예를 고려하여 이해될 것이다.
실시예
실시예 1
프로토 1, 프로토 1S, 프로토 2S 및 프로토 3S 벡터의 생성
문헌[Nathwani 등, US 특허 출원 제2013/0024960A1호(2013년 1월 24일에 공개됨, 이는 그 전체가 참고로 본원에 편입되어 있음), 및 McIntosh 등, Blood 121:3335-3344, 2013]에 상세히 기재된 UCL SQ 벡터는 대형, 즉, 5.0 kb보다 더 큰 AAV 벡터이다. 도 1에 나타난 바와 같이, UCL SQ 벡터는 좌측에서 우측으로, AAV 혈청형 2 (AAV2) 5' ITR, 야생형 AAV2 바이러스 서열, 34개 염기의 인간 아포지질단백질 E (ApoE)/C1 인핸서, 32개 염기의 인간 알파 항-트립신 (AAT) 프로모터 원위 X 영역, 42개 염기의 5' 미번역된 영역 (UTR) 서열을 포함하는 186개 염기의 인간 AAT 프로모터, B 도메인이 14개 아미노산 SQ 서열로 치환된 코돈-최적화된 인간 FVIII 서열, 49개 염기의 합성 폴리아데닐화 서열, 야생형 AAV2 바이러스 서열, 및 AAV2 3'ITR을 포함한다. 상기 UCL SQ 벡터는 5081개의 염기 길이를 갖는다.
UCL SQ 벡터보다 더 작은 벡터를 수득하기 위해, 본 발명자들이 FVIII 발현 및/또는 활성에, 또는 AAV 비리온 생산에 불필요한 것으로 판단한 DNA 서열들을 UCL SQ 벡터 서열로부터 제거하였다. AAV2 5'ITR에 대해 3'에 있는 53개 염기의 AAV2 바이러스 서열, AAV2 3'ITR에 대해 5'에 있는 46개 염기의 AAV2 바이러스 서열, 및 코돈-최적화된 FVIII SQ 코딩 영역에 인접한 11개의 염기를 포함하는, 이질적인 DNA 서열을 제거하였다. 수득된 4970개 염기 길이의 프로토 1 벡터가 도 2A에 도식적인 형태로 나타나 있으며, 상기 서열은 서열번호 1에 제시되어 있다. 프로토 1은 감염성 바이러스를 생산하였고 기능적 인자 VIII 폴리펩타이드를 인코딩한다.
AAV2 ITR 내의 헤어핀 루프에 인접한 서열들은 또한 재조합 AAV 벡터에서 불필요할 수 있다 (Srivastava 등, US 특허 제6,521,225호; Wang 등, J. Virol. 70:1668-1677, 1996; 및 Wang 등, J. Virol. 71:3077-3082, 1997). 프로토 1 벡터의 크기를 더 줄이기 위해, AAV2 5'ITR 내의 헤어핀 루프에 대해 바로 3'에 있는 10개 염기의 AAV2 서열을 제거하였고 AAV2 3'ITR 내의 헤어핀 루프에 대해 바로 5'에 있는 10개 염기의 AAV2 서열을 제거하였다. 수득된 4950개의 염기 길이의 프로토 1S 벡터가 도 2B에 도식적인 형태로 나타나 있으며, 상기 서열은 서열번호 2에 제시되어 있다.
프로토 1S 벡터에서 FVIII SQ 변이체의 발현을 증가시키고자, 코돈-최적화된 FVIII 서열 내의 엑손 1 및 2 사이에 100개 염기의 합성 인트론을 삽입하였다. 인트론의 삽입은, 예를 들면 인터페론 유전자와 같은 인트론이 없는 유전자에서의 mRNA 발현 수준의 증가를 야기할 수 있는 것으로 알려져 있다.
인핸서는 거리- 및 방향-독립적 방식으로 작동하는 것으로 정의된다. 문헌[Gray 등, US 특허 제8,030,065호 (FIX 발현) 및 Nathwani 등, US 특허 출원 공개 제2013/0024960호 (FVIII 발현) (이 둘 모두는 그 전체가 참고로 본원에 편입되어 있음)]에서 추정상의 인핸서 활성에 의해 예시된 바와 같이, 34개 염기의 ApoE/C1 인핸서는 FVIII 발현에 대하여 거리- 및 방향-독립적 방식으로 작동한다. 문헌[Di Simone 등, EMBO J. 6:2759-2766, 1987]에 기재된, 32개 염기의 인간 AAT 프로모터 원위 X 영역은 이종성 프로모터의 발현을 향상시키는 조절 도메인 내에 위치한다.
프로토 1S 벡터에서 FVIII SQ 변이체의 발현을 더 증가시키고자, 상기 합성 인트론 서열을 34개 염기의 인간 ApoE/C1 인핸서 및 32개 염기의 인간 AAT 프로모터 원위 X 영역을 혼입하였고, 이는 인간 AAT 프로모터의 업스트림에 있는 그의 위치로부터 이동되었다. 이들 두 개의 조절 요소를 프로토 1S에서의 이들의 방향에 대해 역방향으로 삽입하였다. 수득된 4983개 염기 길이의 프로토 2S 벡터가 도식적 형태로 도 2C에 나타나 있으며, 상기 서열은 서열번호 3에서 제시되어 있다.
인간 AAT 프로모터 원위 X 영역은 앞서 인트론 내의 전사 개시 부위로부터 다운스트림으로 기능하는 것으로 나타나지 않았으므로, 프로토 2S 벡터에서의 이 조절 요소를 인트론 내의 인핸서의 제1카피와 동일한 방향으로 34개 염기의 인간 ApoE/C1 인핸서의 제2카피로 치환하였다. 수득된 4985개 염기 길이의 프로토 3S 벡터가 도식적인 형태로 도 2D에 나타나 있으며, 상기 서열은 서열번호 4에서 제시되어 있다.
상기 프로토 1, 프로토 1S, 프로토 2S 및 프로토 3S 벡터 핵산을 pUC19 박테리아 발현 플라스미드 내로 클로닝하였고, 이로써 이중-가닥 형태의 AAV FVIII 벡터를 생성하였다.
실시예 2
프로토 4, 프로토 5, 프로토 6 및 프로토 7 벡터의 생성
프로토 1 벡터의 크기를 더 줄이고/거나 프로토 1 벡터와 비교하여 FVIII의 발현을 증가시키기 위해, 경쇄 또는 C 도메인에 인접하여 위치한 a3 도메인을 결실시켰다. 상기 a3 도메인은 폰 빌레브란트(von Willenbrand) 인자에의 결합에 관여하지만, 생체내에서 기능적 활성 FVIII에 대해 불필요할 수 있다.
프로토 1 벡터로부터 시작하여, 14개 아미노산의 SQ 서열 및 41개 아미노산의 a3 도메인 (야생형 FVIII의 아미노산 1649-1689에 상응함)을 결실시켰다. 수득한 4805개 염기의 길이의 프로토 4 벡터가 도식적인 형태로 도 3A에 나타나 있으며, 상기 서열은 서열번호 5에 제시되어 있다.
B 도메인 및 a3 도메인 결실된 FVIII의 발현을 증가시키고자, 129 염기의 말단이 절단된 FVIII 인트론을 프로토 4 벡터에서의 코돈-최적화된 FVIII 서열 내의 엑손 1 및 2 사이에 삽입하였다. 수득된 4934개 염기의 길이의 프로토 5 벡터가 도식적 형태로 도 3B에 나타나 있으며, 상기 서열은 서열번호 6에 제시되어 있다.
B 도메인 및 a3 도메인 결실된 FVIII의 발현을 더 증가시키고자, 34개 염기의 인간 ApoE/C1 인핸서의 제2 카피를 프로토 5 벡터에 정방향 또는 역방향 중 하나로 삽입하였다. 4934개 염기 길이이며 정방향으로 인트론 ApoE/C1 인핸서를 갖는, 수득된 프로토 6 벡터가 도식적 형태로 도 3C에 나타나 있으며, 상기 서열은 서열번호 7에 제시되어 있다.
4934개 염기 길이이며 역방향으로 인트론 ApoE/C1 인핸서를 갖는 프로토 7 벡터가 도식적 형태로 도 3D에 나타나 있으며, 상기 서열은 서열번호 8에 제시되어 있다.
상기 프로토 4, 프로토 5, 프로토 6 및 프로토 7 벡터 핵산을 pUC19 박테리아 발현 플라스미드 내로 클로닝하였고, 이로써 이중-가닥 형태의 AAV FVIII 벡터를 생성하였다.
실시예 3
AAV FVIII 벡터의 발현 및 활성을 시험하기 위한 분석
본 발명의 AAV FVIII 벡터를 시험하기 위한 분석은, 예를 들면, (1) 간-특이적 mRNA 발현 및 스플라이싱, 및 시험관내에서 FVIII 단백질 생산 및 분비를 확인하기 위해, 인간 간으로부터 유래된 세포주인 HepG2 세포에서 AAV 벡터 핵산을 포함하는 이중-가닥 DNA 플라스미드의 일시적 형질감염; (2) 293 세포 및 배큘로바이러스-감염된 곤충 세포에서 AAV FVIII 벡터를 포함하는 AAV 비리온의 생산; (3) 알칼리성 겔 분석 및 복제 분석에 의한 AAV 벡터 핵산의 평가; 및 (4) Rag2 마우스에서 FVIII 발현, FVIII 활성, 및 FVIII 특이적 활성의 평가를 포함한다.
일시적 형질감염 분석 .
본 발명의 AAV FVIII로부터의 FVIII 발현 및 활성을 UCL SQ 벡터로부터의 FVIII 발현 및 활성과 비교하기 위하여, 예비 시험관내 분석을 수행한다. 이중-가닥 형태의 본 발명의 AAV FVIII 벡터를 인간 간 세포주인 HepG2 내로 일시적으로 형질감염시킨다. 형질감염 후, 예를 들면, 24 또는 48시간 후, 배양 상청액에서의 FVIII 항원 및 활성을 측정한다.
이 분석을 이용시, 프로토 1, 프로토 1S 및 프로토 2S 벡터로 일시적으로 형질감염된 HepG2 세포에서의 FVIII 활성은 UCL SQ 벡터를 이용하여 수득된 FVIII 활성과 유사하였는데, 이는 상기 프로토 1, 프로토 1S 및 프로토 2S 벡터가 기능적 인자 VIII 단백질을 발현할 수 있었음을 입증한다.
293 세포 및 배큘로바이러스 -감염된 곤충 세포에서 AAV 비리온의 생산 .
본 발명의 AAV FVIII 벡터가 FVIII를 인코딩하는 핵산을 실제 패키징한다는 것을 입증하기 위해, 실시예 1 및 2에 기재된 바와 같이 생성된 이중-가닥 형태의 AAV FVIII 벡터를 AAV 비리온을 생산할 수 있는 세포 내로 도입한다. 제1 AAV 바이러스 생산 시스템에서는, 이중-가닥 형태의 AAV FVIII 벡터 핵산을 포함하는 플라스미드를 AAV Cap 및 Rep 단백질을 발현하는 플라스미드 및 AAV 비리온 생산에 필요한 아데노바이러스 헬퍼 기능을 발현하는 플라스미드와 함께 293 세포 내로 형질감염시킨다. 제2 AAV 바이러스 생산 시스템에서는, AAV FVIII 벡터 핵산 및 AAV Cap 및 Rep 단백질을 발현하는 배큘로바이러스 작제물을 생성한 다음, 곤충 Sf9 세포 내로 공동-감염시킨다. 일시적으로 형질감염된 293 세포 또는 배큘로바이러스-감염된 Sf9 세포에서 생산된 수득된 AAV 비리온을 정제하고 당해분야에서 공지된 표준 방법에 의해 분석한다.
알칼리성 겔 및 복제 분석에 의한 평가
알칼리성 겔 전기영동 분석을 사용하여 패키징된 핵산의 크기를 결정한다. 복제 센터 분석을 사용하여 어떤 AAV FVIII 벡터들이 두 가지 패키징 방법에 의해 온전한 형태로 패키징되는지 결정한다.
프라이머 연장 분석을 사용하여 완전한 말단을 갖는, 즉, AAV2 5'ITR (센스 가닥) 또는 3'ITR (안티-센스 가닥) 내의 헤어핀 루프의 5' 말단에서 종결하는 말단을 갖는 AAV FVIII 벡터 핵산의 양을 정량한다.
대안적으로, PCR 분석을 사용하여 AAV FVIII 벡터 핵산이 완전한 말단을 갖는지, 즉, AAV2 5'ITR (센스 가닥) 또는 3'ITR (안티-센스 가닥) 내의 헤어핀 루프의 5' 말단에서 종결되는 말단을 갖는지 결정한다.
Rag2 마우스에서의 평가
일시적으로 형질감염된 293 세포에서 생산된 AAV 비리온 또는 배큘로바이러스-감염된 Sf9 세포 패키징된 벡터를 대상으로, 2e11, 2e12, 및 2e13 바이러스 게놈 (vg)/kg을 정맥내로 주입한 Rag2 마우스에서 FVIII 발현 및 활성을 시험한다. Rag2 마우스는 FVIII 발현 및/또는 활성이 AAV 바이러스 또는 인간 FVIII 단백질에 대한 숙주 면역 반응의 존재에 의해 복잡해지지 않기 때문에 이 분석에서 사용된다.
FVIII 항원을 ELISA-기반 분석을 이용하여 결정한다. FVIII 활성을 FXa 활성화 분석 및/또는 응고 분석을 이용하여 결정한다. FVIII 항원 및 활성 분석을 이용하여, FVIII 특이적 활성을 결정한다.
이들의 현재 바람직한 구현예를 고려할 때 당업자에게 본 발명을 실행함에 있어 많은 변형 및 변화가 일어날 것임이 예상된다. 결과적으로, 첨부된 청구항에 나타나 있는 것에만 본 발명의 범위가 제한되어야 한다.
실시예 4
향상된 프로모터/ 인핸서 서열을 갖는 작제물의 생성
기능적 FVIII의 발현을 증가시키는 강한 프로모터를 갖는 추가적인 AAV 벡터를 생성하기 위해, 변형된 인핸서 및/또는 프로모터 서열을 갖는 작제물을 생성하였다. 일부 구현예에서, 상기 작제물은 단축된 형태의 ApoE 또는 μ-글로불린 인핸서를 포함하였다. 이들 작제물은 표준 DNA 클로닝 기술을 이용하여 생성하였고 이들의 서열은 서열번호 9-45에 나타나 있다.
실시예 5
AAV 바이러스 입자의 생성
재조합 백미드(Bacmid)의 생성
DH10 Bac 컴피턴트 세포를 얼음 상에서 해동시켰다. 재조합 셔틀 플라스미드 (예를 들면, pFB-GFP)를 첨가하고, 상기 컴피턴트 세포와 부드럽게 혼합하고, 얼음 상에서 30분 동안 배양하였다. 그리고 나서, 상기 컴피턴트 세포를 대략 42℃의 온도에서 30초간 열처리한 다음 얼음 상에서 2분간 냉각시켰다. 상기 세포에 SOC를 부가하고 37℃에서 4시간 동안 진탕하면서 배양하여 재조합이 일어나게 하였다. 배양 기간 동안, 형질전환을 위해 X-gal을 2개의 LB-플레이트 (추가로 다양한 항생제 (예를 들면, 카나마이신, 겐타마이신 및 테트라사이클린)를 함유함) 상에 스프레딩한 다음 IPTG를 스프레딩하였다.
상기 배양 혼합물 중 일정량을 얻고, 희석한 다음, 2개의 LB-플레이트 상에 스프레딩하고 37℃에서 대략 30-48시간 동안 배양하였다. 각 플레이트로부터 몇개의 백색 콜로니를 선택하고 LB-플레이트에서 제공된 항생제의 동일한 조합을 함유하는 LB 배지에서 밤새 배양하였다. 다음으로, 백미드 DNA 및 글리세롤 스톡을 제조하고 -80℃에서 보관하였다.
재조합 백미드 DNA의 정제
일정량의 백미드 글리세롤 스톡을 제거하고 실시예 1에 기재된 LB-플레이트에 제공된 동일한 조합의 항생제를 함유하는 LB 배지에 접종하였다. 배양물을 교반하면서 37℃에서 밤새 성장시켰다. 다음으로, 일정량의 배양물을 최대 속도로 대략 30초 동안 마이크로원심분리기에서 회전시킨다.
펠렛을 피펫을 이용하여 재현탁 버퍼에 재현탁시킨 다음, 용해 버퍼에 재현탁시키고, 튜브를 몇 번 역전시켜 버퍼를 혼합한 다음, 실온에서 대략 5분간 배양하였다. 예시적인 재현탁 버퍼는 50 mM 트리스-CL, pH 8.0, 10 mM EDTA 및 100ug/mL RNase A를 포함한다. 예시적인 용해 버퍼는 200 mM NaOH 및 1% SDS를 포함한다. 일정량의 침전 버퍼 (예를 들면, 3.0 M 칼륨 아세테이트, pH 5.5를 포함하는 버퍼)를 서서히 부가하고 튜브를 몇 번 역전시켜 버퍼를 혼합한 다음, 얼음 상에서 대략 10분 동안 배양하였다. 상기 튜브를 대략 10분 동안 최대 속도로 원심분리하고 상청액을 이소프로판올을 함유하는 튜브에 붓는다. 튜브를 몇 번 역전시켜 상기 용액을 혼합한다.
그 다음, 상기 용액을 실온에서 최대 속도로 대략 15분간 원심분리하고 원심분리기 후 곧바로 피펫을 이용하여 상청액을 제거한다.
일정량의 70% 에탄올을 부가하여 펠렛을 세정하고 최대 속도로 1분간 다시 원심분리하였다. 그리고 나서, 에탄올을 제거하고 상기 용액을 다시 원심분리하여 미량의 에탄올을 제거하였다. 각 튜브에 일정량의 TE/EB 완충제를 부가하고, 상기 펠렛을 피펫에 의해 조심스레 용해시킨다. 즉시 사용하지 않으면, 상기 용액을 -20℃에서 보관하였다.
재조합 배큘로바이러스의 P0 스톡의 생산
Sf9 세포를 6-웰 플레이트에 대략 1 x 106 세포/웰 (또는 10-cm 플레이트에 6 x 106 세포 또는 15-cm 디쉬에 1.7 x 107 세포)로 시딩하고, 형질감염 전 적어도 1시간 동안 상기 세포를 부착시켰다.
형질감염 용액 A 및 B는 하기와 같이 제조한다: 용액 A: 일정량의 백미드를 15-mL 튜브에서 항생제가 없는 일정량의 무혈청 배지 내로 희석하였다. 용액 B: 일정량의 CellFectin을 15-mL 튜브에서 항생제가 없는 일정량의 무혈청 배지 내로 희석하였다. 용액 B를 용액 A에 부가하고 피펫으로 대략 3회 피펫팅하여 부드럽게 혼합하고, 실온에서 30 ~ 45분 동안 배양하였다. 그 다음, 상기 플레이트로부터 배지를 흡입하고 항생제가 없는 일정량의 무혈청 배지를 부가하여 상기 세포를 세척하였다. 항생제가 없는 일정량의 SF900II를 지질-DNA 혼합물을 함유하는 각 튜브에 부가하였다.
상기 세포로부터 배지를 흡입하고, 상기 세포에 형질감염 용액을 부가하고, 세포를 28℃에서 대략 5시간 동안 배양하였다. 형질감염 용액을 제거하고 일정량의 무혈청 배지 + 항생제를 부가하고, 28℃에서 대략 4일간 배양하였다. 재조합 배큘로바이러스를 함유하는 배지를 수집하고 1000 rpm에서 대략 5분간 원심분리하여 세포 잔해를 제거하였다. 상기 배큘로바이러스를 4℃ 암실에서 보관하였다.
배큘로바이러스 (P1)의 증폭
Sf9 세포를 대략 4 x 106 세포/mL로 성장시키고 진탕 플라스크에서 신선한 배지를 이용하여 대략 2 x 106 세포/mL로 희석시켰다. 일정량의 Sf9 세포를 일정량의 P0 스톡 배큘로바이러스로 감염시켰다. 감염 다중도 (MOI)는 대략 0.1이다.
Sf9 세포를 대략 3일간 배양하고 배큘로바이러스를 수확하였다. 상기 세포를 2,000 rpm에서 5분 동안 원심분리하여 세포를 펠렛화하고 상청액을 수집하여 4℃ 암실에서 보관하였다. 배큘로바이러스의 역가를 Clontech's Rapid Titer Kit 프로토콜에 따라 결정하였다.
P1 재조합 배큘로바이러스를 이용한 AAV의 생산
Sf9 세포를 약 1 x 107 세포/mL로 성장시키고 약 5 x 106 세포/mL로 희석하였다. 일정량의 희석된 Sf9 세포를 Bac-벡터 (5Moi) 및 Bac-헬퍼 (15Moi)로 3일간 감염시켰다. 3일째에 세포 생존력을 평가하였다 (대략 50% ~ 70% 죽은 세포가 관찰됨).
3000 rpm에서 10분 동안 원심분리하여 세포 펠렛을 수확하였다. 배지를 제거하고 세포를 용해시켰다(또는 즉시 사용하지 않으면, 세포 펠렛을 -20℃에서 보관하였다).
용해 및 밴딩 (banding) 프로토콜
일정량의 Sf9 용해 버퍼 및 벤조나제를 각 세포 펠렛에 부가하고 철저히 볼텍싱하여 세포를 재현탁시켰다. 상기 재현탁된 Sf9 세포를 얼음 상에서 대략 10분간 배양하여 용해물을 냉각시켰다. 상기 용해물을 대략 20초간 초음파처리하여 세포를 철저히 용해시킨 다음 37℃에서 대략 30분간 배양하였다.
일정량의 5M NaCl을 부가하고 상기 혼합물을 볼텍싱한 다음, 37℃에서 30분간 더 배양한다. 일정량의 NaCl을 부가하여 염 농도를 약 500mM로 맞추고, 볼텍싱하고, 15℃에서 8,000 rpm에서 20분 동안 원심분리하여 청징된 용해물을 생산하였다.
상기 청징된 용해물을 초원심분리 단계로 진행한다. 긴 바늘을 갖는 주사기를 통해 청징된 용해물을 먼저 부가한 다음, 일정량의 1.32g/cc 및 일정량의 1.55g/cc CsCl 용액을 부가하여 CsCl-구배를 준비하였다. CsCl 용액 간의 계면을 표시하였다. PBS를 원심분리 튜브의 상부까지 부가하고, 상기 튜브를 조심스레 조정하고 밀봉한다.
상기 튜브를 15℃에서 55,000 rpm에서 대략 20시간 동안 원심분리하였다. 각 튜브의 상부에 구멍을 뚫고 2개의 CsCl 용액의 계면 표시보다 약간 위에 위치한 AAV 밴드를 표시한다.
상기 AAV 용액을 70.1 Ti 로터(rotor)에 대한 원심분리 튜브로 옮기고 일정량의 CsCl 용액을 상기 튜브의 상부 근처까지 부기함으로써 제2 CsCl 원심분리를 수행한다. 상기 튜브를 조정하고 밀봉한다. 상기 튜브를 65,000rpm에서 대략 20시간 동안 원심분리하고 AAV 밴드 (더 낮은 밴드, 더 높은 밴드는 비어있는 캡시드임)를 수집한다.
실시예 5
Rag2 마우스에서 작제물의 평가
UCL SQ, 프로토 1, 프로토 S1, 프로토 S2 및 프로토 S3 작제물을 이용한 배큘로바이러스 및 293 세포를 이용하여 코돈 최적화된 SQ FVIII-인코딩 유전자 서열을 포함하는 AAV 게놈을 생성하였다. 패키징 한계는 배큘로바이러스의 경우 4800bp이고 293 세포의 경우 4950이다.
도 5에 나타난 바와 같이, 말단이 절단된 또는 말단이 절단되지 않은 게놈을 갖는 프로토 1은 UCL SQ 작제물와 유사하게 FVIII를 형질도입한다. AAV5.2가 4-12% 비스-트리스 겔 상에서 측정된 바와 같이 배큘로바이러스 및 293T 세포 용해물로부터 생산되었다. 도 6에 나타난 바와 같이, 각 샘플은 VP1, VP2 및 VP3 단백질을 발현하였다. 도 7에 나타난 바와 같이, AAV 샘플로부터의 게놈 DNA를 0.8% 알칼리성 아가로스 겔 상에서 진행시켰다.
프로토 1의 형질도입은 이들 AAV가 배큘로바이러스 시스템에 의해 제조될 때 UCL SQ 작제물와 유사하였다. Proto2S 및 3S를 함유하는 인트론의 봉입체는 프로토 1보다 더 잘 형질도입하지 않았다. 293 세포에서 만들어진 AAV 측접 서열을 함유하는 UCL SQ 벡터는 배큘로바이러스에서 만들어진 AAV 서열이 결여된 UCL SQ보다 더 강력하였다. 그 결과, 효능을 증가시키고자 부가적인 인핸서를 프로토 1에 부가하였다 (예를 들면 작제물 101, 102, 102 및 104).
실시예 6
개선된 프로모터/인핸서 서열을 갖는 AAV FVIII 벡터의 발현 및 활성
작제물 99 내지 작제물 106을 포함하는 AAV 벡터의 발현 및 활성을 유체역학적 주사 프로토콜을 이용하여 시험하였다. 유체역학적 전달은 생체내에서 간 프로모터를 스크리닝하는 빠른 방법이다. 실시예 5에 기재된 방법을 이용하여 AAV 플라스미드 DNA를 생성한 다음, TransIT-QR 유체역학적 전달 용액에서 희석하였다. 상기 플라스미드 DNA를 (마우스 중량 (g)/10) = 0.1 ml 전달 용액)에 의해 결정된 용량으로 5-6주령 C57Bl/6 마우스 (18-25 g)의 꼬리 정맥 내로 주사하였다. 주사 시간은 5초 미만이었다. 주사 후 48시간에 각 마우스로부터 혈장을 수집하고 ELISA 분석을 이용하여 발현된 FVIII 항원의 양을 측정하였다.
증가하는 용량의 프로토 1 플라스미드 (2.5, 5, 12.5 및 50 μg)를 마우스의 꼬리 정맥 내로 주사하였다. ELISA 시험을 이용하여 상기 주사된 마우스의 혈장 내의 FVIII의 양을 측정하고 재조합 FVIII (Xyntha SQ 동등물)을 비교를 위한 표준으로서 사용하였다.
작제물 p100-400, 작제물 100(p100), 작제물 FVIII-BMN001 (pFVIII-BMN001), 프로토1, 작제물 100AT (p100-AT), 작제물 100 bGH poly A (p100-bGHPA), 작제물 101 (p101) 및 작제물 104 (p104)의 개선된 프로모터/인핸서 요소의 발현을 조사하였다. 도 8에 나타난 바와 같이, 모든 작제물은 다양한 효율 수준으로 기능적 FVIII을 생산하였다.
도 9 및 10은 1 μg의 다양한 작제물의 플라스미드의 주사에 대한 데이터를 제공한다. 도 8에 나타난 바와 같이, 작제물 FVIII-BMN001, 작제물 FVIII-BMN002, 작제물 102 (p102), 작제물 103 (p103) 및 작제물 104 (p104)의 주사는 10마리의 마우스 중 5마리에서 적어도 20 ng의 FVIII의 발현을 야기하였다. 도 9에 나타난 바와 같이, 작제물 FVIII-BMN001, 작제물 103 (p103), 작제물 103-AT (p103-AT; 398 bp hAAT 프로모터), 작제물 100 (p100), 작제물 100AT (p100-AT; 398 bp hAAT 프로모터)의 주사는 10마리의 마우스 중 5마리에서 적어도 100 ng의 FVIII의 발현을 야기하였다.
<110> BIOMARIN PHARMACEUTICAL INC. UNIVERSITY COLLEGE LONDON <120> ADENO-ASSOCIATED VIRUS FACTOR VIII VECTORS <130> 30610/48689 <150> US-61/877,042 <151> 2013-09-12 <160> 45 <170> KopatentIn 3.0 <210> 1 <211> 4970 <212> DNA <213> Adeno-Associated Virus <400> 1 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgtttg ctgcttgcaa tgtttgccca ttttagggtg 180 gacacaggac gctgtggttt ctgagccagg gggcgactca gatcccagcc agtggactta 240 gcccctgttt gctcctccga taactggggt gaccttggtt aatattcacc agcagcctcc 300 cccgttgccc ctctggatcc actgcttaaa tacggacgag gacagggccc tgtctcctca 360 gcttcaggca ccaccactga cctgggacag tgaatcgcca ccatgcagat tgagctgagc 420 acctgcttct tcctgtgcct gctgaggttc tgcttctctg ccaccaggag atactacctg 480 ggggctgtgg agctgagctg ggactacatg cagtctgacc tgggggagct gcctgtggat 540 gccaggttcc cccccagagt gcccaagagc ttccccttca acacctctgt ggtgtacaag 600 aagaccctgt ttgtggagtt cactgaccac ctgttcaaca ttgccaagcc caggcccccc 660 tggatgggcc tgctgggccc caccatccag gctgaggtgt atgacactgt ggtgatcacc 720 ctgaagaaca tggccagcca ccctgtgagc ctgcatgctg tgggggtgag ctactggaag 780 gcctctgagg gggctgagta tgatgaccag accagccaga gggagaagga ggatgacaag 840 gtgttccctg ggggcagcca cacctatgtg tggcaggtgc tgaaggagaa tggccccatg 900 gcctctgacc ccctgtgcct gacctacagc tacctgagcc atgtggacct ggtgaaggac 960 ctgaactctg gcctgattgg ggccctgctg gtgtgcaggg agggcagcct ggccaaggag 1020 aagacccaga ccctgcacaa gttcatcctg ctgtttgctg tgtttgatga gggcaagagc 1080 tggcactctg aaaccaagaa cagcctgatg caggacaggg atgctgcctc tgccagggcc 1140 tggcccaaga tgcacactgt gaatggctat gtgaacagga gcctgcctgg cctgattggc 1200 tgccacagga agtctgtgta ctggcatgtg attggcatgg gcaccacccc tgaggtgcac 1260 agcatcttcc tggagggcca caccttcctg gtcaggaacc acaggcaggc cagcctggag 1320 atcagcccca tcaccttcct gactgcccag accctgctga tggacctggg ccagttcctg 1380 ctgttctgcc acatcagcag ccaccagcat gatggcatgg aggcctatgt gaaggtggac 1440 agctgccctg aggagcccca gctgaggatg aagaacaatg aggaggctga ggactatgat 1500 gatgacctga ctgactctga gatggatgtg gtgaggtttg atgatgacaa cagccccagc 1560 ttcatccaga tcaggtctgt ggccaagaag caccccaaga cctgggtgca ctacattgct 1620 gctgaggagg aggactggga ctatgccccc ctggtgctgg cccctgatga caggagctac 1680 aagagccagt acctgaacaa tggcccccag aggattggca ggaagtacaa gaaggtcagg 1740 ttcatggcct acactgatga aaccttcaag accagggagg ccatccagca tgagtctggc 1800 atcctgggcc ccctgctgta tggggaggtg ggggacaccc tgctgatcat cttcaagaac 1860 caggccagca ggccctacaa catctacccc catggcatca ctgatgtgag gcccctgtac 1920 agcaggaggc tgcccaaggg ggtgaagcac ctgaaggact tccccatcct gcctggggag 1980 atcttcaagt acaagtggac tgtgactgtg gaggatggcc ccaccaagtc tgaccccagg 2040 tgcctgacca gatactacag cagctttgtg aacatggaga gggacctggc ctctggcctg 2100 attggccccc tgctgatctg ctacaaggag tctgtggacc agaggggcaa ccagatcatg 2160 tctgacaaga ggaatgtgat cctgttctct gtgtttgatg agaacaggag ctggtacctg 2220 actgagaaca tccagaggtt cctgcccaac cctgctgggg tgcagctgga ggaccctgag 2280 ttccaggcca gcaacatcat gcacagcatc aatggctatg tgtttgacag cctgcagctg 2340 tctgtgtgcc tgcatgaggt ggcctactgg tacatcctga gcattggggc ccagactgac 2400 ttcctgtctg tgttcttctc tggctacacc ttcaagcaca agatggtgta tgaggacacc 2460 ctgaccctgt tccccttctc tggggagact gtgttcatga gcatggagaa ccctggcctg 2520 tggattctgg gctgccacaa ctctgacttc aggaacaggg gcatgactgc cctgctgaaa 2580 gtctccagct gtgacaagaa cactggggac tactatgagg acagctatga ggacatctct 2640 gcctacctgc tgagcaagaa caatgccatt gagcccagga gcttcagcca gaacccccca 2700 gtgctgaaga ggcaccagag ggagatcacc aggaccaccc tgcagtctga ccaggaggag 2760 attgactatg atgacaccat ctctgtggag atgaagaagg aggactttga catctacgac 2820 gaggacgaga accagagccc caggagcttc cagaagaaga ccaggcacta cttcattgct 2880 gctgtggaga ggctgtggga ctatggcatg agcagcagcc cccatgtgct gaggaacagg 2940 gcccagtctg gctctgtgcc ccagttcaag aaggtggtgt tccaggagtt cactgatggc 3000 agcttcaccc agcccctgta cagaggggag ctgaatgagc acctgggcct gctgggcccc 3060 tacatcaggg ctgaggtgga ggacaacatc atggtgacct tcaggaacca ggccagcagg 3120 ccctacagct tctacagcag cctgatcagc tatgaggagg accagaggca gggggctgag 3180 cccaggaaga actttgtgaa gcccaatgaa accaagacct acttctggaa ggtgcagcac 3240 cacatggccc ccaccaagga tgagtttgac tgcaaggcct gggcctactt ctctgatgtg 3300 gacctggaga aggatgtgca ctctggcctg attggccccc tgctggtgtg ccacaccaac 3360 accctgaacc ctgcccatgg caggcaggtg actgtgcagg agtttgccct gttcttcacc 3420 atctttgatg aaaccaagag ctggtacttc actgagaaca tggagaggaa ctgcagggcc 3480 ccctgcaaca tccagatgga ggaccccacc ttcaaggaga actacaggtt ccatgccatc 3540 aatggctaca tcatggacac cctgcctggc ctggtgatgg cccaggacca gaggatcagg 3600 tggtacctgc tgagcatggg cagcaatgag aacatccaca gcatccactt ctctggccat 3660 gtgttcactg tgaggaagaa ggaggagtac aagatggccc tgtacaacct gtaccctggg 3720 gtgtttgaga ctgtggagat gctgcccagc aaggctggca tctggagggt ggagtgcctg 3780 attggggagc acctgcatgc tggcatgagc accctgttcc tggtgtacag caacaagtgc 3840 cagacccccc tgggcatggc ctctggccac atcagggact tccagatcac tgcctctggc 3900 cagtatggcc agtgggcccc caagctggcc aggctgcact actctggcag catcaatgcc 3960 tggagcacca aggagccctt cagctggatc aaggtggacc tgctggcccc catgatcatc 4020 catggcatca agacccaggg ggccaggcag aagttcagca gcctgtacat cagccagttc 4080 atcatcatgt acagcctgga tggcaagaag tggcagacct acaggggcaa cagcactggc 4140 accctgatgg tgttctttgg caatgtggac agctctggca tcaagcacaa catcttcaac 4200 ccccccatca ttgccagata catcaggctg caccccaccc actacagcat caggagcacc 4260 ctgaggatgg agctgatggg ctgtgacctg aacagctgca gcatgcccct gggcatggag 4320 agcaaggcca tctctgatgc ccagatcact gccagcagct acttcaccaa catgtttgcc 4380 acctggagcc ccagcaaggc caggctgcac ctgcagggca ggagcaatgc ctggaggccc 4440 caggtcaaca accccaagga gtggctgcag gtggacttcc agaagaccat gaaggtgact 4500 ggggtgacca cccagggggt gaagagcctg ctgaccagca tgtatgtgaa ggagttcctg 4560 atcagcagca gccaggatgg ccaccagtgg accctgttct tccagaatgg caaggtgaag 4620 gtgttccagg gcaaccagga cagcttcacc cctgtggtga acagcctgga cccccccctg 4680 ctgaccagat acctgaggat tcacccccag agctgggtgc accagattgc cctgaggatg 4740 gaggtgctgg gctgtgaggc ccaggacctg tactgaaata aaagatcttt attttcatta 4800 gatctgtgtg ttggtttttt gtgtgaggaa cccctagtga tggagttggc cactccctct 4860 ctgcgcgctc gctcgctcac tgaggccggg cgaccaaagg tcgcccgacg cccgggcttt 4920 gcccgggcgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa 4970 <210> 2 <211> 4950 <212> DNA <213> Adeno-Associated Virus <400> 2 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactgtttg ctgcttgcaa tgtttgccca ttttagggtg gacacaggac 180 gctgtggttt ctgagccagg gggcgactca gatcccagcc agtggactta gcccctgttt 240 gctcctccga taactggggt gaccttggtt aatattcacc agcagcctcc cccgttgccc 300 ctctggatcc actgcttaaa tacggacgag gacagggccc tgtctcctca gcttcaggca 360 ccaccactga cctgggacag tgaatcgcca ccatgcagat tgagctgagc acctgcttct 420 tcctgtgcct gctgaggttc tgcttctctg ccaccaggag atactacctg ggggctgtgg 480 agctgagctg ggactacatg cagtctgacc tgggggagct gcctgtggat gccaggttcc 540 cccccagagt gcccaagagc ttccccttca acacctctgt ggtgtacaag aagaccctgt 600 ttgtggagtt cactgaccac ctgttcaaca ttgccaagcc caggcccccc tggatgggcc 660 tgctgggccc caccatccag gctgaggtgt atgacactgt ggtgatcacc ctgaagaaca 720 tggccagcca ccctgtgagc ctgcatgctg tgggggtgag ctactggaag gcctctgagg 780 gggctgagta tgatgaccag accagccaga gggagaagga ggatgacaag gtgttccctg 840 ggggcagcca cacctatgtg tggcaggtgc tgaaggagaa tggccccatg gcctctgacc 900 ccctgtgcct gacctacagc tacctgagcc atgtggacct ggtgaaggac ctgaactctg 960 gcctgattgg ggccctgctg gtgtgcaggg agggcagcct ggccaaggag aagacccaga 1020 ccctgcacaa gttcatcctg ctgtttgctg tgtttgatga gggcaagagc tggcactctg 1080 aaaccaagaa cagcctgatg caggacaggg atgctgcctc tgccagggcc tggcccaaga 1140 tgcacactgt gaatggctat gtgaacagga gcctgcctgg cctgattggc tgccacagga 1200 agtctgtgta ctggcatgtg attggcatgg gcaccacccc tgaggtgcac agcatcttcc 1260 tggagggcca caccttcctg gtcaggaacc acaggcaggc cagcctggag atcagcccca 1320 tcaccttcct gactgcccag accctgctga tggacctggg ccagttcctg ctgttctgcc 1380 acatcagcag ccaccagcat gatggcatgg aggcctatgt gaaggtggac agctgccctg 1440 aggagcccca gctgaggatg aagaacaatg aggaggctga ggactatgat gatgacctga 1500 ctgactctga gatggatgtg gtgaggtttg atgatgacaa cagccccagc ttcatccaga 1560 tcaggtctgt ggccaagaag caccccaaga cctgggtgca ctacattgct gctgaggagg 1620 aggactggga ctatgccccc ctggtgctgg cccctgatga caggagctac aagagccagt 1680 acctgaacaa tggcccccag aggattggca ggaagtacaa gaaggtcagg ttcatggcct 1740 acactgatga aaccttcaag accagggagg ccatccagca tgagtctggc atcctgggcc 1800 ccctgctgta tggggaggtg ggggacaccc tgctgatcat cttcaagaac caggccagca 1860 ggccctacaa catctacccc catggcatca ctgatgtgag gcccctgtac agcaggaggc 1920 tgcccaaggg ggtgaagcac ctgaaggact tccccatcct gcctggggag atcttcaagt 1980 acaagtggac tgtgactgtg gaggatggcc ccaccaagtc tgaccccagg tgcctgacca 2040 gatactacag cagctttgtg aacatggaga gggacctggc ctctggcctg attggccccc 2100 tgctgatctg ctacaaggag tctgtggacc agaggggcaa ccagatcatg tctgacaaga 2160 ggaatgtgat cctgttctct gtgtttgatg agaacaggag ctggtacctg actgagaaca 2220 tccagaggtt cctgcccaac cctgctgggg tgcagctgga ggaccctgag ttccaggcca 2280 gcaacatcat gcacagcatc aatggctatg tgtttgacag cctgcagctg tctgtgtgcc 2340 tgcatgaggt ggcctactgg tacatcctga gcattggggc ccagactgac ttcctgtctg 2400 tgttcttctc tggctacacc ttcaagcaca agatggtgta tgaggacacc ctgaccctgt 2460 tccccttctc tggggagact gtgttcatga gcatggagaa ccctggcctg tggattctgg 2520 gctgccacaa ctctgacttc aggaacaggg gcatgactgc cctgctgaaa gtctccagct 2580 gtgacaagaa cactggggac tactatgagg acagctatga ggacatctct gcctacctgc 2640 tgagcaagaa caatgccatt gagcccagga gcttcagcca gaacccccca gtgctgaaga 2700 ggcaccagag ggagatcacc aggaccaccc tgcagtctga ccaggaggag attgactatg 2760 atgacaccat ctctgtggag atgaagaagg aggactttga catctacgac gaggacgaga 2820 accagagccc caggagcttc cagaagaaga ccaggcacta cttcattgct gctgtggaga 2880 ggctgtggga ctatggcatg agcagcagcc cccatgtgct gaggaacagg gcccagtctg 2940 gctctgtgcc ccagttcaag aaggtggtgt tccaggagtt cactgatggc agcttcaccc 3000 agcccctgta cagaggggag ctgaatgagc acctgggcct gctgggcccc tacatcaggg 3060 ctgaggtgga ggacaacatc atggtgacct tcaggaacca ggccagcagg ccctacagct 3120 tctacagcag cctgatcagc tatgaggagg accagaggca gggggctgag cccaggaaga 3180 actttgtgaa gcccaatgaa accaagacct acttctggaa ggtgcagcac cacatggccc 3240 ccaccaagga tgagtttgac tgcaaggcct gggcctactt ctctgatgtg gacctggaga 3300 aggatgtgca ctctggcctg attggccccc tgctggtgtg ccacaccaac accctgaacc 3360 ctgcccatgg caggcaggtg actgtgcagg agtttgccct gttcttcacc atctttgatg 3420 aaaccaagag ctggtacttc actgagaaca tggagaggaa ctgcagggcc ccctgcaaca 3480 tccagatgga ggaccccacc ttcaaggaga actacaggtt ccatgccatc aatggctaca 3540 tcatggacac cctgcctggc ctggtgatgg cccaggacca gaggatcagg tggtacctgc 3600 tgagcatggg cagcaatgag aacatccaca gcatccactt ctctggccat gtgttcactg 3660 tgaggaagaa ggaggagtac aagatggccc tgtacaacct gtaccctggg gtgtttgaga 3720 ctgtggagat gctgcccagc aaggctggca tctggagggt ggagtgcctg attggggagc 3780 acctgcatgc tggcatgagc accctgttcc tggtgtacag caacaagtgc cagacccccc 3840 tgggcatggc ctctggccac atcagggact tccagatcac tgcctctggc cagtatggcc 3900 agtgggcccc caagctggcc aggctgcact actctggcag catcaatgcc tggagcacca 3960 aggagccctt cagctggatc aaggtggacc tgctggcccc catgatcatc catggcatca 4020 agacccaggg ggccaggcag aagttcagca gcctgtacat cagccagttc atcatcatgt 4080 acagcctgga tggcaagaag tggcagacct acaggggcaa cagcactggc accctgatgg 4140 tgttctttgg caatgtggac agctctggca tcaagcacaa catcttcaac ccccccatca 4200 ttgccagata catcaggctg caccccaccc actacagcat caggagcacc ctgaggatgg 4260 agctgatggg ctgtgacctg aacagctgca gcatgcccct gggcatggag agcaaggcca 4320 tctctgatgc ccagatcact gccagcagct acttcaccaa catgtttgcc acctggagcc 4380 ccagcaaggc caggctgcac ctgcagggca ggagcaatgc ctggaggccc caggtcaaca 4440 accccaagga gtggctgcag gtggacttcc agaagaccat gaaggtgact ggggtgacca 4500 cccagggggt gaagagcctg ctgaccagca tgtatgtgaa ggagttcctg atcagcagca 4560 gccaggatgg ccaccagtgg accctgttct tccagaatgg caaggtgaag gtgttccagg 4620 gcaaccagga cagcttcacc cctgtggtga acagcctgga cccccccctg ctgaccagat 4680 acctgaggat tcacccccag agctgggtgc accagattgc cctgaggatg gaggtgctgg 4740 gctgtgaggc ccaggacctg tactgaaata aaagatcttt attttcatta gatctgtgtg 4800 ttggtttttt gtgtgagtga tggagttggc cactccctct ctgcgcgctc gctcgctcac 4860 tgaggccggg cgaccaaagg tcgcccgacg cccgggcttt gcccgggcgg cctcagtgag 4920 cgagcgagcg cgcagagagg gagtggccaa 4950 <210> 3 <211> 4983 <212> DNA <213> Adeno-Associated Virus <400> 3 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactgggcg actcagatcc cagccagtgg acttagcccc tgtttgctcc 180 tccgataact ggggtgacct tggttaatat tcaccagcag cctcccccgt tgcccctctg 240 gatccactgc ttaaatacgg acgaggacag ggccctgtct cctcagcttc aggcaccacc 300 actgacctgg gacagtgaat cgccaccatg cagattgagc tgagcacctg cttcttcctg 360 tgcctgctga gattctgctt tagtgccacc agaagatact acctgggtgc agtggaactg 420 tcatgggact atatgcaaag tgatctcggt gagctgcctg tggacgcaag gtaaatgccc 480 taaaatgggc aaacattgca agcagcaaac aacctggctc agaaaccaca gcgtcctgtg 540 tccattctaa tttttccttt cttcacgcag atttcctcct agagtgccaa aatcttttcc 600 attcaacacc tcagtcgtgt acaaaaagac tctgtttgta gaattcacgg atcacctttt 660 caacatcgct aagcccaggc ccccctggat gggcctgctg ggccccacca tccaggctga 720 ggtgtatgac actgtggtga tcaccctgaa gaacatggcc agccaccctg tgagcctgca 780 tgctgtgggg gtgagctact ggaaggcctc tgagggggct gagtatgatg accagaccag 840 ccagagggag aaggaggatg acaaggtgtt ccctgggggc agccacacct atgtgtggca 900 ggtgctgaag gagaatggcc ccatggcctc tgaccccctg tgcctgacct acagctacct 960 gagccatgtg gacctggtga aggacctgaa ctctggcctg attggggccc tgctggtgtg 1020 cagggagggc agcctggcca aggagaagac ccagaccctg cacaagttca tcctgctgtt 1080 tgctgtgttt gatgagggca agagctggca ctctgaaacc aagaacagcc tgatgcagga 1140 cagggatgct gcctctgcca gggcctggcc caagatgcac actgtgaatg gctatgtgaa 1200 caggagcctg cctggcctga ttggctgcca caggaagtct gtgtactggc atgtgattgg 1260 catgggcacc acccctgagg tgcacagcat cttcctggag ggccacacct tcctggtcag 1320 gaaccacagg caggccagcc tggagatcag ccccatcacc ttcctgactg cccagaccct 1380 gctgatggac ctgggccagt tcctgctgtt ctgccacatc agcagccacc agcatgatgg 1440 catggaggcc tatgtgaagg tggacagctg ccctgaggag ccccagctga ggatgaagaa 1500 caatgaggag gctgaggact atgatgatga cctgactgac tctgagatgg atgtggtgag 1560 gtttgatgat gacaacagcc ccagcttcat ccagatcagg tctgtggcca agaagcaccc 1620 caagacctgg gtgcactaca ttgctgctga ggaggaggac tgggactatg cccccctggt 1680 gctggcccct gatgacagga gctacaagag ccagtacctg aacaatggcc cccagaggat 1740 tggcaggaag tacaagaagg tcaggttcat ggcctacact gatgaaacct tcaagaccag 1800 ggaggccatc cagcatgagt ctggcatcct gggccccctg ctgtatgggg aggtggggga 1860 caccctgctg atcatcttca agaaccaggc cagcaggccc tacaacatct acccccatgg 1920 catcactgat gtgaggcccc tgtacagcag gaggctgccc aagggggtga agcacctgaa 1980 ggacttcccc atcctgcctg gggagatctt caagtacaag tggactgtga ctgtggagga 2040 tggccccacc aagtctgacc ccaggtgcct gaccagatac tacagcagct ttgtgaacat 2100 ggagagggac ctggcctctg gcctgattgg ccccctgctg atctgctaca aggagtctgt 2160 ggaccagagg ggcaaccaga tcatgtctga caagaggaat gtgatcctgt tctctgtgtt 2220 tgatgagaac aggagctggt acctgactga gaacatccag aggttcctgc ccaaccctgc 2280 tggggtgcag ctggaggacc ctgagttcca ggccagcaac atcatgcaca gcatcaatgg 2340 ctatgtgttt gacagcctgc agctgtctgt gtgcctgcat gaggtggcct actggtacat 2400 cctgagcatt ggggcccaga ctgacttcct gtctgtgttc ttctctggct acaccttcaa 2460 gcacaagatg gtgtatgagg acaccctgac cctgttcccc ttctctgggg agactgtgtt 2520 catgagcatg gagaaccctg gcctgtggat tctgggctgc cacaactctg acttcaggaa 2580 caggggcatg actgccctgc tgaaagtctc cagctgtgac aagaacactg gggactacta 2640 tgaggacagc tatgaggaca tctctgccta cctgctgagc aagaacaatg ccattgagcc 2700 caggagcttc agccagaacc ccccagtgct gaagaggcac cagagggaga tcaccaggac 2760 caccctgcag tctgaccagg aggagattga ctatgatgac accatctctg tggagatgaa 2820 gaaggaggac tttgacatct acgacgagga cgagaaccag agccccagga gcttccagaa 2880 gaagaccagg cactacttca ttgctgctgt ggagaggctg tgggactatg gcatgagcag 2940 cagcccccat gtgctgagga acagggccca gtctggctct gtgccccagt tcaagaaggt 3000 ggtgttccag gagttcactg atggcagctt cacccagccc ctgtacagag gggagctgaa 3060 tgagcacctg ggcctgctgg gcccctacat cagggctgag gtggaggaca acatcatggt 3120 gaccttcagg aaccaggcca gcaggcccta cagcttctac agcagcctga tcagctatga 3180 ggaggaccag aggcaggggg ctgagcccag gaagaacttt gtgaagccca atgaaaccaa 3240 gacctacttc tggaaggtgc agcaccacat ggcccccacc aaggatgagt ttgactgcaa 3300 ggcctgggcc tacttctctg atgtggacct ggagaaggat gtgcactctg gcctgattgg 3360 ccccctgctg gtgtgccaca ccaacaccct gaaccctgcc catggcaggc aggtgactgt 3420 gcaggagttt gccctgttct tcaccatctt tgatgaaacc aagagctggt acttcactga 3480 gaacatggag aggaactgca gggccccctg caacatccag atggaggacc ccaccttcaa 3540 ggagaactac aggttccatg ccatcaatgg ctacatcatg gacaccctgc ctggcctggt 3600 gatggcccag gaccagagga tcaggtggta cctgctgagc atgggcagca atgagaacat 3660 ccacagcatc cacttctctg gccatgtgtt cactgtgagg aagaaggagg agtacaagat 3720 ggccctgtac aacctgtacc ctggggtgtt tgagactgtg gagatgctgc ccagcaaggc 3780 tggcatctgg agggtggagt gcctgattgg ggagcacctg catgctggca tgagcaccct 3840 gttcctggtg tacagcaaca agtgccagac ccccctgggc atggcctctg gccacatcag 3900 ggacttccag atcactgcct ctggccagta tggccagtgg gcccccaagc tggccaggct 3960 gcactactct ggcagcatca atgcctggag caccaaggag cccttcagct ggatcaaggt 4020 ggacctgctg gcccccatga tcatccatgg catcaagacc cagggggcca ggcagaagtt 4080 cagcagcctg tacatcagcc agttcatcat catgtacagc ctggatggca agaagtggca 4140 gacctacagg ggcaacagca ctggcaccct gatggtgttc tttggcaatg tggacagctc 4200 tggcatcaag cacaacatct tcaacccccc catcattgcc agatacatca ggctgcaccc 4260 cacccactac agcatcagga gcaccctgag gatggagctg atgggctgtg acctgaacag 4320 ctgcagcatg cccctgggca tggagagcaa ggccatctct gatgcccaga tcactgccag 4380 cagctacttc accaacatgt ttgccacctg gagccccagc aaggccaggc tgcacctgca 4440 gggcaggagc aatgcctgga ggccccaggt caacaacccc aaggagtggc tgcaggtgga 4500 cttccagaag accatgaagg tgactggggt gaccacccag ggggtgaaga gcctgctgac 4560 cagcatgtat gtgaaggagt tcctgatcag cagcagccag gatggccacc agtggaccct 4620 gttcttccag aatggcaagg tgaaggtgtt ccagggcaac caggacagct tcacccctgt 4680 ggtgaacagc ctggaccccc ccctgctgac cagatacctg aggattcacc cccagagctg 4740 ggtgcaccag attgccctga ggatggaggt gctgggctgt gaggcccagg acctgtacta 4800 ataaaagatc tttattttca ttagatctgt gtgttggttt tttgtgtgag tgatggagtt 4860 ggccactccc tctctgcgcg ctcgctcgct cactgaggcc gggcgaccaa aggtcgcccg 4920 acgcccgggc tttgcccggg cggcctcagt gagcgagcga gcgcgcagag agggagtggc 4980 caa 4983 <210> 4 <211> 4984 <212> DNA <213> Adeno-Associated Virus <400> 4 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactgggcg actcagatcc cagccagtgg acttagcccc tgtttgctcc 180 tccgataact ggggtgacct tggttaatat tcaccagcag cctcccccgt tgcccctctg 240 gatccactgc ttaaatacgg acgaggacag ggccctgtct cctcagcttc aggcaccacc 300 actgacctgg gacagtgaat cgccaccatg cagattgagc tgagcacctg cttcttcctg 360 tgcctgctga gattctgctt tagtgccacc agaagatact acctgggtgc agtggaactg 420 tcatgggact atatgcaaag tgatctcggt gagctgcctg tggacgcaag gtaaatgccc 480 taaaatgggc aaacattgca agcagcaaac accctaaaat gggcaaacat tgcaagcagc 540 aaacattcta atttttcctt tcttcacgca gatttcctcc tagagtgcca aaatcttttc 600 cattcaacac ctcagtcgtg tacaaaaaga ctctgtttgt agaattcacg gatcaccttt 660 tcaacatcgc taagcccagg cccccctgga tgggcctgct gggccccacc atccaggctg 720 aggtgtatga cactgtggtg atcaccctga agaacatggc cagccaccct gtgagcctgc 780 atgctgtggg ggtgagctac tggaaggcct ctgagggggc tgagtatgat gaccagacca 840 gccagaggga gaaggaggat gacaaggtgt tccctggggg cagccacacc tatgtgtggc 900 aggtgctgaa ggagaatggc cccatggcct ctgaccccct gtgcctgacc tacagctacc 960 tgagccatgt ggacctggtg aaggacctga actctggcct gattggggcc ctgctggtgt 1020 gcagggaggg cagcctggcc aaggagaaga cccagaccct gcacaagttc atcctgctgt 1080 ttgctgtgtt tgatgagggc aagagctggc actctgaaac caagaacagc ctgatgcagg 1140 acagggatgc tgcctctgcc agggcctggc ccaagatgca cactgtgaat ggctatgtga 1200 acaggagcct gcctggcctg attggctgcc acaggaagtc tgtgtactgg catgtgattg 1260 gcatgggcac cacccctgag gtgcacagca tcttcctgga gggccacacc ttcctggtca 1320 ggaaccacag gcaggccagc ctggagatca gccccatcac cttcctgact gcccagaccc 1380 tgctgatgga cctgggccag ttcctgctgt tctgccacat cagcagccac cagcatgatg 1440 gcatggaggc ctatgtgaag gtggacagct gccctgagga gccccagctg aggatgaaga 1500 acaatgagga ggctgaggac tatgatgatg acctgactga ctctgagatg gatgtggtga 1560 ggtttgatga tgacaacagc cccagcttca tccagatcag gtctgtggcc aagaagcacc 1620 ccaagacctg ggtgcactac attgctgctg aggaggagga ctgggactat gcccccctgg 1680 tgctggcccc tgatgacagg agctacaaga gccagtacct gaacaatggc ccccagagga 1740 ttggcaggaa gtacaagaag gtcaggttca tggcctacac tgatgaaacc ttcaagacca 1800 gggaggccat ccagcatgag tctggcatcc tgggccccct gctgtatggg gaggtggggg 1860 acaccctgct gatcatcttc aagaaccagg ccagcaggcc ctacaacatc tacccccatg 1920 gcatcactga tgtgaggccc ctgtacagca ggaggctgcc caagggggtg aagcacctga 1980 aggacttccc catcctgcct ggggagatct tcaagtacaa gtggactgtg actgtggagg 2040 atggccccac caagtctgac cccaggtgcc tgaccagata ctacagcagc tttgtgaaca 2100 tggagaggga cctggcctct ggcctgattg gccccctgct gatctgctac aaggagtctg 2160 tggaccagag gggcaaccag atcatgtctg acaagaggaa tgtgatcctg ttctctgtgt 2220 ttgatgagaa caggagctgg tacctgactg agaacatcca gaggttcctg cccaaccctg 2280 ctggggtgca gctggaggac cctgagttcc aggccagcaa catcatgcac agcatcaatg 2340 gctatgtgtt tgacagcctg cagctgtctg tgtgcctgca tgaggtggcc tactggtaca 2400 tcctgagcat tggggcccag actgacttcc tgtctgtgtt cttctctggc tacaccttca 2460 agcacaagat ggtgtatgag gacaccctga ccctgttccc cttctctggg gagactgtgt 2520 tcatgagcat ggagaaccct ggcctgtgga ttctgggctg ccacaactct gacttcagga 2580 acaggggcat gactgccctg ctgaaagtct ccagctgtga caagaacact ggggactact 2640 atgaggacag ctatgaggac atctctgcct acctgctgag caagaacaat gccattgagc 2700 ccaggagctt cagccagaac cccccagtgc tgaagaggca ccagagggag atcaccagga 2760 ccaccctgca gtctgaccag gaggagattg actatgatga caccatctct gtggagatga 2820 agaaggagga ctttgacatc tacgacgagg acgagaacca gagccccagg agcttccaga 2880 agaagaccag gcactacttc attgctgctg tggagaggct gtgggactat ggcatgagca 2940 gcagccccca tgtgctgagg aacagggccc agtctggctc tgtgccccag ttcaagaagg 3000 tggtgttcca ggagttcact gatggcagct tcacccagcc cctgtacaga ggggagctga 3060 atgagcacct gggcctgctg ggcccctaca tcagggctga ggtggaggac aacatcatgg 3120 tgaccttcag gaaccaggcc agcaggccct acagcttcta cagcagcctg atcagctatg 3180 aggaggacca gaggcagggg gctgagccca ggaagaactt tgtgaagccc aatgaaacca 3240 agacctactt ctggaaggtg cagcaccaca tggcccccac caaggatgag tttgactgca 3300 aggcctgggc ctacttctct gatgtggacc tggagaagga tgtgcactct ggcctgattg 3360 gccccctgct ggtgtgccac accaacaccc tgaaccctgc ccatggcagg caggtgactg 3420 tgcaggagtt tgccctgttc ttcaccatct ttgatgaaac caagagctgg tacttcactg 3480 agaacatgga gaggaactgc agggccccct gcaacatcca gatggaggac cccaccttca 3540 aggagaacta caggttccat gccatcaatg gctacatcat ggacaccctg cctggcctgg 3600 tgatggccca ggaccagagg atcaggtggt acctgctgag catgggcagc aatgagaaca 3660 tccacagcat ccacttctct ggccatgtgt tcactgtgag gaagaaggag gagtacaaga 3720 tggccctgta caacctgtac cctggggtgt ttgagactgt ggagatgctg cccagcaagg 3780 ctggcatctg gagggtggag tgcctgattg gggagcacct gcatgctggc atgagcaccc 3840 tgttcctggt gtacagcaac aagtgccaga cccccctggg catggcctct ggccacatca 3900 gggacttcca gatcactgcc tctggccagt atggccagtg ggcccccaag ctggccaggc 3960 tgcactactc tggcagcatc aatgcctgga gcaccaagga gcccttcagc tggatcaagg 4020 tggacctgct ggcccccatg atcatccatg gcatcaagac ccagggggcc aggcagaagt 4080 tcagcagcct gtacatcagc cagttcatca tcatgtacag cctggatggc aagaagtggc 4140 agacctacag gggcaacagc actggcaccc tgatggtgtt ctttggcaat gtggacagct 4200 ctggcatcaa gcacaacatc ttcaaccccc ccatcattgc cagatacatc aggctgcacc 4260 ccacccacta cagcatcagg agcaccctga ggatggagct gatgggctgt gacctgaaca 4320 gctgcagcat gcccctgggc atggagagca aggccatctc tgatgcccag atcactgcca 4380 gcagctactt caccaacatg tttgccacct ggagccccag caaggccagg ctgcacctgc 4440 agggcaggag caatgcctgg aggccccagg tcaacaaccc caaggagtgg ctgcaggtgg 4500 acttccagaa gaccatgaag gtgactgggg tgaccaccca gggggtgaag agcctgctga 4560 ccagcatgta tgtgaaggag ttcctgatca gcagcagcca ggatggccac cagtggaccc 4620 tgttcttcca gaatggcaag gtgaaggtgt tccagggcaa ccaggacagc ttcacccctg 4680 tggtgaacag cctggacccc cccctgctga ccagatacct gaggattcac ccccagagct 4740 gggtgcacca gattgccctg aggatggagg tgctgggctg tgaggcccag gacctgtact 4800 aataaaagat ctttattttc attagatctg tgtgttggtt ttttgtgtga gtgatggagt 4860 tggccactcc ctctctgcgc gctcgctcgc tcactgaggc cgggcgacca aaggtcgccc 4920 gacgcccggg ctttgcccgg gcggcctcag tgagcgagcg agcgcgcaga gagggagtgg 4980 ccaa 4984 <210> 5 <211> 4805 <212> DNA <213> Adeno-Associated Virus <400> 5 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgtttg ctgcttgcaa tgtttgccca ttttagggtg 180 gacacaggac gctgtggttt ctgagccagg gggcgactca gatcccagcc agtggactta 240 gcccctgttt gctcctccga taactggggt gaccttggtt aatattcacc agcagcctcc 300 cccgttgccc ctctggatcc actgcttaaa tacggacgag gacagggccc tgtctcctca 360 gcttcaggca ccaccactga cctgggacag tgaatcgcca ccatgcagat tgagctgagc 420 acctgcttct tcctgtgcct gctgaggttc tgcttctctg ccaccaggag atactacctg 480 ggggctgtgg agctgagctg ggactacatg cagtctgacc tgggggagct gcctgtggat 540 gccaggttcc cccccagagt gcccaagagc ttccccttca acacctctgt ggtgtacaag 600 aagaccctgt ttgtggagtt cactgaccac ctgttcaaca ttgccaagcc caggcccccc 660 tggatgggcc tgctgggccc caccatccag gctgaggtgt atgacactgt ggtgatcacc 720 ctgaagaaca tggccagcca ccctgtgagc ctgcatgctg tgggggtgag ctactggaag 780 gcctctgagg gggctgagta tgatgaccag accagccaga gggagaagga ggatgacaag 840 gtgttccctg ggggcagcca cacctatgtg tggcaggtgc tgaaggagaa tggccccatg 900 gcctctgacc ccctgtgcct gacctacagc tacctgagcc atgtggacct ggtgaaggac 960 ctgaactctg gcctgattgg ggccctgctg gtgtgcaggg agggcagcct ggccaaggag 1020 aagacccaga ccctgcacaa gttcatcctg ctgtttgctg tgtttgatga gggcaagagc 1080 tggcactctg aaaccaagaa cagcctgatg caggacaggg atgctgcctc tgccagggcc 1140 tggcccaaga tgcacactgt gaatggctat gtgaacagga gcctgcctgg cctgattggc 1200 tgccacagga agtctgtgta ctggcatgtg attggcatgg gcaccacccc tgaggtgcac 1260 agcatcttcc tggagggcca caccttcctg gtcaggaacc acaggcaggc cagcctggag 1320 atcagcccca tcaccttcct gactgcccag accctgctga tggacctggg ccagttcctg 1380 ctgttctgcc acatcagcag ccaccagcat gatggcatgg aggcctatgt gaaggtggac 1440 agctgccctg aggagcccca gctgaggatg aagaacaatg aggaggctga ggactatgat 1500 gatgacctga ctgactctga gatggatgtg gtgaggtttg atgatgacaa cagccccagc 1560 ttcatccaga tcaggtctgt ggccaagaag caccccaaga cctgggtgca ctacattgct 1620 gctgaggagg aggactggga ctatgccccc ctggtgctgg cccctgatga caggagctac 1680 aagagccagt acctgaacaa tggcccccag aggattggca ggaagtacaa gaaggtcagg 1740 ttcatggcct acactgatga aaccttcaag accagggagg ccatccagca tgagtctggc 1800 atcctgggcc ccctgctgta tggggaggtg ggggacaccc tgctgatcat cttcaagaac 1860 caggccagca ggccctacaa catctacccc catggcatca ctgatgtgag gcccctgtac 1920 agcaggaggc tgcccaaggg ggtgaagcac ctgaaggact tccccatcct gcctggggag 1980 atcttcaagt acaagtggac tgtgactgtg gaggatggcc ccaccaagtc tgaccccagg 2040 tgcctgacca gatactacag cagctttgtg aacatggaga gggacctggc ctctggcctg 2100 attggccccc tgctgatctg ctacaaggag tctgtggacc agaggggcaa ccagatcatg 2160 tctgacaaga ggaatgtgat cctgttctct gtgtttgatg agaacaggag ctggtacctg 2220 actgagaaca tccagaggtt cctgcccaac cctgctgggg tgcagctgga ggaccctgag 2280 ttccaggcca gcaacatcat gcacagcatc aatggctatg tgtttgacag cctgcagctg 2340 tctgtgtgcc tgcatgaggt ggcctactgg tacatcctga gcattggggc ccagactgac 2400 ttcctgtctg tgttcttctc tggctacacc ttcaagcaca agatggtgta tgaggacacc 2460 ctgaccctgt tccccttctc tggggagact gtgttcatga gcatggagaa ccctggcctg 2520 tggattctgg gctgccacaa ctctgacttc aggaacaggg gcatgactgc cctgctgaaa 2580 gtctccagct gtgacaagaa cactggggac tactatgagg acagctatga ggacatctct 2640 gcctacctgc tgagcaagaa caatgccatt gagcccagga gcttccagaa gaagaccagg 2700 cactacttca ttgctgctgt ggagaggctg tgggactatg gcatgagcag cagcccccat 2760 gtgctgagga acagggccca gtctggctct gtgccccagt tcaagaaggt ggtgttccag 2820 gagttcactg atggcagctt cacccagccc ctgtacagag gggagctgaa tgagcacctg 2880 ggcctgctgg gcccctacat cagggctgag gtggaggaca acatcatggt gaccttcagg 2940 aaccaggcca gcaggcccta cagcttctac agcagcctga tcagctatga ggaggaccag 3000 aggcaggggg ctgagcccag gaagaacttt gtgaagccca atgaaaccaa gacctacttc 3060 tggaaggtgc agcaccacat ggcccccacc aaggatgagt ttgactgcaa ggcctgggcc 3120 tacttctctg atgtggacct ggagaaggat gtgcactctg gcctgattgg ccccctgctg 3180 gtgtgccaca ccaacaccct gaaccctgcc catggcaggc aggtgactgt gcaggagttt 3240 gccctgttct tcaccatctt tgatgaaacc aagagctggt acttcactga gaacatggag 3300 aggaactgca gggccccctg caacatccag atggaggacc ccaccttcaa ggagaactac 3360 aggttccatg ccatcaatgg ctacatcatg gacaccctgc ctggcctggt gatggcccag 3420 gaccagagga tcaggtggta cctgctgagc atgggcagca atgagaacat ccacagcatc 3480 cacttctctg gccatgtgtt cactgtgagg aagaaggagg agtacaagat ggccctgtac 3540 aacctgtacc ctggggtgtt tgagactgtg gagatgctgc ccagcaaggc tggcatctgg 3600 agggtggagt gcctgattgg ggagcacctg catgctggca tgagcaccct gttcctggtg 3660 tacagcaaca agtgccagac ccccctgggc atggcctctg gccacatcag ggacttccag 3720 atcactgcct ctggccagta tggccagtgg gcccccaagc tggccaggct gcactactct 3780 ggcagcatca atgcctggag caccaaggag cccttcagct ggatcaaggt ggacctgctg 3840 gcccccatga tcatccatgg catcaagacc cagggggcca ggcagaagtt cagcagcctg 3900 tacatcagcc agttcatcat catgtacagc ctggatggca agaagtggca gacctacagg 3960 ggcaacagca ctggcaccct gatggtgttc tttggcaatg tggacagctc tggcatcaag 4020 cacaacatct tcaacccccc catcattgcc agatacatca ggctgcaccc cacccactac 4080 agcatcagga gcaccctgag gatggagctg atgggctgtg acctgaacag ctgcagcatg 4140 cccctgggca tggagagcaa ggccatctct gatgcccaga tcactgccag cagctacttc 4200 accaacatgt ttgccacctg gagccccagc aaggccaggc tgcacctgca gggcaggagc 4260 aatgcctgga ggccccaggt caacaacccc aaggagtggc tgcaggtgga cttccagaag 4320 accatgaagg tgactggggt gaccacccag ggggtgaaga gcctgctgac cagcatgtat 4380 gtgaaggagt tcctgatcag cagcagccag gatggccacc agtggaccct gttcttccag 4440 aatggcaagg tgaaggtgtt ccagggcaac caggacagct tcacccctgt ggtgaacagc 4500 ctggaccccc ccctgctgac cagatacctg aggattcacc cccagagctg ggtgcaccag 4560 attgccctga ggatggaggt gctgggctgt gaggcccagg acctgtactg aaataaaaga 4620 tctttatttt cattagatct gtgtgttggt tttttgtgtg aggaacccct agtgatggag 4680 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc 4740 cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc gagcgcgcag agagggagtg 4800 gccaa 4805 <210> 6 <211> 4934 <212> DNA <213> Adeno-Associated Virus <400> 6 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgtttg ctgcttgcaa tgtttgccca ttttagggtg 180 gacacaggac gctgtggttt ctgagccagg gggcgactca gatcccagcc agtggactta 240 gcccctgttt gctcctccga taactggggt gaccttggtt aatattcacc agcagcctcc 300 cccgttgccc ctctggatcc actgcttaaa tacggacgag gacagggccc tgtctcctca 360 gcttcaggca ccaccactga cctgggacag tgaatcgcca ccatgcagat tgagctgagc 420 acctgcttct tcctgtgcct gctgagattc tgctttagtg ccaccagaag atactacctg 480 ggtgcagtgg aactgtcatg ggactatatg caaagtgatc tcggtgagct gcctgtggac 540 gcaaggtaaa ggcatgtcct gtagggtctg atcggggcca ggattgtggg gatgtaagtc 600 tgcttggagg aaggtgcaga catcgggtta ggatggttgt gatgctattc tgactttttc 660 ctttcttcac gcagatttcc tcctagagtg ccaaaatctt ttccattcaa cacctcagtc 720 gtgtacaaaa agactctgtt tgtagaattc acggatcacc ttttcaacat cgctaagccc 780 aggcccccct ggatgggcct gctgggcccc accatccagg ctgaggtgta tgacactgtg 840 gtgatcaccc tgaagaacat ggccagccac cctgtgagcc tgcatgctgt gggggtgagc 900 tactggaagg cctctgaggg ggctgagtat gatgaccaga ccagccagag ggagaaggag 960 gatgacaagg tgttccctgg gggcagccac acctatgtgt ggcaggtgct gaaggagaat 1020 ggccccatgg cctctgaccc cctgtgcctg acctacagct acctgagcca tgtggacctg 1080 gtgaaggacc tgaactctgg cctgattggg gccctgctgg tgtgcaggga gggcagcctg 1140 gccaaggaga agacccagac cctgcacaag ttcatcctgc tgtttgctgt gtttgatgag 1200 ggcaagagct ggcactctga aaccaagaac agcctgatgc aggacaggga tgctgcctct 1260 gccagggcct ggcccaagat gcacactgtg aatggctatg tgaacaggag cctgcctggc 1320 ctgattggct gccacaggaa gtctgtgtac tggcatgtga ttggcatggg caccacccct 1380 gaggtgcaca gcatcttcct ggagggccac accttcctgg tcaggaacca caggcaggcc 1440 agcctggaga tcagccccat caccttcctg actgcccaga ccctgctgat ggacctgggc 1500 cagttcctgc tgttctgcca catcagcagc caccagcatg atggcatgga ggcctatgtg 1560 aaggtggaca gctgccctga ggagccccag ctgaggatga agaacaatga ggaggctgag 1620 gactatgatg atgacctgac tgactctgag atggatgtgg tgaggtttga tgatgacaac 1680 agccccagct tcatccagat caggtctgtg gccaagaagc accccaagac ctgggtgcac 1740 tacattgctg ctgaggagga ggactgggac tatgcccccc tggtgctggc ccctgatgac 1800 aggagctaca agagccagta cctgaacaat ggcccccaga ggattggcag gaagtacaag 1860 aaggtcaggt tcatggccta cactgatgaa accttcaaga ccagggaggc catccagcat 1920 gagtctggca tcctgggccc cctgctgtat ggggaggtgg gggacaccct gctgatcatc 1980 ttcaagaacc aggccagcag gccctacaac atctaccccc atggcatcac tgatgtgagg 2040 cccctgtaca gcaggaggct gcccaagggg gtgaagcacc tgaaggactt ccccatcctg 2100 cctggggaga tcttcaagta caagtggact gtgactgtgg aggatggccc caccaagtct 2160 gaccccaggt gcctgaccag atactacagc agctttgtga acatggagag ggacctggcc 2220 tctggcctga ttggccccct gctgatctgc tacaaggagt ctgtggacca gaggggcaac 2280 cagatcatgt ctgacaagag gaatgtgatc ctgttctctg tgtttgatga gaacaggagc 2340 tggtacctga ctgagaacat ccagaggttc ctgcccaacc ctgctggggt gcagctggag 2400 gaccctgagt tccaggccag caacatcatg cacagcatca atggctatgt gtttgacagc 2460 ctgcagctgt ctgtgtgcct gcatgaggtg gcctactggt acatcctgag cattggggcc 2520 cagactgact tcctgtctgt gttcttctct ggctacacct tcaagcacaa gatggtgtat 2580 gaggacaccc tgaccctgtt ccccttctct ggggagactg tgttcatgag catggagaac 2640 cctggcctgt ggattctggg ctgccacaac tctgacttca ggaacagggg catgactgcc 2700 ctgctgaaag tctccagctg tgacaagaac actggggact actatgagga cagctatgag 2760 gacatctctg cctacctgct gagcaagaac aatgccattg agcccaggag cttccagaag 2820 aagaccaggc actacttcat tgctgctgtg gagaggctgt gggactatgg catgagcagc 2880 agcccccatg tgctgaggaa cagggcccag tctggctctg tgccccagtt caagaaggtg 2940 gtgttccagg agttcactga tggcagcttc acccagcccc tgtacagagg ggagctgaat 3000 gagcacctgg gcctgctggg cccctacatc agggctgagg tggaggacaa catcatggtg 3060 accttcagga accaggccag caggccctac agcttctaca gcagcctgat cagctatgag 3120 gaggaccaga ggcagggggc tgagcccagg aagaactttg tgaagcccaa tgaaaccaag 3180 acctacttct ggaaggtgca gcaccacatg gcccccacca aggatgagtt tgactgcaag 3240 gcctgggcct acttctctga tgtggacctg gagaaggatg tgcactctgg cctgattggc 3300 cccctgctgg tgtgccacac caacaccctg aaccctgccc atggcaggca ggtgactgtg 3360 caggagtttg ccctgttctt caccatcttt gatgaaacca agagctggta cttcactgag 3420 aacatggaga ggaactgcag ggccccctgc aacatccaga tggaggaccc caccttcaag 3480 gagaactaca ggttccatgc catcaatggc tacatcatgg acaccctgcc tggcctggtg 3540 atggcccagg accagaggat caggtggtac ctgctgagca tgggcagcaa tgagaacatc 3600 cacagcatcc acttctctgg ccatgtgttc actgtgagga agaaggagga gtacaagatg 3660 gccctgtaca acctgtaccc tggggtgttt gagactgtgg agatgctgcc cagcaaggct 3720 ggcatctgga gggtggagtg cctgattggg gagcacctgc atgctggcat gagcaccctg 3780 ttcctggtgt acagcaacaa gtgccagacc cccctgggca tggcctctgg ccacatcagg 3840 gacttccaga tcactgcctc tggccagtat ggccagtggg cccccaagct ggccaggctg 3900 cactactctg gcagcatcaa tgcctggagc accaaggagc ccttcagctg gatcaaggtg 3960 gacctgctgg cccccatgat catccatggc atcaagaccc agggggccag gcagaagttc 4020 agcagcctgt acatcagcca gttcatcatc atgtacagcc tggatggcaa gaagtggcag 4080 acctacaggg gcaacagcac tggcaccctg atggtgttct ttggcaatgt ggacagctct 4140 ggcatcaagc acaacatctt caaccccccc atcattgcca gatacatcag gctgcacccc 4200 acccactaca gcatcaggag caccctgagg atggagctga tgggctgtga cctgaacagc 4260 tgcagcatgc ccctgggcat ggagagcaag gccatctctg atgcccagat cactgccagc 4320 agctacttca ccaacatgtt tgccacctgg agccccagca aggccaggct gcacctgcag 4380 ggcaggagca atgcctggag gccccaggtc aacaacccca aggagtggct gcaggtggac 4440 ttccagaaga ccatgaaggt gactggggtg accacccagg gggtgaagag cctgctgacc 4500 agcatgtatg tgaaggagtt cctgatcagc agcagccagg atggccacca gtggaccctg 4560 ttcttccaga atggcaaggt gaaggtgttc cagggcaacc aggacagctt cacccctgtg 4620 gtgaacagcc tggacccccc cctgctgacc agatacctga ggattcaccc ccagagctgg 4680 gtgcaccaga ttgccctgag gatggaggtg ctgggctgtg aggcccagga cctgtactga 4740 aataaaagat ctttattttc attagatctg tgtgttggtt ttttgtgtga ggaaccccta 4800 gtgatggagt tggccactcc ctctctgcgc gctcgctcgc tcactgaggc cgggcgacca 4860 aaggtcgccc gacgcccggg ctttgcccgg gcggcctcag tgagcgagcg agcgcgcaga 4920 gagggagtgg ccaa 4934 <210> 7 <211> 4934 <212> DNA <213> Adeno-Associated Virus <400> 7 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgtttg ctgcttgcaa tgtttgccca ttttagggtg 180 gacacaggac gctgtggttt ctgagccagg gggcgactca gatcccagcc agtggactta 240 gcccctgttt gctcctccga taactggggt gaccttggtt aatattcacc agcagcctcc 300 cccgttgccc ctctggatcc actgcttaaa tacggacgag gacagggccc tgtctcctca 360 gcttcaggca ccaccactga cctgggacag tgaatcgcca ccatgcagat tgagctgagc 420 acctgcttct tcctgtgcct gctgagattc tgctttagtg ccaccagaag atactacctg 480 ggtgcagtgg aactgtcatg ggactatatg caaagtgatc tcggtgagct gcctgtggac 540 gcaaggtaaa ggctgtttgc tgcttgcaat gtttgcccat tttagggggg gatgtaagtc 600 tgcttggagg aaggtgcaga catcgggtta ggatggttgt gatgctattc tgactttttc 660 ctttcttcac gcagatttcc tcctagagtg ccaaaatctt ttccattcaa cacctcagtc 720 gtgtacaaaa agactctgtt tgtagaattc acggatcacc ttttcaacat cgctaagccc 780 aggcccccct ggatgggcct gctgggcccc accatccagg ctgaggtgta tgacactgtg 840 gtgatcaccc tgaagaacat ggccagccac cctgtgagcc tgcatgctgt gggggtgagc 900 tactggaagg cctctgaggg ggctgagtat gatgaccaga ccagccagag ggagaaggag 960 gatgacaagg tgttccctgg gggcagccac acctatgtgt ggcaggtgct gaaggagaat 1020 ggccccatgg cctctgaccc cctgtgcctg acctacagct acctgagcca tgtggacctg 1080 gtgaaggacc tgaactctgg cctgattggg gccctgctgg tgtgcaggga gggcagcctg 1140 gccaaggaga agacccagac cctgcacaag ttcatcctgc tgtttgctgt gtttgatgag 1200 ggcaagagct ggcactctga aaccaagaac agcctgatgc aggacaggga tgctgcctct 1260 gccagggcct ggcccaagat gcacactgtg aatggctatg tgaacaggag cctgcctggc 1320 ctgattggct gccacaggaa gtctgtgtac tggcatgtga ttggcatggg caccacccct 1380 gaggtgcaca gcatcttcct ggagggccac accttcctgg tcaggaacca caggcaggcc 1440 agcctggaga tcagccccat caccttcctg actgcccaga ccctgctgat ggacctgggc 1500 cagttcctgc tgttctgcca catcagcagc caccagcatg atggcatgga ggcctatgtg 1560 aaggtggaca gctgccctga ggagccccag ctgaggatga agaacaatga ggaggctgag 1620 gactatgatg atgacctgac tgactctgag atggatgtgg tgaggtttga tgatgacaac 1680 agccccagct tcatccagat caggtctgtg gccaagaagc accccaagac ctgggtgcac 1740 tacattgctg ctgaggagga ggactgggac tatgcccccc tggtgctggc ccctgatgac 1800 aggagctaca agagccagta cctgaacaat ggcccccaga ggattggcag gaagtacaag 1860 aaggtcaggt tcatggccta cactgatgaa accttcaaga ccagggaggc catccagcat 1920 gagtctggca tcctgggccc cctgctgtat ggggaggtgg gggacaccct gctgatcatc 1980 ttcaagaacc aggccagcag gccctacaac atctaccccc atggcatcac tgatgtgagg 2040 cccctgtaca gcaggaggct gcccaagggg gtgaagcacc tgaaggactt ccccatcctg 2100 cctggggaga tcttcaagta caagtggact gtgactgtgg aggatggccc caccaagtct 2160 gaccccaggt gcctgaccag atactacagc agctttgtga acatggagag ggacctggcc 2220 tctggcctga ttggccccct gctgatctgc tacaaggagt ctgtggacca gaggggcaac 2280 cagatcatgt ctgacaagag gaatgtgatc ctgttctctg tgtttgatga gaacaggagc 2340 tggtacctga ctgagaacat ccagaggttc ctgcccaacc ctgctggggt gcagctggag 2400 gaccctgagt tccaggccag caacatcatg cacagcatca atggctatgt gtttgacagc 2460 ctgcagctgt ctgtgtgcct gcatgaggtg gcctactggt acatcctgag cattggggcc 2520 cagactgact tcctgtctgt gttcttctct ggctacacct tcaagcacaa gatggtgtat 2580 gaggacaccc tgaccctgtt ccccttctct ggggagactg tgttcatgag catggagaac 2640 cctggcctgt ggattctggg ctgccacaac tctgacttca ggaacagggg catgactgcc 2700 ctgctgaaag tctccagctg tgacaagaac actggggact actatgagga cagctatgag 2760 gacatctctg cctacctgct gagcaagaac aatgccattg agcccaggag cttccagaag 2820 aagaccaggc actacttcat tgctgctgtg gagaggctgt gggactatgg catgagcagc 2880 agcccccatg tgctgaggaa cagggcccag tctggctctg tgccccagtt caagaaggtg 2940 gtgttccagg agttcactga tggcagcttc acccagcccc tgtacagagg ggagctgaat 3000 gagcacctgg gcctgctggg cccctacatc agggctgagg tggaggacaa catcatggtg 3060 accttcagga accaggccag caggccctac agcttctaca gcagcctgat cagctatgag 3120 gaggaccaga ggcagggggc tgagcccagg aagaactttg tgaagcccaa tgaaaccaag 3180 acctacttct ggaaggtgca gcaccacatg gcccccacca aggatgagtt tgactgcaag 3240 gcctgggcct acttctctga tgtggacctg gagaaggatg tgcactctgg cctgattggc 3300 cccctgctgg tgtgccacac caacaccctg aaccctgccc atggcaggca ggtgactgtg 3360 caggagtttg ccctgttctt caccatcttt gatgaaacca agagctggta cttcactgag 3420 aacatggaga ggaactgcag ggccccctgc aacatccaga tggaggaccc caccttcaag 3480 gagaactaca ggttccatgc catcaatggc tacatcatgg acaccctgcc tggcctggtg 3540 atggcccagg accagaggat caggtggtac ctgctgagca tgggcagcaa tgagaacatc 3600 cacagcatcc acttctctgg ccatgtgttc actgtgagga agaaggagga gtacaagatg 3660 gccctgtaca acctgtaccc tggggtgttt gagactgtgg agatgctgcc cagcaaggct 3720 ggcatctgga gggtggagtg cctgattggg gagcacctgc atgctggcat gagcaccctg 3780 ttcctggtgt acagcaacaa gtgccagacc cccctgggca tggcctctgg ccacatcagg 3840 gacttccaga tcactgcctc tggccagtat ggccagtggg cccccaagct ggccaggctg 3900 cactactctg gcagcatcaa tgcctggagc accaaggagc ccttcagctg gatcaaggtg 3960 gacctgctgg cccccatgat catccatggc atcaagaccc agggggccag gcagaagttc 4020 agcagcctgt acatcagcca gttcatcatc atgtacagcc tggatggcaa gaagtggcag 4080 acctacaggg gcaacagcac tggcaccctg atggtgttct ttggcaatgt ggacagctct 4140 ggcatcaagc acaacatctt caaccccccc atcattgcca gatacatcag gctgcacccc 4200 acccactaca gcatcaggag caccctgagg atggagctga tgggctgtga cctgaacagc 4260 tgcagcatgc ccctgggcat ggagagcaag gccatctctg atgcccagat cactgccagc 4320 agctacttca ccaacatgtt tgccacctgg agccccagca aggccaggct gcacctgcag 4380 ggcaggagca atgcctggag gccccaggtc aacaacccca aggagtggct gcaggtggac 4440 ttccagaaga ccatgaaggt gactggggtg accacccagg gggtgaagag cctgctgacc 4500 agcatgtatg tgaaggagtt cctgatcagc agcagccagg atggccacca gtggaccctg 4560 ttcttccaga atggcaaggt gaaggtgttc cagggcaacc aggacagctt cacccctgtg 4620 gtgaacagcc tggacccccc cctgctgacc agatacctga ggattcaccc ccagagctgg 4680 gtgcaccaga ttgccctgag gatggaggtg ctgggctgtg aggcccagga cctgtactga 4740 aataaaagat ctttattttc attagatctg tgtgttggtt ttttgtgtga ggaaccccta 4800 gtgatggagt tggccactcc ctctctgcgc gctcgctcgc tcactgaggc cgggcgacca 4860 aaggtcgccc gacgcccggg ctttgcccgg gcggcctcag tgagcgagcg agcgcgcaga 4920 gagggagtgg ccaa 4934 <210> 8 <211> 4934 <212> DNA <213> Adeno-Associated Virus <400> 8 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgtttg ctgcttgcaa tgtttgccca ttttagggtg 180 gacacaggac gctgtggttt ctgagccagg gggcgactca gatcccagcc agtggactta 240 gcccctgttt gctcctccga taactggggt gaccttggtt aatattcacc agcagcctcc 300 cccgttgccc ctctggatcc actgcttaaa tacggacgag gacagggccc tgtctcctca 360 gcttcaggca ccaccactga cctgggacag tgaatcgcca ccatgcagat tgagctgagc 420 acctgcttct tcctgtgcct gctgagattc tgctttagtg ccaccagaag atactacctg 480 ggtgcagtgg aactgtcatg ggactatatg caaagtgatc tcggtgagct gcctgtggac 540 gcaaggtaaa ggcatgtcct gtagggtctg atcggggcca ggattgtggg gatgtaagtc 600 tgcttggagg aagccctaaa atgggcaaac attgcaagca gcaaacattc tgactttttc 660 ctttcttcac gcagatttcc tcctagagtg ccaaaatctt ttccattcaa cacctcagtc 720 gtgtacaaaa agactctgtt tgtagaattc acggatcacc ttttcaacat cgctaagccc 780 aggcccccct ggatgggcct gctgggcccc accatccagg ctgaggtgta tgacactgtg 840 gtgatcaccc tgaagaacat ggccagccac cctgtgagcc tgcatgctgt gggggtgagc 900 tactggaagg cctctgaggg ggctgagtat gatgaccaga ccagccagag ggagaaggag 960 gatgacaagg tgttccctgg gggcagccac acctatgtgt ggcaggtgct gaaggagaat 1020 ggccccatgg cctctgaccc cctgtgcctg acctacagct acctgagcca tgtggacctg 1080 gtgaaggacc tgaactctgg cctgattggg gccctgctgg tgtgcaggga gggcagcctg 1140 gccaaggaga agacccagac cctgcacaag ttcatcctgc tgtttgctgt gtttgatgag 1200 ggcaagagct ggcactctga aaccaagaac agcctgatgc aggacaggga tgctgcctct 1260 gccagggcct ggcccaagat gcacactgtg aatggctatg tgaacaggag cctgcctggc 1320 ctgattggct gccacaggaa gtctgtgtac tggcatgtga ttggcatggg caccacccct 1380 gaggtgcaca gcatcttcct ggagggccac accttcctgg tcaggaacca caggcaggcc 1440 agcctggaga tcagccccat caccttcctg actgcccaga ccctgctgat ggacctgggc 1500 cagttcctgc tgttctgcca catcagcagc caccagcatg atggcatgga ggcctatgtg 1560 aaggtggaca gctgccctga ggagccccag ctgaggatga agaacaatga ggaggctgag 1620 gactatgatg atgacctgac tgactctgag atggatgtgg tgaggtttga tgatgacaac 1680 agccccagct tcatccagat caggtctgtg gccaagaagc accccaagac ctgggtgcac 1740 tacattgctg ctgaggagga ggactgggac tatgcccccc tggtgctggc ccctgatgac 1800 aggagctaca agagccagta cctgaacaat ggcccccaga ggattggcag gaagtacaag 1860 aaggtcaggt tcatggccta cactgatgaa accttcaaga ccagggaggc catccagcat 1920 gagtctggca tcctgggccc cctgctgtat ggggaggtgg gggacaccct gctgatcatc 1980 ttcaagaacc aggccagcag gccctacaac atctaccccc atggcatcac tgatgtgagg 2040 cccctgtaca gcaggaggct gcccaagggg gtgaagcacc tgaaggactt ccccatcctg 2100 cctggggaga tcttcaagta caagtggact gtgactgtgg aggatggccc caccaagtct 2160 gaccccaggt gcctgaccag atactacagc agctttgtga acatggagag ggacctggcc 2220 tctggcctga ttggccccct gctgatctgc tacaaggagt ctgtggacca gaggggcaac 2280 cagatcatgt ctgacaagag gaatgtgatc ctgttctctg tgtttgatga gaacaggagc 2340 tggtacctga ctgagaacat ccagaggttc ctgcccaacc ctgctggggt gcagctggag 2400 gaccctgagt tccaggccag caacatcatg cacagcatca atggctatgt gtttgacagc 2460 ctgcagctgt ctgtgtgcct gcatgaggtg gcctactggt acatcctgag cattggggcc 2520 cagactgact tcctgtctgt gttcttctct ggctacacct tcaagcacaa gatggtgtat 2580 gaggacaccc tgaccctgtt ccccttctct ggggagactg tgttcatgag catggagaac 2640 cctggcctgt ggattctggg ctgccacaac tctgacttca ggaacagggg catgactgcc 2700 ctgctgaaag tctccagctg tgacaagaac actggggact actatgagga cagctatgag 2760 gacatctctg cctacctgct gagcaagaac aatgccattg agcccaggag cttccagaag 2820 aagaccaggc actacttcat tgctgctgtg gagaggctgt gggactatgg catgagcagc 2880 agcccccatg tgctgaggaa cagggcccag tctggctctg tgccccagtt caagaaggtg 2940 gtgttccagg agttcactga tggcagcttc acccagcccc tgtacagagg ggagctgaat 3000 gagcacctgg gcctgctggg cccctacatc agggctgagg tggaggacaa catcatggtg 3060 accttcagga accaggccag caggccctac agcttctaca gcagcctgat cagctatgag 3120 gaggaccaga ggcagggggc tgagcccagg aagaactttg tgaagcccaa tgaaaccaag 3180 acctacttct ggaaggtgca gcaccacatg gcccccacca aggatgagtt tgactgcaag 3240 gcctgggcct acttctctga tgtggacctg gagaaggatg tgcactctgg cctgattggc 3300 cccctgctgg tgtgccacac caacaccctg aaccctgccc atggcaggca ggtgactgtg 3360 caggagtttg ccctgttctt caccatcttt gatgaaacca agagctggta cttcactgag 3420 aacatggaga ggaactgcag ggccccctgc aacatccaga tggaggaccc caccttcaag 3480 gagaactaca ggttccatgc catcaatggc tacatcatgg acaccctgcc tggcctggtg 3540 atggcccagg accagaggat caggtggtac ctgctgagca tgggcagcaa tgagaacatc 3600 cacagcatcc acttctctgg ccatgtgttc actgtgagga agaaggagga gtacaagatg 3660 gccctgtaca acctgtaccc tggggtgttt gagactgtgg agatgctgcc cagcaaggct 3720 ggcatctgga gggtggagtg cctgattggg gagcacctgc atgctggcat gagcaccctg 3780 ttcctggtgt acagcaacaa gtgccagacc cccctgggca tggcctctgg ccacatcagg 3840 gacttccaga tcactgcctc tggccagtat ggccagtggg cccccaagct ggccaggctg 3900 cactactctg gcagcatcaa tgcctggagc accaaggagc ccttcagctg gatcaaggtg 3960 gacctgctgg cccccatgat catccatggc atcaagaccc agggggccag gcagaagttc 4020 agcagcctgt acatcagcca gttcatcatc atgtacagcc tggatggcaa gaagtggcag 4080 acctacaggg gcaacagcac tggcaccctg atggtgttct ttggcaatgt ggacagctct 4140 ggcatcaagc acaacatctt caaccccccc atcattgcca gatacatcag gctgcacccc 4200 acccactaca gcatcaggag caccctgagg atggagctga tgggctgtga cctgaacagc 4260 tgcagcatgc ccctgggcat ggagagcaag gccatctctg atgcccagat cactgccagc 4320 agctacttca ccaacatgtt tgccacctgg agccccagca aggccaggct gcacctgcag 4380 ggcaggagca atgcctggag gccccaggtc aacaacccca aggagtggct gcaggtggac 4440 ttccagaaga ccatgaaggt gactggggtg accacccagg gggtgaagag cctgctgacc 4500 agcatgtatg tgaaggagtt cctgatcagc agcagccagg atggccacca gtggaccctg 4560 ttcttccaga atggcaaggt gaaggtgttc cagggcaacc aggacagctt cacccctgtg 4620 gtgaacagcc tggacccccc cctgctgacc agatacctga ggattcaccc ccagagctgg 4680 gtgcaccaga ttgccctgag gatggaggtg ctgggctgtg aggcccagga cctgtactga 4740 aataaaagat ctttattttc attagatctg tgtgttggtt ttttgtgtga ggaaccccta 4800 gtgatggagt tggccactcc ctctctgcgc gctcgctcgc tcactgaggc cgggcgacca 4860 aaggtcgccc gacgcccggg ctttgcccgg gcggcctcag tgagcgagcg agcgcgcaga 4920 gagggagtgg ccaa 4934 <210> 9 <211> 5511 <212> DNA <213> Adeno-Associated Virus 2 <400> 9 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ttttcgaccc ctctcacact 180 acctaaacca cgccaggaca acctctgctc ctctccaccg aaattccaag gggtcgagtg 240 gatgttggag gtggcatggg cccagagagg tctctgacct ctgccccagc tccaaggtca 300 gcaggcaggg agggctgtgt gtttgctgtt tgctgcttgc aatgtttgcc cattttaggg 360 acatgagtag gctgaagttt gttcagtgtg gacttcagag gcagcacaca aacagctgct 420 ggaggatggg aactgagggg ttggaagggg gcagggtgag cccagaaact cctgtgtgcc 480 tctgagcctg cagacgcgaa acgtcgactg gacacaggac gctgtggttt ctgagccagg 540 gggcgactca gatcccagcc agtggactta gcccctgttt gctcctccga taactggggt 600 gaccttggtt aatattcacc agcagcctcc cccgttgccc ctctggatcc actgcttaaa 660 tacggacgag gacagggccc tgtctcctca gcttcaggca ccaccactga cctgggacag 720 tgaatcgtaa gtactagcag ctacaatcca gctaccattc tgcttttatt ttatggttgg 780 gataaggctg gattattctg agtccaagct aggccctttt gctaatcatg ttcatacctc 840 ttatcttcct cccacagctc ctgggcaacg tgctggtctg tgtgctggcc catcactttg 900 gcaaagaatt gcgatcgcca ccatgcagat tgagctgagc acctgcttct tcctgtgcct 960 gctgaggttc tgcttctctg ccaccaggag atactacctg ggggctgtgg agctgagctg 1020 ggactacatg cagtctgacc tgggggagct gcctgtggat gccaggttcc cccccagagt 1080 gcccaagagc ttccccttca acacctctgt ggtgtacaag aagaccctgt ttgtggagtt 1140 cactgaccac ctgttcaaca ttgccaagcc caggcccccc tggatgggcc tgctgggccc 1200 caccatccag gctgaggtgt atgacactgt ggtgatcacc ctgaagaaca tggccagcca 1260 ccctgtgagc ctgcatgctg tgggggtgag ctactggaag gcctctgagg gggctgagta 1320 tgatgaccag accagccaga gggagaagga ggatgacaag gtgttccctg ggggcagcca 1380 cacctatgtg tggcaggtgc tgaaggagaa tggccccatg gcctctgacc ccctgtgcct 1440 gacctacagc tacctgagcc atgtggacct ggtgaaggac ctgaactctg gcctgattgg 1500 ggccctgctg gtgtgcaggg agggcagcct ggccaaggag aagacccaga ccctgcacaa 1560 gttcatcctg ctgtttgctg tgtttgatga gggcaagagc tggcactctg aaaccaagaa 1620 cagcctgatg caggacaggg atgctgcctc tgccagggcc tggcccaaga tgcacactgt 1680 gaatggctat gtgaacagga gcctgcctgg cctgattggc tgccacagga agtctgtgta 1740 ctggcatgtg attggcatgg gcaccacccc tgaggtgcac agcatcttcc tggagggcca 1800 caccttcctg gtcaggaacc acaggcaggc cagcctggag atcagcccca tcaccttcct 1860 gactgcccag accctgctga tggacctggg ccagttcctg ctgttctgcc acatcagcag 1920 ccaccagcat gatggcatgg aggcctatgt gaaggtggac agctgccctg aggagcccca 1980 gctgaggatg aagaacaatg aggaggctga ggactatgat gatgacctga ctgactctga 2040 gatggatgtg gtgaggtttg atgatgacaa cagccccagc ttcatccaga tcaggtctgt 2100 ggccaagaag caccccaaga cctgggtgca ctacattgct gctgaggagg aggactggga 2160 ctatgccccc ctggtgctgg cccctgatga caggagctac aagagccagt acctgaacaa 2220 tggcccccag aggattggca ggaagtacaa gaaggtcagg ttcatggcct acactgatga 2280 aaccttcaag accagggagg ccatccagca tgagtctggc atcctgggcc ccctgctgta 2340 tggggaggtg ggggacaccc tgctgatcat cttcaagaac caggccagca ggccctacaa 2400 catctacccc catggcatca ctgatgtgag gcccctgtac agcaggaggc tgcccaaggg 2460 ggtgaagcac ctgaaggact tccccatcct gcctggggag atcttcaagt acaagtggac 2520 tgtgactgtg gaggatggcc ccaccaagtc tgaccccagg tgcctgacca gatactacag 2580 cagctttgtg aacatggaga gggacctggc ctctggcctg attggccccc tgctgatctg 2640 ctacaaggag tctgtggacc agaggggcaa ccagatcatg tctgacaaga ggaatgtgat 2700 cctgttctct gtgtttgatg agaacaggag ctggtacctg actgagaaca tccagaggtt 2760 cctgcccaac cctgctgggg tgcagctgga ggaccctgag ttccaggcca gcaacatcat 2820 gcacagcatc aatggctatg tgtttgacag cctgcagctg tctgtgtgcc tgcatgaggt 2880 ggcctactgg tacatcctga gcattggggc ccagactgac ttcctgtctg tgttcttctc 2940 tggctacacc ttcaagcaca agatggtgta tgaggacacc ctgaccctgt tccccttctc 3000 tggggagact gtgttcatga gcatggagaa ccctggcctg tggattctgg gctgccacaa 3060 ctctgacttc aggaacaggg gcatgactgc cctgctgaaa gtctccagct gtgacaagaa 3120 cactggggac tactatgagg acagctatga ggacatctct gcctacctgc tgagcaagaa 3180 caatgccatt gagcccagga gcttcagcca gaacccccca gtgctgaaga ggcaccagag 3240 ggagatcacc aggaccaccc tgcagtctga ccaggaggag attgactatg atgacaccat 3300 ctctgtggag atgaagaagg aggactttga catctacgac gaggacgaga accagagccc 3360 caggagcttc cagaagaaga ccaggcacta cttcattgct gctgtggaga ggctgtggga 3420 ctatggcatg agcagcagcc cccatgtgct gaggaacagg gcccagtctg gctctgtgcc 3480 ccagttcaag aaggtggtgt tccaggagtt cactgatggc agcttcaccc agcccctgta 3540 cagaggggag ctgaatgagc acctgggcct gctgggcccc tacatcaggg ctgaggtgga 3600 ggacaacatc atggtgacct tcaggaacca ggccagcagg ccctacagct tctacagcag 3660 cctgatcagc tatgaggagg accagaggca gggggctgag cccaggaaga actttgtgaa 3720 gcccaatgaa accaagacct acttctggaa ggtgcagcac cacatggccc ccaccaagga 3780 tgagtttgac tgcaaggcct gggcctactt ctctgatgtg gacctggaga aggatgtgca 3840 ctctggcctg attggccccc tgctggtgtg ccacaccaac accctgaacc ctgcccatgg 3900 caggcaggtg actgtgcagg agtttgccct gttcttcacc atctttgatg aaaccaagag 3960 ctggtacttc actgagaaca tggagaggaa ctgcagggcc ccctgcaaca tccagatgga 4020 ggaccccacc ttcaaggaga actacaggtt ccatgccatc aatggctaca tcatggacac 4080 cctgcctggc ctggtgatgg cccaggacca gaggatcagg tggtacctgc tgagcatggg 4140 cagcaatgag aacatccaca gcatccactt ctctggccat gtgttcactg tgaggaagaa 4200 ggaggagtac aagatggccc tgtacaacct gtaccctggg gtgtttgaga ctgtggagat 4260 gctgcccagc aaggctggca tctggagggt ggagtgcctg attggggagc acctgcatgc 4320 tggcatgagc accctgttcc tggtgtacag caacaagtgc cagacccccc tgggcatggc 4380 ctctggccac atcagggact tccagatcac tgcctctggc cagtatggcc agtgggcccc 4440 caagctggcc aggctgcact actctggcag catcaatgcc tggagcacca aggagccctt 4500 cagctggatc aaggtggacc tgctggcccc catgatcatc catggcatca agacccaggg 4560 ggccaggcag aagttcagca gcctgtacat cagccagttc atcatcatgt acagcctgga 4620 tggcaagaag tggcagacct acaggggcaa cagcactggc accctgatgg tgttctttgg 4680 caatgtggac agctctggca tcaagcacaa catcttcaac ccccccatca ttgccagata 4740 catcaggctg caccccaccc actacagcat caggagcacc ctgaggatgg agctgatggg 4800 ctgtgacctg aacagctgca gcatgcccct gggcatggag agcaaggcca tctctgatgc 4860 ccagatcact gccagcagct acttcaccaa catgtttgcc acctggagcc ccagcaaggc 4920 caggctgcac ctgcagggca ggagcaatgc ctggaggccc caggtcaaca accccaagga 4980 gtggctgcag gtggacttcc agaagaccat gaaggtgact ggggtgacca cccagggggt 5040 gaagagcctg ctgaccagca tgtatgtgaa ggagttcctg atcagcagca gccaggatgg 5100 ccaccagtgg accctgttct tccagaatgg caaggtgaag gtgttccagg gcaaccagga 5160 cagcttcacc cctgtggtga acagcctgga cccccccctg ctgaccagat acctgaggat 5220 tcacccccag agctgggtgc accagattgc cctgaggatg gaggtgctgg gctgtgaggc 5280 ccaggacctg tactgacctc gaggaataaa ggaaatttat tttcattgca atagtgtgtt 5340 ggttttttgt gtcacgtggc ggccgcagga acccctagtg atggagttgg ccactccctc 5400 tctgcgcgct cgctcgctca ctgaggccgg gcgaccaaag gtcgcccgac gcccgggctt 5460 tgcccgggcg gcctcagtga gcgagcgagc gcgcagagag ggagtggcca a 5511 <210> 10 <211> 5688 <212> DNA <213> Adeno-Associated Virus 2 <400> 10 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ttttcgaccc ctctcacact 180 acctaaacca cgccaggaca acctctgctc ctctccaccg aaattccaag gggtcgagtg 240 gatgttggag gtggcatggg cccagagagg tctctgacct ctgccccagc tccaaggtca 300 gcaggcaggg agggctgtgt gtttgctgtt tgctgcttgc aatgtttgcc cattttaggg 360 acatgagtag gctgaagttt gttcagtgtg gacttcagag gcagcacaca aacagctgct 420 ggaggatggg aactgagggg ttggaagggg gcagggtgag cccagaaact cctgtgtgcc 480 tctgagcctg cagacgcgaa acgtcgactg gacacaggac gctgtggttt ctgagccagg 540 gggcgactca gatcccagcc agtggactta gcccctgttt gctcctccga taactggggt 600 gaccttggtt aatattcacc agcagcctcc cccgttgccc ctctggatcc actgcttaaa 660 tacggacgag gacagggccc tgtctcctca gcttcaggca ccaccactga cctgggacag 720 tgaatcgtaa gtactagcag ctacaatcca gctaccattc tgcttttatt ttatggttgg 780 gataaggctg gattattctg agtccaagct aggccctttt gctaatcatg ttcatacctc 840 ttatcttcct cccacagctc ctgggcaacg tgctggtctg tgtgctggcc catcactttg 900 gcaaagaatt gcgatcgcca ccatgcagat tgagctgagc acctgcttct tcctgtgcct 960 gctgaggttc tgcttctctg ccaccaggag atactacctg ggggctgtgg agctgagctg 1020 ggactacatg cagtctgacc tgggggagct gcctgtggat gccaggttcc cccccagagt 1080 gcccaagagc ttccccttca acacctctgt ggtgtacaag aagaccctgt ttgtggagtt 1140 cactgaccac ctgttcaaca ttgccaagcc caggcccccc tggatgggcc tgctgggccc 1200 caccatccag gctgaggtgt atgacactgt ggtgatcacc ctgaagaaca tggccagcca 1260 ccctgtgagc ctgcatgctg tgggggtgag ctactggaag gcctctgagg gggctgagta 1320 tgatgaccag accagccaga gggagaagga ggatgacaag gtgttccctg ggggcagcca 1380 cacctatgtg tggcaggtgc tgaaggagaa tggccccatg gcctctgacc ccctgtgcct 1440 gacctacagc tacctgagcc atgtggacct ggtgaaggac ctgaactctg gcctgattgg 1500 ggccctgctg gtgtgcaggg agggcagcct ggccaaggag aagacccaga ccctgcacaa 1560 gttcatcctg ctgtttgctg tgtttgatga gggcaagagc tggcactctg aaaccaagaa 1620 cagcctgatg caggacaggg atgctgcctc tgccagggcc tggcccaaga tgcacactgt 1680 gaatggctat gtgaacagga gcctgcctgg cctgattggc tgccacagga agtctgtgta 1740 ctggcatgtg attggcatgg gcaccacccc tgaggtgcac agcatcttcc tggagggcca 1800 caccttcctg gtcaggaacc acaggcaggc cagcctggag atcagcccca tcaccttcct 1860 gactgcccag accctgctga tggacctggg ccagttcctg ctgttctgcc acatcagcag 1920 ccaccagcat gatggcatgg aggcctatgt gaaggtggac agctgccctg aggagcccca 1980 gctgaggatg aagaacaatg aggaggctga ggactatgat gatgacctga ctgactctga 2040 gatggatgtg gtgaggtttg atgatgacaa cagccccagc ttcatccaga tcaggtctgt 2100 ggccaagaag caccccaaga cctgggtgca ctacattgct gctgaggagg aggactggga 2160 ctatgccccc ctggtgctgg cccctgatga caggagctac aagagccagt acctgaacaa 2220 tggcccccag aggattggca ggaagtacaa gaaggtcagg ttcatggcct acactgatga 2280 aaccttcaag accagggagg ccatccagca tgagtctggc atcctgggcc ccctgctgta 2340 tggggaggtg ggggacaccc tgctgatcat cttcaagaac caggccagca ggccctacaa 2400 catctacccc catggcatca ctgatgtgag gcccctgtac agcaggaggc tgcccaaggg 2460 ggtgaagcac ctgaaggact tccccatcct gcctggggag atcttcaagt acaagtggac 2520 tgtgactgtg gaggatggcc ccaccaagtc tgaccccagg tgcctgacca gatactacag 2580 cagctttgtg aacatggaga gggacctggc ctctggcctg attggccccc tgctgatctg 2640 ctacaaggag tctgtggacc agaggggcaa ccagatcatg tctgacaaga ggaatgtgat 2700 cctgttctct gtgtttgatg agaacaggag ctggtacctg actgagaaca tccagaggtt 2760 cctgcccaac cctgctgggg tgcagctgga ggaccctgag ttccaggcca gcaacatcat 2820 gcacagcatc aatggctatg tgtttgacag cctgcagctg tctgtgtgcc tgcatgaggt 2880 ggcctactgg tacatcctga gcattggggc ccagactgac ttcctgtctg tgttcttctc 2940 tggctacacc ttcaagcaca agatggtgta tgaggacacc ctgaccctgt tccccttctc 3000 tggggagact gtgttcatga gcatggagaa ccctggcctg tggattctgg gctgccacaa 3060 ctctgacttc aggaacaggg gcatgactgc cctgctgaaa gtctccagct gtgacaagaa 3120 cactggggac tactatgagg acagctatga ggacatctct gcctacctgc tgagcaagaa 3180 caatgccatt gagcccagga gcttcagcca gaacccccca gtgctgaaga ggcaccagag 3240 ggagatcacc aggaccaccc tgcagtctga ccaggaggag attgactatg atgacaccat 3300 ctctgtggag atgaagaagg aggactttga catctacgac gaggacgaga accagagccc 3360 caggagcttc cagaagaaga ccaggcacta cttcattgct gctgtggaga ggctgtggga 3420 ctatggcatg agcagcagcc cccatgtgct gaggaacagg gcccagtctg gctctgtgcc 3480 ccagttcaag aaggtggtgt tccaggagtt cactgatggc agcttcaccc agcccctgta 3540 cagaggggag ctgaatgagc acctgggcct gctgggcccc tacatcaggg ctgaggtgga 3600 ggacaacatc atggtgacct tcaggaacca ggccagcagg ccctacagct tctacagcag 3660 cctgatcagc tatgaggagg accagaggca gggggctgag cccaggaaga actttgtgaa 3720 gcccaatgaa accaagacct acttctggaa ggtgcagcac cacatggccc ccaccaagga 3780 tgagtttgac tgcaaggcct gggcctactt ctctgatgtg gacctggaga aggatgtgca 3840 ctctggcctg attggccccc tgctggtgtg ccacaccaac accctgaacc ctgcccatgg 3900 caggcaggtg actgtgcagg agtttgccct gttcttcacc atctttgatg aaaccaagag 3960 ctggtacttc actgagaaca tggagaggaa ctgcagggcc ccctgcaaca tccagatgga 4020 ggaccccacc ttcaaggaga actacaggtt ccatgccatc aatggctaca tcatggacac 4080 cctgcctggc ctggtgatgg cccaggacca gaggatcagg tggtacctgc tgagcatggg 4140 cagcaatgag aacatccaca gcatccactt ctctggccat gtgttcactg tgaggaagaa 4200 ggaggagtac aagatggccc tgtacaacct gtaccctggg gtgtttgaga ctgtggagat 4260 gctgcccagc aaggctggca tctggagggt ggagtgcctg attggggagc acctgcatgc 4320 tggcatgagc accctgttcc tggtgtacag caacaagtgc cagacccccc tgggcatggc 4380 ctctggccac atcagggact tccagatcac tgcctctggc cagtatggcc agtgggcccc 4440 caagctggcc aggctgcact actctggcag catcaatgcc tggagcacca aggagccctt 4500 cagctggatc aaggtggacc tgctggcccc catgatcatc catggcatca agacccaggg 4560 ggccaggcag aagttcagca gcctgtacat cagccagttc atcatcatgt acagcctgga 4620 tggcaagaag tggcagacct acaggggcaa cagcactggc accctgatgg tgttctttgg 4680 caatgtggac agctctggca tcaagcacaa catcttcaac ccccccatca ttgccagata 4740 catcaggctg caccccaccc actacagcat caggagcacc ctgaggatgg agctgatggg 4800 ctgtgacctg aacagctgca gcatgcccct gggcatggag agcaaggcca tctctgatgc 4860 ccagatcact gccagcagct acttcaccaa catgtttgcc acctggagcc ccagcaaggc 4920 caggctgcac ctgcagggca ggagcaatgc ctggaggccc caggtcaaca accccaagga 4980 gtggctgcag gtggacttcc agaagaccat gaaggtgact ggggtgacca cccagggggt 5040 gaagagcctg ctgaccagca tgtatgtgaa ggagttcctg atcagcagca gccaggatgg 5100 ccaccagtgg accctgttct tccagaatgg caaggtgaag gtgttccagg gcaaccagga 5160 cagcttcacc cctgtggtga acagcctgga cccccccctg ctgaccagat acctgaggat 5220 tcacccccag agctgggtgc accagattgc cctgaggatg gaggtgctgg gctgtgaggc 5280 ccaggacctg tactgacctc gaggtgtgcc ttctagttgc cagccatctg ttgtttgccc 5340 ctcccccgtg ccttccttga ccctggaagg tgccactccc actgtccttt cctaataaaa 5400 tgaggaaatt gcatcgcatt gtctgagtag gtgtcattct attctggggg gtggggtggg 5460 gcaggacagc aagggggagg attgggaaga caatagcagg catgctgggg atgcggtggg 5520 ctctatgggc acgtggcggc cgcaggaacc cctagtgatg gagttggcca ctccctctct 5580 gcgcgctcgc tcgctcactg aggccgggcg accaaaggtc gcccgacgcc cgggctttgc 5640 ccgggcggcc tcagtgagcg agcgagcgcg cagagaggga gtggccaa 5688 <210> 11 <211> 5613 <212> DNA <213> Adeno-Associated Virus 2 <400> 11 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ttttcgaccc ctctcacact 180 acctaaacca cgccaggaca acctctgctc ctctccaccg aaattccaag gggtcgagtg 240 gatgttggag gtggcatggg cccagagagg tctctgacct ctgccccagc tccaaggtca 300 gcaggcaggg agggctgtgt gtttgctgtt tgctgcttgc aatgtttgcc cattttaggg 360 acatgagtag gctgaagttt gttcagtgtg gacttcagag gcagcacaca aacagctgct 420 ggaggatggg aactgagggg ttggaagggg gcagggtgag cccagaaact cctgtgtgcc 480 tctgagcctg cagacgcgaa acgtcgactg gacacaggac gctgtggttt ctgagccagg 540 gggcgactca gatcccagcc agtggactta gcccctgttt gctcctccga taactggggt 600 gaccttggtt aatattcacc agcagcctcc cccgttgccc ctctggatcc actgcttaaa 660 tacggacgag gacagggccc tgtctcctca gcttcaggca ccaccactga cctgggacag 720 tgaatcgtaa gtactagcag ctacaatcca gctaccattc tgcttttatt ttatggttgg 780 gataaggctg gattattctg agtccaagct aggccctttt gctaatcatg ttcatacctc 840 ttatcttcct cccacagctc ctgggcaacg tgctggtctg tgtgctggcc catcactttg 900 gcaaagaatt gcgatcgcca ccatgcagat tgagctgagc acctgcttct tcctgtgcct 960 gctgaggttc tgcttctctg ccaccaggag atactacctg ggggctgtgg agctgagctg 1020 ggactacatg cagtctgacc tgggggagct gcctgtggat gccaggttcc cccccagagt 1080 gcccaagagc ttccccttca acacctctgt ggtgtacaag aagaccctgt ttgtggagtt 1140 cactgaccac ctgttcaaca ttgccaagcc caggcccccc tggatgggcc tgctgggccc 1200 caccatccag gctgaggtgt atgacactgt ggtgatcacc ctgaagaaca tggccagcca 1260 ccctgtgagc ctgcatgctg tgggggtgag ctactggaag gcctctgagg gggctgagta 1320 tgatgaccag accagccaga gggagaagga ggatgacaag gtgttccctg ggggcagcca 1380 cacctatgtg tggcaggtgc tgaaggagaa tggccccatg gcctctgacc ccctgtgcct 1440 gacctacagc tacctgagcc atgtggacct ggtgaaggac ctgaactctg gcctgattgg 1500 ggccctgctg gtgtgcaggg agggcagcct ggccaaggag aagacccaga ccctgcacaa 1560 gttcatcctg ctgtttgctg tgtttgatga gggcaagagc tggcactctg aaaccaagaa 1620 cagcctgatg caggacaggg atgctgcctc tgccagggcc tggcccaaga tgcacactgt 1680 gaatggctat gtgaacagga gcctgcctgg cctgattggc tgccacagga agtctgtgta 1740 ctggcatgtg attggcatgg gcaccacccc tgaggtgcac agcatcttcc tggagggcca 1800 caccttcctg gtcaggaacc acaggcaggc cagcctggag atcagcccca tcaccttcct 1860 gactgcccag accctgctga tggacctggg ccagttcctg ctgttctgcc acatcagcag 1920 ccaccagcat gatggcatgg aggcctatgt gaaggtggac agctgccctg aggagcccca 1980 gctgaggatg aagaacaatg aggaggctga ggactatgat gatgacctga ctgactctga 2040 gatggatgtg gtgaggtttg atgatgacaa cagccccagc ttcatccaga tcaggtctgt 2100 ggccaagaag caccccaaga cctgggtgca ctacattgct gctgaggagg aggactggga 2160 ctatgccccc ctggtgctgg cccctgatga caggagctac aagagccagt acctgaacaa 2220 tggcccccag aggattggca ggaagtacaa gaaggtcagg ttcatggcct acactgatga 2280 aaccttcaag accagggagg ccatccagca tgagtctggc atcctgggcc ccctgctgta 2340 tggggaggtg ggggacaccc tgctgatcat cttcaagaac caggccagca ggccctacaa 2400 catctacccc catggcatca ctgatgtgag gcccctgtac agcaggaggc tgcccaaggg 2460 ggtgaagcac ctgaaggact tccccatcct gcctggggag atcttcaagt acaagtggac 2520 tgtgactgtg gaggatggcc ccaccaagtc tgaccccagg tgcctgacca gatactacag 2580 cagctttgtg aacatggaga gggacctggc ctctggcctg attggccccc tgctgatctg 2640 ctacaaggag tctgtggacc agaggggcaa ccagatcatg tctgacaaga ggaatgtgat 2700 cctgttctct gtgtttgatg agaacaggag ctggtacctg actgagaaca tccagaggtt 2760 cctgcccaac cctgctgggg tgcagctgga ggaccctgag ttccaggcca gcaacatcat 2820 gcacagcatc aatggctatg tgtttgacag cctgcagctg tctgtgtgcc tgcatgaggt 2880 ggcctactgg tacatcctga gcattggggc ccagactgac ttcctgtctg tgttcttctc 2940 tggctacacc ttcaagcaca agatggtgta tgaggacacc ctgaccctgt tccccttctc 3000 tggggagact gtgttcatga gcatggagaa ccctggcctg tggattctgg gctgccacaa 3060 ctctgacttc aggaacaggg gcatgactgc cctgctgaaa gtctccagct gtgacaagaa 3120 cactggggac tactatgagg acagctatga ggacatctct gcctacctgc tgagcaagaa 3180 caatgccatt gagcccagga gcttcagcca gaacccccca gtgctgaaga ggcaccagag 3240 ggagatcacc aggaccaccc tgcagtctga ccaggaggag attgactatg atgacaccat 3300 ctctgtggag atgaagaagg aggactttga catctacgac gaggacgaga accagagccc 3360 caggagcttc cagaagaaga ccaggcacta cttcattgct gctgtggaga ggctgtggga 3420 ctatggcatg agcagcagcc cccatgtgct gaggaacagg gcccagtctg gctctgtgcc 3480 ccagttcaag aaggtggtgt tccaggagtt cactgatggc agcttcaccc agcccctgta 3540 cagaggggag ctgaatgagc acctgggcct gctgggcccc tacatcaggg ctgaggtgga 3600 ggacaacatc atggtgacct tcaggaacca ggccagcagg ccctacagct tctacagcag 3660 cctgatcagc tatgaggagg accagaggca gggggctgag cccaggaaga actttgtgaa 3720 gcccaatgaa accaagacct acttctggaa ggtgcagcac cacatggccc ccaccaagga 3780 tgagtttgac tgcaaggcct gggcctactt ctctgatgtg gacctggaga aggatgtgca 3840 ctctggcctg attggccccc tgctggtgtg ccacaccaac accctgaacc ctgcccatgg 3900 caggcaggtg actgtgcagg agtttgccct gttcttcacc atctttgatg aaaccaagag 3960 ctggtacttc actgagaaca tggagaggaa ctgcagggcc ccctgcaaca tccagatgga 4020 ggaccccacc ttcaaggaga actacaggtt ccatgccatc aatggctaca tcatggacac 4080 cctgcctggc ctggtgatgg cccaggacca gaggatcagg tggtacctgc tgagcatggg 4140 cagcaatgag aacatccaca gcatccactt ctctggccat gtgttcactg tgaggaagaa 4200 ggaggagtac aagatggccc tgtacaacct gtaccctggg gtgtttgaga ctgtggagat 4260 gctgcccagc aaggctggca tctggagggt ggagtgcctg attggggagc acctgcatgc 4320 tggcatgagc accctgttcc tggtgtacag caacaagtgc cagacccccc tgggcatggc 4380 ctctggccac atcagggact tccagatcac tgcctctggc cagtatggcc agtgggcccc 4440 caagctggcc aggctgcact actctggcag catcaatgcc tggagcacca aggagccctt 4500 cagctggatc aaggtggacc tgctggcccc catgatcatc catggcatca agacccaggg 4560 ggccaggcag aagttcagca gcctgtacat cagccagttc atcatcatgt acagcctgga 4620 tggcaagaag tggcagacct acaggggcaa cagcactggc accctgatgg tgttctttgg 4680 caatgtggac agctctggca tcaagcacaa catcttcaac ccccccatca ttgccagata 4740 catcaggctg caccccaccc actacagcat caggagcacc ctgaggatgg agctgatggg 4800 ctgtgacctg aacagctgca gcatgcccct gggcatggag agcaaggcca tctctgatgc 4860 ccagatcact gccagcagct acttcaccaa catgtttgcc acctggagcc ccagcaaggc 4920 caggctgcac ctgcagggca ggagcaatgc ctggaggccc caggtcaaca accccaagga 4980 gtggctgcag gtggacttcc agaagaccat gaaggtgact ggggtgacca cccagggggt 5040 gaagagcctg ctgaccagca tgtatgtgaa ggagttcctg atcagcagca gccaggatgg 5100 ccaccagtgg accctgttct tccagaatgg caaggtgaag gtgttccagg gcaaccagga 5160 cagcttcacc cctgtggtga acagcctgga cccccccctg ctgaccagat acctgaggat 5220 tcacccccag agctgggtgc accagattgc cctgaggatg gaggtgctgg gctgtgaggc 5280 ccaggacctg tactgacctc gaggcactgt cctttcctaa taaaatgagg aaattgcatc 5340 gcattgtctg agtaggtgtc attctattct ggggggtggg gtggggcagg acagcaaggg 5400 ggaggattgg gaagacaata gcaggcatgc tggggatgcg gtgggctcta tgggcacgtg 5460 gcggccgcag gaacccctag tgatggagtt ggccactccc tctctgcgcg ctcgctcgct 5520 cactgaggcc gggcgaccaa aggtcgcccg acgcccgggc tttgcccggg cggcctcagt 5580 gagcgagcga gcgcgcagag agggagtggc caa 5613 <210> 12 <211> 5362 <212> DNA <213> Adeno-Associated Virus 2 <400> 12 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ttttcgactg tttgctgttt 180 gctgcttgca atgtttgccc attttaggga catgtttgct gtttgctgct tgcaatgttt 240 gcccatttta gggacatgtt tgctgtttgc tgcttgcaat gtttgcccat tttagggaca 300 tgtttgctgt ttgctgcttg caatgtttgc ccattttagg gacaacgcga aacgtcgact 360 ggacacagga cgctgtggtt tctgagccag ggggcgactc agatcccagc cagtggactt 420 agcccctgtt tgctcctccg ataactgggg tgaccttggt taatattcac cagcagcctc 480 ccccgttgcc cctctggatc cactgcttaa atacggacga ggacagggcc ctgtctcctc 540 agcttcaggc accaccactg acctgggaca gtgaatcgta agtactagca gctacaatcc 600 agctaccatt ctgcttttat tttatggttg ggataaggct ggattattct gagtccaagc 660 taggcccttt tgctaatcat gttcatacct cttatcttcc tcccacagct cctgggcaac 720 gtgctggtct gtgtgctggc ccatcacttt ggcaaagaat tgcgatcgcc accatgcaga 780 ttgagctgag cacctgcttc ttcctgtgcc tgctgaggtt ctgcttctct gccaccagga 840 gatactacct gggggctgtg gagctgagct gggactacat gcagtctgac ctgggggagc 900 tgcctgtgga tgccaggttc ccccccagag tgcccaagag cttccccttc aacacctctg 960 tggtgtacaa gaagaccctg tttgtggagt tcactgacca cctgttcaac attgccaagc 1020 ccaggccccc ctggatgggc ctgctgggcc ccaccatcca ggctgaggtg tatgacactg 1080 tggtgatcac cctgaagaac atggccagcc accctgtgag cctgcatgct gtgggggtga 1140 gctactggaa ggcctctgag ggggctgagt atgatgacca gaccagccag agggagaagg 1200 aggatgacaa ggtgttccct gggggcagcc acacctatgt gtggcaggtg ctgaaggaga 1260 atggccccat ggcctctgac cccctgtgcc tgacctacag ctacctgagc catgtggacc 1320 tggtgaagga cctgaactct ggcctgattg gggccctgct ggtgtgcagg gagggcagcc 1380 tggccaagga gaagacccag accctgcaca agttcatcct gctgtttgct gtgtttgatg 1440 agggcaagag ctggcactct gaaaccaaga acagcctgat gcaggacagg gatgctgcct 1500 ctgccagggc ctggcccaag atgcacactg tgaatggcta tgtgaacagg agcctgcctg 1560 gcctgattgg ctgccacagg aagtctgtgt actggcatgt gattggcatg ggcaccaccc 1620 ctgaggtgca cagcatcttc ctggagggcc acaccttcct ggtcaggaac cacaggcagg 1680 ccagcctgga gatcagcccc atcaccttcc tgactgccca gaccctgctg atggacctgg 1740 gccagttcct gctgttctgc cacatcagca gccaccagca tgatggcatg gaggcctatg 1800 tgaaggtgga cagctgccct gaggagcccc agctgaggat gaagaacaat gaggaggctg 1860 aggactatga tgatgacctg actgactctg agatggatgt ggtgaggttt gatgatgaca 1920 acagccccag cttcatccag atcaggtctg tggccaagaa gcaccccaag acctgggtgc 1980 actacattgc tgctgaggag gaggactggg actatgcccc cctggtgctg gcccctgatg 2040 acaggagcta caagagccag tacctgaaca atggccccca gaggattggc aggaagtaca 2100 agaaggtcag gttcatggcc tacactgatg aaaccttcaa gaccagggag gccatccagc 2160 atgagtctgg catcctgggc cccctgctgt atggggaggt gggggacacc ctgctgatca 2220 tcttcaagaa ccaggccagc aggccctaca acatctaccc ccatggcatc actgatgtga 2280 ggcccctgta cagcaggagg ctgcccaagg gggtgaagca cctgaaggac ttccccatcc 2340 tgcctgggga gatcttcaag tacaagtgga ctgtgactgt ggaggatggc cccaccaagt 2400 ctgaccccag gtgcctgacc agatactaca gcagctttgt gaacatggag agggacctgg 2460 cctctggcct gattggcccc ctgctgatct gctacaagga gtctgtggac cagaggggca 2520 accagatcat gtctgacaag aggaatgtga tcctgttctc tgtgtttgat gagaacagga 2580 gctggtacct gactgagaac atccagaggt tcctgcccaa ccctgctggg gtgcagctgg 2640 aggaccctga gttccaggcc agcaacatca tgcacagcat caatggctat gtgtttgaca 2700 gcctgcagct gtctgtgtgc ctgcatgagg tggcctactg gtacatcctg agcattgggg 2760 cccagactga cttcctgtct gtgttcttct ctggctacac cttcaagcac aagatggtgt 2820 atgaggacac cctgaccctg ttccccttct ctggggagac tgtgttcatg agcatggaga 2880 accctggcct gtggattctg ggctgccaca actctgactt caggaacagg ggcatgactg 2940 ccctgctgaa agtctccagc tgtgacaaga acactgggga ctactatgag gacagctatg 3000 aggacatctc tgcctacctg ctgagcaaga acaatgccat tgagcccagg agcttcagcc 3060 agaacccccc agtgctgaag aggcaccaga gggagatcac caggaccacc ctgcagtctg 3120 accaggagga gattgactat gatgacacca tctctgtgga gatgaagaag gaggactttg 3180 acatctacga cgaggacgag aaccagagcc ccaggagctt ccagaagaag accaggcact 3240 acttcattgc tgctgtggag aggctgtggg actatggcat gagcagcagc ccccatgtgc 3300 tgaggaacag ggcccagtct ggctctgtgc cccagttcaa gaaggtggtg ttccaggagt 3360 tcactgatgg cagcttcacc cagcccctgt acagagggga gctgaatgag cacctgggcc 3420 tgctgggccc ctacatcagg gctgaggtgg aggacaacat catggtgacc ttcaggaacc 3480 aggccagcag gccctacagc ttctacagca gcctgatcag ctatgaggag gaccagaggc 3540 agggggctga gcccaggaag aactttgtga agcccaatga aaccaagacc tacttctgga 3600 aggtgcagca ccacatggcc cccaccaagg atgagtttga ctgcaaggcc tgggcctact 3660 tctctgatgt ggacctggag aaggatgtgc actctggcct gattggcccc ctgctggtgt 3720 gccacaccaa caccctgaac cctgcccatg gcaggcaggt gactgtgcag gagtttgccc 3780 tgttcttcac catctttgat gaaaccaaga gctggtactt cactgagaac atggagagga 3840 actgcagggc cccctgcaac atccagatgg aggaccccac cttcaaggag aactacaggt 3900 tccatgccat caatggctac atcatggaca ccctgcctgg cctggtgatg gcccaggacc 3960 agaggatcag gtggtacctg ctgagcatgg gcagcaatga gaacatccac agcatccact 4020 tctctggcca tgtgttcact gtgaggaaga aggaggagta caagatggcc ctgtacaacc 4080 tgtaccctgg ggtgtttgag actgtggaga tgctgcccag caaggctggc atctggaggg 4140 tggagtgcct gattggggag cacctgcatg ctggcatgag caccctgttc ctggtgtaca 4200 gcaacaagtg ccagaccccc ctgggcatgg cctctggcca catcagggac ttccagatca 4260 ctgcctctgg ccagtatggc cagtgggccc ccaagctggc caggctgcac tactctggca 4320 gcatcaatgc ctggagcacc aaggagccct tcagctggat caaggtggac ctgctggccc 4380 ccatgatcat ccatggcatc aagacccagg gggccaggca gaagttcagc agcctgtaca 4440 tcagccagtt catcatcatg tacagcctgg atggcaagaa gtggcagacc tacaggggca 4500 acagcactgg caccctgatg gtgttctttg gcaatgtgga cagctctggc atcaagcaca 4560 acatcttcaa cccccccatc attgccagat acatcaggct gcaccccacc cactacagca 4620 tcaggagcac cctgaggatg gagctgatgg gctgtgacct gaacagctgc agcatgcccc 4680 tgggcatgga gagcaaggcc atctctgatg cccagatcac tgccagcagc tacttcacca 4740 acatgtttgc cacctggagc cccagcaagg ccaggctgca cctgcagggc aggagcaatg 4800 cctggaggcc ccaggtcaac aaccccaagg agtggctgca ggtggacttc cagaagacca 4860 tgaaggtgac tggggtgacc acccaggggg tgaagagcct gctgaccagc atgtatgtga 4920 aggagttcct gatcagcagc agccaggatg gccaccagtg gaccctgttc ttccagaatg 4980 gcaaggtgaa ggtgttccag ggcaaccagg acagcttcac ccctgtggtg aacagcctgg 5040 acccccccct gctgaccaga tacctgagga ttcaccccca gagctgggtg caccagattg 5100 ccctgaggat ggaggtgctg ggctgtgagg cccaggacct gtactgacct cgaggaataa 5160 aggaaattta ttttcattgc aatagtgtgt tggttttttg tgtcacgtgg cggccgcagg 5220 aacccctagt gatggagttg gccactccct ctctgcgcgc tcgctcgctc actgaggccg 5280 ggcgaccaaa ggtcgcccga cgcccgggct ttgcccgggc ggcctcagtg agcgagcgag 5340 cgcgcagaga gggagtggcc aa 5362 <210> 13 <211> 5464 <212> DNA <213> Adeno-Associated Virus 2 <400> 13 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ttttcgactg tttgctgttt 180 gctgcttgca atgtttgccc attttaggga catgtttgct gtttgctgct tgcaatgttt 240 gcccatttta gggacatgtt tgctgtttgc tgcttgcaat gtttgcccat tttagggaca 300 tgtttgctgt ttgctgcttg caatgtttgc ccattttagg gacaacgcga aacgtcgact 360 ggacacagga cgctgtggtt tctgagccag ggggcgactc agatcccagc cagtggactt 420 agcccctgtt tgctcctccg ataactgggg tgaccttggt taatattcac cagcagcctc 480 ccccgttgcc cctctggatc cactgcttaa atacggacga ggacagggcc ctgtctcctc 540 agcttcaggc accaccactg acctgggaca gtgaatcgta agtactagca gctacaatcc 600 agctaccatt ctgcttttat tttatggttg ggataaggct ggattattct gagtccaagc 660 taggcccttt tgctaatcat gttcatacct cttatcttcc tcccacagct cctgggcaac 720 gtgctggtct gtgtgctggc ccatcacttt ggcaaagaat tgcgatcgcc accatgcaga 780 ttgagctgag cacctgcttc ttcctgtgcc tgctgaggtt ctgcttctct gccaccagga 840 gatactacct gggggctgtg gagctgagct gggactacat gcagtctgac ctgggggagc 900 tgcctgtgga tgccaggttc ccccccagag tgcccaagag cttccccttc aacacctctg 960 tggtgtacaa gaagaccctg tttgtggagt tcactgacca cctgttcaac attgccaagc 1020 ccaggccccc ctggatgggc ctgctgggcc ccaccatcca ggctgaggtg tatgacactg 1080 tggtgatcac cctgaagaac atggccagcc accctgtgag cctgcatgct gtgggggtga 1140 gctactggaa ggcctctgag ggggctgagt atgatgacca gaccagccag agggagaagg 1200 aggatgacaa ggtgttccct gggggcagcc acacctatgt gtggcaggtg ctgaaggaga 1260 atggccccat ggcctctgac cccctgtgcc tgacctacag ctacctgagc catgtggacc 1320 tggtgaagga cctgaactct ggcctgattg gggccctgct ggtgtgcagg gagggcagcc 1380 tggccaagga gaagacccag accctgcaca agttcatcct gctgtttgct gtgtttgatg 1440 agggcaagag ctggcactct gaaaccaaga acagcctgat gcaggacagg gatgctgcct 1500 ctgccagggc ctggcccaag atgcacactg tgaatggcta tgtgaacagg agcctgcctg 1560 gcctgattgg ctgccacagg aagtctgtgt actggcatgt gattggcatg ggcaccaccc 1620 ctgaggtgca cagcatcttc ctggagggcc acaccttcct ggtcaggaac cacaggcagg 1680 ccagcctgga gatcagcccc atcaccttcc tgactgccca gaccctgctg atggacctgg 1740 gccagttcct gctgttctgc cacatcagca gccaccagca tgatggcatg gaggcctatg 1800 tgaaggtgga cagctgccct gaggagcccc agctgaggat gaagaacaat gaggaggctg 1860 aggactatga tgatgacctg actgactctg agatggatgt ggtgaggttt gatgatgaca 1920 acagccccag cttcatccag atcaggtctg tggccaagaa gcaccccaag acctgggtgc 1980 actacattgc tgctgaggag gaggactggg actatgcccc cctggtgctg gcccctgatg 2040 acaggagcta caagagccag tacctgaaca atggccccca gaggattggc aggaagtaca 2100 agaaggtcag gttcatggcc tacactgatg aaaccttcaa gaccagggag gccatccagc 2160 atgagtctgg catcctgggc cccctgctgt atggggaggt gggggacacc ctgctgatca 2220 tcttcaagaa ccaggccagc aggccctaca acatctaccc ccatggcatc actgatgtga 2280 ggcccctgta cagcaggagg ctgcccaagg gggtgaagca cctgaaggac ttccccatcc 2340 tgcctgggga gatcttcaag tacaagtgga ctgtgactgt ggaggatggc cccaccaagt 2400 ctgaccccag gtgcctgacc agatactaca gcagctttgt gaacatggag agggacctgg 2460 cctctggcct gattggcccc ctgctgatct gctacaagga gtctgtggac cagaggggca 2520 accagatcat gtctgacaag aggaatgtga tcctgttctc tgtgtttgat gagaacagga 2580 gctggtacct gactgagaac atccagaggt tcctgcccaa ccctgctggg gtgcagctgg 2640 aggaccctga gttccaggcc agcaacatca tgcacagcat caatggctat gtgtttgaca 2700 gcctgcagct gtctgtgtgc ctgcatgagg tggcctactg gtacatcctg agcattgggg 2760 cccagactga cttcctgtct gtgttcttct ctggctacac cttcaagcac aagatggtgt 2820 atgaggacac cctgaccctg ttccccttct ctggggagac tgtgttcatg agcatggaga 2880 accctggcct gtggattctg ggctgccaca actctgactt caggaacagg ggcatgactg 2940 ccctgctgaa agtctccagc tgtgacaaga acactgggga ctactatgag gacagctatg 3000 aggacatctc tgcctacctg ctgagcaaga acaatgccat tgagcccagg agcttcagcc 3060 agaacccccc agtgctgaag aggcaccaga gggagatcac caggaccacc ctgcagtctg 3120 accaggagga gattgactat gatgacacca tctctgtgga gatgaagaag gaggactttg 3180 acatctacga cgaggacgag aaccagagcc ccaggagctt ccagaagaag accaggcact 3240 acttcattgc tgctgtggag aggctgtggg actatggcat gagcagcagc ccccatgtgc 3300 tgaggaacag ggcccagtct ggctctgtgc cccagttcaa gaaggtggtg ttccaggagt 3360 tcactgatgg cagcttcacc cagcccctgt acagagggga gctgaatgag cacctgggcc 3420 tgctgggccc ctacatcagg gctgaggtgg aggacaacat catggtgacc ttcaggaacc 3480 aggccagcag gccctacagc ttctacagca gcctgatcag ctatgaggag gaccagaggc 3540 agggggctga gcccaggaag aactttgtga agcccaatga aaccaagacc tacttctgga 3600 aggtgcagca ccacatggcc cccaccaagg atgagtttga ctgcaaggcc tgggcctact 3660 tctctgatgt ggacctggag aaggatgtgc actctggcct gattggcccc ctgctggtgt 3720 gccacaccaa caccctgaac cctgcccatg gcaggcaggt gactgtgcag gagtttgccc 3780 tgttcttcac catctttgat gaaaccaaga gctggtactt cactgagaac atggagagga 3840 actgcagggc cccctgcaac atccagatgg aggaccccac cttcaaggag aactacaggt 3900 tccatgccat caatggctac atcatggaca ccctgcctgg cctggtgatg gcccaggacc 3960 agaggatcag gtggtacctg ctgagcatgg gcagcaatga gaacatccac agcatccact 4020 tctctggcca tgtgttcact gtgaggaaga aggaggagta caagatggcc ctgtacaacc 4080 tgtaccctgg ggtgtttgag actgtggaga tgctgcccag caaggctggc atctggaggg 4140 tggagtgcct gattggggag cacctgcatg ctggcatgag caccctgttc ctggtgtaca 4200 gcaacaagtg ccagaccccc ctgggcatgg cctctggcca catcagggac ttccagatca 4260 ctgcctctgg ccagtatggc cagtgggccc ccaagctggc caggctgcac tactctggca 4320 gcatcaatgc ctggagcacc aaggagccct tcagctggat caaggtggac ctgctggccc 4380 ccatgatcat ccatggcatc aagacccagg gggccaggca gaagttcagc agcctgtaca 4440 tcagccagtt catcatcatg tacagcctgg atggcaagaa gtggcagacc tacaggggca 4500 acagcactgg caccctgatg gtgttctttg gcaatgtgga cagctctggc atcaagcaca 4560 acatcttcaa cccccccatc attgccagat acatcaggct gcaccccacc cactacagca 4620 tcaggagcac cctgaggatg gagctgatgg gctgtgacct gaacagctgc agcatgcccc 4680 tgggcatgga gagcaaggcc atctctgatg cccagatcac tgccagcagc tacttcacca 4740 acatgtttgc cacctggagc cccagcaagg ccaggctgca cctgcagggc aggagcaatg 4800 cctggaggcc ccaggtcaac aaccccaagg agtggctgca ggtggacttc cagaagacca 4860 tgaaggtgac tggggtgacc acccaggggg tgaagagcct gctgaccagc atgtatgtga 4920 aggagttcct gatcagcagc agccaggatg gccaccagtg gaccctgttc ttccagaatg 4980 gcaaggtgaa ggtgttccag ggcaaccagg acagcttcac ccctgtggtg aacagcctgg 5040 acccccccct gctgaccaga tacctgagga ttcaccccca gagctgggtg caccagattg 5100 ccctgaggat ggaggtgctg ggctgtgagg cccaggacct gtactgacct cgaggcactg 5160 tcctttccta ataaaatgag gaaattgcat cgcattgtct gagtaggtgt cattctattc 5220 tggggggtgg ggtggggcag gacagcaagg gggaggattg ggaagacaat agcaggcatg 5280 ctggggatgc ggtgggctct atgggcacgt ggcggccgca ggaaccccta gtgatggagt 5340 tggccactcc ctctctgcgc gctcgctcgc tcactgaggc cgggcgacca aaggtcgccc 5400 gacgcccggg ctttgcccgg gcggcctcag tgagcgagcg agcgcgcaga gagggagtgg 5460 ccaa 5464 <210> 14 <211> 6354 <212> DNA <213> Adeno-Associated Virus 2 <400> 14 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg tttaaacgtc gacaggttaa 180 tttttaaaaa gcagtcaaaa gtccaagtgg cccttggcag catttactct ctctgtttgc 240 tctggttaat aatctcagga gcacaaacat tcctggaggc aggagaagaa atcaacatcc 300 tggacttatc ctctgggcct ctccccaccc ccaggagagg ctcaggttaa tttttaaaaa 360 gcagtcaaaa gtccaagtgg cccttggcag catttactct ctctgtttgc tctggttaat 420 aatctcagga gcacaaacat tcctggaggc aggagaagaa atcaacatcc tggacttatc 480 ctctgggcct ctccccaccc ccaggagagg ctgtcgactg gacacaggac gctgtggttt 540 ctgagccagg gggcgactca gatcccagcc agtggactta gcccctgttt gctcctccga 600 taactggggt gaccttggtt aatattcacc agcagcctcc cccgttgccc ctctggatcc 660 actgcttaaa tacggacgag gacagggccc tgtctcctca gcttcaggca ccaccactga 720 cctgggacag tgaatcgtaa gtactagcag ctacaatcca gctaccattc tgcttttatt 780 ttatggttgg gataaggctg gattattctg agtccaagct aggccctttt gctaatcatg 840 ttcatacctc ttatcttcct cccacagctc ctgggcaacg tgctggtctg tgtgctggcc 900 catcactttg gcaaagaatt gcgatcgcca ccatgcagat tgagctgagc acctgcttct 960 tcctgtgcct gctgaggttc tgcttctctg ccaccaggag atactacctg ggggctgtgg 1020 agctgagctg ggactacatg cagtctgacc tgggggagct gcctgtggat gccaggttcc 1080 cccccagagt gcccaagagc ttccccttca acacctctgt ggtgtacaag aagaccctgt 1140 ttgtggagtt cactgaccac ctgttcaaca ttgccaagcc caggcccccc tggatgggcc 1200 tgctgggccc caccatccag gctgaggtgt atgacactgt ggtgatcacc ctgaagaaca 1260 tggccagcca ccctgtgagc ctgcatgctg tgggggtgag ctactggaag gcctctgagg 1320 gggctgagta tgatgaccag accagccaga gggagaagga ggatgacaag gtgttccctg 1380 ggggcagcca cacctatgtg tggcaggtgc tgaaggagaa tggccccatg gcctctgacc 1440 ccctgtgcct gacctacagc tacctgagcc atgtggacct ggtgaaggac ctgaactctg 1500 gcctgattgg ggccctgctg gtgtgcaggg agggcagcct ggccaaggag aagacccaga 1560 ccctgcacaa gttcatcctg ctgtttgctg tgtttgatga gggcaagagc tggcactctg 1620 aaaccaagaa cagcctgatg caggacaggg atgctgcctc tgccagggcc tggcccaaga 1680 tgcacactgt gaatggctat gtgaacagga gcctgcctgg cctgattggc tgccacagga 1740 agtctgtgta ctggcatgtg attggcatgg gcaccacccc tgaggtgcac agcatcttcc 1800 tggagggcca caccttcctg gtcaggaacc acaggcaggc cagcctggag atcagcccca 1860 tcaccttcct gactgcccag accctgctga tggacctggg ccagttcctg ctgttctgcc 1920 acatcagcag ccaccagcat gatggcatgg aggcctatgt gaaggtggac agctgccctg 1980 aggagcccca gctgaggatg aagaacaatg aggaggctga ggactatgat gatgacctga 2040 ctgactctga gatggatgtg gtgaggtttg atgatgacaa cagccccagc ttcatccaga 2100 tcaggtctgt ggccaagaag caccccaaga cctgggtgca ctacattgct gctgaggagg 2160 aggactggga ctatgccccc ctggtgctgg cccctgatga caggagctac aagagccagt 2220 acctgaacaa tggcccccag aggattggca ggaagtacaa gaaggtcagg ttcatggcct 2280 acactgatga aaccttcaag accagggagg ccatccagca tgagtctggc atcctgggcc 2340 ccctgctgta tggggaggtg ggggacaccc tgctgatcat cttcaagaac caggccagca 2400 ggccctacaa catctacccc catggcatca ctgatgtgag gcccctgtac agcaggaggc 2460 tgcccaaggg ggtgaagcac ctgaaggact tccccatcct gcctggggag atcttcaagt 2520 acaagtggac tgtgactgtg gaggatggcc ccaccaagtc tgaccccagg tgcctgacca 2580 gatactacag cagctttgtg aacatggaga gggacctggc ctctggcctg attggccccc 2640 tgctgatctg ctacaaggag tctgtggacc agaggggcaa ccagatcatg tctgacaaga 2700 ggaatgtgat cctgttctct gtgtttgatg agaacaggag ctggtacctg actgagaaca 2760 tccagaggtt cctgcccaac cctgctgggg tgcagctgga ggaccctgag ttccaggcca 2820 gcaacatcat gcacagcatc aatggctatg tgtttgacag cctgcagctg tctgtgtgcc 2880 tgcatgaggt ggcctactgg tacatcctga gcattggggc ccagactgac ttcctgtctg 2940 tgttcttctc tggctacacc ttcaagcaca agatggtgta tgaggacacc ctgaccctgt 3000 tccccttctc tggggagact gtgttcatga gcatggagaa ccctggcctg tggattctgg 3060 gctgccacaa ctctgacttc aggaacaggg gcatgactgc cctgctgaaa gtctccagct 3120 gtgacaagaa cactggggac tactatgagg acagctatga ggacatctct gcctacctgc 3180 tgagcaagaa caatgccatt gagcccagga gcttcagcca gaacccccca gtgctgaaga 3240 ggcaccagag ggagatcacc aggaccaccc tgcagtctga ccaggaggag attgactatg 3300 atgacaccat ctctgtggag atgaagaagg aggactttga catctacgac gaggacgaga 3360 accagagccc caggagcttc cagaagaaga ccaggcacta cttcattgct gctgtggaga 3420 ggctgtggga ctatggcatg agcagcagcc cccatgtgct gaggaacagg gcccagtctg 3480 gctctgtgcc ccagttcaag aaggtggtgt tccaggagtt cactgatggc agcttcaccc 3540 agcccctgta cagaggggag ctgaatgagc acctgggcct gctgggcccc tacatcaggg 3600 ctgaggtgga ggacaacatc atggtgacct tcaggaacca ggccagcagg ccctacagct 3660 tctacagcag cctgatcagc tatgaggagg accagaggca gggggctgag cccaggaaga 3720 actttgtgaa gcccaatgaa accaagacct acttctggaa ggtgcagcac cacatggccc 3780 ccaccaagga tgagtttgac tgcaaggcct gggcctactt ctctgatgtg gacctggaga 3840 aggatgtgca ctctggcctg attggccccc tgctggtgtg ccacaccaac accctgaacc 3900 ctgcccatgg caggcaggtg actgtgcagg agtttgccct gttcttcacc atctttgatg 3960 aaaccaagag ctggtacttc actgagaaca tggagaggaa ctgcagggcc ccctgcaaca 4020 tccagatgga ggaccccacc ttcaaggaga actacaggtt ccatgccatc aatggctaca 4080 tcatggacac cctgcctggc ctggtgatgg cccaggacca gaggatcagg tggtacctgc 4140 tgagcatggg cagcaatgag aacatccaca gcatccactt ctctggccat gtgttcactg 4200 tgaggaagaa ggaggagtac aagatggccc tgtacaacct gtaccctggg gtgtttgaga 4260 ctgtggagat gctgcccagc aaggctggca tctggagggt ggagtgcctg attggggagc 4320 acctgcatgc tggcatgagc accctgttcc tggtgtacag caacaagtgc cagacccccc 4380 tgggcatggc ctctggccac atcagggact tccagatcac tgcctctggc cagtatggcc 4440 agtgggcccc caagctggcc aggctgcact actctggcag catcaatgcc tggagcacca 4500 aggagccctt cagctggatc aaggtggacc tgctggcccc catgatcatc catggcatca 4560 agacccaggg ggccaggcag aagttcagca gcctgtacat cagccagttc atcatcatgt 4620 acagcctgga tggcaagaag tggcagacct acaggggcaa cagcactggc accctgatgg 4680 tgttctttgg caatgtggac agctctggca tcaagcacaa catcttcaac ccccccatca 4740 ttgccagata catcaggctg caccccaccc actacagcat caggagcacc ctgaggatgg 4800 agctgatggg ctgtgacctg aacagctgca gcatgcccct gggcatggag agcaaggcca 4860 tctctgatgc ccagatcact gccagcagct acttcaccaa catgtttgcc acctggagcc 4920 ccagcaaggc caggctgcac ctgcagggca ggagcaatgc ctggaggccc caggtcaaca 4980 accccaagga gtggctgcag gtggacttcc agaagaccat gaaggtgact ggggtgacca 5040 cccagggggt gaagagcctg ctgaccagca tgtatgtgaa ggagttcctg atcagcagca 5100 gccaggatgg ccaccagtgg accctgttct tccagaatgg caaggtgaag gtgttccagg 5160 gcaaccagga cagcttcacc cctgtggtga acagcctgga cccccccctg ctgaccagat 5220 acctgaggat tcacccccag agctgggtgc accagattgc cctgaggatg gaggtgctgg 5280 gctgtgaggc ccaggacctg tactgacctc gaggtgtgcc ttctagttgc cagccatctg 5340 ttgtttgccc ctcccccgtg ccttccttga ccctggaagg tgccactccc actgtccttt 5400 cctaataaaa tgaggaaatt gcatcgcatt gtctgagtag gtgtcattct attctggggg 5460 gtggggtggg gcaggacagc aagggggagg attgggaaga caatagcagg catgctgggg 5520 atgcggtggg ctctatgggc acgtgccctc tcacactacc taaaccacgc caggacaacc 5580 tctgctcctc tccaccgaaa ttccaagggg tcgagtggat gttggaggtg gcatgggccc 5640 agagaggtct ctgacctctg ccccagctcc aaggtcagca ggcagggagg gctgtgtgtt 5700 tgctgtttgc tgcttgcaat gtttgcccat tttagggaca tgagtaggct gaagtttgtt 5760 cagtgtggac ttcagaggca gcacacaaac agctgctgga ggatgggaac tgaggggttg 5820 gaagggggca gggtgagccc agaaactcct gtgtgcctct gagcctgcag ccctctcaca 5880 ctacctaaac cacgccagga caacctctgc tcctctccac cgaaattcca aggggtcgag 5940 tggatgttgg aggtggcatg ggcccagaga ggtctctgac ctctgcccca gctccaaggt 6000 cagcaggcag ggagggctgt gtgtttgctg tttgctgctt gcaatgtttg cccattttag 6060 ggacatgagt aggctgaagt ttgttcagtg tggacttcag aggcagcaca caaacagctg 6120 ctggaggatg ggaactgagg ggttggaagg gggcagggtg agcccagaaa ctcctgtgtg 6180 cctctgagcc tgcagcacgt ggcggccgca ggaaccccta gtgatggagt tggccactcc 6240 ctctctgcgc gctcgctcgc tcactgaggc cgggcgacca aaggtcgccc gacgcccggg 6300 ctttgcccgg gcggcctcag tgagcgagcg agcgcgcaga gagggagtgg ccaa 6354 <210> 15 <211> 6308 <212> DNA <213> Adeno-Associated Virus 2 <400> 15 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ttaattttta aaaagcagtc 180 aaaagtccaa gtggcccttg gcagcattta ctctctctgt ttgctctggt taataatctc 240 aggagcacaa acattcctgg aggcaggaga agaaatcaac atcctggact tatcctctgg 300 gcctgttaat ttttaaaaag cagtcaaaag tccaagtggc ccttggcagc atttactctc 360 tctgtttgct ctggttaata atctcaggag cacaaacatt cctggaggca ggagaagaaa 420 tcaacatcct ggacttatcc tctgggccta ggcctgaggc tggtcaaaat tgaacctcct 480 cctgctctga gcagcctggg gggcagacta agcagagggc tgtgcagacc cacataaaga 540 gcctactgtg tgccaggcac ttcacccgag gcacttcaca agcatgcttg ggaatgaaac 600 ttccaactct ttgggatgca ggtgaaacag ttcctggttc agagaggtga agcggcctgc 660 ctgaggcagc acagctcttc tttacagatg tgcttcccca cctctaccct gtctcacggc 720 cccccatgcc agcctgacgg ttgtgtctgc ctcagtcatg ctccattttt ccatcgggac 780 catcaagagg gtgtttgtgt ctaaggctga ctgggtaact ttggatgagc ggtctctccg 840 ctctgagcct gtttcctcat ctgtcaaatg ggctctaacc cactctgatc tcccagggcg 900 gcagtaagtc ttcagcatca ggcattttgg ggtgactcag taaatggtag atcttgctac 960 cagtggaaca gccactaagg attctgcagt gagagcagag ggccagctaa gtggtactct 1020 cccagagact gtctgactca cgccaccccc tccaccttgg acacaggacg ctgtggtttc 1080 tgagccaggt acaatgactc ctttcggtaa gtgcagtgga agctgtacac tgcccaggca 1140 aagcgtccgg gcagcgtagg cgggcgactc agatcccagc cagtggactt agcccctgtt 1200 tgctcctccg ataactgggg tgaccttggt taatattcac cagcagcctc ccccgttgcc 1260 cctctggatc cactgcttaa atacggacga ggacagggcc ctgtctcctc agcttcaggc 1320 accaccactg acctgggaca gtgaatcgta agtactagca gctacaatcc agctaccatt 1380 ctgcttttat tttatggttg ggataaggct ggattattct gagtccaagc taggcccttt 1440 tgctaatcat gttcatacct cttatcttcc tcccacagct cctgggcaac gtgctggtct 1500 gtgtgctggc ccatcacttt ggcaaagaat tgcgatcgcc accatgcaga ttgagctgag 1560 cacctgcttc ttcctgtgcc tgctgaggtt ctgcttctct gccaccagga gatactacct 1620 gggggctgtg gagctgagct gggactacat gcagtctgac ctgggggagc tgcctgtgga 1680 tgccaggttc ccccccagag tgcccaagag cttccccttc aacacctctg tggtgtacaa 1740 gaagaccctg tttgtggagt tcactgacca cctgttcaac attgccaagc ccaggccccc 1800 ctggatgggc ctgctgggcc ccaccatcca ggctgaggtg tatgacactg tggtgatcac 1860 cctgaagaac atggccagcc accctgtgag cctgcatgct gtgggggtga gctactggaa 1920 ggcctctgag ggggctgagt atgatgacca gaccagccag agggagaagg aggatgacaa 1980 ggtgttccct gggggcagcc acacctatgt gtggcaggtg ctgaaggaga atggccccat 2040 ggcctctgac cccctgtgcc tgacctacag ctacctgagc catgtggacc tggtgaagga 2100 cctgaactct ggcctgattg gggccctgct ggtgtgcagg gagggcagcc tggccaagga 2160 gaagacccag accctgcaca agttcatcct gctgtttgct gtgtttgatg agggcaagag 2220 ctggcactct gaaaccaaga acagcctgat gcaggacagg gatgctgcct ctgccagggc 2280 ctggcccaag atgcacactg tgaatggcta tgtgaacagg agcctgcctg gcctgattgg 2340 ctgccacagg aagtctgtgt actggcatgt gattggcatg ggcaccaccc ctgaggtgca 2400 cagcatcttc ctggagggcc acaccttcct ggtcaggaac cacaggcagg ccagcctgga 2460 gatcagcccc atcaccttcc tgactgccca gaccctgctg atggacctgg gccagttcct 2520 gctgttctgc cacatcagca gccaccagca tgatggcatg gaggcctatg tgaaggtgga 2580 cagctgccct gaggagcccc agctgaggat gaagaacaat gaggaggctg aggactatga 2640 tgatgacctg actgactctg agatggatgt ggtgaggttt gatgatgaca acagccccag 2700 cttcatccag atcaggtctg tggccaagaa gcaccccaag acctgggtgc actacattgc 2760 tgctgaggag gaggactggg actatgcccc cctggtgctg gcccctgatg acaggagcta 2820 caagagccag tacctgaaca atggccccca gaggattggc aggaagtaca agaaggtcag 2880 gttcatggcc tacactgatg aaaccttcaa gaccagggag gccatccagc atgagtctgg 2940 catcctgggc cccctgctgt atggggaggt gggggacacc ctgctgatca tcttcaagaa 3000 ccaggccagc aggccctaca acatctaccc ccatggcatc actgatgtga ggcccctgta 3060 cagcaggagg ctgcccaagg gggtgaagca cctgaaggac ttccccatcc tgcctgggga 3120 gatcttcaag tacaagtgga ctgtgactgt ggaggatggc cccaccaagt ctgaccccag 3180 gtgcctgacc agatactaca gcagctttgt gaacatggag agggacctgg cctctggcct 3240 gattggcccc ctgctgatct gctacaagga gtctgtggac cagaggggca accagatcat 3300 gtctgacaag aggaatgtga tcctgttctc tgtgtttgat gagaacagga gctggtacct 3360 gactgagaac atccagaggt tcctgcccaa ccctgctggg gtgcagctgg aggaccctga 3420 gttccaggcc agcaacatca tgcacagcat caatggctat gtgtttgaca gcctgcagct 3480 gtctgtgtgc ctgcatgagg tggcctactg gtacatcctg agcattgggg cccagactga 3540 cttcctgtct gtgttcttct ctggctacac cttcaagcac aagatggtgt atgaggacac 3600 cctgaccctg ttccccttct ctggggagac tgtgttcatg agcatggaga accctggcct 3660 gtggattctg ggctgccaca actctgactt caggaacagg ggcatgactg ccctgctgaa 3720 agtctccagc tgtgacaaga acactgggga ctactatgag gacagctatg aggacatctc 3780 tgcctacctg ctgagcaaga acaatgccat tgagcccagg agcttcagcc agaacccccc 3840 agtgctgaag aggcaccaga gggagatcac caggaccacc ctgcagtctg accaggagga 3900 gattgactat gatgacacca tctctgtgga gatgaagaag gaggactttg acatctacga 3960 cgaggacgag aaccagagcc ccaggagctt ccagaagaag accaggcact acttcattgc 4020 tgctgtggag aggctgtggg actatggcat gagcagcagc ccccatgtgc tgaggaacag 4080 ggcccagtct ggctctgtgc cccagttcaa gaaggtggtg ttccaggagt tcactgatgg 4140 cagcttcacc cagcccctgt acagagggga gctgaatgag cacctgggcc tgctgggccc 4200 ctacatcagg gctgaggtgg aggacaacat catggtgacc ttcaggaacc aggccagcag 4260 gccctacagc ttctacagca gcctgatcag ctatgaggag gaccagaggc agggggctga 4320 gcccaggaag aactttgtga agcccaatga aaccaagacc tacttctgga aggtgcagca 4380 ccacatggcc cccaccaagg atgagtttga ctgcaaggcc tgggcctact tctctgatgt 4440 ggacctggag aaggatgtgc actctggcct gattggcccc ctgctggtgt gccacaccaa 4500 caccctgaac cctgcccatg gcaggcaggt gactgtgcag gagtttgccc tgttcttcac 4560 catctttgat gaaaccaaga gctggtactt cactgagaac atggagagga actgcagggc 4620 cccctgcaac atccagatgg aggaccccac cttcaaggag aactacaggt tccatgccat 4680 caatggctac atcatggaca ccctgcctgg cctggtgatg gcccaggacc agaggatcag 4740 gtggtacctg ctgagcatgg gcagcaatga gaacatccac agcatccact tctctggcca 4800 tgtgttcact gtgaggaaga aggaggagta caagatggcc ctgtacaacc tgtaccctgg 4860 ggtgtttgag actgtggaga tgctgcccag caaggctggc atctggaggg tggagtgcct 4920 gattggggag cacctgcatg ctggcatgag caccctgttc ctggtgtaca gcaacaagtg 4980 ccagaccccc ctgggcatgg cctctggcca catcagggac ttccagatca ctgcctctgg 5040 ccagtatggc cagtgggccc ccaagctggc caggctgcac tactctggca gcatcaatgc 5100 ctggagcacc aaggagccct tcagctggat caaggtggac ctgctggccc ccatgatcat 5160 ccatggcatc aagacccagg gggccaggca gaagttcagc agcctgtaca tcagccagtt 5220 catcatcatg tacagcctgg atggcaagaa gtggcagacc tacaggggca acagcactgg 5280 caccctgatg gtgttctttg gcaatgtgga cagctctggc atcaagcaca acatcttcaa 5340 cccccccatc attgccagat acatcaggct gcaccccacc cactacagca tcaggagcac 5400 cctgaggatg gagctgatgg gctgtgacct gaacagctgc agcatgcccc tgggcatgga 5460 gagcaaggcc atctctgatg cccagatcac tgccagcagc tacttcacca acatgtttgc 5520 cacctggagc cccagcaagg ccaggctgca cctgcagggc aggagcaatg cctggaggcc 5580 ccaggtcaac aaccccaagg agtggctgca ggtggacttc cagaagacca tgaaggtgac 5640 tggggtgacc acccaggggg tgaagagcct gctgaccagc atgtatgtga aggagttcct 5700 gatcagcagc agccaggatg gccaccagtg gaccctgttc ttccagaatg gcaaggtgaa 5760 ggtgttccag ggcaaccagg acagcttcac ccctgtggtg aacagcctgg acccccccct 5820 gctgaccaga tacctgagga ttcaccccca gagctgggtg caccagattg ccctgaggat 5880 ggaggtgctg ggctgtgagg cccaggacct gtactgacct cgagctgtgc cttctagttg 5940 ccagccatct gttgtttgcc cctcccccgt gccttccttg accctggaag gtgccactcc 6000 cactgtcctt tcctaataaa atgaggaaat tgcatcgcat tgtctgagta ggtgtcattc 6060 tattctgggg ggtggggtgg ggcaggacag caagggggag gattgggaag acaatagcag 6120 gcatgctggg gatgcggtgg gctctatgga ccggtgcggc cgcaggaacc cctagtgatg 6180 gagttggcca ctccctctct gcgcgctcgc tcgctcactg aggccgggcg accaaaggtc 6240 gcccgacgcc cgggctttgc ccgggcggcc tcagtgagcg agcgagcgcg cagagaggga 6300 gtggccaa 6308 <210> 16 <211> 5635 <212> DNA <213> Adeno-Associate Virus 2 <400> 16 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ttaattttta aaaagcagtc 180 aaaagtccaa gtggcccttg gcagcattta ctctctctgt ttgctctggt taataatctc 240 aggagcacaa acattcctgg aggcaggaga agaaatcaac atcctggact tatcctctgg 300 gcctgttaat ttttaaaaag cagtcaaaag tccaagtggc ccttggcagc atttactctc 360 tctgtttgct ctggttaata atctcaggag cacaaacatt cctggaggca ggagaagaaa 420 tcaacatcct ggacttatcc tctgggccta gtcgactgga cacaggacgc tgtggtttct 480 gagccagggg gcgactcaga tcccagccag tggacttagc ccctgtttgc tcctccgata 540 actggggtga ccttggttaa tattcaccag cagcctcccc cgttgcccct ctggatccac 600 tgcttaaata cggacgagga cagggccctg tctcctcagc ttcaggcacc accactgacc 660 tgggacagtg aatcgtaagt actagcagct acaatccagc taccattctg cttttatttt 720 atggttggga taaggctgga ttattctgag tccaagctag gcccttttgc taatcatgtt 780 catacctctt atcttcctcc cacagctcct gggcaacgtg ctggtctgtg tgctggccca 840 tcactttggc aaagaattgc gatcgccacc atgcagattg agctgagcac ctgcttcttc 900 ctgtgcctgc tgaggttctg cttctctgcc accaggagat actacctggg ggctgtggag 960 ctgagctggg actacatgca gtctgacctg ggggagctgc ctgtggatgc caggttcccc 1020 cccagagtgc ccaagagctt ccccttcaac acctctgtgg tgtacaagaa gaccctgttt 1080 gtggagttca ctgaccacct gttcaacatt gccaagccca ggcccccctg gatgggcctg 1140 ctgggcccca ccatccaggc tgaggtgtat gacactgtgg tgatcaccct gaagaacatg 1200 gccagccacc ctgtgagcct gcatgctgtg ggggtgagct actggaaggc ctctgagggg 1260 gctgagtatg atgaccagac cagccagagg gagaaggagg atgacaaggt gttccctggg 1320 ggcagccaca cctatgtgtg gcaggtgctg aaggagaatg gccccatggc ctctgacccc 1380 ctgtgcctga cctacagcta cctgagccat gtggacctgg tgaaggacct gaactctggc 1440 ctgattgggg ccctgctggt gtgcagggag ggcagcctgg ccaaggagaa gacccagacc 1500 ctgcacaagt tcatcctgct gtttgctgtg tttgatgagg gcaagagctg gcactctgaa 1560 accaagaaca gcctgatgca ggacagggat gctgcctctg ccagggcctg gcccaagatg 1620 cacactgtga atggctatgt gaacaggagc ctgcctggcc tgattggctg ccacaggaag 1680 tctgtgtact ggcatgtgat tggcatgggc accacccctg aggtgcacag catcttcctg 1740 gagggccaca ccttcctggt caggaaccac aggcaggcca gcctggagat cagccccatc 1800 accttcctga ctgcccagac cctgctgatg gacctgggcc agttcctgct gttctgccac 1860 atcagcagcc accagcatga tggcatggag gcctatgtga aggtggacag ctgccctgag 1920 gagccccagc tgaggatgaa gaacaatgag gaggctgagg actatgatga tgacctgact 1980 gactctgaga tggatgtggt gaggtttgat gatgacaaca gccccagctt catccagatc 2040 aggtctgtgg ccaagaagca ccccaagacc tgggtgcact acattgctgc tgaggaggag 2100 gactgggact atgcccccct ggtgctggcc cctgatgaca ggagctacaa gagccagtac 2160 ctgaacaatg gcccccagag gattggcagg aagtacaaga aggtcaggtt catggcctac 2220 actgatgaaa ccttcaagac cagggaggcc atccagcatg agtctggcat cctgggcccc 2280 ctgctgtatg gggaggtggg ggacaccctg ctgatcatct tcaagaacca ggccagcagg 2340 ccctacaaca tctaccccca tggcatcact gatgtgaggc ccctgtacag caggaggctg 2400 cccaaggggg tgaagcacct gaaggacttc cccatcctgc ctggggagat cttcaagtac 2460 aagtggactg tgactgtgga ggatggcccc accaagtctg accccaggtg cctgaccaga 2520 tactacagca gctttgtgaa catggagagg gacctggcct ctggcctgat tggccccctg 2580 ctgatctgct acaaggagtc tgtggaccag aggggcaacc agatcatgtc tgacaagagg 2640 aatgtgatcc tgttctctgt gtttgatgag aacaggagct ggtacctgac tgagaacatc 2700 cagaggttcc tgcccaaccc tgctggggtg cagctggagg accctgagtt ccaggccagc 2760 aacatcatgc acagcatcaa tggctatgtg tttgacagcc tgcagctgtc tgtgtgcctg 2820 catgaggtgg cctactggta catcctgagc attggggccc agactgactt cctgtctgtg 2880 ttcttctctg gctacacctt caagcacaag atggtgtatg aggacaccct gaccctgttc 2940 cccttctctg gggagactgt gttcatgagc atggagaacc ctggcctgtg gattctgggc 3000 tgccacaact ctgacttcag gaacaggggc atgactgccc tgctgaaagt ctccagctgt 3060 gacaagaaca ctggggacta ctatgaggac agctatgagg acatctctgc ctacctgctg 3120 agcaagaaca atgccattga gcccaggagc ttcagccaga accccccagt gctgaagagg 3180 caccagaggg agatcaccag gaccaccctg cagtctgacc aggaggagat tgactatgat 3240 gacaccatct ctgtggagat gaagaaggag gactttgaca tctacgacga ggacgagaac 3300 cagagcccca ggagcttcca gaagaagacc aggcactact tcattgctgc tgtggagagg 3360 ctgtgggact atggcatgag cagcagcccc catgtgctga ggaacagggc ccagtctggc 3420 tctgtgcccc agttcaagaa ggtggtgttc caggagttca ctgatggcag cttcacccag 3480 cccctgtaca gaggggagct gaatgagcac ctgggcctgc tgggccccta catcagggct 3540 gaggtggagg acaacatcat ggtgaccttc aggaaccagg ccagcaggcc ctacagcttc 3600 tacagcagcc tgatcagcta tgaggaggac cagaggcagg gggctgagcc caggaagaac 3660 tttgtgaagc ccaatgaaac caagacctac ttctggaagg tgcagcacca catggccccc 3720 accaaggatg agtttgactg caaggcctgg gcctacttct ctgatgtgga cctggagaag 3780 gatgtgcact ctggcctgat tggccccctg ctggtgtgcc acaccaacac cctgaaccct 3840 gcccatggca ggcaggtgac tgtgcaggag tttgccctgt tcttcaccat ctttgatgaa 3900 accaagagct ggtacttcac tgagaacatg gagaggaact gcagggcccc ctgcaacatc 3960 cagatggagg accccacctt caaggagaac tacaggttcc atgccatcaa tggctacatc 4020 atggacaccc tgcctggcct ggtgatggcc caggaccaga ggatcaggtg gtacctgctg 4080 agcatgggca gcaatgagaa catccacagc atccacttct ctggccatgt gttcactgtg 4140 aggaagaagg aggagtacaa gatggccctg tacaacctgt accctggggt gtttgagact 4200 gtggagatgc tgcccagcaa ggctggcatc tggagggtgg agtgcctgat tggggagcac 4260 ctgcatgctg gcatgagcac cctgttcctg gtgtacagca acaagtgcca gacccccctg 4320 ggcatggcct ctggccacat cagggacttc cagatcactg cctctggcca gtatggccag 4380 tgggccccca agctggccag gctgcactac tctggcagca tcaatgcctg gagcaccaag 4440 gagcccttca gctggatcaa ggtggacctg ctggccccca tgatcatcca tggcatcaag 4500 acccaggggg ccaggcagaa gttcagcagc ctgtacatca gccagttcat catcatgtac 4560 agcctggatg gcaagaagtg gcagacctac aggggcaaca gcactggcac cctgatggtg 4620 ttctttggca atgtggacag ctctggcatc aagcacaaca tcttcaaccc ccccatcatt 4680 gccagataca tcaggctgca ccccacccac tacagcatca ggagcaccct gaggatggag 4740 ctgatgggct gtgacctgaa cagctgcagc atgcccctgg gcatggagag caaggccatc 4800 tctgatgccc agatcactgc cagcagctac ttcaccaaca tgtttgccac ctggagcccc 4860 agcaaggcca ggctgcacct gcagggcagg agcaatgcct ggaggcccca ggtcaacaac 4920 cccaaggagt ggctgcaggt ggacttccag aagaccatga aggtgactgg ggtgaccacc 4980 cagggggtga agagcctgct gaccagcatg tatgtgaagg agttcctgat cagcagcagc 5040 caggatggcc accagtggac cctgttcttc cagaatggca aggtgaaggt gttccagggc 5100 aaccaggaca gcttcacccc tgtggtgaac agcctggacc cccccctgct gaccagatac 5160 ctgaggattc acccccagag ctgggtgcac cagattgccc tgaggatgga ggtgctgggc 5220 tgtgaggccc aggacctgta ctgacctcga gctgtgcctt ctagttgcca gccatctgtt 5280 gtttgcccct cccccgtgcc ttccttgacc ctggaaggtg ccactcccac tgtcctttcc 5340 taataaaatg aggaaattgc atcgcattgt ctgagtaggt gtcattctat tctggggggt 5400 ggggtggggc aggacagcaa gggggaggat tgggaagaca atagcaggca tgctggggat 5460 gcggtgggct ctatggaccg gtgcggccgc aggaacccct agtgatggag ttggccactc 5520 cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc cgacgcccgg 5580 gctttgcccg ggcggcctca gtgagcgagc gagcgcgcag agagggagtg gccaa 5635 <210> 17 <211> 6962 <212> DNA <213> Adeno-Associated Virus 2 <400> 17 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgta ggctcagagg cacacaggag 180 tttctgggct caccctgccc ccttccaacc cctcagttcc catcctccag cagctgtttg 240 tgtgctgcct ctgaagtcca cactgaacaa acttcagcct actcatgtcc ctaaaatggg 300 caaacattgc aagcagcaaa cagcaaacac acagccctcc ctgcctgctg accttggagc 360 tggggcagag gtcagagacc tctctgggcc catgccacct ccaacatcca ctcgacccct 420 tggaatttcg gtggagagga gcagaggttg tcctggcgtg gtttaggtag tgtgagaggg 480 gtcgacaggc tcagaggcac acaggagttt ctgggctcac cctgccccct tccaacccct 540 cagttcccat cctccagcag ctgtttgtgt gctgcctctg aagtccacac tgaacaaact 600 tcagcctact catgtcccta aaatgggcaa acattgcaag cagcaaacag caaacacaca 660 gccctccctg cctgctgacc ttggagctgg ggcagaggtc agagacctct ctgggcccat 720 gccacctcca acatccactc gaccccttgg aatttcggtg gagaggagca gaggttgtcc 780 tggcgtggtt taggtagtgt gagaggggtc gacgttaatt tttaaaaagc agtcaaaagt 840 ccaagtggcc cttggcagca tttactctct ctgtttgctc tggttaataa tctcaggagc 900 acaaacattc ctggaggcag gagaagaaat caacatcctg gacttatcct ctgggcctgt 960 taatttttaa aaagcagtca aaagtccaag tggcccttgg cagcatttac tctctctgtt 1020 tgctctggtt aataatctca ggagcacaaa cattcctgga ggcaggagaa gaaatcaaca 1080 tcctggactt atcctctggg cctaggcctg aggctggtca aaattgaacc tcctcctgct 1140 ctgagcagcc tggggggcag actaagcaga gggctgtgca gacccacata aagagcctac 1200 tgtgtgccag gcacttcacc cgaggcactt cacaagcatg cttgggaatg aaacttccaa 1260 ctctttggga tgcaggtgaa acagttcctg gttcagagag gtgaagcggc ctgcctgagg 1320 cagcacagct cttctttaca gatgtgcttc cccacctcta ccctgtctca cggcccccca 1380 tgccagcctg acggttgtgt ctgcctcagt catgctccat ttttccatcg ggaccatcaa 1440 gagggtgttt gtgtctaagg ctgactgggt aactttggat gagcggtctc tccgctctga 1500 gcctgtttcc tcatctgtca aatgggctct aacccactct gatctcccag ggcggcagta 1560 agtcttcagc atcaggcatt ttggggtgac tcagtaaatg gtagatcttg ctaccagtgg 1620 aacagccact aaggattctg cagtgagagc agagggccag ctaagtggta ctctcccaga 1680 gactgtctga ctcacgccac cccctccacc ttggacacag gacgctgtgg tttctgagcc 1740 aggtacaatg actcctttcg gtaagtgcag tggaagctgt acactgccca ggcaaagcgt 1800 ccgggcagcg taggcgggcg actcagatcc cagccagtgg acttagcccc tgtttgctcc 1860 tccgataact ggggtgacct tggttaatat tcaccagcag cctcccccgt tgcccctctg 1920 gatccactgc ttaaatacgg acgaggacag ggccctgtct cctcagcttc aggcaccacc 1980 actgacctgg gacagtgaat cgtaagtact agcagctaca atccagctac cattctgctt 2040 ttattttatg gttgggataa ggctggatta ttctgagtcc aagctaggcc cttttgctaa 2100 tcatgttcat acctcttatc ttcctcccac agctcctggg caacgtgctg gtctgtgtgc 2160 tggcccatca ctttggcaaa gaattgcgat cgccaccatg cagattgagc tgagcacctg 2220 cttcttcctg tgcctgctga ggttctgctt ctctgccacc aggagatact acctgggggc 2280 tgtggagctg agctgggact acatgcagtc tgacctgggg gagctgcctg tggatgccag 2340 gttccccccc agagtgccca agagcttccc cttcaacacc tctgtggtgt acaagaagac 2400 cctgtttgtg gagttcactg accacctgtt caacattgcc aagcccaggc ccccctggat 2460 gggcctgctg ggccccacca tccaggctga ggtgtatgac actgtggtga tcaccctgaa 2520 gaacatggcc agccaccctg tgagcctgca tgctgtgggg gtgagctact ggaaggcctc 2580 tgagggggct gagtatgatg accagaccag ccagagggag aaggaggatg acaaggtgtt 2640 ccctgggggc agccacacct atgtgtggca ggtgctgaag gagaatggcc ccatggcctc 2700 tgaccccctg tgcctgacct acagctacct gagccatgtg gacctggtga aggacctgaa 2760 ctctggcctg attggggccc tgctggtgtg cagggagggc agcctggcca aggagaagac 2820 ccagaccctg cacaagttca tcctgctgtt tgctgtgttt gatgagggca agagctggca 2880 ctctgaaacc aagaacagcc tgatgcagga cagggatgct gcctctgcca gggcctggcc 2940 caagatgcac actgtgaatg gctatgtgaa caggagcctg cctggcctga ttggctgcca 3000 caggaagtct gtgtactggc atgtgattgg catgggcacc acccctgagg tgcacagcat 3060 cttcctggag ggccacacct tcctggtcag gaaccacagg caggccagcc tggagatcag 3120 ccccatcacc ttcctgactg cccagaccct gctgatggac ctgggccagt tcctgctgtt 3180 ctgccacatc agcagccacc agcatgatgg catggaggcc tatgtgaagg tggacagctg 3240 ccctgaggag ccccagctga ggatgaagaa caatgaggag gctgaggact atgatgatga 3300 cctgactgac tctgagatgg atgtggtgag gtttgatgat gacaacagcc ccagcttcat 3360 ccagatcagg tctgtggcca agaagcaccc caagacctgg gtgcactaca ttgctgctga 3420 ggaggaggac tgggactatg cccccctggt gctggcccct gatgacagga gctacaagag 3480 ccagtacctg aacaatggcc cccagaggat tggcaggaag tacaagaagg tcaggttcat 3540 ggcctacact gatgaaacct tcaagaccag ggaggccatc cagcatgagt ctggcatcct 3600 gggccccctg ctgtatgggg aggtggggga caccctgctg atcatcttca agaaccaggc 3660 cagcaggccc tacaacatct acccccatgg catcactgat gtgaggcccc tgtacagcag 3720 gaggctgccc aagggggtga agcacctgaa ggacttcccc atcctgcctg gggagatctt 3780 caagtacaag tggactgtga ctgtggagga tggccccacc aagtctgacc ccaggtgcct 3840 gaccagatac tacagcagct ttgtgaacat ggagagggac ctggcctctg gcctgattgg 3900 ccccctgctg atctgctaca aggagtctgt ggaccagagg ggcaaccaga tcatgtctga 3960 caagaggaat gtgatcctgt tctctgtgtt tgatgagaac aggagctggt acctgactga 4020 gaacatccag aggttcctgc ccaaccctgc tggggtgcag ctggaggacc ctgagttcca 4080 ggccagcaac atcatgcaca gcatcaatgg ctatgtgttt gacagcctgc agctgtctgt 4140 gtgcctgcat gaggtggcct actggtacat cctgagcatt ggggcccaga ctgacttcct 4200 gtctgtgttc ttctctggct acaccttcaa gcacaagatg gtgtatgagg acaccctgac 4260 cctgttcccc ttctctgggg agactgtgtt catgagcatg gagaaccctg gcctgtggat 4320 tctgggctgc cacaactctg acttcaggaa caggggcatg actgccctgc tgaaagtctc 4380 cagctgtgac aagaacactg gggactacta tgaggacagc tatgaggaca tctctgccta 4440 cctgctgagc aagaacaatg ccattgagcc caggagcttc agccagaacc ccccagtgct 4500 gaagaggcac cagagggaga tcaccaggac caccctgcag tctgaccagg aggagattga 4560 ctatgatgac accatctctg tggagatgaa gaaggaggac tttgacatct acgacgagga 4620 cgagaaccag agccccagga gcttccagaa gaagaccagg cactacttca ttgctgctgt 4680 ggagaggctg tgggactatg gcatgagcag cagcccccat gtgctgagga acagggccca 4740 gtctggctct gtgccccagt tcaagaaggt ggtgttccag gagttcactg atggcagctt 4800 cacccagccc ctgtacagag gggagctgaa tgagcacctg ggcctgctgg gcccctacat 4860 cagggctgag gtggaggaca acatcatggt gaccttcagg aaccaggcca gcaggcccta 4920 cagcttctac agcagcctga tcagctatga ggaggaccag aggcaggggg ctgagcccag 4980 gaagaacttt gtgaagccca atgaaaccaa gacctacttc tggaaggtgc agcaccacat 5040 ggcccccacc aaggatgagt ttgactgcaa ggcctgggcc tacttctctg atgtggacct 5100 ggagaaggat gtgcactctg gcctgattgg ccccctgctg gtgtgccaca ccaacaccct 5160 gaaccctgcc catggcaggc aggtgactgt gcaggagttt gccctgttct tcaccatctt 5220 tgatgaaacc aagagctggt acttcactga gaacatggag aggaactgca gggccccctg 5280 caacatccag atggaggacc ccaccttcaa ggagaactac aggttccatg ccatcaatgg 5340 ctacatcatg gacaccctgc ctggcctggt gatggcccag gaccagagga tcaggtggta 5400 cctgctgagc atgggcagca atgagaacat ccacagcatc cacttctctg gccatgtgtt 5460 cactgtgagg aagaaggagg agtacaagat ggccctgtac aacctgtacc ctggggtgtt 5520 tgagactgtg gagatgctgc ccagcaaggc tggcatctgg agggtggagt gcctgattgg 5580 ggagcacctg catgctggca tgagcaccct gttcctggtg tacagcaaca agtgccagac 5640 ccccctgggc atggcctctg gccacatcag ggacttccag atcactgcct ctggccagta 5700 tggccagtgg gcccccaagc tggccaggct gcactactct ggcagcatca atgcctggag 5760 caccaaggag cccttcagct ggatcaaggt ggacctgctg gcccccatga tcatccatgg 5820 catcaagacc cagggggcca ggcagaagtt cagcagcctg tacatcagcc agttcatcat 5880 catgtacagc ctggatggca agaagtggca gacctacagg ggcaacagca ctggcaccct 5940 gatggtgttc tttggcaatg tggacagctc tggcatcaag cacaacatct tcaacccccc 6000 catcattgcc agatacatca ggctgcaccc cacccactac agcatcagga gcaccctgag 6060 gatggagctg atgggctgtg acctgaacag ctgcagcatg cccctgggca tggagagcaa 6120 ggccatctct gatgcccaga tcactgccag cagctacttc accaacatgt ttgccacctg 6180 gagccccagc aaggccaggc tgcacctgca gggcaggagc aatgcctgga ggccccaggt 6240 caacaacccc aaggagtggc tgcaggtgga cttccagaag accatgaagg tgactggggt 6300 gaccacccag ggggtgaaga gcctgctgac cagcatgtat gtgaaggagt tcctgatcag 6360 cagcagccag gatggccacc agtggaccct gttcttccag aatggcaagg tgaaggtgtt 6420 ccagggcaac caggacagct tcacccctgt ggtgaacagc ctggaccccc ccctgctgac 6480 cagatacctg aggattcacc cccagagctg ggtgcaccag attgccctga ggatggaggt 6540 gctgggctgt gaggcccagg acctgtactg acctcgagct gtgccttcta gttgccagcc 6600 atctgttgtt tgcccctccc ccgtgccttc cttgaccctg gaaggtgcca ctcccactgt 6660 cctttcctaa taaaatgagg aaattgcatc gcattgtctg agtaggtgtc attctattct 6720 ggggggtggg gtggggcagg acagcaaggg ggaggattgg gaagacaata gcaggcatgc 6780 tggggatgcg gtgggctcta tggaccggtg cggccgcagg aacccctagt gatggagttg 6840 gccactccct ctctgcgcgc tcgctcgctc actgaggccg ggcgaccaaa ggtcgcccga 6900 cgcccgggct ttgcccgggc ggcctcagtg agcgagcgag cgcgcagaga gggagtggcc 6960 aa 6962 <210> 18 <211> 6289 <212> DNA <213> Adeno-Associated Virus 2 <400> 18 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgta ggctcagagg cacacaggag 180 tttctgggct caccctgccc ccttccaacc cctcagttcc catcctccag cagctgtttg 240 tgtgctgcct ctgaagtcca cactgaacaa acttcagcct actcatgtcc ctaaaatggg 300 caaacattgc aagcagcaaa cagcaaacac acagccctcc ctgcctgctg accttggagc 360 tggggcagag gtcagagacc tctctgggcc catgccacct ccaacatcca ctcgacccct 420 tggaatttcg gtggagagga gcagaggttg tcctggcgtg gtttaggtag tgtgagaggg 480 gtcgacaggc tcagaggcac acaggagttt ctgggctcac cctgccccct tccaacccct 540 cagttcccat cctccagcag ctgtttgtgt gctgcctctg aagtccacac tgaacaaact 600 tcagcctact catgtcccta aaatgggcaa acattgcaag cagcaaacag caaacacaca 660 gccctccctg cctgctgacc ttggagctgg ggcagaggtc agagacctct ctgggcccat 720 gccacctcca acatccactc gaccccttgg aatttcggtg gagaggagca gaggttgtcc 780 tggcgtggtt taggtagtgt gagaggggtc gacgttaatt tttaaaaagc agtcaaaagt 840 ccaagtggcc cttggcagca tttactctct ctgtttgctc tggttaataa tctcaggagc 900 acaaacattc ctggaggcag gagaagaaat caacatcctg gacttatcct ctgggcctgt 960 taatttttaa aaagcagtca aaagtccaag tggcccttgg cagcatttac tctctctgtt 1020 tgctctggtt aataatctca ggagcacaaa cattcctgga ggcaggagaa gaaatcaaca 1080 tcctggactt atcctctggg cctagtcgac tggacacagg acgctgtggt ttctgagcca 1140 gggggcgact cagatcccag ccagtggact tagcccctgt ttgctcctcc gataactggg 1200 gtgaccttgg ttaatattca ccagcagcct cccccgttgc ccctctggat ccactgctta 1260 aatacggacg aggacagggc cctgtctcct cagcttcagg caccaccact gacctgggac 1320 agtgaatcgt aagtactagc agctacaatc cagctaccat tctgctttta ttttatggtt 1380 gggataaggc tggattattc tgagtccaag ctaggccctt ttgctaatca tgttcatacc 1440 tcttatcttc ctcccacagc tcctgggcaa cgtgctggtc tgtgtgctgg cccatcactt 1500 tggcaaagaa ttgcgatcgc caccatgcag attgagctga gcacctgctt cttcctgtgc 1560 ctgctgaggt tctgcttctc tgccaccagg agatactacc tgggggctgt ggagctgagc 1620 tgggactaca tgcagtctga cctgggggag ctgcctgtgg atgccaggtt cccccccaga 1680 gtgcccaaga gcttcccctt caacacctct gtggtgtaca agaagaccct gtttgtggag 1740 ttcactgacc acctgttcaa cattgccaag cccaggcccc cctggatggg cctgctgggc 1800 cccaccatcc aggctgaggt gtatgacact gtggtgatca ccctgaagaa catggccagc 1860 caccctgtga gcctgcatgc tgtgggggtg agctactgga aggcctctga gggggctgag 1920 tatgatgacc agaccagcca gagggagaag gaggatgaca aggtgttccc tgggggcagc 1980 cacacctatg tgtggcaggt gctgaaggag aatggcccca tggcctctga ccccctgtgc 2040 ctgacctaca gctacctgag ccatgtggac ctggtgaagg acctgaactc tggcctgatt 2100 ggggccctgc tggtgtgcag ggagggcagc ctggccaagg agaagaccca gaccctgcac 2160 aagttcatcc tgctgtttgc tgtgtttgat gagggcaaga gctggcactc tgaaaccaag 2220 aacagcctga tgcaggacag ggatgctgcc tctgccaggg cctggcccaa gatgcacact 2280 gtgaatggct atgtgaacag gagcctgcct ggcctgattg gctgccacag gaagtctgtg 2340 tactggcatg tgattggcat gggcaccacc cctgaggtgc acagcatctt cctggagggc 2400 cacaccttcc tggtcaggaa ccacaggcag gccagcctgg agatcagccc catcaccttc 2460 ctgactgccc agaccctgct gatggacctg ggccagttcc tgctgttctg ccacatcagc 2520 agccaccagc atgatggcat ggaggcctat gtgaaggtgg acagctgccc tgaggagccc 2580 cagctgagga tgaagaacaa tgaggaggct gaggactatg atgatgacct gactgactct 2640 gagatggatg tggtgaggtt tgatgatgac aacagcccca gcttcatcca gatcaggtct 2700 gtggccaaga agcaccccaa gacctgggtg cactacattg ctgctgagga ggaggactgg 2760 gactatgccc ccctggtgct ggcccctgat gacaggagct acaagagcca gtacctgaac 2820 aatggccccc agaggattgg caggaagtac aagaaggtca ggttcatggc ctacactgat 2880 gaaaccttca agaccaggga ggccatccag catgagtctg gcatcctggg ccccctgctg 2940 tatggggagg tgggggacac cctgctgatc atcttcaaga accaggccag caggccctac 3000 aacatctacc cccatggcat cactgatgtg aggcccctgt acagcaggag gctgcccaag 3060 ggggtgaagc acctgaagga cttccccatc ctgcctgggg agatcttcaa gtacaagtgg 3120 actgtgactg tggaggatgg ccccaccaag tctgacccca ggtgcctgac cagatactac 3180 agcagctttg tgaacatgga gagggacctg gcctctggcc tgattggccc cctgctgatc 3240 tgctacaagg agtctgtgga ccagaggggc aaccagatca tgtctgacaa gaggaatgtg 3300 atcctgttct ctgtgtttga tgagaacagg agctggtacc tgactgagaa catccagagg 3360 ttcctgccca accctgctgg ggtgcagctg gaggaccctg agttccaggc cagcaacatc 3420 atgcacagca tcaatggcta tgtgtttgac agcctgcagc tgtctgtgtg cctgcatgag 3480 gtggcctact ggtacatcct gagcattggg gcccagactg acttcctgtc tgtgttcttc 3540 tctggctaca ccttcaagca caagatggtg tatgaggaca ccctgaccct gttccccttc 3600 tctggggaga ctgtgttcat gagcatggag aaccctggcc tgtggattct gggctgccac 3660 aactctgact tcaggaacag gggcatgact gccctgctga aagtctccag ctgtgacaag 3720 aacactgggg actactatga ggacagctat gaggacatct ctgcctacct gctgagcaag 3780 aacaatgcca ttgagcccag gagcttcagc cagaaccccc cagtgctgaa gaggcaccag 3840 agggagatca ccaggaccac cctgcagtct gaccaggagg agattgacta tgatgacacc 3900 atctctgtgg agatgaagaa ggaggacttt gacatctacg acgaggacga gaaccagagc 3960 cccaggagct tccagaagaa gaccaggcac tacttcattg ctgctgtgga gaggctgtgg 4020 gactatggca tgagcagcag cccccatgtg ctgaggaaca gggcccagtc tggctctgtg 4080 ccccagttca agaaggtggt gttccaggag ttcactgatg gcagcttcac ccagcccctg 4140 tacagagggg agctgaatga gcacctgggc ctgctgggcc cctacatcag ggctgaggtg 4200 gaggacaaca tcatggtgac cttcaggaac caggccagca ggccctacag cttctacagc 4260 agcctgatca gctatgagga ggaccagagg cagggggctg agcccaggaa gaactttgtg 4320 aagcccaatg aaaccaagac ctacttctgg aaggtgcagc accacatggc ccccaccaag 4380 gatgagtttg actgcaaggc ctgggcctac ttctctgatg tggacctgga gaaggatgtg 4440 cactctggcc tgattggccc cctgctggtg tgccacacca acaccctgaa ccctgcccat 4500 ggcaggcagg tgactgtgca ggagtttgcc ctgttcttca ccatctttga tgaaaccaag 4560 agctggtact tcactgagaa catggagagg aactgcaggg ccccctgcaa catccagatg 4620 gaggacccca ccttcaagga gaactacagg ttccatgcca tcaatggcta catcatggac 4680 accctgcctg gcctggtgat ggcccaggac cagaggatca ggtggtacct gctgagcatg 4740 ggcagcaatg agaacatcca cagcatccac ttctctggcc atgtgttcac tgtgaggaag 4800 aaggaggagt acaagatggc cctgtacaac ctgtaccctg gggtgtttga gactgtggag 4860 atgctgccca gcaaggctgg catctggagg gtggagtgcc tgattgggga gcacctgcat 4920 gctggcatga gcaccctgtt cctggtgtac agcaacaagt gccagacccc cctgggcatg 4980 gcctctggcc acatcaggga cttccagatc actgcctctg gccagtatgg ccagtgggcc 5040 cccaagctgg ccaggctgca ctactctggc agcatcaatg cctggagcac caaggagccc 5100 ttcagctgga tcaaggtgga cctgctggcc cccatgatca tccatggcat caagacccag 5160 ggggccaggc agaagttcag cagcctgtac atcagccagt tcatcatcat gtacagcctg 5220 gatggcaaga agtggcagac ctacaggggc aacagcactg gcaccctgat ggtgttcttt 5280 ggcaatgtgg acagctctgg catcaagcac aacatcttca acccccccat cattgccaga 5340 tacatcaggc tgcaccccac ccactacagc atcaggagca ccctgaggat ggagctgatg 5400 ggctgtgacc tgaacagctg cagcatgccc ctgggcatgg agagcaaggc catctctgat 5460 gcccagatca ctgccagcag ctacttcacc aacatgtttg ccacctggag ccccagcaag 5520 gccaggctgc acctgcaggg caggagcaat gcctggaggc cccaggtcaa caaccccaag 5580 gagtggctgc aggtggactt ccagaagacc atgaaggtga ctggggtgac cacccagggg 5640 gtgaagagcc tgctgaccag catgtatgtg aaggagttcc tgatcagcag cagccaggat 5700 ggccaccagt ggaccctgtt cttccagaat ggcaaggtga aggtgttcca gggcaaccag 5760 gacagcttca cccctgtggt gaacagcctg gacccccccc tgctgaccag atacctgagg 5820 attcaccccc agagctgggt gcaccagatt gccctgagga tggaggtgct gggctgtgag 5880 gcccaggacc tgtactgacc tcgagctgtg ccttctagtt gccagccatc tgttgtttgc 5940 ccctcccccg tgccttcctt gaccctggaa ggtgccactc ccactgtcct ttcctaataa 6000 aatgaggaaa ttgcatcgca ttgtctgagt aggtgtcatt ctattctggg gggtggggtg 6060 gggcaggaca gcaaggggga ggattgggaa gacaatagca ggcatgctgg ggatgcggtg 6120 ggctctatgg accggtgcgg ccgcaggaac ccctagtgat ggagttggcc actccctctc 6180 tgcgcgctcg ctcgctcact gaggccgggc gaccaaaggt cgcccgacgc ccgggctttg 6240 cccgggcggc ctcagtgagc gagcgagcgc gcagagaggg agtggccaa 6289 <210> 19 <211> 5430 <212> DNA <213> Adeno-Associated Virus 2 <400> 19 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ttttcgacgt ggacttagcc 180 cctgtttgct cctccgataa ctggggtgac cttggttaat attcaccagc agcctccccg 240 tggacttagc ccctgtttgc tcctccgata actggggtga ccttggttaa tattcaccag 300 cagcctcccc acgcgaaacg tcgactggac acaggacgct gtggtttctg agccaggggg 360 cgactcagat cccagccagt ggacttagcc cctgtttgct cctccgataa ctggggtgac 420 cttggttaat attcaccagc agcctccccc gttgcccctc tggatccact gcttaaatac 480 ggacgaggac agggccctgt ctcctcagct tcaggcacca ccactgacct gggacagtga 540 atcgtaagta ctagcagcta caatccagct accattctgc ttttatttta tggttgggat 600 aaggctggat tattctgagt ccaagctagg cccttttgct aatcatgttc atacctctta 660 tcttcctccc acagctcctg ggcaacgtgc tggtctgtgt gctggcccat cactttggca 720 aagaattgcg atcgccacca tgcagattga gctgagcacc tgcttcttcc tgtgcctgct 780 gaggttctgc ttctctgcca ccaggagata ctacctgggg gctgtggagc tgagctggga 840 ctacatgcag tctgacctgg gggagctgcc tgtggatgcc aggttccccc ccagagtgcc 900 caagagcttc cccttcaaca cctctgtggt gtacaagaag accctgtttg tggagttcac 960 tgaccacctg ttcaacattg ccaagcccag gcccccctgg atgggcctgc tgggccccac 1020 catccaggct gaggtgtatg acactgtggt gatcaccctg aagaacatgg ccagccaccc 1080 tgtgagcctg catgctgtgg gggtgagcta ctggaaggcc tctgaggggg ctgagtatga 1140 tgaccagacc agccagaggg agaaggagga tgacaaggtg ttccctgggg gcagccacac 1200 ctatgtgtgg caggtgctga aggagaatgg ccccatggcc tctgaccccc tgtgcctgac 1260 ctacagctac ctgagccatg tggacctggt gaaggacctg aactctggcc tgattggggc 1320 cctgctggtg tgcagggagg gcagcctggc caaggagaag acccagaccc tgcacaagtt 1380 catcctgctg tttgctgtgt ttgatgaggg caagagctgg cactctgaaa ccaagaacag 1440 cctgatgcag gacagggatg ctgcctctgc cagggcctgg cccaagatgc acactgtgaa 1500 tggctatgtg aacaggagcc tgcctggcct gattggctgc cacaggaagt ctgtgtactg 1560 gcatgtgatt ggcatgggca ccacccctga ggtgcacagc atcttcctgg agggccacac 1620 cttcctggtc aggaaccaca ggcaggccag cctggagatc agccccatca ccttcctgac 1680 tgcccagacc ctgctgatgg acctgggcca gttcctgctg ttctgccaca tcagcagcca 1740 ccagcatgat ggcatggagg cctatgtgaa ggtggacagc tgccctgagg agccccagct 1800 gaggatgaag aacaatgagg aggctgagga ctatgatgat gacctgactg actctgagat 1860 ggatgtggtg aggtttgatg atgacaacag ccccagcttc atccagatca ggtctgtggc 1920 caagaagcac cccaagacct gggtgcacta cattgctgct gaggaggagg actgggacta 1980 tgcccccctg gtgctggccc ctgatgacag gagctacaag agccagtacc tgaacaatgg 2040 cccccagagg attggcagga agtacaagaa ggtcaggttc atggcctaca ctgatgaaac 2100 cttcaagacc agggaggcca tccagcatga gtctggcatc ctgggccccc tgctgtatgg 2160 ggaggtgggg gacaccctgc tgatcatctt caagaaccag gccagcaggc cctacaacat 2220 ctacccccat ggcatcactg atgtgaggcc cctgtacagc aggaggctgc ccaagggggt 2280 gaagcacctg aaggacttcc ccatcctgcc tggggagatc ttcaagtaca agtggactgt 2340 gactgtggag gatggcccca ccaagtctga ccccaggtgc ctgaccagat actacagcag 2400 ctttgtgaac atggagaggg acctggcctc tggcctgatt ggccccctgc tgatctgcta 2460 caaggagtct gtggaccaga ggggcaacca gatcatgtct gacaagagga atgtgatcct 2520 gttctctgtg tttgatgaga acaggagctg gtacctgact gagaacatcc agaggttcct 2580 gcccaaccct gctggggtgc agctggagga ccctgagttc caggccagca acatcatgca 2640 cagcatcaat ggctatgtgt ttgacagcct gcagctgtct gtgtgcctgc atgaggtggc 2700 ctactggtac atcctgagca ttggggccca gactgacttc ctgtctgtgt tcttctctgg 2760 ctacaccttc aagcacaaga tggtgtatga ggacaccctg accctgttcc ccttctctgg 2820 ggagactgtg ttcatgagca tggagaaccc tggcctgtgg attctgggct gccacaactc 2880 tgacttcagg aacaggggca tgactgccct gctgaaagtc tccagctgtg acaagaacac 2940 tggggactac tatgaggaca gctatgagga catctctgcc tacctgctga gcaagaacaa 3000 tgccattgag cccaggagct tcagccagaa ccccccagtg ctgaagaggc accagaggga 3060 gatcaccagg accaccctgc agtctgacca ggaggagatt gactatgatg acaccatctc 3120 tgtggagatg aagaaggagg actttgacat ctacgacgag gacgagaacc agagccccag 3180 gagcttccag aagaagacca ggcactactt cattgctgct gtggagaggc tgtgggacta 3240 tggcatgagc agcagccccc atgtgctgag gaacagggcc cagtctggct ctgtgcccca 3300 gttcaagaag gtggtgttcc aggagttcac tgatggcagc ttcacccagc ccctgtacag 3360 aggggagctg aatgagcacc tgggcctgct gggcccctac atcagggctg aggtggagga 3420 caacatcatg gtgaccttca ggaaccaggc cagcaggccc tacagcttct acagcagcct 3480 gatcagctat gaggaggacc agaggcaggg ggctgagccc aggaagaact ttgtgaagcc 3540 caatgaaacc aagacctact tctggaaggt gcagcaccac atggccccca ccaaggatga 3600 gtttgactgc aaggcctggg cctacttctc tgatgtggac ctggagaagg atgtgcactc 3660 tggcctgatt ggccccctgc tggtgtgcca caccaacacc ctgaaccctg cccatggcag 3720 gcaggtgact gtgcaggagt ttgccctgtt cttcaccatc tttgatgaaa ccaagagctg 3780 gtacttcact gagaacatgg agaggaactg cagggccccc tgcaacatcc agatggagga 3840 ccccaccttc aaggagaact acaggttcca tgccatcaat ggctacatca tggacaccct 3900 gcctggcctg gtgatggccc aggaccagag gatcaggtgg tacctgctga gcatgggcag 3960 caatgagaac atccacagca tccacttctc tggccatgtg ttcactgtga ggaagaagga 4020 ggagtacaag atggccctgt acaacctgta ccctggggtg tttgagactg tggagatgct 4080 gcccagcaag gctggcatct ggagggtgga gtgcctgatt ggggagcacc tgcatgctgg 4140 catgagcacc ctgttcctgg tgtacagcaa caagtgccag acccccctgg gcatggcctc 4200 tggccacatc agggacttcc agatcactgc ctctggccag tatggccagt gggcccccaa 4260 gctggccagg ctgcactact ctggcagcat caatgcctgg agcaccaagg agcccttcag 4320 ctggatcaag gtggacctgc tggcccccat gatcatccat ggcatcaaga cccagggggc 4380 caggcagaag ttcagcagcc tgtacatcag ccagttcatc atcatgtaca gcctggatgg 4440 caagaagtgg cagacctaca ggggcaacag cactggcacc ctgatggtgt tctttggcaa 4500 tgtggacagc tctggcatca agcacaacat cttcaacccc cccatcattg ccagatacat 4560 caggctgcac cccacccact acagcatcag gagcaccctg aggatggagc tgatgggctg 4620 tgacctgaac agctgcagca tgcccctggg catggagagc aaggccatct ctgatgccca 4680 gatcactgcc agcagctact tcaccaacat gtttgccacc tggagcccca gcaaggccag 4740 gctgcacctg cagggcagga gcaatgcctg gaggccccag gtcaacaacc ccaaggagtg 4800 gctgcaggtg gacttccaga agaccatgaa ggtgactggg gtgaccaccc agggggtgaa 4860 gagcctgctg accagcatgt atgtgaagga gttcctgatc agcagcagcc aggatggcca 4920 ccagtggacc ctgttcttcc agaatggcaa ggtgaaggtg ttccagggca accaggacag 4980 cttcacccct gtggtgaaca gcctggaccc ccccctgctg accagatacc tgaggattca 5040 cccccagagc tgggtgcacc agattgccct gaggatggag gtgctgggct gtgaggccca 5100 ggacctgtac tgacctcgag gcactgtcct ttcctaataa aatgaggaaa ttgcatcgca 5160 ttgtctgagt aggtgtcatt ctattctggg gggtggggtg gggcaggaca gcaaggggga 5220 ggattgggaa gacaatagca ggcatgctgg ggatgcggtg ggctctatgg gcacgtggcg 5280 gccgcaggaa cccctagtga tggagttggc cactccctct ctgcgcgctc gctcgctcac 5340 tgaggccggg cgaccaaagg tcgcccgacg cccgggcttt gcccgggcgg cctcagtgag 5400 cgagcgagcg cgcagagagg gagtggccaa 5430 <210> 20 <211> 5779 <212> DNA <213> Adeno-Associated Virus 2 <400> 20 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ttttcgacgt ggacttagcc 180 cctgtttgct cctccgataa ctggggtgac cttggttaat attcaccagc agcctccccg 240 tggacttagc ccctgtttgc tcctccgata actggggtga ccttggttaa tattcaccag 300 cagcctcccc acgcgaaacg tcgactggac acaggacgct gtggtttctg agccaggggg 360 cgactcagat cccagccagt ggacttagcc cctgtttgct cctccgataa ctggggtgac 420 cttggttaat attcaccagc agcctccccc gttgcccctc tggatccact gcttaaatac 480 ggacgaggac agggccctgt ctcctcagct tcaggcacca ccactgacct gggacagtga 540 atcgtaagta ctagcagcta caatccagct accattctgc ttttatttta tggttgggat 600 aaggctggat tattctgagt ccaagctagg cccttttgct aatcatgttc atacctctta 660 tcttcctccc acagctcctg ggcaacgtgc tggtctgtgt gctggcccat cactttggca 720 aagaattgcg atcgccacca tgcagattga gctgagcacc tgcttcttcc tgtgcctgct 780 gaggttctgc ttctctgcca ccaggagata ctacctgggg gctgtggagc tgagctggga 840 ctacatgcag tctgacctgg gggagctgcc tgtggatgcc aggttccccc ccagagtgcc 900 caagagcttc cccttcaaca cctctgtggt gtacaagaag accctgtttg tggagttcac 960 tgaccacctg ttcaacattg ccaagcccag gcccccctgg atgggcctgc tgggccccac 1020 catccaggct gaggtgtatg acactgtggt gatcaccctg aagaacatgg ccagccaccc 1080 tgtgagcctg catgctgtgg gggtgagcta ctggaaggcc tctgaggggg ctgagtatga 1140 tgaccagacc agccagaggg agaaggagga tgacaaggtg ttccctgggg gcagccacac 1200 ctatgtgtgg caggtgctga aggagaatgg ccccatggcc tctgaccccc tgtgcctgac 1260 ctacagctac ctgagccatg tggacctggt gaaggacctg aactctggcc tgattggggc 1320 cctgctggtg tgcagggagg gcagcctggc caaggagaag acccagaccc tgcacaagtt 1380 catcctgctg tttgctgtgt ttgatgaggg caagagctgg cactctgaaa ccaagaacag 1440 cctgatgcag gacagggatg ctgcctctgc cagggcctgg cccaagatgc acactgtgaa 1500 tggctatgtg aacaggagcc tgcctggcct gattggctgc cacaggaagt ctgtgtactg 1560 gcatgtgatt ggcatgggca ccacccctga ggtgcacagc atcttcctgg agggccacac 1620 cttcctggtc aggaaccaca ggcaggccag cctggagatc agccccatca ccttcctgac 1680 tgcccagacc ctgctgatgg acctgggcca gttcctgctg ttctgccaca tcagcagcca 1740 ccagcatgat ggcatggagg cctatgtgaa ggtggacagc tgccctgagg agccccagct 1800 gaggatgaag aacaatgagg aggctgagga ctatgatgat gacctgactg actctgagat 1860 ggatgtggtg aggtttgatg atgacaacag ccccagcttc atccagatca ggtctgtggc 1920 caagaagcac cccaagacct gggtgcacta cattgctgct gaggaggagg actgggacta 1980 tgcccccctg gtgctggccc ctgatgacag gagctacaag agccagtacc tgaacaatgg 2040 cccccagagg attggcagga agtacaagaa ggtcaggttc atggcctaca ctgatgaaac 2100 cttcaagacc agggaggcca tccagcatga gtctggcatc ctgggccccc tgctgtatgg 2160 ggaggtgggg gacaccctgc tgatcatctt caagaaccag gccagcaggc cctacaacat 2220 ctacccccat ggcatcactg atgtgaggcc cctgtacagc aggaggctgc ccaagggggt 2280 gaagcacctg aaggacttcc ccatcctgcc tggggagatc ttcaagtaca agtggactgt 2340 gactgtggag gatggcccca ccaagtctga ccccaggtgc ctgaccagat actacagcag 2400 ctttgtgaac atggagaggg acctggcctc tggcctgatt ggccccctgc tgatctgcta 2460 caaggagtct gtggaccaga ggggcaacca gatcatgtct gacaagagga atgtgatcct 2520 gttctctgtg tttgatgaga acaggagctg gtacctgact gagaacatcc agaggttcct 2580 gcccaaccct gctggggtgc agctggagga ccctgagttc caggccagca acatcatgca 2640 cagcatcaat ggctatgtgt ttgacagcct gcagctgtct gtgtgcctgc atgaggtggc 2700 ctactggtac atcctgagca ttggggccca gactgacttc ctgtctgtgt tcttctctgg 2760 ctacaccttc aagcacaaga tggtgtatga ggacaccctg accctgttcc ccttctctgg 2820 ggagactgtg ttcatgagca tggagaaccc tggcctgtgg attctgggct gccacaactc 2880 tgacttcagg aacaggggca tgactgccct gctgaaagtc tccagctgtg acaagaacac 2940 tggggactac tatgaggaca gctatgagga catctctgcc tacctgctga gcaagaacaa 3000 tgccattgag cccaggagct tcagccagaa ccccccagtg ctgaagaggc accagaggga 3060 gatcaccagg accaccctgc agtctgacca ggaggagatt gactatgatg acaccatctc 3120 tgtggagatg aagaaggagg actttgacat ctacgacgag gacgagaacc agagccccag 3180 gagcttccag aagaagacca ggcactactt cattgctgct gtggagaggc tgtgggacta 3240 tggcatgagc agcagccccc atgtgctgag gaacagggcc cagtctggct ctgtgcccca 3300 gttcaagaag gtggtgttcc aggagttcac tgatggcagc ttcacccagc ccctgtacag 3360 aggggagctg aatgagcacc tgggcctgct gggcccctac atcagggctg aggtggagga 3420 caacatcatg gtgaccttca ggaaccaggc cagcaggccc tacagcttct acagcagcct 3480 gatcagctat gaggaggacc agaggcaggg ggctgagccc aggaagaact ttgtgaagcc 3540 caatgaaacc aagacctact tctggaaggt gcagcaccac atggccccca ccaaggatga 3600 gtttgactgc aaggcctggg cctacttctc tgatgtggac ctggagaagg atgtgcactc 3660 tggcctgatt ggccccctgc tggtgtgcca caccaacacc ctgaaccctg cccatggcag 3720 gcaggtgact gtgcaggagt ttgccctgtt cttcaccatc tttgatgaaa ccaagagctg 3780 gtacttcact gagaacatgg agaggaactg cagggccccc tgcaacatcc agatggagga 3840 ccccaccttc aaggagaact acaggttcca tgccatcaat ggctacatca tggacaccct 3900 gcctggcctg gtgatggccc aggaccagag gatcaggtgg tacctgctga gcatgggcag 3960 caatgagaac atccacagca tccacttctc tggccatgtg ttcactgtga ggaagaagga 4020 ggagtacaag atggccctgt acaacctgta ccctggggtg tttgagactg tggagatgct 4080 gcccagcaag gctggcatct ggagggtgga gtgcctgatt ggggagcacc tgcatgctgg 4140 catgagcacc ctgttcctgg tgtacagcaa caagtgccag acccccctgg gcatggcctc 4200 tggccacatc agggacttcc agatcactgc ctctggccag tatggccagt gggcccccaa 4260 gctggccagg ctgcactact ctggcagcat caatgcctgg agcaccaagg agcccttcag 4320 ctggatcaag gtggacctgc tggcccccat gatcatccat ggcatcaaga cccagggggc 4380 caggcagaag ttcagcagcc tgtacatcag ccagttcatc atcatgtaca gcctggatgg 4440 caagaagtgg cagacctaca ggggcaacag cactggcacc ctgatggtgt tctttggcaa 4500 tgtggacagc tctggcatca agcacaacat cttcaacccc cccatcattg ccagatacat 4560 caggctgcac cccacccact acagcatcag gagcaccctg aggatggagc tgatgggctg 4620 tgacctgaac agctgcagca tgcccctggg catggagagc aaggccatct ctgatgccca 4680 gatcactgcc agcagctact tcaccaacat gtttgccacc tggagcccca gcaaggccag 4740 gctgcacctg cagggcagga gcaatgcctg gaggccccag gtcaacaacc ccaaggagtg 4800 gctgcaggtg gacttccaga agaccatgaa ggtgactggg gtgaccaccc agggggtgaa 4860 gagcctgctg accagcatgt atgtgaagga gttcctgatc agcagcagcc aggatggcca 4920 ccagtggacc ctgttcttcc agaatggcaa ggtgaaggtg ttccagggca accaggacag 4980 cttcacccct gtggtgaaca gcctggaccc ccccctgctg accagatacc tgaggattca 5040 cccccagagc tgggtgcacc agattgccct gaggatggag gtgctgggct gtgaggccca 5100 ggacctgtac tgacctcgag gcactgtcct ttcctaataa aatgaggaaa ttgcatcgca 5160 ttgtctgagt aggtgtcatt ctattctggg gggtggggtg gggcaggaca gcaaggggga 5220 ggattgggaa gacaatagca ggcatgctgg ggatgcggtg ggctctatgg gcactcgaca 5280 ggttaatttt taaaaagcag tcaaaagtcc aagtggccct tggcagcatt tactctctct 5340 gtttgctctg gttaataatc tcaggagcac aaacattcct ggaggcagga gaagaaatca 5400 acatcctgga cttatcctct gggcctctcc ccacccccag gagaggctca ggttaatttt 5460 taaaaagcag tcaaaagtcc aagtggccct tggcagcatt tactctctct gtttgctctg 5520 gttaataatc tcaggagcac aaacattcct ggaggcagga gaagaaatca acatcctgga 5580 cttatcctct gggcctctcc ccacccccag gagaggctgt cgagtggcgg ccgcaggaac 5640 ccctagtgat ggagttggcc actccctctc tgcgcgctcg ctcgctcact gaggccgggc 5700 gaccaaaggt cgcccgacgc ccgggctttg cccgggcggc ctcagtgagc gagcgagcgc 5760 gcagagaggg agtggccaa 5779 <210> 21 <211> 5962 <212> DNA <213> Adeno-Associated Virus 2 <400> 21 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ttttcgaccc ctctcacact 180 acctaaacca cgccaggaca acctctgctc ctctccaccg aaattccaag gggtcgagtg 240 gatgttggag gtggcatggg cccagagagg tctctgacct ctgccccagc tccaaggtca 300 gcaggcaggg agggctgtgt gtttgctgtt tgctgcttgc aatgtttgcc cattttaggg 360 acatgagtag gctgaagttt gttcagtgtg gacttcagag gcagcacaca aacagctgct 420 ggaggatggg aactgagggg ttggaagggg gcagggtgag cccagaaact cctgtgtgcc 480 tctgagcctg cagacgcgaa acgtcgactg gacacaggac gctgtggttt ctgagccagg 540 gggcgactca gatcccagcc agtggactta gcccctgttt gctcctccga taactggggt 600 gaccttggtt aatattcacc agcagcctcc cccgttgccc ctctggatcc actgcttaaa 660 tacggacgag gacagggccc tgtctcctca gcttcaggca ccaccactga cctgggacag 720 tgaatcgtaa gtactagcag ctacaatcca gctaccattc tgcttttatt ttatggttgg 780 gataaggctg gattattctg agtccaagct aggccctttt gctaatcatg ttcatacctc 840 ttatcttcct cccacagctc ctgggcaacg tgctggtctg tgtgctggcc catcactttg 900 gcaaagaatt gcgatcgcca ccatgcagat tgagctgagc acctgcttct tcctgtgcct 960 gctgaggttc tgcttctctg ccaccaggag atactacctg ggggctgtgg agctgagctg 1020 ggactacatg cagtctgacc tgggggagct gcctgtggat gccaggttcc cccccagagt 1080 gcccaagagc ttccccttca acacctctgt ggtgtacaag aagaccctgt ttgtggagtt 1140 cactgaccac ctgttcaaca ttgccaagcc caggcccccc tggatgggcc tgctgggccc 1200 caccatccag gctgaggtgt atgacactgt ggtgatcacc ctgaagaaca tggccagcca 1260 ccctgtgagc ctgcatgctg tgggggtgag ctactggaag gcctctgagg gggctgagta 1320 tgatgaccag accagccaga gggagaagga ggatgacaag gtgttccctg ggggcagcca 1380 cacctatgtg tggcaggtgc tgaaggagaa tggccccatg gcctctgacc ccctgtgcct 1440 gacctacagc tacctgagcc atgtggacct ggtgaaggac ctgaactctg gcctgattgg 1500 ggccctgctg gtgtgcaggg agggcagcct ggccaaggag aagacccaga ccctgcacaa 1560 gttcatcctg ctgtttgctg tgtttgatga gggcaagagc tggcactctg aaaccaagaa 1620 cagcctgatg caggacaggg atgctgcctc tgccagggcc tggcccaaga tgcacactgt 1680 gaatggctat gtgaacagga gcctgcctgg cctgattggc tgccacagga agtctgtgta 1740 ctggcatgtg attggcatgg gcaccacccc tgaggtgcac agcatcttcc tggagggcca 1800 caccttcctg gtcaggaacc acaggcaggc cagcctggag atcagcccca tcaccttcct 1860 gactgcccag accctgctga tggacctggg ccagttcctg ctgttctgcc acatcagcag 1920 ccaccagcat gatggcatgg aggcctatgt gaaggtggac agctgccctg aggagcccca 1980 gctgaggatg aagaacaatg aggaggctga ggactatgat gatgacctga ctgactctga 2040 gatggatgtg gtgaggtttg atgatgacaa cagccccagc ttcatccaga tcaggtctgt 2100 ggccaagaag caccccaaga cctgggtgca ctacattgct gctgaggagg aggactggga 2160 ctatgccccc ctggtgctgg cccctgatga caggagctac aagagccagt acctgaacaa 2220 tggcccccag aggattggca ggaagtacaa gaaggtcagg ttcatggcct acactgatga 2280 aaccttcaag accagggagg ccatccagca tgagtctggc atcctgggcc ccctgctgta 2340 tggggaggtg ggggacaccc tgctgatcat cttcaagaac caggccagca ggccctacaa 2400 catctacccc catggcatca ctgatgtgag gcccctgtac agcaggaggc tgcccaaggg 2460 ggtgaagcac ctgaaggact tccccatcct gcctggggag atcttcaagt acaagtggac 2520 tgtgactgtg gaggatggcc ccaccaagtc tgaccccagg tgcctgacca gatactacag 2580 cagctttgtg aacatggaga gggacctggc ctctggcctg attggccccc tgctgatctg 2640 ctacaaggag tctgtggacc agaggggcaa ccagatcatg tctgacaaga ggaatgtgat 2700 cctgttctct gtgtttgatg agaacaggag ctggtacctg actgagaaca tccagaggtt 2760 cctgcccaac cctgctgggg tgcagctgga ggaccctgag ttccaggcca gcaacatcat 2820 gcacagcatc aatggctatg tgtttgacag cctgcagctg tctgtgtgcc tgcatgaggt 2880 ggcctactgg tacatcctga gcattggggc ccagactgac ttcctgtctg tgttcttctc 2940 tggctacacc ttcaagcaca agatggtgta tgaggacacc ctgaccctgt tccccttctc 3000 tggggagact gtgttcatga gcatggagaa ccctggcctg tggattctgg gctgccacaa 3060 ctctgacttc aggaacaggg gcatgactgc cctgctgaaa gtctccagct gtgacaagaa 3120 cactggggac tactatgagg acagctatga ggacatctct gcctacctgc tgagcaagaa 3180 caatgccatt gagcccagga gcttcagcca gaacccccca gtgctgaaga ggcaccagag 3240 ggagatcacc aggaccaccc tgcagtctga ccaggaggag attgactatg atgacaccat 3300 ctctgtggag atgaagaagg aggactttga catctacgac gaggacgaga accagagccc 3360 caggagcttc cagaagaaga ccaggcacta cttcattgct gctgtggaga ggctgtggga 3420 ctatggcatg agcagcagcc cccatgtgct gaggaacagg gcccagtctg gctctgtgcc 3480 ccagttcaag aaggtggtgt tccaggagtt cactgatggc agcttcaccc agcccctgta 3540 cagaggggag ctgaatgagc acctgggcct gctgggcccc tacatcaggg ctgaggtgga 3600 ggacaacatc atggtgacct tcaggaacca ggccagcagg ccctacagct tctacagcag 3660 cctgatcagc tatgaggagg accagaggca gggggctgag cccaggaaga actttgtgaa 3720 gcccaatgaa accaagacct acttctggaa ggtgcagcac cacatggccc ccaccaagga 3780 tgagtttgac tgcaaggcct gggcctactt ctctgatgtg gacctggaga aggatgtgca 3840 ctctggcctg attggccccc tgctggtgtg ccacaccaac accctgaacc ctgcccatgg 3900 caggcaggtg actgtgcagg agtttgccct gttcttcacc atctttgatg aaaccaagag 3960 ctggtacttc actgagaaca tggagaggaa ctgcagggcc ccctgcaaca tccagatgga 4020 ggaccccacc ttcaaggaga actacaggtt ccatgccatc aatggctaca tcatggacac 4080 cctgcctggc ctggtgatgg cccaggacca gaggatcagg tggtacctgc tgagcatggg 4140 cagcaatgag aacatccaca gcatccactt ctctggccat gtgttcactg tgaggaagaa 4200 ggaggagtac aagatggccc tgtacaacct gtaccctggg gtgtttgaga ctgtggagat 4260 gctgcccagc aaggctggca tctggagggt ggagtgcctg attggggagc acctgcatgc 4320 tggcatgagc accctgttcc tggtgtacag caacaagtgc cagacccccc tgggcatggc 4380 ctctggccac atcagggact tccagatcac tgcctctggc cagtatggcc agtgggcccc 4440 caagctggcc aggctgcact actctggcag catcaatgcc tggagcacca aggagccctt 4500 cagctggatc aaggtggacc tgctggcccc catgatcatc catggcatca agacccaggg 4560 ggccaggcag aagttcagca gcctgtacat cagccagttc atcatcatgt acagcctgga 4620 tggcaagaag tggcagacct acaggggcaa cagcactggc accctgatgg tgttctttgg 4680 caatgtggac agctctggca tcaagcacaa catcttcaac ccccccatca ttgccagata 4740 catcaggctg caccccaccc actacagcat caggagcacc ctgaggatgg agctgatggg 4800 ctgtgacctg aacagctgca gcatgcccct gggcatggag agcaaggcca tctctgatgc 4860 ccagatcact gccagcagct acttcaccaa catgtttgcc acctggagcc ccagcaaggc 4920 caggctgcac ctgcagggca ggagcaatgc ctggaggccc caggtcaaca accccaagga 4980 gtggctgcag gtggacttcc agaagaccat gaaggtgact ggggtgacca cccagggggt 5040 gaagagcctg ctgaccagca tgtatgtgaa ggagttcctg atcagcagca gccaggatgg 5100 ccaccagtgg accctgttct tccagaatgg caaggtgaag gtgttccagg gcaaccagga 5160 cagcttcacc cctgtggtga acagcctgga cccccccctg ctgaccagat acctgaggat 5220 tcacccccag agctgggtgc accagattgc cctgaggatg gaggtgctgg gctgtgaggc 5280 ccaggacctg tactgacctc gaggcactgt cctttcctaa taaaatgagg aaattgcatc 5340 gcattgtctg agtaggtgtc attctattct ggggggtggg gtggggcagg acagcaaggg 5400 ggaggattgg gaagacaata gcaggcatgc tggggatgcg gtgggctcta tgggcactcg 5460 acaggttaat ttttaaaaag cagtcaaaag tccaagtggc ccttggcagc atttactctc 5520 tctgtttgct ctggttaata atctcaggag cacaaacatt cctggaggca ggagaagaaa 5580 tcaacatcct ggacttatcc tctgggcctc tccccacccc caggagaggc tcaggttaat 5640 ttttaaaaag cagtcaaaag tccaagtggc ccttggcagc atttactctc tctgtttgct 5700 ctggttaata atctcaggag cacaaacatt cctggaggca ggagaagaaa tcaacatcct 5760 ggacttatcc tctgggcctc tccccacccc caggagaggc tgtcgagtgg cggccgcagg 5820 aacccctagt gatggagttg gccactccct ctctgcgcgc tcgctcgctc actgaggccg 5880 ggcgaccaaa ggtcgcccga cgcccgggct ttgcccgggc ggcctcagtg agcgagcgag 5940 cgcgcagaga gggagtggcc aa 5962 <210> 22 <211> 5919 <212> DNA <213> Adeno-Associated Virus 2 <400> 22 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgta ggctcagagg cacacaggag 180 tttctgggct caccctgccc ccttccaacc cctcagttcc catcctccag cagctgtttg 240 tgtgctgcct ctgaagtcca cactgaacaa acttcagcct actcatgtcc ctaaaatggg 300 caaacattgc aagcagcaaa cagcaaacac acagccctcc ctgcctgctg accttggagc 360 tggggcagag gtcagagacc tctctgggcc catgccacct ccaacatcca ctcgacccct 420 tggaatttcg gtggagagga gcagaggttg tcctggcgtg gtttaggtag tgtgagaggg 480 gtcgacgatc ttgctaccag tggaacagcc actaaggatt ctgcagtgag agcagagggc 540 cagctaagtg gtactctccc agagactgtc tgactcacgc caccccctcc accttggaca 600 caggacgctg tggtttctga gccaggtaca atgactcctt tcggtaagtg cagtggaagc 660 tgtacactgc ccaggcaaag cgtccgggca gcgtaggcgg gcgactcaga tcccagccag 720 tggacttagc ccctgtttgc tcctccgata actggggtga ccttggttaa tattcaccag 780 cagcctcccc cgttgcccct ctggatccac tgcttaaata cggacgagga cagggccctg 840 tctcctcagc ttcaggcacc accactgacc tgggacagtg aatcgtaagt atgcctttca 900 ctgcgagagg ttctggagag gcttctgagc tccccatggc ccaggcaggc agcaggtctg 960 gggcaggagg ggggttgtgg agtgggtatc cgcctgctga ggtgcagggc agatcatcat 1020 gtgccttgac tcggggcctg gcccccccat ctctgtcttg caggacaatt gccgtcttct 1080 gtctcgtggg gcatcctcct gctggcaggc ctgtgctgcc tggtccctgt ctccctggct 1140 gaggaccggc caccatgcag attgagctga gcacctgctt cttcctgtgc ctgctgaggt 1200 tctgcttctc tgccaccagg agatactacc tgggggctgt ggagctgagc tgggactaca 1260 tgcagtctga cctgggggag ctgcctgtgg atgccaggtt cccccccaga gtgcccaaga 1320 gcttcccctt caacacctct gtggtgtaca agaagaccct gtttgtggag ttcactgacc 1380 acctgttcaa cattgccaag cccaggcccc cctggatggg cctgctgggc cccaccatcc 1440 aggctgaggt gtatgacact gtggtgatca ccctgaagaa catggccagc caccctgtga 1500 gcctgcatgc tgtgggggtg agctactgga aggcctctga gggggctgag tatgatgacc 1560 agaccagcca gagggagaag gaggatgaca aggtgttccc tgggggcagc cacacctatg 1620 tgtggcaggt gctgaaggag aatggcccca tggcctctga ccccctgtgc ctgacctaca 1680 gctacctgag ccatgtggac ctggtgaagg acctgaactc tggcctgatt ggggccctgc 1740 tggtgtgcag ggagggcagc ctggccaagg agaagaccca gaccctgcac aagttcatcc 1800 tgctgtttgc tgtgtttgat gagggcaaga gctggcactc tgaaaccaag aacagcctga 1860 tgcaggacag ggatgctgcc tctgccaggg cctggcccaa gatgcacact gtgaatggct 1920 atgtgaacag gagcctgcct ggcctgattg gctgccacag gaagtctgtg tactggcatg 1980 tgattggcat gggcaccacc cctgaggtgc acagcatctt cctggagggc cacaccttcc 2040 tggtcaggaa ccacaggcag gccagcctgg agatcagccc catcaccttc ctgactgccc 2100 agaccctgct gatggacctg ggccagttcc tgctgttctg ccacatcagc agccaccagc 2160 atgatggcat ggaggcctat gtgaaggtgg acagctgccc tgaggagccc cagctgagga 2220 tgaagaacaa tgaggaggct gaggactatg atgatgacct gactgactct gagatggatg 2280 tggtgaggtt tgatgatgac aacagcccca gcttcatcca gatcaggtct gtggccaaga 2340 agcaccccaa gacctgggtg cactacattg ctgctgagga ggaggactgg gactatgccc 2400 ccctggtgct ggcccctgat gacaggagct acaagagcca gtacctgaac aatggccccc 2460 agaggattgg caggaagtac aagaaggtca ggttcatggc ctacactgat gaaaccttca 2520 agaccaggga ggccatccag catgagtctg gcatcctggg ccccctgctg tatggggagg 2580 tgggggacac cctgctgatc atcttcaaga accaggccag caggccctac aacatctacc 2640 cccatggcat cactgatgtg aggcccctgt acagcaggag gctgcccaag ggggtgaagc 2700 acctgaagga cttccccatc ctgcctgggg agatcttcaa gtacaagtgg actgtgactg 2760 tggaggatgg ccccaccaag tctgacccca ggtgcctgac cagatactac agcagctttg 2820 tgaacatgga gagggacctg gcctctggcc tgattggccc cctgctgatc tgctacaagg 2880 agtctgtgga ccagaggggc aaccagatca tgtctgacaa gaggaatgtg atcctgttct 2940 ctgtgtttga tgagaacagg agctggtacc tgactgagaa catccagagg ttcctgccca 3000 accctgctgg ggtgcagctg gaggaccctg agttccaggc cagcaacatc atgcacagca 3060 tcaatggcta tgtgtttgac agcctgcagc tgtctgtgtg cctgcatgag gtggcctact 3120 ggtacatcct gagcattggg gcccagactg acttcctgtc tgtgttcttc tctggctaca 3180 ccttcaagca caagatggtg tatgaggaca ccctgaccct gttccccttc tctggggaga 3240 ctgtgttcat gagcatggag aaccctggcc tgtggattct gggctgccac aactctgact 3300 tcaggaacag gggcatgact gccctgctga aagtctccag ctgtgacaag aacactgggg 3360 actactatga ggacagctat gaggacatct ctgcctacct gctgagcaag aacaatgcca 3420 ttgagcccag gagcttcagc cagaaccccc cagtgctgaa gaggcaccag agggagatca 3480 ccaggaccac cctgcagtct gaccaggagg agattgacta tgatgacacc atctctgtgg 3540 agatgaagaa ggaggacttt gacatctacg acgaggacga gaaccagagc cccaggagct 3600 tccagaagaa gaccaggcac tacttcattg ctgctgtgga gaggctgtgg gactatggca 3660 tgagcagcag cccccatgtg ctgaggaaca gggcccagtc tggctctgtg ccccagttca 3720 agaaggtggt gttccaggag ttcactgatg gcagcttcac ccagcccctg tacagagggg 3780 agctgaatga gcacctgggc ctgctgggcc cctacatcag ggctgaggtg gaggacaaca 3840 tcatggtgac cttcaggaac caggccagca ggccctacag cttctacagc agcctgatca 3900 gctatgagga ggaccagagg cagggggctg agcccaggaa gaactttgtg aagcccaatg 3960 aaaccaagac ctacttctgg aaggtgcagc accacatggc ccccaccaag gatgagtttg 4020 actgcaaggc ctgggcctac ttctctgatg tggacctgga gaaggatgtg cactctggcc 4080 tgattggccc cctgctggtg tgccacacca acaccctgaa ccctgcccat ggcaggcagg 4140 tgactgtgca ggagtttgcc ctgttcttca ccatctttga tgaaaccaag agctggtact 4200 tcactgagaa catggagagg aactgcaggg ccccctgcaa catccagatg gaggacccca 4260 ccttcaagga gaactacagg ttccatgcca tcaatggcta catcatggac accctgcctg 4320 gcctggtgat ggcccaggac cagaggatca ggtggtacct gctgagcatg ggcagcaatg 4380 agaacatcca cagcatccac ttctctggcc atgtgttcac tgtgaggaag aaggaggagt 4440 acaagatggc cctgtacaac ctgtaccctg gggtgtttga gactgtggag atgctgccca 4500 gcaaggctgg catctggagg gtggagtgcc tgattgggga gcacctgcat gctggcatga 4560 gcaccctgtt cctggtgtac agcaacaagt gccagacccc cctgggcatg gcctctggcc 4620 acatcaggga cttccagatc actgcctctg gccagtatgg ccagtgggcc cccaagctgg 4680 ccaggctgca ctactctggc agcatcaatg cctggagcac caaggagccc ttcagctgga 4740 tcaaggtgga cctgctggcc cccatgatca tccatggcat caagacccag ggggccaggc 4800 agaagttcag cagcctgtac atcagccagt tcatcatcat gtacagcctg gatggcaaga 4860 agtggcagac ctacaggggc aacagcactg gcaccctgat ggtgttcttt ggcaatgtgg 4920 acagctctgg catcaagcac aacatcttca acccccccat cattgccaga tacatcaggc 4980 tgcaccccac ccactacagc atcaggagca ccctgaggat ggagctgatg ggctgtgacc 5040 tgaacagctg cagcatgccc ctgggcatgg agagcaaggc catctctgat gcccagatca 5100 ctgccagcag ctacttcacc aacatgtttg ccacctggag ccccagcaag gccaggctgc 5160 acctgcaggg caggagcaat gcctggaggc cccaggtcaa caaccccaag gagtggctgc 5220 aggtggactt ccagaagacc atgaaggtga ctggggtgac cacccagggg gtgaagagcc 5280 tgctgaccag catgtatgtg aaggagttcc tgatcagcag cagccaggat ggccaccagt 5340 ggaccctgtt cttccagaat ggcaaggtga aggtgttcca gggcaaccag gacagcttca 5400 cccctgtggt gaacagcctg gacccccccc tgctgaccag atacctgagg attcaccccc 5460 agagctgggt gcaccagatt gccctgagga tggaggtgct gggctgtgag gcccaggacc 5520 tgtactgagc tcgagctgtg ccttctagtt gccagccatc tgttgtttgc ccctcccccg 5580 tgccttcctt gaccctggaa ggtgccactc ccactgtcct ttcctaataa aatgaggaaa 5640 ttgcatcgca ttgtctgagt aggtgtcatt ctattctggg gggtggggtg gggcaggaca 5700 gcaaggggga ggattgggaa gacaatagca ggcatgctgg ggatgcggtg ggctctatgg 5760 accggtgcgg ccgcaggaac ccctagtgat ggagttggcc actccctctc tgcgcgctcg 5820 ctcgctcact gaggccgggc gaccaaaggt cgcccgacgc ccgggctttg cccgggcggc 5880 ctcagtgagc gagcgagcgc gcagagaggg agtggccaa 5919 <210> 23 <211> 5306 <212> DNA <213> Adeno-Associated Virus 2 <400> 23 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ttttaaacgt cgaccctaaa 180 atgggcaaac attgcaagca gcaaacagca aactgacctt ggagctgggg cagaggtcag 240 agacctctct gggcactcga ccccttggaa tttcggtgga gaggagcaga ggtacacagc 300 cctccctgcc tgccccatgc cacctccaac atctgtcctg gcgtggttta ggtagtgtga 360 gaggggaatg actcctttcg gtaagtgcag tggaagctgt acactgccca ggcaaagcgt 420 ccgggcagcg taggcgggcg actcagatcc cagccagtgg acttagcccc tgtttgctcc 480 tccgataact ggggtgacct tggttaatat tcaccagcag cctcccccgt tgcccctctg 540 gatccactgc ttaaatacgg acgaggacag ggccctgtct cctcagcttc aggcaccacc 600 actgacctgg gacagtgaat cgcgatcgca ctgcttaaat acggacgagg acagggccct 660 gtctcctcag cttcaggcac caccactgac ctgggacagt gaatcgcgat cgccaccatg 720 cagattgagc tgagcacctg cttcttcctg tgcctgctga ggttctgctt ctctgccacc 780 aggagatact acctgggggc tgtggagctg agctgggact acatgcagtc tgacctgggg 840 gagctgcctg tggatgccag gttccccccc agagtgccca agagcttccc cttcaacacc 900 tctgtggtgt acaagaagac cctgtttgtg gagttcactg accacctgtt caacattgcc 960 aagcccaggc ccccctggat gggcctgctg ggccccacca tccaggctga ggtgtatgac 1020 actgtggtga tcaccctgaa gaacatggcc agccaccctg tgagcctgca tgctgtgggg 1080 gtgagctact ggaaggcctc tgagggggct gagtatgatg accagaccag ccagagggag 1140 aaggaggatg acaaggtgtt ccctgggggc agccacacct atgtgtggca ggtgctgaag 1200 gagaatggcc ccatggcctc tgaccccctg tgcctgacct acagctacct gagccatgtg 1260 gacctggtga aggacctgaa ctctggcctg attggggccc tgctggtgtg cagggagggc 1320 agcctggcca aggagaagac ccagaccctg cacaagttca tcctgctgtt tgctgtgttt 1380 gatgagggca agagctggca ctctgaaacc aagaacagcc tgatgcagga cagggatgct 1440 gcctctgcca gggcctggcc caagatgcac actgtgaatg gctatgtgaa caggagcctg 1500 cctggcctga ttggctgcca caggaagtct gtgtactggc atgtgattgg catgggcacc 1560 acccctgagg tgcacagcat cttcctggag ggccacacct tcctggtcag gaaccacagg 1620 caggccagcc tggagatcag ccccatcacc ttcctgactg cccagaccct gctgatggac 1680 ctgggccagt tcctgctgtt ctgccacatc agcagccacc agcatgatgg catggaggcc 1740 tatgtgaagg tggacagctg ccctgaggag ccccagctga ggatgaagaa caatgaggag 1800 gctgaggact atgatgatga cctgactgac tctgagatgg atgtggtgag gtttgatgat 1860 gacaacagcc ccagcttcat ccagatcagg tctgtggcca agaagcaccc caagacctgg 1920 gtgcactaca ttgctgctga ggaggaggac tgggactatg cccccctggt gctggcccct 1980 gatgacagga gctacaagag ccagtacctg aacaatggcc cccagaggat tggcaggaag 2040 tacaagaagg tcaggttcat ggcctacact gatgaaacct tcaagaccag ggaggccatc 2100 cagcatgagt ctggcatcct gggccccctg ctgtatgggg aggtggggga caccctgctg 2160 atcatcttca agaaccaggc cagcaggccc tacaacatct acccccatgg catcactgat 2220 gtgaggcccc tgtacagcag gaggctgccc aagggggtga agcacctgaa ggacttcccc 2280 atcctgcctg gggagatctt caagtacaag tggactgtga ctgtggagga tggccccacc 2340 aagtctgacc ccaggtgcct gaccagatac tacagcagct ttgtgaacat ggagagggac 2400 ctggcctctg gcctgattgg ccccctgctg atctgctaca aggagtctgt ggaccagagg 2460 ggcaaccaga tcatgtctga caagaggaat gtgatcctgt tctctgtgtt tgatgagaac 2520 aggagctggt acctgactga gaacatccag aggttcctgc ccaaccctgc tggggtgcag 2580 ctggaggacc ctgagttcca ggccagcaac atcatgcaca gcatcaatgg ctatgtgttt 2640 gacagcctgc agctgtctgt gtgcctgcat gaggtggcct actggtacat cctgagcatt 2700 ggggcccaga ctgacttcct gtctgtgttc ttctctggct acaccttcaa gcacaagatg 2760 gtgtatgagg acaccctgac cctgttcccc ttctctgggg agactgtgtt catgagcatg 2820 gagaaccctg gcctgtggat tctgggctgc cacaactctg acttcaggaa caggggcatg 2880 actgccctgc tgaaagtctc cagctgtgac aagaacactg gggactacta tgaggacagc 2940 tatgaggaca tctctgccta cctgctgagc aagaacaatg ccattgagcc caggagcttc 3000 agccagaacc ccccagtgct gaagaggcac cagagggaga tcaccaggac caccctgcag 3060 tctgaccagg aggagattga ctatgatgac accatctctg tggagatgaa gaaggaggac 3120 tttgacatct acgacgagga cgagaaccag agccccagga gcttccagaa gaagaccagg 3180 cactacttca ttgctgctgt ggagaggctg tgggactatg gcatgagcag cagcccccat 3240 gtgctgagga acagggccca gtctggctct gtgccccagt tcaagaaggt ggtgttccag 3300 gagttcactg atggcagctt cacccagccc ctgtacagag gggagctgaa tgagcacctg 3360 ggcctgctgg gcccctacat cagggctgag gtggaggaca acatcatggt gaccttcagg 3420 aaccaggcca gcaggcccta cagcttctac agcagcctga tcagctatga ggaggaccag 3480 aggcaggggg ctgagcccag gaagaacttt gtgaagccca atgaaaccaa gacctacttc 3540 tggaaggtgc agcaccacat ggcccccacc aaggatgagt ttgactgcaa ggcctgggcc 3600 tacttctctg atgtggacct ggagaaggat gtgcactctg gcctgattgg ccccctgctg 3660 gtgtgccaca ccaacaccct gaaccctgcc catggcaggc aggtgactgt gcaggagttt 3720 gccctgttct tcaccatctt tgatgaaacc aagagctggt acttcactga gaacatggag 3780 aggaactgca gggccccctg caacatccag atggaggacc ccaccttcaa ggagaactac 3840 aggttccatg ccatcaatgg ctacatcatg gacaccctgc ctggcctggt gatggcccag 3900 gaccagagga tcaggtggta cctgctgagc atgggcagca atgagaacat ccacagcatc 3960 cacttctctg gccatgtgtt cactgtgagg aagaaggagg agtacaagat ggccctgtac 4020 aacctgtacc ctggggtgtt tgagactgtg gagatgctgc ccagcaaggc tggcatctgg 4080 agggtggagt gcctgattgg ggagcacctg catgctggca tgagcaccct gttcctggtg 4140 tacagcaaca agtgccagac ccccctgggc atggcctctg gccacatcag ggacttccag 4200 atcactgcct ctggccagta tggccagtgg gcccccaagc tggccaggct gcactactct 4260 ggcagcatca atgcctggag caccaaggag cccttcagct ggatcaaggt ggacctgctg 4320 gcccccatga tcatccatgg catcaagacc cagggggcca ggcagaagtt cagcagcctg 4380 tacatcagcc agttcatcat catgtacagc ctggatggca agaagtggca gacctacagg 4440 ggcaacagca ctggcaccct gatggtgttc tttggcaatg tggacagctc tggcatcaag 4500 cacaacatct tcaacccccc catcattgcc agatacatca ggctgcaccc cacccactac 4560 agcatcagga gcaccctgag gatggagctg atgggctgtg acctgaacag ctgcagcatg 4620 cccctgggca tggagagcaa ggccatctct gatgcccaga tcactgccag cagctacttc 4680 accaacatgt ttgccacctg gagccccagc aaggccaggc tgcacctgca gggcaggagc 4740 aatgcctgga ggccccaggt caacaacccc aaggagtggc tgcaggtgga cttccagaag 4800 accatgaagg tgactggggt gaccacccag ggggtgaaga gcctgctgac cagcatgtat 4860 gtgaaggagt tcctgatcag cagcagccag gatggccacc agtggaccct gttcttccag 4920 aatggcaagg tgaaggtgtt ccagggcaac caggacagct tcacccctgt ggtgaacagc 4980 ctggaccccc ccctgctgac cagatacctg aggattcacc cccagagctg ggtgcaccag 5040 attgccctga ggatggaggt gctgggctgt gaggcccagg acctgtactg acctcgagga 5100 ataaaggaaa tttattttca ttgcaatagt gtgttggttt tttgtgtcac gtggcggccg 5160 caggaacccc tagtgatgga gttggccact ccctctctgc gcgctcgctc gctcactgag 5220 gccgggcgac caaaggtcgc ccgacgcccg ggctttgccc gggcggcctc agtgagcgag 5280 cgagcgcgca gagagggagt ggccaa 5306 <210> 24 <211> 5461 <212> DNA <213> Adeno-Associated Virus 2 <400> 24 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ttttcgactt tatttgccac 180 aaaaacccta tcagatgggc gtctttatca tttccattgt acagatgggg aaacaggctt 240 cggggtcggg gcatagccac ttactgacga ctccccaccc agcaagtggt tttgaacccg 300 gaccctctca cactacctaa accacgccag gacaacctct gctcctctcc accgaaattc 360 caaggggtcg agtggatgtt ggaggtggca tgggcccaga gaggtctctg acctctgccc 420 cagctccaag gtcagcaggc agggagggct gtgtgtttgc tgtttgctgc ttgcaatgtt 480 tgcccatttt agggacatga gtaggctgaa gtttgttcag tgtggacttc agaggcagca 540 cacaaacagc tgctggagga tgggaactga ggggttggaa gggggcaggg tgagcccaga 600 aactcctgtg tgcctctgag cctgcagacg cgaaacgtcg actggacaca ggacgctgtg 660 gtttctgagc cagggggcga ctcagatccc agccagtgga cttagcccct gtttgctcct 720 ccgataactg gggtgacctt ggttaatatt caccagcagc ctcccccgtt gcccctctgg 780 atccactgct taaatacgga cgaggacagg gccctgtctc ctcagcttca ggcaccacca 840 ctgacctggg acagtgaatc gcgatcgcca ccatgcagat tgagctgagc acctgcttct 900 tcctgtgcct gctgaggttc tgcttctctg ccaccaggag atactacctg ggggctgtgg 960 agctgagctg ggactacatg cagtctgacc tgggggagct gcctgtggat gccaggttcc 1020 cccccagagt gcccaagagc ttccccttca acacctctgt ggtgtacaag aagaccctgt 1080 ttgtggagtt cactgaccac ctgttcaaca ttgccaagcc caggcccccc tggatgggcc 1140 tgctgggccc caccatccag gctgaggtgt atgacactgt ggtgatcacc ctgaagaaca 1200 tggccagcca ccctgtgagc ctgcatgctg tgggggtgag ctactggaag gcctctgagg 1260 gggctgagta tgatgaccag accagccaga gggagaagga ggatgacaag gtgttccctg 1320 ggggcagcca cacctatgtg tggcaggtgc tgaaggagaa tggccccatg gcctctgacc 1380 ccctgtgcct gacctacagc tacctgagcc atgtggacct ggtgaaggac ctgaactctg 1440 gcctgattgg ggccctgctg gtgtgcaggg agggcagcct ggccaaggag aagacccaga 1500 ccctgcacaa gttcatcctg ctgtttgctg tgtttgatga gggcaagagc tggcactctg 1560 aaaccaagaa cagcctgatg caggacaggg atgctgcctc tgccagggcc tggcccaaga 1620 tgcacactgt gaatggctat gtgaacagga gcctgcctgg cctgattggc tgccacagga 1680 agtctgtgta ctggcatgtg attggcatgg gcaccacccc tgaggtgcac agcatcttcc 1740 tggagggcca caccttcctg gtcaggaacc acaggcaggc cagcctggag atcagcccca 1800 tcaccttcct gactgcccag accctgctga tggacctggg ccagttcctg ctgttctgcc 1860 acatcagcag ccaccagcat gatggcatgg aggcctatgt gaaggtggac agctgccctg 1920 aggagcccca gctgaggatg aagaacaatg aggaggctga ggactatgat gatgacctga 1980 ctgactctga gatggatgtg gtgaggtttg atgatgacaa cagccccagc ttcatccaga 2040 tcaggtctgt ggccaagaag caccccaaga cctgggtgca ctacattgct gctgaggagg 2100 aggactggga ctatgccccc ctggtgctgg cccctgatga caggagctac aagagccagt 2160 acctgaacaa tggcccccag aggattggca ggaagtacaa gaaggtcagg ttcatggcct 2220 acactgatga aaccttcaag accagggagg ccatccagca tgagtctggc atcctgggcc 2280 ccctgctgta tggggaggtg ggggacaccc tgctgatcat cttcaagaac caggccagca 2340 ggccctacaa catctacccc catggcatca ctgatgtgag gcccctgtac agcaggaggc 2400 tgcccaaggg ggtgaagcac ctgaaggact tccccatcct gcctggggag atcttcaagt 2460 acaagtggac tgtgactgtg gaggatggcc ccaccaagtc tgaccccagg tgcctgacca 2520 gatactacag cagctttgtg aacatggaga gggacctggc ctctggcctg attggccccc 2580 tgctgatctg ctacaaggag tctgtggacc agaggggcaa ccagatcatg tctgacaaga 2640 ggaatgtgat cctgttctct gtgtttgatg agaacaggag ctggtacctg actgagaaca 2700 tccagaggtt cctgcccaac cctgctgggg tgcagctgga ggaccctgag ttccaggcca 2760 gcaacatcat gcacagcatc aatggctatg tgtttgacag cctgcagctg tctgtgtgcc 2820 tgcatgaggt ggcctactgg tacatcctga gcattggggc ccagactgac ttcctgtctg 2880 tgttcttctc tggctacacc ttcaagcaca agatggtgta tgaggacacc ctgaccctgt 2940 tccccttctc tggggagact gtgttcatga gcatggagaa ccctggcctg tggattctgg 3000 gctgccacaa ctctgacttc aggaacaggg gcatgactgc cctgctgaaa gtctccagct 3060 gtgacaagaa cactggggac tactatgagg acagctatga ggacatctct gcctacctgc 3120 tgagcaagaa caatgccatt gagcccagga gcttcagcca gaacccccca gtgctgaaga 3180 ggcaccagag ggagatcacc aggaccaccc tgcagtctga ccaggaggag attgactatg 3240 atgacaccat ctctgtggag atgaagaagg aggactttga catctacgac gaggacgaga 3300 accagagccc caggagcttc cagaagaaga ccaggcacta cttcattgct gctgtggaga 3360 ggctgtggga ctatggcatg agcagcagcc cccatgtgct gaggaacagg gcccagtctg 3420 gctctgtgcc ccagttcaag aaggtggtgt tccaggagtt cactgatggc agcttcaccc 3480 agcccctgta cagaggggag ctgaatgagc acctgggcct gctgggcccc tacatcaggg 3540 ctgaggtgga ggacaacatc atggtgacct tcaggaacca ggccagcagg ccctacagct 3600 tctacagcag cctgatcagc tatgaggagg accagaggca gggggctgag cccaggaaga 3660 actttgtgaa gcccaatgaa accaagacct acttctggaa ggtgcagcac cacatggccc 3720 ccaccaagga tgagtttgac tgcaaggcct gggcctactt ctctgatgtg gacctggaga 3780 aggatgtgca ctctggcctg attggccccc tgctggtgtg ccacaccaac accctgaacc 3840 ctgcccatgg caggcaggtg actgtgcagg agtttgccct gttcttcacc atctttgatg 3900 aaaccaagag ctggtacttc actgagaaca tggagaggaa ctgcagggcc ccctgcaaca 3960 tccagatgga ggaccccacc ttcaaggaga actacaggtt ccatgccatc aatggctaca 4020 tcatggacac cctgcctggc ctggtgatgg cccaggacca gaggatcagg tggtacctgc 4080 tgagcatggg cagcaatgag aacatccaca gcatccactt ctctggccat gtgttcactg 4140 tgaggaagaa ggaggagtac aagatggccc tgtacaacct gtaccctggg gtgtttgaga 4200 ctgtggagat gctgcccagc aaggctggca tctggagggt ggagtgcctg attggggagc 4260 acctgcatgc tggcatgagc accctgttcc tggtgtacag caacaagtgc cagacccccc 4320 tgggcatggc ctctggccac atcagggact tccagatcac tgcctctggc cagtatggcc 4380 agtgggcccc caagctggcc aggctgcact actctggcag catcaatgcc tggagcacca 4440 aggagccctt cagctggatc aaggtggacc tgctggcccc catgatcatc catggcatca 4500 agacccaggg ggccaggcag aagttcagca gcctgtacat cagccagttc atcatcatgt 4560 acagcctgga tggcaagaag tggcagacct acaggggcaa cagcactggc accctgatgg 4620 tgttctttgg caatgtggac agctctggca tcaagcacaa catcttcaac ccccccatca 4680 ttgccagata catcaggctg caccccaccc actacagcat caggagcacc ctgaggatgg 4740 agctgatggg ctgtgacctg aacagctgca gcatgcccct gggcatggag agcaaggcca 4800 tctctgatgc ccagatcact gccagcagct acttcaccaa catgtttgcc acctggagcc 4860 ccagcaaggc caggctgcac ctgcagggca ggagcaatgc ctggaggccc caggtcaaca 4920 accccaagga gtggctgcag gtggacttcc agaagaccat gaaggtgact ggggtgacca 4980 cccagggggt gaagagcctg ctgaccagca tgtatgtgaa ggagttcctg atcagcagca 5040 gccaggatgg ccaccagtgg accctgttct tccagaatgg caaggtgaag gtgttccagg 5100 gcaaccagga cagcttcacc cctgtggtga acagcctgga cccccccctg ctgaccagat 5160 acctgaggat tcacccccag agctgggtgc accagattgc cctgaggatg gaggtgctgg 5220 gctgtgaggc ccaggacctg tactgacctc gaggaataaa ggaaatttat tttcattgca 5280 atagtgtgtt ggttttttgt gtcacgtggc ggccgcagga acccctagtg atggagttgg 5340 ccactccctc tctgcgcgct cgctcgctca ctgaggccgg gcgaccaaag gtcgcccgac 5400 gcccgggctt tgcccgggcg gcctcagtga gcgagcgagc gcgcagagag ggagtggcca 5460 a 5461 <210> 25 <211> 5327 <212> DNA <213> Adeno-Associated Virus 2 <400> 25 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ttttcgaccc ctctcacact 180 acctaaacca cgccaggaca acctctgctc ctctccaccg aaattccaag gggtcgagtg 240 gatgttggag gtggcatggg cccagagagg tctctgacct ctgccccagc tccaaggtca 300 gcaggcaggg agggctgtgt gtttgctgtt tgctgcttgc aatgtttgcc cattttaggg 360 acatgagtag gctgaagttt gttcagtgtg gacttcagag gcagcacaca aacagctgct 420 ggaggatggg aactgagggg ttggaagggg gcagggtgag cccagaaact cctgtgtgcc 480 tctgagcctg cagacgcgaa acgtcgactg gacacaggac gctgtggttt ctgagccagg 540 gggcgactca gatcccagcc agtggactta gcccctgttt gctcctccga taactggggt 600 gaccttggtt aatattcacc agcagcctcc cccgttgccc ctctggatcc actgcttaaa 660 tacggacgag gacagggccc tgtctcctca gcttcaggca ccaccactga cctgggacag 720 tgaatcgcga tcgccaccat gcagattgag ctgagcacct gcttcttcct gtgcctgctg 780 aggttctgct tctctgccac caggagatac tacctggggg ctgtggagct gagctgggac 840 tacatgcagt ctgacctggg ggagctgcct gtggatgcca ggttcccccc cagagtgccc 900 aagagcttcc ccttcaacac ctctgtggtg tacaagaaga ccctgtttgt ggagttcact 960 gaccacctgt tcaacattgc caagcccagg cccccctgga tgggcctgct gggccccacc 1020 atccaggctg aggtgtatga cactgtggtg atcaccctga agaacatggc cagccaccct 1080 gtgagcctgc atgctgtggg ggtgagctac tggaaggcct ctgagggggc tgagtatgat 1140 gaccagacca gccagaggga gaaggaggat gacaaggtgt tccctggggg cagccacacc 1200 tatgtgtggc aggtgctgaa ggagaatggc cccatggcct ctgaccccct gtgcctgacc 1260 tacagctacc tgagccatgt ggacctggtg aaggacctga actctggcct gattggggcc 1320 ctgctggtgt gcagggaggg cagcctggcc aaggagaaga cccagaccct gcacaagttc 1380 atcctgctgt ttgctgtgtt tgatgagggc aagagctggc actctgaaac caagaacagc 1440 ctgatgcagg acagggatgc tgcctctgcc agggcctggc ccaagatgca cactgtgaat 1500 ggctatgtga acaggagcct gcctggcctg attggctgcc acaggaagtc tgtgtactgg 1560 catgtgattg gcatgggcac cacccctgag gtgcacagca tcttcctgga gggccacacc 1620 ttcctggtca ggaaccacag gcaggccagc ctggagatca gccccatcac cttcctgact 1680 gcccagaccc tgctgatgga cctgggccag ttcctgctgt tctgccacat cagcagccac 1740 cagcatgatg gcatggaggc ctatgtgaag gtggacagct gccctgagga gccccagctg 1800 aggatgaaga acaatgagga ggctgaggac tatgatgatg acctgactga ctctgagatg 1860 gatgtggtga ggtttgatga tgacaacagc cccagcttca tccagatcag gtctgtggcc 1920 aagaagcacc ccaagacctg ggtgcactac attgctgctg aggaggagga ctgggactat 1980 gcccccctgg tgctggcccc tgatgacagg agctacaaga gccagtacct gaacaatggc 2040 ccccagagga ttggcaggaa gtacaagaag gtcaggttca tggcctacac tgatgaaacc 2100 ttcaagacca gggaggccat ccagcatgag tctggcatcc tgggccccct gctgtatggg 2160 gaggtggggg acaccctgct gatcatcttc aagaaccagg ccagcaggcc ctacaacatc 2220 tacccccatg gcatcactga tgtgaggccc ctgtacagca ggaggctgcc caagggggtg 2280 aagcacctga aggacttccc catcctgcct ggggagatct tcaagtacaa gtggactgtg 2340 actgtggagg atggccccac caagtctgac cccaggtgcc tgaccagata ctacagcagc 2400 tttgtgaaca tggagaggga cctggcctct ggcctgattg gccccctgct gatctgctac 2460 aaggagtctg tggaccagag gggcaaccag atcatgtctg acaagaggaa tgtgatcctg 2520 ttctctgtgt ttgatgagaa caggagctgg tacctgactg agaacatcca gaggttcctg 2580 cccaaccctg ctggggtgca gctggaggac cctgagttcc aggccagcaa catcatgcac 2640 agcatcaatg gctatgtgtt tgacagcctg cagctgtctg tgtgcctgca tgaggtggcc 2700 tactggtaca tcctgagcat tggggcccag actgacttcc tgtctgtgtt cttctctggc 2760 tacaccttca agcacaagat ggtgtatgag gacaccctga ccctgttccc cttctctggg 2820 gagactgtgt tcatgagcat ggagaaccct ggcctgtgga ttctgggctg ccacaactct 2880 gacttcagga acaggggcat gactgccctg ctgaaagtct ccagctgtga caagaacact 2940 ggggactact atgaggacag ctatgaggac atctctgcct acctgctgag caagaacaat 3000 gccattgagc ccaggagctt cagccagaac cccccagtgc tgaagaggca ccagagggag 3060 atcaccagga ccaccctgca gtctgaccag gaggagattg actatgatga caccatctct 3120 gtggagatga agaaggagga ctttgacatc tacgacgagg acgagaacca gagccccagg 3180 agcttccaga agaagaccag gcactacttc attgctgctg tggagaggct gtgggactat 3240 ggcatgagca gcagccccca tgtgctgagg aacagggccc agtctggctc tgtgccccag 3300 ttcaagaagg tggtgttcca ggagttcact gatggcagct tcacccagcc cctgtacaga 3360 ggggagctga atgagcacct gggcctgctg ggcccctaca tcagggctga ggtggaggac 3420 aacatcatgg tgaccttcag gaaccaggcc agcaggccct acagcttcta cagcagcctg 3480 atcagctatg aggaggacca gaggcagggg gctgagccca ggaagaactt tgtgaagccc 3540 aatgaaacca agacctactt ctggaaggtg cagcaccaca tggcccccac caaggatgag 3600 tttgactgca aggcctgggc ctacttctct gatgtggacc tggagaagga tgtgcactct 3660 ggcctgattg gccccctgct ggtgtgccac accaacaccc tgaaccctgc ccatggcagg 3720 caggtgactg tgcaggagtt tgccctgttc ttcaccatct ttgatgaaac caagagctgg 3780 tacttcactg agaacatgga gaggaactgc agggccccct gcaacatcca gatggaggac 3840 cccaccttca aggagaacta caggttccat gccatcaatg gctacatcat ggacaccctg 3900 cctggcctgg tgatggccca ggaccagagg atcaggtggt acctgctgag catgggcagc 3960 aatgagaaca tccacagcat ccacttctct ggccatgtgt tcactgtgag gaagaaggag 4020 gagtacaaga tggccctgta caacctgtac cctggggtgt ttgagactgt ggagatgctg 4080 cccagcaagg ctggcatctg gagggtggag tgcctgattg gggagcacct gcatgctggc 4140 atgagcaccc tgttcctggt gtacagcaac aagtgccaga cccccctggg catggcctct 4200 ggccacatca gggacttcca gatcactgcc tctggccagt atggccagtg ggcccccaag 4260 ctggccaggc tgcactactc tggcagcatc aatgcctgga gcaccaagga gcccttcagc 4320 tggatcaagg tggacctgct ggcccccatg atcatccatg gcatcaagac ccagggggcc 4380 aggcagaagt tcagcagcct gtacatcagc cagttcatca tcatgtacag cctggatggc 4440 aagaagtggc agacctacag gggcaacagc actggcaccc tgatggtgtt ctttggcaat 4500 gtggacagct ctggcatcaa gcacaacatc ttcaaccccc ccatcattgc cagatacatc 4560 aggctgcacc ccacccacta cagcatcagg agcaccctga ggatggagct gatgggctgt 4620 gacctgaaca gctgcagcat gcccctgggc atggagagca aggccatctc tgatgcccag 4680 atcactgcca gcagctactt caccaacatg tttgccacct ggagccccag caaggccagg 4740 ctgcacctgc agggcaggag caatgcctgg aggccccagg tcaacaaccc caaggagtgg 4800 ctgcaggtgg acttccagaa gaccatgaag gtgactgggg tgaccaccca gggggtgaag 4860 agcctgctga ccagcatgta tgtgaaggag ttcctgatca gcagcagcca ggatggccac 4920 cagtggaccc tgttcttcca gaatggcaag gtgaaggtgt tccagggcaa ccaggacagc 4980 ttcacccctg tggtgaacag cctggacccc cccctgctga ccagatacct gaggattcac 5040 ccccagagct gggtgcacca gattgccctg aggatggagg tgctgggctg tgaggcccag 5100 gacctgtact gacctcgagg aataaaggaa atttattttc attgcaatag tgtgttggtt 5160 ttttgtgtca cgtggcggcc gcaggaaccc ctagtgatgg agttggccac tccctctctg 5220 cgcgctcgct cgctcactga ggccgggcga ccaaaggtcg cccgacgccc gggctttgcc 5280 cgggcggcct cagtgagcga gcgagcgcgc agagagggag tggccaa 5327 <210> 26 <211> 5309 <212> DNA <213> Adeno-Associated Virus 2 <400> 26 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtc tgcaggctca gaggcacaca 180 ggagtttctg ggctcaccct gcccccttcc aacccctcag ttcccatcct ccagcagctg 240 tttgtgtgct gcctctgaag tccacactga acaaacttca gcctactcat gtccctaaaa 300 tgggcaaaca ttgcaagcag caaacagcaa acacacagcc ctccctgcct gctgaccttg 360 gagctggggc agaggtcaga gacctctctg ggcccatgcc acctccaaca tccactcgac 420 cccttggaat ttcggtggag aggagcagag gttgtcctgg cgtggtttag gtagtgtgag 480 aggggtcgac tggacacagg acgctgtggt ttctgagcca gggggcgact cagatcccag 540 ccagtggact tagcccctgt ttgctcctcc gataactggg gtgaccttgg ttaatattca 600 ccagcagcct cccccgttgc ccctctggat ccactgctta aatacggacg aggacagggc 660 cctgtctcct cagcttcagg caccaccact gacctgggac agtgaatcgc gatcgccacc 720 atgcagattg agctgagcac ctgcttcttc ctgtgcctgc tgaggttctg cttctctgcc 780 accaggagat actacctggg ggctgtggag ctgagctggg actacatgca gtctgacctg 840 ggggagctgc ctgtggatgc caggttcccc cccagagtgc ccaagagctt ccccttcaac 900 acctctgtgg tgtacaagaa gaccctgttt gtggagttca ctgaccacct gttcaacatt 960 gccaagccca ggcccccctg gatgggcctg ctgggcccca ccatccaggc tgaggtgtat 1020 gacactgtgg tgatcaccct gaagaacatg gccagccacc ctgtgagcct gcatgctgtg 1080 ggggtgagct actggaaggc ctctgagggg gctgagtatg atgaccagac cagccagagg 1140 gagaaggagg atgacaaggt gttccctggg ggcagccaca cctatgtgtg gcaggtgctg 1200 aaggagaatg gccccatggc ctctgacccc ctgtgcctga cctacagcta cctgagccat 1260 gtggacctgg tgaaggacct gaactctggc ctgattgggg ccctgctggt gtgcagggag 1320 ggcagcctgg ccaaggagaa gacccagacc ctgcacaagt tcatcctgct gtttgctgtg 1380 tttgatgagg gcaagagctg gcactctgaa accaagaaca gcctgatgca ggacagggat 1440 gctgcctctg ccagggcctg gcccaagatg cacactgtga atggctatgt gaacaggagc 1500 ctgcctggcc tgattggctg ccacaggaag tctgtgtact ggcatgtgat tggcatgggc 1560 accacccctg aggtgcacag catcttcctg gagggccaca ccttcctggt caggaaccac 1620 aggcaggcca gcctggagat cagccccatc accttcctga ctgcccagac cctgctgatg 1680 gacctgggcc agttcctgct gttctgccac atcagcagcc accagcatga tggcatggag 1740 gcctatgtga aggtggacag ctgccctgag gagccccagc tgaggatgaa gaacaatgag 1800 gaggctgagg actatgatga tgacctgact gactctgaga tggatgtggt gaggtttgat 1860 gatgacaaca gccccagctt catccagatc aggtctgtgg ccaagaagca ccccaagacc 1920 tgggtgcact acattgctgc tgaggaggag gactgggact atgcccccct ggtgctggcc 1980 cctgatgaca ggagctacaa gagccagtac ctgaacaatg gcccccagag gattggcagg 2040 aagtacaaga aggtcaggtt catggcctac actgatgaaa ccttcaagac cagggaggcc 2100 atccagcatg agtctggcat cctgggcccc ctgctgtatg gggaggtggg ggacaccctg 2160 ctgatcatct tcaagaacca ggccagcagg ccctacaaca tctaccccca tggcatcact 2220 gatgtgaggc ccctgtacag caggaggctg cccaaggggg tgaagcacct gaaggacttc 2280 cccatcctgc ctggggagat cttcaagtac aagtggactg tgactgtgga ggatggcccc 2340 accaagtctg accccaggtg cctgaccaga tactacagca gctttgtgaa catggagagg 2400 gacctggcct ctggcctgat tggccccctg ctgatctgct acaaggagtc tgtggaccag 2460 aggggcaacc agatcatgtc tgacaagagg aatgtgatcc tgttctctgt gtttgatgag 2520 aacaggagct ggtacctgac tgagaacatc cagaggttcc tgcccaaccc tgctggggtg 2580 cagctggagg accctgagtt ccaggccagc aacatcatgc acagcatcaa tggctatgtg 2640 tttgacagcc tgcagctgtc tgtgtgcctg catgaggtgg cctactggta catcctgagc 2700 attggggccc agactgactt cctgtctgtg ttcttctctg gctacacctt caagcacaag 2760 atggtgtatg aggacaccct gaccctgttc cccttctctg gggagactgt gttcatgagc 2820 atggagaacc ctggcctgtg gattctgggc tgccacaact ctgacttcag gaacaggggc 2880 atgactgccc tgctgaaagt ctccagctgt gacaagaaca ctggggacta ctatgaggac 2940 agctatgagg acatctctgc ctacctgctg agcaagaaca atgccattga gcccaggagc 3000 ttcagccaga accccccagt gctgaagagg caccagaggg agatcaccag gaccaccctg 3060 cagtctgacc aggaggagat tgactatgat gacaccatct ctgtggagat gaagaaggag 3120 gactttgaca tctacgacga ggacgagaac cagagcccca ggagcttcca gaagaagacc 3180 aggcactact tcattgctgc tgtggagagg ctgtgggact atggcatgag cagcagcccc 3240 catgtgctga ggaacagggc ccagtctggc tctgtgcccc agttcaagaa ggtggtgttc 3300 caggagttca ctgatggcag cttcacccag cccctgtaca gaggggagct gaatgagcac 3360 ctgggcctgc tgggccccta catcagggct gaggtggagg acaacatcat ggtgaccttc 3420 aggaaccagg ccagcaggcc ctacagcttc tacagcagcc tgatcagcta tgaggaggac 3480 cagaggcagg gggctgagcc caggaagaac tttgtgaagc ccaatgaaac caagacctac 3540 ttctggaagg tgcagcacca catggccccc accaaggatg agtttgactg caaggcctgg 3600 gcctacttct ctgatgtgga cctggagaag gatgtgcact ctggcctgat tggccccctg 3660 ctggtgtgcc acaccaacac cctgaaccct gcccatggca ggcaggtgac tgtgcaggag 3720 tttgccctgt tcttcaccat ctttgatgaa accaagagct ggtacttcac tgagaacatg 3780 gagaggaact gcagggcccc ctgcaacatc cagatggagg accccacctt caaggagaac 3840 tacaggttcc atgccatcaa tggctacatc atggacaccc tgcctggcct ggtgatggcc 3900 caggaccaga ggatcaggtg gtacctgctg agcatgggca gcaatgagaa catccacagc 3960 atccacttct ctggccatgt gttcactgtg aggaagaagg aggagtacaa gatggccctg 4020 tacaacctgt accctggggt gtttgagact gtggagatgc tgcccagcaa ggctggcatc 4080 tggagggtgg agtgcctgat tggggagcac ctgcatgctg gcatgagcac cctgttcctg 4140 gtgtacagca acaagtgcca gacccccctg ggcatggcct ctggccacat cagggacttc 4200 cagatcactg cctctggcca gtatggccag tgggccccca agctggccag gctgcactac 4260 tctggcagca tcaatgcctg gagcaccaag gagcccttca gctggatcaa ggtggacctg 4320 ctggccccca tgatcatcca tggcatcaag acccaggggg ccaggcagaa gttcagcagc 4380 ctgtacatca gccagttcat catcatgtac agcctggatg gcaagaagtg gcagacctac 4440 aggggcaaca gcactggcac cctgatggtg ttctttggca atgtggacag ctctggcatc 4500 aagcacaaca tcttcaaccc ccccatcatt gccagataca tcaggctgca ccccacccac 4560 tacagcatca ggagcaccct gaggatggag ctgatgggct gtgacctgaa cagctgcagc 4620 atgcccctgg gcatggagag caaggccatc tctgatgccc agatcactgc cagcagctac 4680 ttcaccaaca tgtttgccac ctggagcccc agcaaggcca ggctgcacct gcagggcagg 4740 agcaatgcct ggaggcccca ggtcaacaac cccaaggagt ggctgcaggt ggacttccag 4800 aagaccatga aggtgactgg ggtgaccacc cagggggtga agagcctgct gaccagcatg 4860 tatgtgaagg agttcctgat cagcagcagc caggatggcc accagtggac cctgttcttc 4920 cagaatggca aggtgaaggt gttccagggc aaccaggaca gcttcacccc tgtggtgaac 4980 agcctggacc cccccctgct gaccagatac ctgaggattc acccccagag ctgggtgcac 5040 cagattgccc tgaggatgga ggtgctgggc tgtgaggccc aggacctgta ctgacctcga 5100 ggaataaagg aaatttattt tcattgcaat agtgtgttgg ttttttgtgt cacgtggcgg 5160 ccgcaggaac ccctagtgat ggagttggcc actccctctc tgcgcgctcg ctcgctcact 5220 gaggccgggc gaccaaaggt cgcccgacgc ccgggctttg cccgggcggc ctcagtgagc 5280 gagcgagcgc gcagagaggg agtggccaa 5309 <210> 27 <211> 5532 <212> DNA <213> Adeno-Associated Virus 2 <400> 27 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ttttcgaccc ctctcacact 180 acctaaacca cgccaggaca acctctgctc ctctccaccg aaattccaag gggtcgagtg 240 gatgttggag gtggcatggg cccagagagg tctctgacct ctgccccagc tccaaggtca 300 gcaggcaggg agggctgtgt gtttgctgtt tgctgcttgc aatgtttgcc cattttaggg 360 acatgagtag gctgaagttt gttcagtgtg gacttcagag gcagcacaca aacagctgct 420 ggaggatggg aactgagggg ttggaagggg gcagggtgag cccagaaact cctgtgtgcc 480 tctgagcctg cagacgcgaa acgtcgactg gacacaggac gctgtggttt ctgagccagg 540 gggcgactca gatcccagcc agtggactta gcccctgttt gctcctccga taactggggt 600 gaccttggtt aatattcacc agcagcctcc cccgttgccc ctctggatcc actgcttaaa 660 tacggacgag gacagggccc tgtctcctca gcttcaggca ccaccactga cctgggacag 720 tgaatcgtaa gtatgccttt cactgcgaga ggttctggag aggcttctga gctccccatg 780 gcccaggcag gcagcaggtc tggggcagga ggggggttgt ggagtgcctt gactcggggc 840 ctggcccccc catctctgtc ttgcaggaca attgccgtct tctgtctcgt ggggcatcct 900 cctgctggca ggcctgtgct gcctggtccc tgcgatcgcc accatgcaga ttgagctgag 960 cacctgcttc ttcctgtgcc tgctgaggtt ctgcttctct gccaccagga gatactacct 1020 gggggctgtg gagctgagct gggactacat gcagtctgac ctgggggagc tgcctgtgga 1080 tgccaggttc ccccccagag tgcccaagag cttccccttc aacacctctg tggtgtacaa 1140 gaagaccctg tttgtggagt tcactgacca cctgttcaac attgccaagc ccaggccccc 1200 ctggatgggc ctgctgggcc ccaccatcca ggctgaggtg tatgacactg tggtgatcac 1260 cctgaagaac atggccagcc accctgtgag cctgcatgct gtgggggtga gctactggaa 1320 ggcctctgag ggggctgagt atgatgacca gaccagccag agggagaagg aggatgacaa 1380 ggtgttccct gggggcagcc acacctatgt gtggcaggtg ctgaaggaga atggccccat 1440 ggcctctgac cccctgtgcc tgacctacag ctacctgagc catgtggacc tggtgaagga 1500 cctgaactct ggcctgattg gggccctgct ggtgtgcagg gagggcagcc tggccaagga 1560 gaagacccag accctgcaca agttcatcct gctgtttgct gtgtttgatg agggcaagag 1620 ctggcactct gaaaccaaga acagcctgat gcaggacagg gatgctgcct ctgccagggc 1680 ctggcccaag atgcacactg tgaatggcta tgtgaacagg agcctgcctg gcctgattgg 1740 ctgccacagg aagtctgtgt actggcatgt gattggcatg ggcaccaccc ctgaggtgca 1800 cagcatcttc ctggagggcc acaccttcct ggtcaggaac cacaggcagg ccagcctgga 1860 gatcagcccc atcaccttcc tgactgccca gaccctgctg atggacctgg gccagttcct 1920 gctgttctgc cacatcagca gccaccagca tgatggcatg gaggcctatg tgaaggtgga 1980 cagctgccct gaggagcccc agctgaggat gaagaacaat gaggaggctg aggactatga 2040 tgatgacctg actgactctg agatggatgt ggtgaggttt gatgatgaca acagccccag 2100 cttcatccag atcaggtctg tggccaagaa gcaccccaag acctgggtgc actacattgc 2160 tgctgaggag gaggactggg actatgcccc cctggtgctg gcccctgatg acaggagcta 2220 caagagccag tacctgaaca atggccccca gaggattggc aggaagtaca agaaggtcag 2280 gttcatggcc tacactgatg aaaccttcaa gaccagggag gccatccagc atgagtctgg 2340 catcctgggc cccctgctgt atggggaggt gggggacacc ctgctgatca tcttcaagaa 2400 ccaggccagc aggccctaca acatctaccc ccatggcatc actgatgtga ggcccctgta 2460 cagcaggagg ctgcccaagg gggtgaagca cctgaaggac ttccccatcc tgcctgggga 2520 gatcttcaag tacaagtgga ctgtgactgt ggaggatggc cccaccaagt ctgaccccag 2580 gtgcctgacc agatactaca gcagctttgt gaacatggag agggacctgg cctctggcct 2640 gattggcccc ctgctgatct gctacaagga gtctgtggac cagaggggca accagatcat 2700 gtctgacaag aggaatgtga tcctgttctc tgtgtttgat gagaacagga gctggtacct 2760 gactgagaac atccagaggt tcctgcccaa ccctgctggg gtgcagctgg aggaccctga 2820 gttccaggcc agcaacatca tgcacagcat caatggctat gtgtttgaca gcctgcagct 2880 gtctgtgtgc ctgcatgagg tggcctactg gtacatcctg agcattgggg cccagactga 2940 cttcctgtct gtgttcttct ctggctacac cttcaagcac aagatggtgt atgaggacac 3000 cctgaccctg ttccccttct ctggggagac tgtgttcatg agcatggaga accctggcct 3060 gtggattctg ggctgccaca actctgactt caggaacagg ggcatgactg ccctgctgaa 3120 agtctccagc tgtgacaaga acactgggga ctactatgag gacagctatg aggacatctc 3180 tgcctacctg ctgagcaaga acaatgccat tgagcccagg agcttcagcc agaacccccc 3240 agtgctgaag aggcaccaga gggagatcac caggaccacc ctgcagtctg accaggagga 3300 gattgactat gatgacacca tctctgtgga gatgaagaag gaggactttg acatctacga 3360 cgaggacgag aaccagagcc ccaggagctt ccagaagaag accaggcact acttcattgc 3420 tgctgtggag aggctgtggg actatggcat gagcagcagc ccccatgtgc tgaggaacag 3480 ggcccagtct ggctctgtgc cccagttcaa gaaggtggtg ttccaggagt tcactgatgg 3540 cagcttcacc cagcccctgt acagagggga gctgaatgag cacctgggcc tgctgggccc 3600 ctacatcagg gctgaggtgg aggacaacat catggtgacc ttcaggaacc aggccagcag 3660 gccctacagc ttctacagca gcctgatcag ctatgaggag gaccagaggc agggggctga 3720 gcccaggaag aactttgtga agcccaatga aaccaagacc tacttctgga aggtgcagca 3780 ccacatggcc cccaccaagg atgagtttga ctgcaaggcc tgggcctact tctctgatgt 3840 ggacctggag aaggatgtgc actctggcct gattggcccc ctgctggtgt gccacaccaa 3900 caccctgaac cctgcccatg gcaggcaggt gactgtgcag gagtttgccc tgttcttcac 3960 catctttgat gaaaccaaga gctggtactt cactgagaac atggagagga actgcagggc 4020 cccctgcaac atccagatgg aggaccccac cttcaaggag aactacaggt tccatgccat 4080 caatggctac atcatggaca ccctgcctgg cctggtgatg gcccaggacc agaggatcag 4140 gtggtacctg ctgagcatgg gcagcaatga gaacatccac agcatccact tctctggcca 4200 tgtgttcact gtgaggaaga aggaggagta caagatggcc ctgtacaacc tgtaccctgg 4260 ggtgtttgag actgtggaga tgctgcccag caaggctggc atctggaggg tggagtgcct 4320 gattggggag cacctgcatg ctggcatgag caccctgttc ctggtgtaca gcaacaagtg 4380 ccagaccccc ctgggcatgg cctctggcca catcagggac ttccagatca ctgcctctgg 4440 ccagtatggc cagtgggccc ccaagctggc caggctgcac tactctggca gcatcaatgc 4500 ctggagcacc aaggagccct tcagctggat caaggtggac ctgctggccc ccatgatcat 4560 ccatggcatc aagacccagg gggccaggca gaagttcagc agcctgtaca tcagccagtt 4620 catcatcatg tacagcctgg atggcaagaa gtggcagacc tacaggggca acagcactgg 4680 caccctgatg gtgttctttg gcaatgtgga cagctctggc atcaagcaca acatcttcaa 4740 cccccccatc attgccagat acatcaggct gcaccccacc cactacagca tcaggagcac 4800 cctgaggatg gagctgatgg gctgtgacct gaacagctgc agcatgcccc tgggcatgga 4860 gagcaaggcc atctctgatg cccagatcac tgccagcagc tacttcacca acatgtttgc 4920 cacctggagc cccagcaagg ccaggctgca cctgcagggc aggagcaatg cctggaggcc 4980 ccaggtcaac aaccccaagg agtggctgca ggtggacttc cagaagacca tgaaggtgac 5040 tggggtgacc acccaggggg tgaagagcct gctgaccagc atgtatgtga aggagttcct 5100 gatcagcagc agccaggatg gccaccagtg gaccctgttc ttccagaatg gcaaggtgaa 5160 ggtgttccag ggcaaccagg acagcttcac ccctgtggtg aacagcctgg acccccccct 5220 gctgaccaga tacctgagga ttcaccccca gagctgggtg caccagattg ccctgaggat 5280 ggaggtgctg ggctgtgagg cccaggacct gtactgacct cgaggaataa aggaaattta 5340 ttttcattgc aatagtgtgt tggttttttg tgtcacgtgg cggccgcagg aacccctagt 5400 gatggagttg gccactccct ctctgcgcgc tcgctcgctc actgaggccg ggcgaccaaa 5460 ggtcgcccga cgcccgggct ttgcccgggc ggcctcagtg agcgagcgag cgcgcagaga 5520 gggagtggcc aa 5532 <210> 28 <211> 5877 <212> DNA <213> Adeno-Associated Virus 2 <400> 28 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ttttcgaccc ctctcacact 180 acctaaacca cgccaggaca acctctgctc ctctccaccg aaattccaag gggtcgagtg 240 gatgttggag gtggcatggg cccagagagg tctctgacct ctgccccagc tccaaggtca 300 gcaggcaggg agggctgtgt gtttgctgtt tgctgcttgc aatgtttgcc cattttaggg 360 acatgagtag gctgaagttt gttcagtgtg gacttcagag gcagcacaca aacagctgct 420 ggaggatggg aactgagggg ttggaagggg gcagggtgag cccagaaact cctgtgtgcc 480 tctgagcctg cagacgcgaa acgtcgacag gttaattttt aaaaagcagt caaaagtcca 540 agtggccctt ggcagcattt actctctctg tttgctctgg ttaataatct caggagcaca 600 aacattcctg gaggcaggag aagaaatcaa catcctggac ttatcctctg ggcctctccc 660 cacccccagg agaggctcag gttaattttt aaaaagcagt caaaagtcca agtggccctt 720 ggcagcattt actctctctg tttgctctgg ttaataatct caggagcaca aacattcctg 780 gaggcaggag aagaaatcaa catcctggac ttatcctctg ggcctctccc cacccccagg 840 agaggctgtc gactggacac aggacgctgt ggtttctgag ccagggggcg actcagatcc 900 cagccagtgg acttagcccc tgtttgctcc tccgataact ggggtgacct tggttaatat 960 tcaccagcag cctcccccgt tgcccctctg gatccactgc ttaaatacgg acgaggacag 1020 ggccctgtct cctcagcttc aggcaccacc actgacctgg gacagtgaat cgtaagtatg 1080 cctttcactg cgagaggttc tggagaggct tctgagctcc ccatggccca ggcaggcagc 1140 aggtctgggg caggaggggg gttgtggagt gccttgactc ggggcctggc ccccccatct 1200 ctgtcttgca ggacaattgc cgtcttctgt ctcgtggggc atcctcctgc tggcaggcct 1260 gtgctgcctg gtccctgcga tcgccaccat gcagattgag ctgagcacct gcttcttcct 1320 gtgcctgctg aggttctgct tctctgccac caggagatac tacctggggg ctgtggagct 1380 gagctgggac tacatgcagt ctgacctggg ggagctgcct gtggatgcca ggttcccccc 1440 cagagtgccc aagagcttcc ccttcaacac ctctgtggtg tacaagaaga ccctgtttgt 1500 ggagttcact gaccacctgt tcaacattgc caagcccagg cccccctgga tgggcctgct 1560 gggccccacc atccaggctg aggtgtatga cactgtggtg atcaccctga agaacatggc 1620 cagccaccct gtgagcctgc atgctgtggg ggtgagctac tggaaggcct ctgagggggc 1680 tgagtatgat gaccagacca gccagaggga gaaggaggat gacaaggtgt tccctggggg 1740 cagccacacc tatgtgtggc aggtgctgaa ggagaatggc cccatggcct ctgaccccct 1800 gtgcctgacc tacagctacc tgagccatgt ggacctggtg aaggacctga actctggcct 1860 gattggggcc ctgctggtgt gcagggaggg cagcctggcc aaggagaaga cccagaccct 1920 gcacaagttc atcctgctgt ttgctgtgtt tgatgagggc aagagctggc actctgaaac 1980 caagaacagc ctgatgcagg acagggatgc tgcctctgcc agggcctggc ccaagatgca 2040 cactgtgaat ggctatgtga acaggagcct gcctggcctg attggctgcc acaggaagtc 2100 tgtgtactgg catgtgattg gcatgggcac cacccctgag gtgcacagca tcttcctgga 2160 gggccacacc ttcctggtca ggaaccacag gcaggccagc ctggagatca gccccatcac 2220 cttcctgact gcccagaccc tgctgatgga cctgggccag ttcctgctgt tctgccacat 2280 cagcagccac cagcatgatg gcatggaggc ctatgtgaag gtggacagct gccctgagga 2340 gccccagctg aggatgaaga acaatgagga ggctgaggac tatgatgatg acctgactga 2400 ctctgagatg gatgtggtga ggtttgatga tgacaacagc cccagcttca tccagatcag 2460 gtctgtggcc aagaagcacc ccaagacctg ggtgcactac attgctgctg aggaggagga 2520 ctgggactat gcccccctgg tgctggcccc tgatgacagg agctacaaga gccagtacct 2580 gaacaatggc ccccagagga ttggcaggaa gtacaagaag gtcaggttca tggcctacac 2640 tgatgaaacc ttcaagacca gggaggccat ccagcatgag tctggcatcc tgggccccct 2700 gctgtatggg gaggtggggg acaccctgct gatcatcttc aagaaccagg ccagcaggcc 2760 ctacaacatc tacccccatg gcatcactga tgtgaggccc ctgtacagca ggaggctgcc 2820 caagggggtg aagcacctga aggacttccc catcctgcct ggggagatct tcaagtacaa 2880 gtggactgtg actgtggagg atggccccac caagtctgac cccaggtgcc tgaccagata 2940 ctacagcagc tttgtgaaca tggagaggga cctggcctct ggcctgattg gccccctgct 3000 gatctgctac aaggagtctg tggaccagag gggcaaccag atcatgtctg acaagaggaa 3060 tgtgatcctg ttctctgtgt ttgatgagaa caggagctgg tacctgactg agaacatcca 3120 gaggttcctg cccaaccctg ctggggtgca gctggaggac cctgagttcc aggccagcaa 3180 catcatgcac agcatcaatg gctatgtgtt tgacagcctg cagctgtctg tgtgcctgca 3240 tgaggtggcc tactggtaca tcctgagcat tggggcccag actgacttcc tgtctgtgtt 3300 cttctctggc tacaccttca agcacaagat ggtgtatgag gacaccctga ccctgttccc 3360 cttctctggg gagactgtgt tcatgagcat ggagaaccct ggcctgtgga ttctgggctg 3420 ccacaactct gacttcagga acaggggcat gactgccctg ctgaaagtct ccagctgtga 3480 caagaacact ggggactact atgaggacag ctatgaggac atctctgcct acctgctgag 3540 caagaacaat gccattgagc ccaggagctt cagccagaac cccccagtgc tgaagaggca 3600 ccagagggag atcaccagga ccaccctgca gtctgaccag gaggagattg actatgatga 3660 caccatctct gtggagatga agaaggagga ctttgacatc tacgacgagg acgagaacca 3720 gagccccagg agcttccaga agaagaccag gcactacttc attgctgctg tggagaggct 3780 gtgggactat ggcatgagca gcagccccca tgtgctgagg aacagggccc agtctggctc 3840 tgtgccccag ttcaagaagg tggtgttcca ggagttcact gatggcagct tcacccagcc 3900 cctgtacaga ggggagctga atgagcacct gggcctgctg ggcccctaca tcagggctga 3960 ggtggaggac aacatcatgg tgaccttcag gaaccaggcc agcaggccct acagcttcta 4020 cagcagcctg atcagctatg aggaggacca gaggcagggg gctgagccca ggaagaactt 4080 tgtgaagccc aatgaaacca agacctactt ctggaaggtg cagcaccaca tggcccccac 4140 caaggatgag tttgactgca aggcctgggc ctacttctct gatgtggacc tggagaagga 4200 tgtgcactct ggcctgattg gccccctgct ggtgtgccac accaacaccc tgaaccctgc 4260 ccatggcagg caggtgactg tgcaggagtt tgccctgttc ttcaccatct ttgatgaaac 4320 caagagctgg tacttcactg agaacatgga gaggaactgc agggccccct gcaacatcca 4380 gatggaggac cccaccttca aggagaacta caggttccat gccatcaatg gctacatcat 4440 ggacaccctg cctggcctgg tgatggccca ggaccagagg atcaggtggt acctgctgag 4500 catgggcagc aatgagaaca tccacagcat ccacttctct ggccatgtgt tcactgtgag 4560 gaagaaggag gagtacaaga tggccctgta caacctgtac cctggggtgt ttgagactgt 4620 ggagatgctg cccagcaagg ctggcatctg gagggtggag tgcctgattg gggagcacct 4680 gcatgctggc atgagcaccc tgttcctggt gtacagcaac aagtgccaga cccccctggg 4740 catggcctct ggccacatca gggacttcca gatcactgcc tctggccagt atggccagtg 4800 ggcccccaag ctggccaggc tgcactactc tggcagcatc aatgcctgga gcaccaagga 4860 gcccttcagc tggatcaagg tggacctgct ggcccccatg atcatccatg gcatcaagac 4920 ccagggggcc aggcagaagt tcagcagcct gtacatcagc cagttcatca tcatgtacag 4980 cctggatggc aagaagtggc agacctacag gggcaacagc actggcaccc tgatggtgtt 5040 ctttggcaat gtggacagct ctggcatcaa gcacaacatc ttcaaccccc ccatcattgc 5100 cagatacatc aggctgcacc ccacccacta cagcatcagg agcaccctga ggatggagct 5160 gatgggctgt gacctgaaca gctgcagcat gcccctgggc atggagagca aggccatctc 5220 tgatgcccag atcactgcca gcagctactt caccaacatg tttgccacct ggagccccag 5280 caaggccagg ctgcacctgc agggcaggag caatgcctgg aggccccagg tcaacaaccc 5340 caaggagtgg ctgcaggtgg acttccagaa gaccatgaag gtgactgggg tgaccaccca 5400 gggggtgaag agcctgctga ccagcatgta tgtgaaggag ttcctgatca gcagcagcca 5460 ggatggccac cagtggaccc tgttcttcca gaatggcaag gtgaaggtgt tccagggcaa 5520 ccaggacagc ttcacccctg tggtgaacag cctggacccc cccctgctga ccagatacct 5580 gaggattcac ccccagagct gggtgcacca gattgccctg aggatggagg tgctgggctg 5640 tgaggcccag gacctgtact gacctcgagg aataaaggaa atttattttc attgcaatag 5700 tgtgttggtt ttttgtgtca cgtggcggcc gcaggaaccc ctagtgatgg agttggccac 5760 tccctctctg cgcgctcgct cgctcactga ggccgggcga ccaaaggtcg cccgacgccc 5820 gggctttgcc cgggcggcct cagtgagcga gcgagcgcgc agagagggag tggccaa 5877 <210> 29 <211> 6054 <212> DNA <213> Adeno-Associated Virus 2 <400> 29 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ttttcgaccc ctctcacact 180 acctaaacca cgccaggaca acctctgctc ctctccaccg aaattccaag gggtcgagtg 240 gatgttggag gtggcatggg cccagagagg tctctgacct ctgccccagc tccaaggtca 300 gcaggcaggg agggctgtgt gtttgctgtt tgctgcttgc aatgtttgcc cattttaggg 360 acatgagtag gctgaagttt gttcagtgtg gacttcagag gcagcacaca aacagctgct 420 ggaggatggg aactgagggg ttggaagggg gcagggtgag cccagaaact cctgtgtgcc 480 tctgagcctg cagacgcgaa acgtcgacag gttaattttt aaaaagcagt caaaagtcca 540 agtggccctt ggcagcattt actctctctg tttgctctgg ttaataatct caggagcaca 600 aacattcctg gaggcaggag aagaaatcaa catcctggac ttatcctctg ggcctctccc 660 cacccccagg agaggctcag gttaattttt aaaaagcagt caaaagtcca agtggccctt 720 ggcagcattt actctctctg tttgctctgg ttaataatct caggagcaca aacattcctg 780 gaggcaggag aagaaatcaa catcctggac ttatcctctg ggcctctccc cacccccagg 840 agaggctgtc gactggacac aggacgctgt ggtttctgag ccagggggcg actcagatcc 900 cagccagtgg acttagcccc tgtttgctcc tccgataact ggggtgacct tggttaatat 960 tcaccagcag cctcccccgt tgcccctctg gatccactgc ttaaatacgg acgaggacag 1020 ggccctgtct cctcagcttc aggcaccacc actgacctgg gacagtgaat cgtaagtatg 1080 cctttcactg cgagaggttc tggagaggct tctgagctcc ccatggccca ggcaggcagc 1140 aggtctgggg caggaggggg gttgtggagt gccttgactc ggggcctggc ccccccatct 1200 ctgtcttgca ggacaattgc cgtcttctgt ctcgtggggc atcctcctgc tggcaggcct 1260 gtgctgcctg gtccctgcga tcgccaccat gcagattgag ctgagcacct gcttcttcct 1320 gtgcctgctg aggttctgct tctctgccac caggagatac tacctggggg ctgtggagct 1380 gagctgggac tacatgcagt ctgacctggg ggagctgcct gtggatgcca ggttcccccc 1440 cagagtgccc aagagcttcc ccttcaacac ctctgtggtg tacaagaaga ccctgtttgt 1500 ggagttcact gaccacctgt tcaacattgc caagcccagg cccccctgga tgggcctgct 1560 gggccccacc atccaggctg aggtgtatga cactgtggtg atcaccctga agaacatggc 1620 cagccaccct gtgagcctgc atgctgtggg ggtgagctac tggaaggcct ctgagggggc 1680 tgagtatgat gaccagacca gccagaggga gaaggaggat gacaaggtgt tccctggggg 1740 cagccacacc tatgtgtggc aggtgctgaa ggagaatggc cccatggcct ctgaccccct 1800 gtgcctgacc tacagctacc tgagccatgt ggacctggtg aaggacctga actctggcct 1860 gattggggcc ctgctggtgt gcagggaggg cagcctggcc aaggagaaga cccagaccct 1920 gcacaagttc atcctgctgt ttgctgtgtt tgatgagggc aagagctggc actctgaaac 1980 caagaacagc ctgatgcagg acagggatgc tgcctctgcc agggcctggc ccaagatgca 2040 cactgtgaat ggctatgtga acaggagcct gcctggcctg attggctgcc acaggaagtc 2100 tgtgtactgg catgtgattg gcatgggcac cacccctgag gtgcacagca tcttcctgga 2160 gggccacacc ttcctggtca ggaaccacag gcaggccagc ctggagatca gccccatcac 2220 cttcctgact gcccagaccc tgctgatgga cctgggccag ttcctgctgt tctgccacat 2280 cagcagccac cagcatgatg gcatggaggc ctatgtgaag gtggacagct gccctgagga 2340 gccccagctg aggatgaaga acaatgagga ggctgaggac tatgatgatg acctgactga 2400 ctctgagatg gatgtggtga ggtttgatga tgacaacagc cccagcttca tccagatcag 2460 gtctgtggcc aagaagcacc ccaagacctg ggtgcactac attgctgctg aggaggagga 2520 ctgggactat gcccccctgg tgctggcccc tgatgacagg agctacaaga gccagtacct 2580 gaacaatggc ccccagagga ttggcaggaa gtacaagaag gtcaggttca tggcctacac 2640 tgatgaaacc ttcaagacca gggaggccat ccagcatgag tctggcatcc tgggccccct 2700 gctgtatggg gaggtggggg acaccctgct gatcatcttc aagaaccagg ccagcaggcc 2760 ctacaacatc tacccccatg gcatcactga tgtgaggccc ctgtacagca ggaggctgcc 2820 caagggggtg aagcacctga aggacttccc catcctgcct ggggagatct tcaagtacaa 2880 gtggactgtg actgtggagg atggccccac caagtctgac cccaggtgcc tgaccagata 2940 ctacagcagc tttgtgaaca tggagaggga cctggcctct ggcctgattg gccccctgct 3000 gatctgctac aaggagtctg tggaccagag gggcaaccag atcatgtctg acaagaggaa 3060 tgtgatcctg ttctctgtgt ttgatgagaa caggagctgg tacctgactg agaacatcca 3120 gaggttcctg cccaaccctg ctggggtgca gctggaggac cctgagttcc aggccagcaa 3180 catcatgcac agcatcaatg gctatgtgtt tgacagcctg cagctgtctg tgtgcctgca 3240 tgaggtggcc tactggtaca tcctgagcat tggggcccag actgacttcc tgtctgtgtt 3300 cttctctggc tacaccttca agcacaagat ggtgtatgag gacaccctga ccctgttccc 3360 cttctctggg gagactgtgt tcatgagcat ggagaaccct ggcctgtgga ttctgggctg 3420 ccacaactct gacttcagga acaggggcat gactgccctg ctgaaagtct ccagctgtga 3480 caagaacact ggggactact atgaggacag ctatgaggac atctctgcct acctgctgag 3540 caagaacaat gccattgagc ccaggagctt cagccagaac cccccagtgc tgaagaggca 3600 ccagagggag atcaccagga ccaccctgca gtctgaccag gaggagattg actatgatga 3660 caccatctct gtggagatga agaaggagga ctttgacatc tacgacgagg acgagaacca 3720 gagccccagg agcttccaga agaagaccag gcactacttc attgctgctg tggagaggct 3780 gtgggactat ggcatgagca gcagccccca tgtgctgagg aacagggccc agtctggctc 3840 tgtgccccag ttcaagaagg tggtgttcca ggagttcact gatggcagct tcacccagcc 3900 cctgtacaga ggggagctga atgagcacct gggcctgctg ggcccctaca tcagggctga 3960 ggtggaggac aacatcatgg tgaccttcag gaaccaggcc agcaggccct acagcttcta 4020 cagcagcctg atcagctatg aggaggacca gaggcagggg gctgagccca ggaagaactt 4080 tgtgaagccc aatgaaacca agacctactt ctggaaggtg cagcaccaca tggcccccac 4140 caaggatgag tttgactgca aggcctgggc ctacttctct gatgtggacc tggagaagga 4200 tgtgcactct ggcctgattg gccccctgct ggtgtgccac accaacaccc tgaaccctgc 4260 ccatggcagg caggtgactg tgcaggagtt tgccctgttc ttcaccatct ttgatgaaac 4320 caagagctgg tacttcactg agaacatgga gaggaactgc agggccccct gcaacatcca 4380 gatggaggac cccaccttca aggagaacta caggttccat gccatcaatg gctacatcat 4440 ggacaccctg cctggcctgg tgatggccca ggaccagagg atcaggtggt acctgctgag 4500 catgggcagc aatgagaaca tccacagcat ccacttctct ggccatgtgt tcactgtgag 4560 gaagaaggag gagtacaaga tggccctgta caacctgtac cctggggtgt ttgagactgt 4620 ggagatgctg cccagcaagg ctggcatctg gagggtggag tgcctgattg gggagcacct 4680 gcatgctggc atgagcaccc tgttcctggt gtacagcaac aagtgccaga cccccctggg 4740 catggcctct ggccacatca gggacttcca gatcactgcc tctggccagt atggccagtg 4800 ggcccccaag ctggccaggc tgcactactc tggcagcatc aatgcctgga gcaccaagga 4860 gcccttcagc tggatcaagg tggacctgct ggcccccatg atcatccatg gcatcaagac 4920 ccagggggcc aggcagaagt tcagcagcct gtacatcagc cagttcatca tcatgtacag 4980 cctggatggc aagaagtggc agacctacag gggcaacagc actggcaccc tgatggtgtt 5040 ctttggcaat gtggacagct ctggcatcaa gcacaacatc ttcaaccccc ccatcattgc 5100 cagatacatc aggctgcacc ccacccacta cagcatcagg agcaccctga ggatggagct 5160 gatgggctgt gacctgaaca gctgcagcat gcccctgggc atggagagca aggccatctc 5220 tgatgcccag atcactgcca gcagctactt caccaacatg tttgccacct ggagccccag 5280 caaggccagg ctgcacctgc agggcaggag caatgcctgg aggccccagg tcaacaaccc 5340 caaggagtgg ctgcaggtgg acttccagaa gaccatgaag gtgactgggg tgaccaccca 5400 gggggtgaag agcctgctga ccagcatgta tgtgaaggag ttcctgatca gcagcagcca 5460 ggatggccac cagtggaccc tgttcttcca gaatggcaag gtgaaggtgt tccagggcaa 5520 ccaggacagc ttcacccctg tggtgaacag cctggacccc cccctgctga ccagatacct 5580 gaggattcac ccccagagct gggtgcacca gattgccctg aggatggagg tgctgggctg 5640 tgaggcccag gacctgtact gacctcgagg tgtgccttct agttgccagc catctgttgt 5700 ttgcccctcc cccgtgcctt ccttgaccct ggaaggtgcc actcccactg tcctttccta 5760 ataaaatgag gaaattgcat cgcattgtct gagtaggtgt cattctattc tggggggtgg 5820 ggtggggcag gacagcaagg gggaggattg ggaagacaat agcaggcatg ctggggatgc 5880 ggtgggctct atgggcacgt ggcggccgca ggaaccccta gtgatggagt tggccactcc 5940 ctctctgcgc gctcgctcgc tcactgaggc cgggcgacca aaggtcgccc gacgcccggg 6000 ctttgcccgg gcggcctcag tgagcgagcg agcgcgcaga gagggagtgg ccaa 6054 <210> 30 <211> 6054 <212> DNA <213> Adeno-Associated Virus 2 <400> 30 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ttttcgaccc ctctcacact 180 acctaaacca cgccaggaca acctctgctc ctctccaccg aaattccaag gggtcgagtg 240 gatgttggag gtggcatggg cccagagagg tctctgacct ctgccccagc tccaaggtca 300 gcaggcaggg agggctgtgt gtttgctgtt tgctgcttgc aatgtttgcc cattttaggg 360 acatgagtag gctgaagttt gttcagtgtg gacttcagag gcagcacaca aacagctgct 420 ggaggatggg aactgagggg ttggaagggg gcagggtgag cccagaaact cctgtgtgcc 480 tctgagcctg cagacgcgaa acgtcgaagc ctctcctggg ggtggggaga ggcccagagg 540 ataagtccag gatgttgatt tcttctcctg cctccaggaa tgtttgtgct cctgagatta 600 ttaaccagag caaacagaga gagtaaatgc tgccaagggc cacttggact tttgactgct 660 ttttaaaaat taacctgagc ctctcctggg ggtggggaga ggcccagagg ataagtccag 720 gatgttgatt tcttctcctg cctccaggaa tgtttgtgct cctgagatta ttaaccagag 780 caaacagaga gagtaaatgc tgccaagggc cacttggact tttgactgct ttttaaaaat 840 taacctggtc gactggacac aggacgctgt ggtttctgag ccagggggcg actcagatcc 900 cagccagtgg acttagcccc tgtttgctcc tccgataact ggggtgacct tggttaatat 960 tcaccagcag cctcccccgt tgcccctctg gatccactgc ttaaatacgg acgaggacag 1020 ggccctgtct cctcagcttc aggcaccacc actgacctgg gacagtgaat cgtaagtatg 1080 cctttcactg cgagaggttc tggagaggct tctgagctcc ccatggccca ggcaggcagc 1140 aggtctgggg caggaggggg gttgtggagt gccttgactc ggggcctggc ccccccatct 1200 ctgtcttgca ggacaattgc cgtcttctgt ctcgtggggc atcctcctgc tggcaggcct 1260 gtgctgcctg gtccctgcga tcgccaccat gcagattgag ctgagcacct gcttcttcct 1320 gtgcctgctg aggttctgct tctctgccac caggagatac tacctggggg ctgtggagct 1380 gagctgggac tacatgcagt ctgacctggg ggagctgcct gtggatgcca ggttcccccc 1440 cagagtgccc aagagcttcc ccttcaacac ctctgtggtg tacaagaaga ccctgtttgt 1500 ggagttcact gaccacctgt tcaacattgc caagcccagg cccccctgga tgggcctgct 1560 gggccccacc atccaggctg aggtgtatga cactgtggtg atcaccctga agaacatggc 1620 cagccaccct gtgagcctgc atgctgtggg ggtgagctac tggaaggcct ctgagggggc 1680 tgagtatgat gaccagacca gccagaggga gaaggaggat gacaaggtgt tccctggggg 1740 cagccacacc tatgtgtggc aggtgctgaa ggagaatggc cccatggcct ctgaccccct 1800 gtgcctgacc tacagctacc tgagccatgt ggacctggtg aaggacctga actctggcct 1860 gattggggcc ctgctggtgt gcagggaggg cagcctggcc aaggagaaga cccagaccct 1920 gcacaagttc atcctgctgt ttgctgtgtt tgatgagggc aagagctggc actctgaaac 1980 caagaacagc ctgatgcagg acagggatgc tgcctctgcc agggcctggc ccaagatgca 2040 cactgtgaat ggctatgtga acaggagcct gcctggcctg attggctgcc acaggaagtc 2100 tgtgtactgg catgtgattg gcatgggcac cacccctgag gtgcacagca tcttcctgga 2160 gggccacacc ttcctggtca ggaaccacag gcaggccagc ctggagatca gccccatcac 2220 cttcctgact gcccagaccc tgctgatgga cctgggccag ttcctgctgt tctgccacat 2280 cagcagccac cagcatgatg gcatggaggc ctatgtgaag gtggacagct gccctgagga 2340 gccccagctg aggatgaaga acaatgagga ggctgaggac tatgatgatg acctgactga 2400 ctctgagatg gatgtggtga ggtttgatga tgacaacagc cccagcttca tccagatcag 2460 gtctgtggcc aagaagcacc ccaagacctg ggtgcactac attgctgctg aggaggagga 2520 ctgggactat gcccccctgg tgctggcccc tgatgacagg agctacaaga gccagtacct 2580 gaacaatggc ccccagagga ttggcaggaa gtacaagaag gtcaggttca tggcctacac 2640 tgatgaaacc ttcaagacca gggaggccat ccagcatgag tctggcatcc tgggccccct 2700 gctgtatggg gaggtggggg acaccctgct gatcatcttc aagaaccagg ccagcaggcc 2760 ctacaacatc tacccccatg gcatcactga tgtgaggccc ctgtacagca ggaggctgcc 2820 caagggggtg aagcacctga aggacttccc catcctgcct ggggagatct tcaagtacaa 2880 gtggactgtg actgtggagg atggccccac caagtctgac cccaggtgcc tgaccagata 2940 ctacagcagc tttgtgaaca tggagaggga cctggcctct ggcctgattg gccccctgct 3000 gatctgctac aaggagtctg tggaccagag gggcaaccag atcatgtctg acaagaggaa 3060 tgtgatcctg ttctctgtgt ttgatgagaa caggagctgg tacctgactg agaacatcca 3120 gaggttcctg cccaaccctg ctggggtgca gctggaggac cctgagttcc aggccagcaa 3180 catcatgcac agcatcaatg gctatgtgtt tgacagcctg cagctgtctg tgtgcctgca 3240 tgaggtggcc tactggtaca tcctgagcat tggggcccag actgacttcc tgtctgtgtt 3300 cttctctggc tacaccttca agcacaagat ggtgtatgag gacaccctga ccctgttccc 3360 cttctctggg gagactgtgt tcatgagcat ggagaaccct ggcctgtgga ttctgggctg 3420 ccacaactct gacttcagga acaggggcat gactgccctg ctgaaagtct ccagctgtga 3480 caagaacact ggggactact atgaggacag ctatgaggac atctctgcct acctgctgag 3540 caagaacaat gccattgagc ccaggagctt cagccagaac cccccagtgc tgaagaggca 3600 ccagagggag atcaccagga ccaccctgca gtctgaccag gaggagattg actatgatga 3660 caccatctct gtggagatga agaaggagga ctttgacatc tacgacgagg acgagaacca 3720 gagccccagg agcttccaga agaagaccag gcactacttc attgctgctg tggagaggct 3780 gtgggactat ggcatgagca gcagccccca tgtgctgagg aacagggccc agtctggctc 3840 tgtgccccag ttcaagaagg tggtgttcca ggagttcact gatggcagct tcacccagcc 3900 cctgtacaga ggggagctga atgagcacct gggcctgctg ggcccctaca tcagggctga 3960 ggtggaggac aacatcatgg tgaccttcag gaaccaggcc agcaggccct acagcttcta 4020 cagcagcctg atcagctatg aggaggacca gaggcagggg gctgagccca ggaagaactt 4080 tgtgaagccc aatgaaacca agacctactt ctggaaggtg cagcaccaca tggcccccac 4140 caaggatgag tttgactgca aggcctgggc ctacttctct gatgtggacc tggagaagga 4200 tgtgcactct ggcctgattg gccccctgct ggtgtgccac accaacaccc tgaaccctgc 4260 ccatggcagg caggtgactg tgcaggagtt tgccctgttc ttcaccatct ttgatgaaac 4320 caagagctgg tacttcactg agaacatgga gaggaactgc agggccccct gcaacatcca 4380 gatggaggac cccaccttca aggagaacta caggttccat gccatcaatg gctacatcat 4440 ggacaccctg cctggcctgg tgatggccca ggaccagagg atcaggtggt acctgctgag 4500 catgggcagc aatgagaaca tccacagcat ccacttctct ggccatgtgt tcactgtgag 4560 gaagaaggag gagtacaaga tggccctgta caacctgtac cctggggtgt ttgagactgt 4620 ggagatgctg cccagcaagg ctggcatctg gagggtggag tgcctgattg gggagcacct 4680 gcatgctggc atgagcaccc tgttcctggt gtacagcaac aagtgccaga cccccctggg 4740 catggcctct ggccacatca gggacttcca gatcactgcc tctggccagt atggccagtg 4800 ggcccccaag ctggccaggc tgcactactc tggcagcatc aatgcctgga gcaccaagga 4860 gcccttcagc tggatcaagg tggacctgct ggcccccatg atcatccatg gcatcaagac 4920 ccagggggcc aggcagaagt tcagcagcct gtacatcagc cagttcatca tcatgtacag 4980 cctggatggc aagaagtggc agacctacag gggcaacagc actggcaccc tgatggtgtt 5040 ctttggcaat gtggacagct ctggcatcaa gcacaacatc ttcaaccccc ccatcattgc 5100 cagatacatc aggctgcacc ccacccacta cagcatcagg agcaccctga ggatggagct 5160 gatgggctgt gacctgaaca gctgcagcat gcccctgggc atggagagca aggccatctc 5220 tgatgcccag atcactgcca gcagctactt caccaacatg tttgccacct ggagccccag 5280 caaggccagg ctgcacctgc agggcaggag caatgcctgg aggccccagg tcaacaaccc 5340 caaggagtgg ctgcaggtgg acttccagaa gaccatgaag gtgactgggg tgaccaccca 5400 gggggtgaag agcctgctga ccagcatgta tgtgaaggag ttcctgatca gcagcagcca 5460 ggatggccac cagtggaccc tgttcttcca gaatggcaag gtgaaggtgt tccagggcaa 5520 ccaggacagc ttcacccctg tggtgaacag cctggacccc cccctgctga ccagatacct 5580 gaggattcac ccccagagct gggtgcacca gattgccctg aggatggagg tgctgggctg 5640 tgaggcccag gacctgtact gacctcgagg tgtgccttct agttgccagc catctgttgt 5700 ttgcccctcc cccgtgcctt ccttgaccct ggaaggtgcc actcccactg tcctttccta 5760 ataaaatgag gaaattgcat cgcattgtct gagtaggtgt cattctattc tggggggtgg 5820 ggtggggcag gacagcaagg gggaggattg ggaagacaat agcaggcatg ctggggatgc 5880 ggtgggctct atgggcacgt ggcggccgca ggaaccccta gtgatggagt tggccactcc 5940 ctctctgcgc gctcgctcgc tcactgaggc cgggcgacca aaggtcgccc gacgcccggg 6000 ctttgcccgg gcggcctcag tgagcgagcg agcgcgcaga gagggagtgg ccaa 6054 <210> 31 <211> 5504 <212> DNA <213> Adeno-Associated Virus 2 <400> 31 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ttttcgaccc ctctcacact 180 acctaaacca cgccaggaca acctctgctc ctctccaccg aaattccaag gggtcgagtg 240 gatgttggag gtggcatggg cccagagagg tctctgacct ctgccccagc tccaaggtca 300 gcaggcaggg agggctgtgt gtttgctgtt tgctgcttgc aatgtttgcc cattttaggg 360 acatgagtag gctgaagttt gttcagtgtg gacttcagag gcagcacaca aacagctgct 420 ggaggatggg aactgagggg ttggaagggg gcagggtgag cccagaaact cctgtgtgcc 480 tctgagcctg cagacgcgaa acgtcgactg gacacaggac gctgtggttt ctgagccagg 540 gggcgactca gatcccagcc agtggactta gcccctgttt gctcctccga taactggggt 600 gaccttggtt aatattcacc agcagcctcc cccgttgccc ctctggatcc actgcttaaa 660 tacggacgag gacagggccc tgtctcctca gcttcaggca ccaccactga cctgggacag 720 tgaatcgcga tcgccaccat gcagattgag ctgagcacct gcttcttcct gtgcctgctg 780 aggttctgct tctctgccac caggagatac tacctggggg ctgtggagct gagctgggac 840 tacatgcagt ctgacctggg ggagctgcct gtggatgcca ggttcccccc cagagtgccc 900 aagagcttcc ccttcaacac ctctgtggtg tacaagaaga ccctgtttgt ggagttcact 960 gaccacctgt tcaacattgc caagcccagg cccccctgga tgggcctgct gggccccacc 1020 atccaggctg aggtgtatga cactgtggtg atcaccctga agaacatggc cagccaccct 1080 gtgagcctgc atgctgtggg ggtgagctac tggaaggcct ctgagggggc tgagtatgat 1140 gaccagacca gccagaggga gaaggaggat gacaaggtgt tccctggggg cagccacacc 1200 tatgtgtggc aggtgctgaa ggagaatggc cccatggcct ctgaccccct gtgcctgacc 1260 tacagctacc tgagccatgt ggacctggtg aaggacctga actctggcct gattggggcc 1320 ctgctggtgt gcagggaggg cagcctggcc aaggagaaga cccagaccct gcacaagttc 1380 atcctgctgt ttgctgtgtt tgatgagggc aagagctggc actctgaaac caagaacagc 1440 ctgatgcagg acagggatgc tgcctctgcc agggcctggc ccaagatgca cactgtgaat 1500 ggctatgtga acaggagcct gcctggcctg attggctgcc acaggaagtc tgtgtactgg 1560 catgtgattg gcatgggcac cacccctgag gtgcacagca tcttcctgga gggccacacc 1620 ttcctggtca ggaaccacag gcaggccagc ctggagatca gccccatcac cttcctgact 1680 gcccagaccc tgctgatgga cctgggccag ttcctgctgt tctgccacat cagcagccac 1740 cagcatgatg gcatggaggc ctatgtgaag gtggacagct gccctgagga gccccagctg 1800 aggatgaaga acaatgagga ggctgaggac tatgatgatg acctgactga ctctgagatg 1860 gatgtggtga ggtttgatga tgacaacagc cccagcttca tccagatcag gtctgtggcc 1920 aagaagcacc ccaagacctg ggtgcactac attgctgctg aggaggagga ctgggactat 1980 gcccccctgg tgctggcccc tgatgacagg agctacaaga gccagtacct gaacaatggc 2040 ccccagagga ttggcaggaa gtacaagaag gtcaggttca tggcctacac tgatgaaacc 2100 ttcaagacca gggaggccat ccagcatgag tctggcatcc tgggccccct gctgtatggg 2160 gaggtggggg acaccctgct gatcatcttc aagaaccagg ccagcaggcc ctacaacatc 2220 tacccccatg gcatcactga tgtgaggccc ctgtacagca ggaggctgcc caagggggtg 2280 aagcacctga aggacttccc catcctgcct ggggagatct tcaagtacaa gtggactgtg 2340 actgtggagg atggccccac caagtctgac cccaggtgcc tgaccagata ctacagcagc 2400 tttgtgaaca tggagaggga cctggcctct ggcctgattg gccccctgct gatctgctac 2460 aaggagtctg tggaccagag gggcaaccag atcatgtctg acaagaggaa tgtgatcctg 2520 ttctctgtgt ttgatgagaa caggagctgg tacctgactg agaacatcca gaggttcctg 2580 cccaaccctg ctggggtgca gctggaggac cctgagttcc aggccagcaa catcatgcac 2640 agcatcaatg gctatgtgtt tgacagcctg cagctgtctg tgtgcctgca tgaggtggcc 2700 tactggtaca tcctgagcat tggggcccag actgacttcc tgtctgtgtt cttctctggc 2760 tacaccttca agcacaagat ggtgtatgag gacaccctga ccctgttccc cttctctggg 2820 gagactgtgt tcatgagcat ggagaaccct ggcctgtgga ttctgggctg ccacaactct 2880 gacttcagga acaggggcat gactgccctg ctgaaagtct ccagctgtga caagaacact 2940 ggggactact atgaggacag ctatgaggac atctctgcct acctgctgag caagaacaat 3000 gccattgagc ccaggagctt cagccagaac cccccagtgc tgaagaggca ccagagggag 3060 atcaccagga ccaccctgca gtctgaccag gaggagattg actatgatga caccatctct 3120 gtggagatga agaaggagga ctttgacatc tacgacgagg acgagaacca gagccccagg 3180 agcttccaga agaagaccag gcactacttc attgctgctg tggagaggct gtgggactat 3240 ggcatgagca gcagccccca tgtgctgagg aacagggccc agtctggctc tgtgccccag 3300 ttcaagaagg tggtgttcca ggagttcact gatggcagct tcacccagcc cctgtacaga 3360 ggggagctga atgagcacct gggcctgctg ggcccctaca tcagggctga ggtggaggac 3420 aacatcatgg tgaccttcag gaaccaggcc agcaggccct acagcttcta cagcagcctg 3480 atcagctatg aggaggacca gaggcagggg gctgagccca ggaagaactt tgtgaagccc 3540 aatgaaacca agacctactt ctggaaggtg cagcaccaca tggcccccac caaggatgag 3600 tttgactgca aggcctgggc ctacttctct gatgtggacc tggagaagga tgtgcactct 3660 ggcctgattg gccccctgct ggtgtgccac accaacaccc tgaaccctgc ccatggcagg 3720 caggtgactg tgcaggagtt tgccctgttc ttcaccatct ttgatgaaac caagagctgg 3780 tacttcactg agaacatgga gaggaactgc agggccccct gcaacatcca gatggaggac 3840 cccaccttca aggagaacta caggttccat gccatcaatg gctacatcat ggacaccctg 3900 cctggcctgg tgatggccca ggaccagagg atcaggtggt acctgctgag catgggcagc 3960 aatgagaaca tccacagcat ccacttctct ggccatgtgt tcactgtgag gaagaaggag 4020 gagtacaaga tggccctgta caacctgtac cctggggtgt ttgagactgt ggagatgctg 4080 cccagcaagg ctggcatctg gagggtggag tgcctgattg gggagcacct gcatgctggc 4140 atgagcaccc tgttcctggt gtacagcaac aagtgccaga cccccctggg catggcctct 4200 ggccacatca gggacttcca gatcactgcc tctggccagt atggccagtg ggcccccaag 4260 ctggccaggc tgcactactc tggcagcatc aatgcctgga gcaccaagga gcccttcagc 4320 tggatcaagg tggacctgct ggcccccatg atcatccatg gcatcaagac ccagggggcc 4380 aggcagaagt tcagcagcct gtacatcagc cagttcatca tcatgtacag cctggatggc 4440 aagaagtggc agacctacag gggcaacagc actggcaccc tgatggtgtt ctttggcaat 4500 gtggacagct ctggcatcaa gcacaacatc ttcaaccccc ccatcattgc cagatacatc 4560 aggctgcacc ccacccacta cagcatcagg agcaccctga ggatggagct gatgggctgt 4620 gacctgaaca gctgcagcat gcccctgggc atggagagca aggccatctc tgatgcccag 4680 atcactgcca gcagctactt caccaacatg tttgccacct ggagccccag caaggccagg 4740 ctgcacctgc agggcaggag caatgcctgg aggccccagg tcaacaaccc caaggagtgg 4800 ctgcaggtgg acttccagaa gaccatgaag gtgactgggg tgaccaccca gggggtgaag 4860 agcctgctga ccagcatgta tgtgaaggag ttcctgatca gcagcagcca ggatggccac 4920 cagtggaccc tgttcttcca gaatggcaag gtgaaggtgt tccagggcaa ccaggacagc 4980 ttcacccctg tggtgaacag cctggacccc cccctgctga ccagatacct gaggattcac 5040 ccccagagct gggtgcacca gattgccctg aggatggagg tgctgggctg tgaggcccag 5100 gacctgtact gacctcgagg tgtgccttct agttgccagc catctgttgt ttgcccctcc 5160 cccgtgcctt ccttgaccct ggaaggtgcc actcccactg tcctttccta ataaaatgag 5220 gaaattgcat cgcattgtct gagtaggtgt cattctattc tggggggtgg ggtggggcag 5280 gacagcaagg gggaggattg ggaagacaat agcaggcatg ctggggatgc ggtgggctct 5340 atgggcacgt ggcggccgca ggaaccccta gtgatggagt tggccactcc ctctctgcgc 5400 gctcgctcgc tcactgaggc cgggcgacca aaggtcgccc gacgcccggg ctttgcccgg 5460 gcggcctcag tgagcgagcg agcgcgcaga gagggagtgg ccaa 5504 <210> 32 <211> 5507 <212> DNA <213> Adeno-Associated Virus 2 <400> 32 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ttttcgaccc ctctcacact 180 acctaaacca cgccaggaca acctctgctc ctctccaccg aaattccaag gggtcgagtg 240 gatgttggag gtggcatggg cccagagagg tctctgacct ctgccccagc tccaaggtca 300 gcaggcaggg agggctgtgt gtttgctgtt tgctgcttgc aatgtttgcc cattttaggg 360 acatgagtag gctgaagttt gttcagtgtg gacttcagag gcagcacaca aacagctgct 420 ggaggatggg aactgagggg ttggaagggg gcagggtgag cccagaaact cctgtgtgcc 480 tctgagcctg cagacgcgaa acgtcgacga tcttgctacc agtggaacag ccactaagga 540 ttctgcagtg agagcagagg gccagctaag tggtactctc ccagagactg tctgactcac 600 gccaccccct ccaccttgga cacaggacgc tgtggtttct gagccaggta caatgactcc 660 tttcggtaag tgcagtggaa gctgtacact gcccaggcaa agcgtccggg cagcgtaggc 720 gggcgactca gatcccagcc agtggactta gcccctgttt gctcctccga taactggggt 780 gaccttggtt aatattcacc agcagcctcc cccgttgccc ctctggatcc actgcttaaa 840 tacggacgag gacagggccc tgtctcctca gcttcaggca ccaccactga cctgggacag 900 tgaatcgcga tcgccaccat gcagattgag ctgagcacct gcttcttcct gtgcctgctg 960 aggttctgct tctctgccac caggagatac tacctggggg ctgtggagct gagctgggac 1020 tacatgcagt ctgacctggg ggagctgcct gtggatgcca ggttcccccc cagagtgccc 1080 aagagcttcc ccttcaacac ctctgtggtg tacaagaaga ccctgtttgt ggagttcact 1140 gaccacctgt tcaacattgc caagcccagg cccccctgga tgggcctgct gggccccacc 1200 atccaggctg aggtgtatga cactgtggtg atcaccctga agaacatggc cagccaccct 1260 gtgagcctgc atgctgtggg ggtgagctac tggaaggcct ctgagggggc tgagtatgat 1320 gaccagacca gccagaggga gaaggaggat gacaaggtgt tccctggggg cagccacacc 1380 tatgtgtggc aggtgctgaa ggagaatggc cccatggcct ctgaccccct gtgcctgacc 1440 tacagctacc tgagccatgt ggacctggtg aaggacctga actctggcct gattggggcc 1500 ctgctggtgt gcagggaggg cagcctggcc aaggagaaga cccagaccct gcacaagttc 1560 atcctgctgt ttgctgtgtt tgatgagggc aagagctggc actctgaaac caagaacagc 1620 ctgatgcagg acagggatgc tgcctctgcc agggcctggc ccaagatgca cactgtgaat 1680 ggctatgtga acaggagcct gcctggcctg attggctgcc acaggaagtc tgtgtactgg 1740 catgtgattg gcatgggcac cacccctgag gtgcacagca tcttcctgga gggccacacc 1800 ttcctggtca ggaaccacag gcaggccagc ctggagatca gccccatcac cttcctgact 1860 gcccagaccc tgctgatgga cctgggccag ttcctgctgt tctgccacat cagcagccac 1920 cagcatgatg gcatggaggc ctatgtgaag gtggacagct gccctgagga gccccagctg 1980 aggatgaaga acaatgagga ggctgaggac tatgatgatg acctgactga ctctgagatg 2040 gatgtggtga ggtttgatga tgacaacagc cccagcttca tccagatcag gtctgtggcc 2100 aagaagcacc ccaagacctg ggtgcactac attgctgctg aggaggagga ctgggactat 2160 gcccccctgg tgctggcccc tgatgacagg agctacaaga gccagtacct gaacaatggc 2220 ccccagagga ttggcaggaa gtacaagaag gtcaggttca tggcctacac tgatgaaacc 2280 ttcaagacca gggaggccat ccagcatgag tctggcatcc tgggccccct gctgtatggg 2340 gaggtggggg acaccctgct gatcatcttc aagaaccagg ccagcaggcc ctacaacatc 2400 tacccccatg gcatcactga tgtgaggccc ctgtacagca ggaggctgcc caagggggtg 2460 aagcacctga aggacttccc catcctgcct ggggagatct tcaagtacaa gtggactgtg 2520 actgtggagg atggccccac caagtctgac cccaggtgcc tgaccagata ctacagcagc 2580 tttgtgaaca tggagaggga cctggcctct ggcctgattg gccccctgct gatctgctac 2640 aaggagtctg tggaccagag gggcaaccag atcatgtctg acaagaggaa tgtgatcctg 2700 ttctctgtgt ttgatgagaa caggagctgg tacctgactg agaacatcca gaggttcctg 2760 cccaaccctg ctggggtgca gctggaggac cctgagttcc aggccagcaa catcatgcac 2820 agcatcaatg gctatgtgtt tgacagcctg cagctgtctg tgtgcctgca tgaggtggcc 2880 tactggtaca tcctgagcat tggggcccag actgacttcc tgtctgtgtt cttctctggc 2940 tacaccttca agcacaagat ggtgtatgag gacaccctga ccctgttccc cttctctggg 3000 gagactgtgt tcatgagcat ggagaaccct ggcctgtgga ttctgggctg ccacaactct 3060 gacttcagga acaggggcat gactgccctg ctgaaagtct ccagctgtga caagaacact 3120 ggggactact atgaggacag ctatgaggac atctctgcct acctgctgag caagaacaat 3180 gccattgagc ccaggagctt cagccagaac cccccagtgc tgaagaggca ccagagggag 3240 atcaccagga ccaccctgca gtctgaccag gaggagattg actatgatga caccatctct 3300 gtggagatga agaaggagga ctttgacatc tacgacgagg acgagaacca gagccccagg 3360 agcttccaga agaagaccag gcactacttc attgctgctg tggagaggct gtgggactat 3420 ggcatgagca gcagccccca tgtgctgagg aacagggccc agtctggctc tgtgccccag 3480 ttcaagaagg tggtgttcca ggagttcact gatggcagct tcacccagcc cctgtacaga 3540 ggggagctga atgagcacct gggcctgctg ggcccctaca tcagggctga ggtggaggac 3600 aacatcatgg tgaccttcag gaaccaggcc agcaggccct acagcttcta cagcagcctg 3660 atcagctatg aggaggacca gaggcagggg gctgagccca ggaagaactt tgtgaagccc 3720 aatgaaacca agacctactt ctggaaggtg cagcaccaca tggcccccac caaggatgag 3780 tttgactgca aggcctgggc ctacttctct gatgtggacc tggagaagga tgtgcactct 3840 ggcctgattg gccccctgct ggtgtgccac accaacaccc tgaaccctgc ccatggcagg 3900 caggtgactg tgcaggagtt tgccctgttc ttcaccatct ttgatgaaac caagagctgg 3960 tacttcactg agaacatgga gaggaactgc agggccccct gcaacatcca gatggaggac 4020 cccaccttca aggagaacta caggttccat gccatcaatg gctacatcat ggacaccctg 4080 cctggcctgg tgatggccca ggaccagagg atcaggtggt acctgctgag catgggcagc 4140 aatgagaaca tccacagcat ccacttctct ggccatgtgt tcactgtgag gaagaaggag 4200 gagtacaaga tggccctgta caacctgtac cctggggtgt ttgagactgt ggagatgctg 4260 cccagcaagg ctggcatctg gagggtggag tgcctgattg gggagcacct gcatgctggc 4320 atgagcaccc tgttcctggt gtacagcaac aagtgccaga cccccctggg catggcctct 4380 ggccacatca gggacttcca gatcactgcc tctggccagt atggccagtg ggcccccaag 4440 ctggccaggc tgcactactc tggcagcatc aatgcctgga gcaccaagga gcccttcagc 4500 tggatcaagg tggacctgct ggcccccatg atcatccatg gcatcaagac ccagggggcc 4560 aggcagaagt tcagcagcct gtacatcagc cagttcatca tcatgtacag cctggatggc 4620 aagaagtggc agacctacag gggcaacagc actggcaccc tgatggtgtt ctttggcaat 4680 gtggacagct ctggcatcaa gcacaacatc ttcaaccccc ccatcattgc cagatacatc 4740 aggctgcacc ccacccacta cagcatcagg agcaccctga ggatggagct gatgggctgt 4800 gacctgaaca gctgcagcat gcccctgggc atggagagca aggccatctc tgatgcccag 4860 atcactgcca gcagctactt caccaacatg tttgccacct ggagccccag caaggccagg 4920 ctgcacctgc agggcaggag caatgcctgg aggccccagg tcaacaaccc caaggagtgg 4980 ctgcaggtgg acttccagaa gaccatgaag gtgactgggg tgaccaccca gggggtgaag 5040 agcctgctga ccagcatgta tgtgaaggag ttcctgatca gcagcagcca ggatggccac 5100 cagtggaccc tgttcttcca gaatggcaag gtgaaggtgt tccagggcaa ccaggacagc 5160 ttcacccctg tggtgaacag cctggacccc cccctgctga ccagatacct gaggattcac 5220 ccccagagct gggtgcacca gattgccctg aggatggagg tgctgggctg tgaggcccag 5280 gacctgtact gacctcgagg aataaaggaa atttattttc attgcaatag tgtgttggtt 5340 ttttgtgtca cgtggcggcc gcaggaaccc ctagtgatgg agttggccac tccctctctg 5400 cgcgctcgct cgctcactga ggccgggcga ccaaaggtcg cccgacgccc gggctttgcc 5460 cgggcggcct cagtgagcga gcgagcgcgc agagagggag tggccaa 5507 <210> 33 <211> 5311 <212> DNA <213> Adeno-Associated Virus 2 <400> 33 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ttttcgacgc agagaggtct 180 ctgacctctg ccccagctcc aaggtcagca ggcagggagg gctgtgtgtt tgctgtttgc 240 tgcttgcaat gtttgcccat tttagggaca tgagtaggct gaagtttgtt cagtgtggac 300 ttcagaggca gcacacaaac agccagagag gtctctgacc tctgccccag ctccaaggtc 360 agcaggcagg gagggctgtg tgtttgctgt ttgctgcttg caatgtttgc ccattttagg 420 gacatgagta ggctgaagtt tgttcagtgt ggacttcaga ggcagcacac aaacagcacg 480 cgaaacgtcg actggacaca ggacgctgtg gtttctgagc cagggggcga ctcagatccc 540 agccagtgga cttagcccct gtttgctcct ccgataactg gggtgacctt ggttaatatt 600 caccagcagc ctcccccgtt gcccctctgg atccactgct taaatacgga cgaggacagg 660 gccctgtctc ctcagcttca ggcaccacca ctgacctggg acagtgaatc gcgatcgcca 720 ccatgcagat tgagctgagc acctgcttct tcctgtgcct gctgaggttc tgcttctctg 780 ccaccaggag atactacctg ggggctgtgg agctgagctg ggactacatg cagtctgacc 840 tgggggagct gcctgtggat gccaggttcc cccccagagt gcccaagagc ttccccttca 900 acacctctgt ggtgtacaag aagaccctgt ttgtggagtt cactgaccac ctgttcaaca 960 ttgccaagcc caggcccccc tggatgggcc tgctgggccc caccatccag gctgaggtgt 1020 atgacactgt ggtgatcacc ctgaagaaca tggccagcca ccctgtgagc ctgcatgctg 1080 tgggggtgag ctactggaag gcctctgagg gggctgagta tgatgaccag accagccaga 1140 gggagaagga ggatgacaag gtgttccctg ggggcagcca cacctatgtg tggcaggtgc 1200 tgaaggagaa tggccccatg gcctctgacc ccctgtgcct gacctacagc tacctgagcc 1260 atgtggacct ggtgaaggac ctgaactctg gcctgattgg ggccctgctg gtgtgcaggg 1320 agggcagcct ggccaaggag aagacccaga ccctgcacaa gttcatcctg ctgtttgctg 1380 tgtttgatga gggcaagagc tggcactctg aaaccaagaa cagcctgatg caggacaggg 1440 atgctgcctc tgccagggcc tggcccaaga tgcacactgt gaatggctat gtgaacagga 1500 gcctgcctgg cctgattggc tgccacagga agtctgtgta ctggcatgtg attggcatgg 1560 gcaccacccc tgaggtgcac agcatcttcc tggagggcca caccttcctg gtcaggaacc 1620 acaggcaggc cagcctggag atcagcccca tcaccttcct gactgcccag accctgctga 1680 tggacctggg ccagttcctg ctgttctgcc acatcagcag ccaccagcat gatggcatgg 1740 aggcctatgt gaaggtggac agctgccctg aggagcccca gctgaggatg aagaacaatg 1800 aggaggctga ggactatgat gatgacctga ctgactctga gatggatgtg gtgaggtttg 1860 atgatgacaa cagccccagc ttcatccaga tcaggtctgt ggccaagaag caccccaaga 1920 cctgggtgca ctacattgct gctgaggagg aggactggga ctatgccccc ctggtgctgg 1980 cccctgatga caggagctac aagagccagt acctgaacaa tggcccccag aggattggca 2040 ggaagtacaa gaaggtcagg ttcatggcct acactgatga aaccttcaag accagggagg 2100 ccatccagca tgagtctggc atcctgggcc ccctgctgta tggggaggtg ggggacaccc 2160 tgctgatcat cttcaagaac caggccagca ggccctacaa catctacccc catggcatca 2220 ctgatgtgag gcccctgtac agcaggaggc tgcccaaggg ggtgaagcac ctgaaggact 2280 tccccatcct gcctggggag atcttcaagt acaagtggac tgtgactgtg gaggatggcc 2340 ccaccaagtc tgaccccagg tgcctgacca gatactacag cagctttgtg aacatggaga 2400 gggacctggc ctctggcctg attggccccc tgctgatctg ctacaaggag tctgtggacc 2460 agaggggcaa ccagatcatg tctgacaaga ggaatgtgat cctgttctct gtgtttgatg 2520 agaacaggag ctggtacctg actgagaaca tccagaggtt cctgcccaac cctgctgggg 2580 tgcagctgga ggaccctgag ttccaggcca gcaacatcat gcacagcatc aatggctatg 2640 tgtttgacag cctgcagctg tctgtgtgcc tgcatgaggt ggcctactgg tacatcctga 2700 gcattggggc ccagactgac ttcctgtctg tgttcttctc tggctacacc ttcaagcaca 2760 agatggtgta tgaggacacc ctgaccctgt tccccttctc tggggagact gtgttcatga 2820 gcatggagaa ccctggcctg tggattctgg gctgccacaa ctctgacttc aggaacaggg 2880 gcatgactgc cctgctgaaa gtctccagct gtgacaagaa cactggggac tactatgagg 2940 acagctatga ggacatctct gcctacctgc tgagcaagaa caatgccatt gagcccagga 3000 gcttcagcca gaacccccca gtgctgaaga ggcaccagag ggagatcacc aggaccaccc 3060 tgcagtctga ccaggaggag attgactatg atgacaccat ctctgtggag atgaagaagg 3120 aggactttga catctacgac gaggacgaga accagagccc caggagcttc cagaagaaga 3180 ccaggcacta cttcattgct gctgtggaga ggctgtggga ctatggcatg agcagcagcc 3240 cccatgtgct gaggaacagg gcccagtctg gctctgtgcc ccagttcaag aaggtggtgt 3300 tccaggagtt cactgatggc agcttcaccc agcccctgta cagaggggag ctgaatgagc 3360 acctgggcct gctgggcccc tacatcaggg ctgaggtgga ggacaacatc atggtgacct 3420 tcaggaacca ggccagcagg ccctacagct tctacagcag cctgatcagc tatgaggagg 3480 accagaggca gggggctgag cccaggaaga actttgtgaa gcccaatgaa accaagacct 3540 acttctggaa ggtgcagcac cacatggccc ccaccaagga tgagtttgac tgcaaggcct 3600 gggcctactt ctctgatgtg gacctggaga aggatgtgca ctctggcctg attggccccc 3660 tgctggtgtg ccacaccaac accctgaacc ctgcccatgg caggcaggtg actgtgcagg 3720 agtttgccct gttcttcacc atctttgatg aaaccaagag ctggtacttc actgagaaca 3780 tggagaggaa ctgcagggcc ccctgcaaca tccagatgga ggaccccacc ttcaaggaga 3840 actacaggtt ccatgccatc aatggctaca tcatggacac cctgcctggc ctggtgatgg 3900 cccaggacca gaggatcagg tggtacctgc tgagcatggg cagcaatgag aacatccaca 3960 gcatccactt ctctggccat gtgttcactg tgaggaagaa ggaggagtac aagatggccc 4020 tgtacaacct gtaccctggg gtgtttgaga ctgtggagat gctgcccagc aaggctggca 4080 tctggagggt ggagtgcctg attggggagc acctgcatgc tggcatgagc accctgttcc 4140 tggtgtacag caacaagtgc cagacccccc tgggcatggc ctctggccac atcagggact 4200 tccagatcac tgcctctggc cagtatggcc agtgggcccc caagctggcc aggctgcact 4260 actctggcag catcaatgcc tggagcacca aggagccctt cagctggatc aaggtggacc 4320 tgctggcccc catgatcatc catggcatca agacccaggg ggccaggcag aagttcagca 4380 gcctgtacat cagccagttc atcatcatgt acagcctgga tggcaagaag tggcagacct 4440 acaggggcaa cagcactggc accctgatgg tgttctttgg caatgtggac agctctggca 4500 tcaagcacaa catcttcaac ccccccatca ttgccagata catcaggctg caccccaccc 4560 actacagcat caggagcacc ctgaggatgg agctgatggg ctgtgacctg aacagctgca 4620 gcatgcccct gggcatggag agcaaggcca tctctgatgc ccagatcact gccagcagct 4680 acttcaccaa catgtttgcc acctggagcc ccagcaaggc caggctgcac ctgcagggca 4740 ggagcaatgc ctggaggccc caggtcaaca accccaagga gtggctgcag gtggacttcc 4800 agaagaccat gaaggtgact ggggtgacca cccagggggt gaagagcctg ctgaccagca 4860 tgtatgtgaa ggagttcctg atcagcagca gccaggatgg ccaccagtgg accctgttct 4920 tccagaatgg caaggtgaag gtgttccagg gcaaccagga cagcttcacc cctgtggtga 4980 acagcctgga cccccccctg ctgaccagat acctgaggat tcacccccag agctgggtgc 5040 accagattgc cctgaggatg gaggtgctgg gctgtgaggc ccaggacctg tactgacctc 5100 gaggaataaa ggaaatttat tttcattgca atagtgtgtt ggttttttgt gtcacgtggc 5160 ggccgcagga acccctagtg atggagttgg ccactccctc tctgcgcgct cgctcgctca 5220 ctgaggccgg gcgaccaaag gtcgcccgac gcccgggctt tgcccgggcg gcctcagtga 5280 gcgagcgagc gcgcagagag ggagtggcca a 5311 <210> 34 <211> 5156 <212> DNA <213> Adeno-Associated Virus 2 <400> 34 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ttttcgacca gagaggtctc 180 tgacctctgc cccagctcca aggtcagcag gcagggaggg ctgtgtgttt gctgtttgct 240 gcttgcaatg tttgcccatt ttagggacat gagtaggctg aagtttgttc agtgtggact 300 tcagaggcag cacacaaaca gcacgcgaaa cgtcgactgg acacaggacg ctgtggtttc 360 tgagccaggg ggcgactcag atcccagcca gtggacttag cccctgtttg ctcctccgat 420 aactggggtg accttggtta atattcacca gcagcctccc ccgttgcccc tctggatcca 480 ctgcttaaat acggacgagg acagggccct gtctcctcag cttcaggcac caccactgac 540 ctgggacagt gaatcgcgat cgccaccatg cagattgagc tgagcacctg cttcttcctg 600 tgcctgctga ggttctgctt ctctgccacc aggagatact acctgggggc tgtggagctg 660 agctgggact acatgcagtc tgacctgggg gagctgcctg tggatgccag gttccccccc 720 agagtgccca agagcttccc cttcaacacc tctgtggtgt acaagaagac cctgtttgtg 780 gagttcactg accacctgtt caacattgcc aagcccaggc ccccctggat gggcctgctg 840 ggccccacca tccaggctga ggtgtatgac actgtggtga tcaccctgaa gaacatggcc 900 agccaccctg tgagcctgca tgctgtgggg gtgagctact ggaaggcctc tgagggggct 960 gagtatgatg accagaccag ccagagggag aaggaggatg acaaggtgtt ccctgggggc 1020 agccacacct atgtgtggca ggtgctgaag gagaatggcc ccatggcctc tgaccccctg 1080 tgcctgacct acagctacct gagccatgtg gacctggtga aggacctgaa ctctggcctg 1140 attggggccc tgctggtgtg cagggagggc agcctggcca aggagaagac ccagaccctg 1200 cacaagttca tcctgctgtt tgctgtgttt gatgagggca agagctggca ctctgaaacc 1260 aagaacagcc tgatgcagga cagggatgct gcctctgcca gggcctggcc caagatgcac 1320 actgtgaatg gctatgtgaa caggagcctg cctggcctga ttggctgcca caggaagtct 1380 gtgtactggc atgtgattgg catgggcacc acccctgagg tgcacagcat cttcctggag 1440 ggccacacct tcctggtcag gaaccacagg caggccagcc tggagatcag ccccatcacc 1500 ttcctgactg cccagaccct gctgatggac ctgggccagt tcctgctgtt ctgccacatc 1560 agcagccacc agcatgatgg catggaggcc tatgtgaagg tggacagctg ccctgaggag 1620 ccccagctga ggatgaagaa caatgaggag gctgaggact atgatgatga cctgactgac 1680 tctgagatgg atgtggtgag gtttgatgat gacaacagcc ccagcttcat ccagatcagg 1740 tctgtggcca agaagcaccc caagacctgg gtgcactaca ttgctgctga ggaggaggac 1800 tgggactatg cccccctggt gctggcccct gatgacagga gctacaagag ccagtacctg 1860 aacaatggcc cccagaggat tggcaggaag tacaagaagg tcaggttcat ggcctacact 1920 gatgaaacct tcaagaccag ggaggccatc cagcatgagt ctggcatcct gggccccctg 1980 ctgtatgggg aggtggggga caccctgctg atcatcttca agaaccaggc cagcaggccc 2040 tacaacatct acccccatgg catcactgat gtgaggcccc tgtacagcag gaggctgccc 2100 aagggggtga agcacctgaa ggacttcccc atcctgcctg gggagatctt caagtacaag 2160 tggactgtga ctgtggagga tggccccacc aagtctgacc ccaggtgcct gaccagatac 2220 tacagcagct ttgtgaacat ggagagggac ctggcctctg gcctgattgg ccccctgctg 2280 atctgctaca aggagtctgt ggaccagagg ggcaaccaga tcatgtctga caagaggaat 2340 gtgatcctgt tctctgtgtt tgatgagaac aggagctggt acctgactga gaacatccag 2400 aggttcctgc ccaaccctgc tggggtgcag ctggaggacc ctgagttcca ggccagcaac 2460 atcatgcaca gcatcaatgg ctatgtgttt gacagcctgc agctgtctgt gtgcctgcat 2520 gaggtggcct actggtacat cctgagcatt ggggcccaga ctgacttcct gtctgtgttc 2580 ttctctggct acaccttcaa gcacaagatg gtgtatgagg acaccctgac cctgttcccc 2640 ttctctgggg agactgtgtt catgagcatg gagaaccctg gcctgtggat tctgggctgc 2700 cacaactctg acttcaggaa caggggcatg actgccctgc tgaaagtctc cagctgtgac 2760 aagaacactg gggactacta tgaggacagc tatgaggaca tctctgccta cctgctgagc 2820 aagaacaatg ccattgagcc caggagcttc agccagaacc ccccagtgct gaagaggcac 2880 cagagggaga tcaccaggac caccctgcag tctgaccagg aggagattga ctatgatgac 2940 accatctctg tggagatgaa gaaggaggac tttgacatct acgacgagga cgagaaccag 3000 agccccagga gcttccagaa gaagaccagg cactacttca ttgctgctgt ggagaggctg 3060 tgggactatg gcatgagcag cagcccccat gtgctgagga acagggccca gtctggctct 3120 gtgccccagt tcaagaaggt ggtgttccag gagttcactg atggcagctt cacccagccc 3180 ctgtacagag gggagctgaa tgagcacctg ggcctgctgg gcccctacat cagggctgag 3240 gtggaggaca acatcatggt gaccttcagg aaccaggcca gcaggcccta cagcttctac 3300 agcagcctga tcagctatga ggaggaccag aggcaggggg ctgagcccag gaagaacttt 3360 gtgaagccca atgaaaccaa gacctacttc tggaaggtgc agcaccacat ggcccccacc 3420 aaggatgagt ttgactgcaa ggcctgggcc tacttctctg atgtggacct ggagaaggat 3480 gtgcactctg gcctgattgg ccccctgctg gtgtgccaca ccaacaccct gaaccctgcc 3540 catggcaggc aggtgactgt gcaggagttt gccctgttct tcaccatctt tgatgaaacc 3600 aagagctggt acttcactga gaacatggag aggaactgca gggccccctg caacatccag 3660 atggaggacc ccaccttcaa ggagaactac aggttccatg ccatcaatgg ctacatcatg 3720 gacaccctgc ctggcctggt gatggcccag gaccagagga tcaggtggta cctgctgagc 3780 atgggcagca atgagaacat ccacagcatc cacttctctg gccatgtgtt cactgtgagg 3840 aagaaggagg agtacaagat ggccctgtac aacctgtacc ctggggtgtt tgagactgtg 3900 gagatgctgc ccagcaaggc tggcatctgg agggtggagt gcctgattgg ggagcacctg 3960 catgctggca tgagcaccct gttcctggtg tacagcaaca agtgccagac ccccctgggc 4020 atggcctctg gccacatcag ggacttccag atcactgcct ctggccagta tggccagtgg 4080 gcccccaagc tggccaggct gcactactct ggcagcatca atgcctggag caccaaggag 4140 cccttcagct ggatcaaggt ggacctgctg gcccccatga tcatccatgg catcaagacc 4200 cagggggcca ggcagaagtt cagcagcctg tacatcagcc agttcatcat catgtacagc 4260 ctggatggca agaagtggca gacctacagg ggcaacagca ctggcaccct gatggtgttc 4320 tttggcaatg tggacagctc tggcatcaag cacaacatct tcaacccccc catcattgcc 4380 agatacatca ggctgcaccc cacccactac agcatcagga gcaccctgag gatggagctg 4440 atgggctgtg acctgaacag ctgcagcatg cccctgggca tggagagcaa ggccatctct 4500 gatgcccaga tcactgccag cagctacttc accaacatgt ttgccacctg gagccccagc 4560 aaggccaggc tgcacctgca gggcaggagc aatgcctgga ggccccaggt caacaacccc 4620 aaggagtggc tgcaggtgga cttccagaag accatgaagg tgactggggt gaccacccag 4680 ggggtgaaga gcctgctgac cagcatgtat gtgaaggagt tcctgatcag cagcagccag 4740 gatggccacc agtggaccct gttcttccag aatggcaagg tgaaggtgtt ccagggcaac 4800 caggacagct tcacccctgt ggtgaacagc ctggaccccc ccctgctgac cagatacctg 4860 aggattcacc cccagagctg ggtgcaccag attgccctga ggatggaggt gctgggctgt 4920 gaggcccagg acctgtactg acctcgagga ataaaggaaa tttattttca ttgcaatagt 4980 gtgttggttt tttgtgtcac gtggcggccg caggaacccc tagtgatgga gttggccact 5040 ccctctctgc gcgctcgctc gctcactgag gccgggcgac caaaggtcgc ccgacgcccg 5100 ggctttgccc gggcggcctc agtgagcgag cgagcgcgca gagagggagt ggccaa 5156 <210> 35 <211> 5178 <212> DNA <213> Adeno-Associated Virus 2 <400> 35 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ttttcgactg tttgctgttt 180 gctgcttgca atgtttgccc attttaggga catgtttgct gtttgctgct tgcaatgttt 240 gcccatttta gggacatgtt tgctgtttgc tgcttgcaat gtttgcccat tttagggaca 300 tgtttgctgt ttgctgcttg caatgtttgc ccattttagg gacaacgcga aacgtcgact 360 ggacacagga cgctgtggtt tctgagccag ggggcgactc agatcccagc cagtggactt 420 agcccctgtt tgctcctccg ataactgggg tgaccttggt taatattcac cagcagcctc 480 ccccgttgcc cctctggatc cactgcttaa atacggacga ggacagggcc ctgtctcctc 540 agcttcaggc accaccactg acctgggaca gtgaatcgcg atcgccacca tgcagattga 600 gctgagcacc tgcttcttcc tgtgcctgct gaggttctgc ttctctgcca ccaggagata 660 ctacctgggg gctgtggagc tgagctggga ctacatgcag tctgacctgg gggagctgcc 720 tgtggatgcc aggttccccc ccagagtgcc caagagcttc cccttcaaca cctctgtggt 780 gtacaagaag accctgtttg tggagttcac tgaccacctg ttcaacattg ccaagcccag 840 gcccccctgg atgggcctgc tgggccccac catccaggct gaggtgtatg acactgtggt 900 gatcaccctg aagaacatgg ccagccaccc tgtgagcctg catgctgtgg gggtgagcta 960 ctggaaggcc tctgaggggg ctgagtatga tgaccagacc agccagaggg agaaggagga 1020 tgacaaggtg ttccctgggg gcagccacac ctatgtgtgg caggtgctga aggagaatgg 1080 ccccatggcc tctgaccccc tgtgcctgac ctacagctac ctgagccatg tggacctggt 1140 gaaggacctg aactctggcc tgattggggc cctgctggtg tgcagggagg gcagcctggc 1200 caaggagaag acccagaccc tgcacaagtt catcctgctg tttgctgtgt ttgatgaggg 1260 caagagctgg cactctgaaa ccaagaacag cctgatgcag gacagggatg ctgcctctgc 1320 cagggcctgg cccaagatgc acactgtgaa tggctatgtg aacaggagcc tgcctggcct 1380 gattggctgc cacaggaagt ctgtgtactg gcatgtgatt ggcatgggca ccacccctga 1440 ggtgcacagc atcttcctgg agggccacac cttcctggtc aggaaccaca ggcaggccag 1500 cctggagatc agccccatca ccttcctgac tgcccagacc ctgctgatgg acctgggcca 1560 gttcctgctg ttctgccaca tcagcagcca ccagcatgat ggcatggagg cctatgtgaa 1620 ggtggacagc tgccctgagg agccccagct gaggatgaag aacaatgagg aggctgagga 1680 ctatgatgat gacctgactg actctgagat ggatgtggtg aggtttgatg atgacaacag 1740 ccccagcttc atccagatca ggtctgtggc caagaagcac cccaagacct gggtgcacta 1800 cattgctgct gaggaggagg actgggacta tgcccccctg gtgctggccc ctgatgacag 1860 gagctacaag agccagtacc tgaacaatgg cccccagagg attggcagga agtacaagaa 1920 ggtcaggttc atggcctaca ctgatgaaac cttcaagacc agggaggcca tccagcatga 1980 gtctggcatc ctgggccccc tgctgtatgg ggaggtgggg gacaccctgc tgatcatctt 2040 caagaaccag gccagcaggc cctacaacat ctacccccat ggcatcactg atgtgaggcc 2100 cctgtacagc aggaggctgc ccaagggggt gaagcacctg aaggacttcc ccatcctgcc 2160 tggggagatc ttcaagtaca agtggactgt gactgtggag gatggcccca ccaagtctga 2220 ccccaggtgc ctgaccagat actacagcag ctttgtgaac atggagaggg acctggcctc 2280 tggcctgatt ggccccctgc tgatctgcta caaggagtct gtggaccaga ggggcaacca 2340 gatcatgtct gacaagagga atgtgatcct gttctctgtg tttgatgaga acaggagctg 2400 gtacctgact gagaacatcc agaggttcct gcccaaccct gctggggtgc agctggagga 2460 ccctgagttc caggccagca acatcatgca cagcatcaat ggctatgtgt ttgacagcct 2520 gcagctgtct gtgtgcctgc atgaggtggc ctactggtac atcctgagca ttggggccca 2580 gactgacttc ctgtctgtgt tcttctctgg ctacaccttc aagcacaaga tggtgtatga 2640 ggacaccctg accctgttcc ccttctctgg ggagactgtg ttcatgagca tggagaaccc 2700 tggcctgtgg attctgggct gccacaactc tgacttcagg aacaggggca tgactgccct 2760 gctgaaagtc tccagctgtg acaagaacac tggggactac tatgaggaca gctatgagga 2820 catctctgcc tacctgctga gcaagaacaa tgccattgag cccaggagct tcagccagaa 2880 ccccccagtg ctgaagaggc accagaggga gatcaccagg accaccctgc agtctgacca 2940 ggaggagatt gactatgatg acaccatctc tgtggagatg aagaaggagg actttgacat 3000 ctacgacgag gacgagaacc agagccccag gagcttccag aagaagacca ggcactactt 3060 cattgctgct gtggagaggc tgtgggacta tggcatgagc agcagccccc atgtgctgag 3120 gaacagggcc cagtctggct ctgtgcccca gttcaagaag gtggtgttcc aggagttcac 3180 tgatggcagc ttcacccagc ccctgtacag aggggagctg aatgagcacc tgggcctgct 3240 gggcccctac atcagggctg aggtggagga caacatcatg gtgaccttca ggaaccaggc 3300 cagcaggccc tacagcttct acagcagcct gatcagctat gaggaggacc agaggcaggg 3360 ggctgagccc aggaagaact ttgtgaagcc caatgaaacc aagacctact tctggaaggt 3420 gcagcaccac atggccccca ccaaggatga gtttgactgc aaggcctggg cctacttctc 3480 tgatgtggac ctggagaagg atgtgcactc tggcctgatt ggccccctgc tggtgtgcca 3540 caccaacacc ctgaaccctg cccatggcag gcaggtgact gtgcaggagt ttgccctgtt 3600 cttcaccatc tttgatgaaa ccaagagctg gtacttcact gagaacatgg agaggaactg 3660 cagggccccc tgcaacatcc agatggagga ccccaccttc aaggagaact acaggttcca 3720 tgccatcaat ggctacatca tggacaccct gcctggcctg gtgatggccc aggaccagag 3780 gatcaggtgg tacctgctga gcatgggcag caatgagaac atccacagca tccacttctc 3840 tggccatgtg ttcactgtga ggaagaagga ggagtacaag atggccctgt acaacctgta 3900 ccctggggtg tttgagactg tggagatgct gcccagcaag gctggcatct ggagggtgga 3960 gtgcctgatt ggggagcacc tgcatgctgg catgagcacc ctgttcctgg tgtacagcaa 4020 caagtgccag acccccctgg gcatggcctc tggccacatc agggacttcc agatcactgc 4080 ctctggccag tatggccagt gggcccccaa gctggccagg ctgcactact ctggcagcat 4140 caatgcctgg agcaccaagg agcccttcag ctggatcaag gtggacctgc tggcccccat 4200 gatcatccat ggcatcaaga cccagggggc caggcagaag ttcagcagcc tgtacatcag 4260 ccagttcatc atcatgtaca gcctggatgg caagaagtgg cagacctaca ggggcaacag 4320 cactggcacc ctgatggtgt tctttggcaa tgtggacagc tctggcatca agcacaacat 4380 cttcaacccc cccatcattg ccagatacat caggctgcac cccacccact acagcatcag 4440 gagcaccctg aggatggagc tgatgggctg tgacctgaac agctgcagca tgcccctggg 4500 catggagagc aaggccatct ctgatgccca gatcactgcc agcagctact tcaccaacat 4560 gtttgccacc tggagcccca gcaaggccag gctgcacctg cagggcagga gcaatgcctg 4620 gaggccccag gtcaacaacc ccaaggagtg gctgcaggtg gacttccaga agaccatgaa 4680 ggtgactggg gtgaccaccc agggggtgaa gagcctgctg accagcatgt atgtgaagga 4740 gttcctgatc agcagcagcc aggatggcca ccagtggacc ctgttcttcc agaatggcaa 4800 ggtgaaggtg ttccagggca accaggacag cttcacccct gtggtgaaca gcctggaccc 4860 ccccctgctg accagatacc tgaggattca cccccagagc tgggtgcacc agattgccct 4920 gaggatggag gtgctgggct gtgaggccca ggacctgtac tgacctcgag gaataaagga 4980 aatttatttt cattgcaata gtgtgttggt tttttgtgtc acgtggcggc cgcaggaacc 5040 cctagtgatg gagttggcca ctccctctct gcgcgctcgc tcgctcactg aggccgggcg 5100 accaaaggtc gcccgacgcc cgggctttgc ccgggcggcc tcagtgagcg agcgagcgcg 5160 cagagaggga gtggccaa 5178 <210> 36 <211> 5160 <212> DNA <213> Adeno-Associated Virus 2 <400> 36 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtt gtccctaaaa tgggcaaaca 180 ttgcaagcag caaacagcaa acatgtccct aaaatgggca aacattgcaa gcagcaaaca 240 gcaaacatgt ccctaaaatg ggcaaacatt gcaagcagca aacagcaaac atgtccctaa 300 aatgggcaaa cattgcaagc agcaaacagc aaacagtcga ctggacacag gacgctgtgg 360 tttctgagcc agggggcgac tcagatccca gccagtggac ttagcccctg tttgctcctc 420 cgataactgg ggtgaccttg gttaatattc accagcagcc tcccccgttg cccctctgga 480 tccactgctt aaatacggac gaggacaggg ccctgtctcc tcagcttcag gcaccaccac 540 tgacctggga cagtgaatcg cgatcgccac catgcagatt gagctgagca cctgcttctt 600 cctgtgcctg ctgaggttct gcttctctgc caccaggaga tactacctgg gggctgtgga 660 gctgagctgg gactacatgc agtctgacct gggggagctg cctgtggatg ccaggttccc 720 ccccagagtg cccaagagct tccccttcaa cacctctgtg gtgtacaaga agaccctgtt 780 tgtggagttc actgaccacc tgttcaacat tgccaagccc aggcccccct ggatgggcct 840 gctgggcccc accatccagg ctgaggtgta tgacactgtg gtgatcaccc tgaagaacat 900 ggccagccac cctgtgagcc tgcatgctgt gggggtgagc tactggaagg cctctgaggg 960 ggctgagtat gatgaccaga ccagccagag ggagaaggag gatgacaagg tgttccctgg 1020 gggcagccac acctatgtgt ggcaggtgct gaaggagaat ggccccatgg cctctgaccc 1080 cctgtgcctg acctacagct acctgagcca tgtggacctg gtgaaggacc tgaactctgg 1140 cctgattggg gccctgctgg tgtgcaggga gggcagcctg gccaaggaga agacccagac 1200 cctgcacaag ttcatcctgc tgtttgctgt gtttgatgag ggcaagagct ggcactctga 1260 aaccaagaac agcctgatgc aggacaggga tgctgcctct gccagggcct ggcccaagat 1320 gcacactgtg aatggctatg tgaacaggag cctgcctggc ctgattggct gccacaggaa 1380 gtctgtgtac tggcatgtga ttggcatggg caccacccct gaggtgcaca gcatcttcct 1440 ggagggccac accttcctgg tcaggaacca caggcaggcc agcctggaga tcagccccat 1500 caccttcctg actgcccaga ccctgctgat ggacctgggc cagttcctgc tgttctgcca 1560 catcagcagc caccagcatg atggcatgga ggcctatgtg aaggtggaca gctgccctga 1620 ggagccccag ctgaggatga agaacaatga ggaggctgag gactatgatg atgacctgac 1680 tgactctgag atggatgtgg tgaggtttga tgatgacaac agccccagct tcatccagat 1740 caggtctgtg gccaagaagc accccaagac ctgggtgcac tacattgctg ctgaggagga 1800 ggactgggac tatgcccccc tggtgctggc ccctgatgac aggagctaca agagccagta 1860 cctgaacaat ggcccccaga ggattggcag gaagtacaag aaggtcaggt tcatggccta 1920 cactgatgaa accttcaaga ccagggaggc catccagcat gagtctggca tcctgggccc 1980 cctgctgtat ggggaggtgg gggacaccct gctgatcatc ttcaagaacc aggccagcag 2040 gccctacaac atctaccccc atggcatcac tgatgtgagg cccctgtaca gcaggaggct 2100 gcccaagggg gtgaagcacc tgaaggactt ccccatcctg cctggggaga tcttcaagta 2160 caagtggact gtgactgtgg aggatggccc caccaagtct gaccccaggt gcctgaccag 2220 atactacagc agctttgtga acatggagag ggacctggcc tctggcctga ttggccccct 2280 gctgatctgc tacaaggagt ctgtggacca gaggggcaac cagatcatgt ctgacaagag 2340 gaatgtgatc ctgttctctg tgtttgatga gaacaggagc tggtacctga ctgagaacat 2400 ccagaggttc ctgcccaacc ctgctggggt gcagctggag gaccctgagt tccaggccag 2460 caacatcatg cacagcatca atggctatgt gtttgacagc ctgcagctgt ctgtgtgcct 2520 gcatgaggtg gcctactggt acatcctgag cattggggcc cagactgact tcctgtctgt 2580 gttcttctct ggctacacct tcaagcacaa gatggtgtat gaggacaccc tgaccctgtt 2640 ccccttctct ggggagactg tgttcatgag catggagaac cctggcctgt ggattctggg 2700 ctgccacaac tctgacttca ggaacagggg catgactgcc ctgctgaaag tctccagctg 2760 tgacaagaac actggggact actatgagga cagctatgag gacatctctg cctacctgct 2820 gagcaagaac aatgccattg agcccaggag cttcagccag aaccccccag tgctgaagag 2880 gcaccagagg gagatcacca ggaccaccct gcagtctgac caggaggaga ttgactatga 2940 tgacaccatc tctgtggaga tgaagaagga ggactttgac atctacgacg aggacgagaa 3000 ccagagcccc aggagcttcc agaagaagac caggcactac ttcattgctg ctgtggagag 3060 gctgtgggac tatggcatga gcagcagccc ccatgtgctg aggaacaggg cccagtctgg 3120 ctctgtgccc cagttcaaga aggtggtgtt ccaggagttc actgatggca gcttcaccca 3180 gcccctgtac agaggggagc tgaatgagca cctgggcctg ctgggcccct acatcagggc 3240 tgaggtggag gacaacatca tggtgacctt caggaaccag gccagcaggc cctacagctt 3300 ctacagcagc ctgatcagct atgaggagga ccagaggcag ggggctgagc ccaggaagaa 3360 ctttgtgaag cccaatgaaa ccaagaccta cttctggaag gtgcagcacc acatggcccc 3420 caccaaggat gagtttgact gcaaggcctg ggcctacttc tctgatgtgg acctggagaa 3480 ggatgtgcac tctggcctga ttggccccct gctggtgtgc cacaccaaca ccctgaaccc 3540 tgcccatggc aggcaggtga ctgtgcagga gtttgccctg ttcttcacca tctttgatga 3600 aaccaagagc tggtacttca ctgagaacat ggagaggaac tgcagggccc cctgcaacat 3660 ccagatggag gaccccacct tcaaggagaa ctacaggttc catgccatca atggctacat 3720 catggacacc ctgcctggcc tggtgatggc ccaggaccag aggatcaggt ggtacctgct 3780 gagcatgggc agcaatgaga acatccacag catccacttc tctggccatg tgttcactgt 3840 gaggaagaag gaggagtaca agatggccct gtacaacctg taccctgggg tgtttgagac 3900 tgtggagatg ctgcccagca aggctggcat ctggagggtg gagtgcctga ttggggagca 3960 cctgcatgct ggcatgagca ccctgttcct ggtgtacagc aacaagtgcc agacccccct 4020 gggcatggcc tctggccaca tcagggactt ccagatcact gcctctggcc agtatggcca 4080 gtgggccccc aagctggcca ggctgcacta ctctggcagc atcaatgcct ggagcaccaa 4140 ggagcccttc agctggatca aggtggacct gctggccccc atgatcatcc atggcatcaa 4200 gacccagggg gccaggcaga agttcagcag cctgtacatc agccagttca tcatcatgta 4260 cagcctggat ggcaagaagt ggcagaccta caggggcaac agcactggca ccctgatggt 4320 gttctttggc aatgtggaca gctctggcat caagcacaac atcttcaacc cccccatcat 4380 tgccagatac atcaggctgc accccaccca ctacagcatc aggagcaccc tgaggatgga 4440 gctgatgggc tgtgacctga acagctgcag catgcccctg ggcatggaga gcaaggccat 4500 ctctgatgcc cagatcactg ccagcagcta cttcaccaac atgtttgcca cctggagccc 4560 cagcaaggcc aggctgcacc tgcagggcag gagcaatgcc tggaggcccc aggtcaacaa 4620 ccccaaggag tggctgcagg tggacttcca gaagaccatg aaggtgactg gggtgaccac 4680 ccagggggtg aagagcctgc tgaccagcat gtatgtgaag gagttcctga tcagcagcag 4740 ccaggatggc caccagtgga ccctgttctt ccagaatggc aaggtgaagg tgttccaggg 4800 caaccaggac agcttcaccc ctgtggtgaa cagcctggac ccccccctgc tgaccagata 4860 cctgaggatt cacccccaga gctgggtgca ccagattgcc ctgaggatgg aggtgctggg 4920 ctgtgaggcc caggacctgt actgacctcg aggaataaag gaaatttatt ttcattgcaa 4980 tagtgtgttg gttttttgtg tcacgtggcg gccgcaggaa cccctagtga tggagttggc 5040 cactccctct ctgcgcgctc gctcgctcac tgaggccggg cgaccaaagg tcgcccgacg 5100 cccgggcttt gcccgggcgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa 5160 5160 <210> 37 <211> 5383 <212> DNA <213> Adeno-Associated Virus 2 <400> 37 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ttttcgactg tttgctgttt 180 gctgcttgca atgtttgccc attttaggga catgtttgct gtttgctgct tgcaatgttt 240 gcccatttta gggacatgtt tgctgtttgc tgcttgcaat gtttgcccat tttagggaca 300 tgtttgctgt ttgctgcttg caatgtttgc ccattttagg gacaacgcga aacgtcgact 360 ggacacagga cgctgtggtt tctgagccag ggggcgactc agatcccagc cagtggactt 420 agcccctgtt tgctcctccg ataactgggg tgaccttggt taatattcac cagcagcctc 480 ccccgttgcc cctctggatc cactgcttaa atacggacga ggacagggcc ctgtctcctc 540 agcttcaggc accaccactg acctgggaca gtgaatcgta agtatgcctt tcactgcgag 600 aggttctgga gaggcttctg agctccccat ggcccaggca ggcagcaggt ctggggcagg 660 aggggggttg tggagtgcct tgactcgggg cctggccccc ccatctctgt cttgcaggac 720 aattgccgtc ttctgtctcg tggggcatcc tcctgctggc aggcctgtgc tgcctggtcc 780 ctgcgatcgc caccatgcag attgagctga gcacctgctt cttcctgtgc ctgctgaggt 840 tctgcttctc tgccaccagg agatactacc tgggggctgt ggagctgagc tgggactaca 900 tgcagtctga cctgggggag ctgcctgtgg atgccaggtt cccccccaga gtgcccaaga 960 gcttcccctt caacacctct gtggtgtaca agaagaccct gtttgtggag ttcactgacc 1020 acctgttcaa cattgccaag cccaggcccc cctggatggg cctgctgggc cccaccatcc 1080 aggctgaggt gtatgacact gtggtgatca ccctgaagaa catggccagc caccctgtga 1140 gcctgcatgc tgtgggggtg agctactgga aggcctctga gggggctgag tatgatgacc 1200 agaccagcca gagggagaag gaggatgaca aggtgttccc tgggggcagc cacacctatg 1260 tgtggcaggt gctgaaggag aatggcccca tggcctctga ccccctgtgc ctgacctaca 1320 gctacctgag ccatgtggac ctggtgaagg acctgaactc tggcctgatt ggggccctgc 1380 tggtgtgcag ggagggcagc ctggccaagg agaagaccca gaccctgcac aagttcatcc 1440 tgctgtttgc tgtgtttgat gagggcaaga gctggcactc tgaaaccaag aacagcctga 1500 tgcaggacag ggatgctgcc tctgccaggg cctggcccaa gatgcacact gtgaatggct 1560 atgtgaacag gagcctgcct ggcctgattg gctgccacag gaagtctgtg tactggcatg 1620 tgattggcat gggcaccacc cctgaggtgc acagcatctt cctggagggc cacaccttcc 1680 tggtcaggaa ccacaggcag gccagcctgg agatcagccc catcaccttc ctgactgccc 1740 agaccctgct gatggacctg ggccagttcc tgctgttctg ccacatcagc agccaccagc 1800 atgatggcat ggaggcctat gtgaaggtgg acagctgccc tgaggagccc cagctgagga 1860 tgaagaacaa tgaggaggct gaggactatg atgatgacct gactgactct gagatggatg 1920 tggtgaggtt tgatgatgac aacagcccca gcttcatcca gatcaggtct gtggccaaga 1980 agcaccccaa gacctgggtg cactacattg ctgctgagga ggaggactgg gactatgccc 2040 ccctggtgct ggcccctgat gacaggagct acaagagcca gtacctgaac aatggccccc 2100 agaggattgg caggaagtac aagaaggtca ggttcatggc ctacactgat gaaaccttca 2160 agaccaggga ggccatccag catgagtctg gcatcctggg ccccctgctg tatggggagg 2220 tgggggacac cctgctgatc atcttcaaga accaggccag caggccctac aacatctacc 2280 cccatggcat cactgatgtg aggcccctgt acagcaggag gctgcccaag ggggtgaagc 2340 acctgaagga cttccccatc ctgcctgggg agatcttcaa gtacaagtgg actgtgactg 2400 tggaggatgg ccccaccaag tctgacccca ggtgcctgac cagatactac agcagctttg 2460 tgaacatgga gagggacctg gcctctggcc tgattggccc cctgctgatc tgctacaagg 2520 agtctgtgga ccagaggggc aaccagatca tgtctgacaa gaggaatgtg atcctgttct 2580 ctgtgtttga tgagaacagg agctggtacc tgactgagaa catccagagg ttcctgccca 2640 accctgctgg ggtgcagctg gaggaccctg agttccaggc cagcaacatc atgcacagca 2700 tcaatggcta tgtgtttgac agcctgcagc tgtctgtgtg cctgcatgag gtggcctact 2760 ggtacatcct gagcattggg gcccagactg acttcctgtc tgtgttcttc tctggctaca 2820 ccttcaagca caagatggtg tatgaggaca ccctgaccct gttccccttc tctggggaga 2880 ctgtgttcat gagcatggag aaccctggcc tgtggattct gggctgccac aactctgact 2940 tcaggaacag gggcatgact gccctgctga aagtctccag ctgtgacaag aacactgggg 3000 actactatga ggacagctat gaggacatct ctgcctacct gctgagcaag aacaatgcca 3060 ttgagcccag gagcttcagc cagaaccccc cagtgctgaa gaggcaccag agggagatca 3120 ccaggaccac cctgcagtct gaccaggagg agattgacta tgatgacacc atctctgtgg 3180 agatgaagaa ggaggacttt gacatctacg acgaggacga gaaccagagc cccaggagct 3240 tccagaagaa gaccaggcac tacttcattg ctgctgtgga gaggctgtgg gactatggca 3300 tgagcagcag cccccatgtg ctgaggaaca gggcccagtc tggctctgtg ccccagttca 3360 agaaggtggt gttccaggag ttcactgatg gcagcttcac ccagcccctg tacagagggg 3420 agctgaatga gcacctgggc ctgctgggcc cctacatcag ggctgaggtg gaggacaaca 3480 tcatggtgac cttcaggaac caggccagca ggccctacag cttctacagc agcctgatca 3540 gctatgagga ggaccagagg cagggggctg agcccaggaa gaactttgtg aagcccaatg 3600 aaaccaagac ctacttctgg aaggtgcagc accacatggc ccccaccaag gatgagtttg 3660 actgcaaggc ctgggcctac ttctctgatg tggacctgga gaaggatgtg cactctggcc 3720 tgattggccc cctgctggtg tgccacacca acaccctgaa ccctgcccat ggcaggcagg 3780 tgactgtgca ggagtttgcc ctgttcttca ccatctttga tgaaaccaag agctggtact 3840 tcactgagaa catggagagg aactgcaggg ccccctgcaa catccagatg gaggacccca 3900 ccttcaagga gaactacagg ttccatgcca tcaatggcta catcatggac accctgcctg 3960 gcctggtgat ggcccaggac cagaggatca ggtggtacct gctgagcatg ggcagcaatg 4020 agaacatcca cagcatccac ttctctggcc atgtgttcac tgtgaggaag aaggaggagt 4080 acaagatggc cctgtacaac ctgtaccctg gggtgtttga gactgtggag atgctgccca 4140 gcaaggctgg catctggagg gtggagtgcc tgattgggga gcacctgcat gctggcatga 4200 gcaccctgtt cctggtgtac agcaacaagt gccagacccc cctgggcatg gcctctggcc 4260 acatcaggga cttccagatc actgcctctg gccagtatgg ccagtgggcc cccaagctgg 4320 ccaggctgca ctactctggc agcatcaatg cctggagcac caaggagccc ttcagctgga 4380 tcaaggtgga cctgctggcc cccatgatca tccatggcat caagacccag ggggccaggc 4440 agaagttcag cagcctgtac atcagccagt tcatcatcat gtacagcctg gatggcaaga 4500 agtggcagac ctacaggggc aacagcactg gcaccctgat ggtgttcttt ggcaatgtgg 4560 acagctctgg catcaagcac aacatcttca acccccccat cattgccaga tacatcaggc 4620 tgcaccccac ccactacagc atcaggagca ccctgaggat ggagctgatg ggctgtgacc 4680 tgaacagctg cagcatgccc ctgggcatgg agagcaaggc catctctgat gcccagatca 4740 ctgccagcag ctacttcacc aacatgtttg ccacctggag ccccagcaag gccaggctgc 4800 acctgcaggg caggagcaat gcctggaggc cccaggtcaa caaccccaag gagtggctgc 4860 aggtggactt ccagaagacc atgaaggtga ctggggtgac cacccagggg gtgaagagcc 4920 tgctgaccag catgtatgtg aaggagttcc tgatcagcag cagccaggat ggccaccagt 4980 ggaccctgtt cttccagaat ggcaaggtga aggtgttcca gggcaaccag gacagcttca 5040 cccctgtggt gaacagcctg gacccccccc tgctgaccag atacctgagg attcaccccc 5100 agagctgggt gcaccagatt gccctgagga tggaggtgct gggctgtgag gcccaggacc 5160 tgtactgacc tcgaggaata aaggaaattt attttcattg caatagtgtg ttggtttttt 5220 gtgtcacgtg gcggccgcag gaacccctag tgatggagtt ggccactccc tctctgcgcg 5280 ctcgctcgct cactgaggcc gggcgaccaa aggtcgcccg acgcccgggc tttgcccggg 5340 cggcctcagt gagcgagcga gcgcgcagag agggagtggc caa 5383 <210> 38 <211> 5728 <212> DNA <213> Adeno-Associated Virus 2 <400> 38 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ttttcgactg tttgctgttt 180 gctgcttgca atgtttgccc attttaggga catgtttgct gtttgctgct tgcaatgttt 240 gcccatttta gggacatgtt tgctgtttgc tgcttgcaat gtttgcccat tttagggaca 300 tgtttgctgt ttgctgcttg caatgtttgc ccattttagg gacaacgcga aacgtcgaca 360 ggttaatttt taaaaagcag tcaaaagtcc aagtggccct tggcagcatt tactctctct 420 gtttgctctg gttaataatc tcaggagcac aaacattcct ggaggcagga gaagaaatca 480 acatcctgga cttatcctct gggcctctcc ccacccccag gagaggctca ggttaatttt 540 taaaaagcag tcaaaagtcc aagtggccct tggcagcatt tactctctct gtttgctctg 600 gttaataatc tcaggagcac aaacattcct ggaggcagga gaagaaatca acatcctgga 660 cttatcctct gggcctctcc ccacccccag gagaggctgt cgactggaca caggacgctg 720 tggtttctga gccagggggc gactcagatc ccagccagtg gacttagccc ctgtttgctc 780 ctccgataac tggggtgacc ttggttaata ttcaccagca gcctcccccg ttgcccctct 840 ggatccactg cttaaatacg gacgaggaca gggccctgtc tcctcagctt caggcaccac 900 cactgacctg ggacagtgaa tcgtaagtat gcctttcact gcgagaggtt ctggagaggc 960 ttctgagctc cccatggccc aggcaggcag caggtctggg gcaggagggg ggttgtggag 1020 tgccttgact cggggcctgg cccccccatc tctgtcttgc aggacaattg ccgtcttctg 1080 tctcgtgggg catcctcctg ctggcaggcc tgtgctgcct ggtccctgcg atcgccacca 1140 tgcagattga gctgagcacc tgcttcttcc tgtgcctgct gaggttctgc ttctctgcca 1200 ccaggagata ctacctgggg gctgtggagc tgagctggga ctacatgcag tctgacctgg 1260 gggagctgcc tgtggatgcc aggttccccc ccagagtgcc caagagcttc cccttcaaca 1320 cctctgtggt gtacaagaag accctgtttg tggagttcac tgaccacctg ttcaacattg 1380 ccaagcccag gcccccctgg atgggcctgc tgggccccac catccaggct gaggtgtatg 1440 acactgtggt gatcaccctg aagaacatgg ccagccaccc tgtgagcctg catgctgtgg 1500 gggtgagcta ctggaaggcc tctgaggggg ctgagtatga tgaccagacc agccagaggg 1560 agaaggagga tgacaaggtg ttccctgggg gcagccacac ctatgtgtgg caggtgctga 1620 aggagaatgg ccccatggcc tctgaccccc tgtgcctgac ctacagctac ctgagccatg 1680 tggacctggt gaaggacctg aactctggcc tgattggggc cctgctggtg tgcagggagg 1740 gcagcctggc caaggagaag acccagaccc tgcacaagtt catcctgctg tttgctgtgt 1800 ttgatgaggg caagagctgg cactctgaaa ccaagaacag cctgatgcag gacagggatg 1860 ctgcctctgc cagggcctgg cccaagatgc acactgtgaa tggctatgtg aacaggagcc 1920 tgcctggcct gattggctgc cacaggaagt ctgtgtactg gcatgtgatt ggcatgggca 1980 ccacccctga ggtgcacagc atcttcctgg agggccacac cttcctggtc aggaaccaca 2040 ggcaggccag cctggagatc agccccatca ccttcctgac tgcccagacc ctgctgatgg 2100 acctgggcca gttcctgctg ttctgccaca tcagcagcca ccagcatgat ggcatggagg 2160 cctatgtgaa ggtggacagc tgccctgagg agccccagct gaggatgaag aacaatgagg 2220 aggctgagga ctatgatgat gacctgactg actctgagat ggatgtggtg aggtttgatg 2280 atgacaacag ccccagcttc atccagatca ggtctgtggc caagaagcac cccaagacct 2340 gggtgcacta cattgctgct gaggaggagg actgggacta tgcccccctg gtgctggccc 2400 ctgatgacag gagctacaag agccagtacc tgaacaatgg cccccagagg attggcagga 2460 agtacaagaa ggtcaggttc atggcctaca ctgatgaaac cttcaagacc agggaggcca 2520 tccagcatga gtctggcatc ctgggccccc tgctgtatgg ggaggtgggg gacaccctgc 2580 tgatcatctt caagaaccag gccagcaggc cctacaacat ctacccccat ggcatcactg 2640 atgtgaggcc cctgtacagc aggaggctgc ccaagggggt gaagcacctg aaggacttcc 2700 ccatcctgcc tggggagatc ttcaagtaca agtggactgt gactgtggag gatggcccca 2760 ccaagtctga ccccaggtgc ctgaccagat actacagcag ctttgtgaac atggagaggg 2820 acctggcctc tggcctgatt ggccccctgc tgatctgcta caaggagtct gtggaccaga 2880 ggggcaacca gatcatgtct gacaagagga atgtgatcct gttctctgtg tttgatgaga 2940 acaggagctg gtacctgact gagaacatcc agaggttcct gcccaaccct gctggggtgc 3000 agctggagga ccctgagttc caggccagca acatcatgca cagcatcaat ggctatgtgt 3060 ttgacagcct gcagctgtct gtgtgcctgc atgaggtggc ctactggtac atcctgagca 3120 ttggggccca gactgacttc ctgtctgtgt tcttctctgg ctacaccttc aagcacaaga 3180 tggtgtatga ggacaccctg accctgttcc ccttctctgg ggagactgtg ttcatgagca 3240 tggagaaccc tggcctgtgg attctgggct gccacaactc tgacttcagg aacaggggca 3300 tgactgccct gctgaaagtc tccagctgtg acaagaacac tggggactac tatgaggaca 3360 gctatgagga catctctgcc tacctgctga gcaagaacaa tgccattgag cccaggagct 3420 tcagccagaa ccccccagtg ctgaagaggc accagaggga gatcaccagg accaccctgc 3480 agtctgacca ggaggagatt gactatgatg acaccatctc tgtggagatg aagaaggagg 3540 actttgacat ctacgacgag gacgagaacc agagccccag gagcttccag aagaagacca 3600 ggcactactt cattgctgct gtggagaggc tgtgggacta tggcatgagc agcagccccc 3660 atgtgctgag gaacagggcc cagtctggct ctgtgcccca gttcaagaag gtggtgttcc 3720 aggagttcac tgatggcagc ttcacccagc ccctgtacag aggggagctg aatgagcacc 3780 tgggcctgct gggcccctac atcagggctg aggtggagga caacatcatg gtgaccttca 3840 ggaaccaggc cagcaggccc tacagcttct acagcagcct gatcagctat gaggaggacc 3900 agaggcaggg ggctgagccc aggaagaact ttgtgaagcc caatgaaacc aagacctact 3960 tctggaaggt gcagcaccac atggccccca ccaaggatga gtttgactgc aaggcctggg 4020 cctacttctc tgatgtggac ctggagaagg atgtgcactc tggcctgatt ggccccctgc 4080 tggtgtgcca caccaacacc ctgaaccctg cccatggcag gcaggtgact gtgcaggagt 4140 ttgccctgtt cttcaccatc tttgatgaaa ccaagagctg gtacttcact gagaacatgg 4200 agaggaactg cagggccccc tgcaacatcc agatggagga ccccaccttc aaggagaact 4260 acaggttcca tgccatcaat ggctacatca tggacaccct gcctggcctg gtgatggccc 4320 aggaccagag gatcaggtgg tacctgctga gcatgggcag caatgagaac atccacagca 4380 tccacttctc tggccatgtg ttcactgtga ggaagaagga ggagtacaag atggccctgt 4440 acaacctgta ccctggggtg tttgagactg tggagatgct gcccagcaag gctggcatct 4500 ggagggtgga gtgcctgatt ggggagcacc tgcatgctgg catgagcacc ctgttcctgg 4560 tgtacagcaa caagtgccag acccccctgg gcatggcctc tggccacatc agggacttcc 4620 agatcactgc ctctggccag tatggccagt gggcccccaa gctggccagg ctgcactact 4680 ctggcagcat caatgcctgg agcaccaagg agcccttcag ctggatcaag gtggacctgc 4740 tggcccccat gatcatccat ggcatcaaga cccagggggc caggcagaag ttcagcagcc 4800 tgtacatcag ccagttcatc atcatgtaca gcctggatgg caagaagtgg cagacctaca 4860 ggggcaacag cactggcacc ctgatggtgt tctttggcaa tgtggacagc tctggcatca 4920 agcacaacat cttcaacccc cccatcattg ccagatacat caggctgcac cccacccact 4980 acagcatcag gagcaccctg aggatggagc tgatgggctg tgacctgaac agctgcagca 5040 tgcccctggg catggagagc aaggccatct ctgatgccca gatcactgcc agcagctact 5100 tcaccaacat gtttgccacc tggagcccca gcaaggccag gctgcacctg cagggcagga 5160 gcaatgcctg gaggccccag gtcaacaacc ccaaggagtg gctgcaggtg gacttccaga 5220 agaccatgaa ggtgactggg gtgaccaccc agggggtgaa gagcctgctg accagcatgt 5280 atgtgaagga gttcctgatc agcagcagcc aggatggcca ccagtggacc ctgttcttcc 5340 agaatggcaa ggtgaaggtg ttccagggca accaggacag cttcacccct gtggtgaaca 5400 gcctggaccc ccccctgctg accagatacc tgaggattca cccccagagc tgggtgcacc 5460 agattgccct gaggatggag gtgctgggct gtgaggccca ggacctgtac tgacctcgag 5520 gaataaagga aatttatttt cattgcaata gtgtgttggt tttttgtgtc acgtggcggc 5580 cgcaggaacc cctagtgatg gagttggcca ctccctctct gcgcgctcgc tcgctcactg 5640 aggccgggcg accaaaggtc gcccgacgcc cgggctttgc ccgggcggcc tcagtgagcg 5700 agcgagcgcg cagagaggga gtggccaa 5728 <210> 39 <211> 5905 <212> DNA <213> Adeno-Associated Virus 2 <400> 39 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ttttcgactg tttgctgttt 180 gctgcttgca atgtttgccc attttaggga catgtttgct gtttgctgct tgcaatgttt 240 gcccatttta gggacatgtt tgctgtttgc tgcttgcaat gtttgcccat tttagggaca 300 tgtttgctgt ttgctgcttg caatgtttgc ccattttagg gacaacgcga aacgtcgaca 360 ggttaatttt taaaaagcag tcaaaagtcc aagtggccct tggcagcatt tactctctct 420 gtttgctctg gttaataatc tcaggagcac aaacattcct ggaggcagga gaagaaatca 480 acatcctgga cttatcctct gggcctctcc ccacccccag gagaggctca ggttaatttt 540 taaaaagcag tcaaaagtcc aagtggccct tggcagcatt tactctctct gtttgctctg 600 gttaataatc tcaggagcac aaacattcct ggaggcagga gaagaaatca acatcctgga 660 cttatcctct gggcctctcc ccacccccag gagaggctgt cgactggaca caggacgctg 720 tggtttctga gccagggggc gactcagatc ccagccagtg gacttagccc ctgtttgctc 780 ctccgataac tggggtgacc ttggttaata ttcaccagca gcctcccccg ttgcccctct 840 ggatccactg cttaaatacg gacgaggaca gggccctgtc tcctcagctt caggcaccac 900 cactgacctg ggacagtgaa tcgtaagtat gcctttcact gcgagaggtt ctggagaggc 960 ttctgagctc cccatggccc aggcaggcag caggtctggg gcaggagggg ggttgtggag 1020 tgccttgact cggggcctgg cccccccatc tctgtcttgc aggacaattg ccgtcttctg 1080 tctcgtgggg catcctcctg ctggcaggcc tgtgctgcct ggtccctgcg atcgccacca 1140 tgcagattga gctgagcacc tgcttcttcc tgtgcctgct gaggttctgc ttctctgcca 1200 ccaggagata ctacctgggg gctgtggagc tgagctggga ctacatgcag tctgacctgg 1260 gggagctgcc tgtggatgcc aggttccccc ccagagtgcc caagagcttc cccttcaaca 1320 cctctgtggt gtacaagaag accctgtttg tggagttcac tgaccacctg ttcaacattg 1380 ccaagcccag gcccccctgg atgggcctgc tgggccccac catccaggct gaggtgtatg 1440 acactgtggt gatcaccctg aagaacatgg ccagccaccc tgtgagcctg catgctgtgg 1500 gggtgagcta ctggaaggcc tctgaggggg ctgagtatga tgaccagacc agccagaggg 1560 agaaggagga tgacaaggtg ttccctgggg gcagccacac ctatgtgtgg caggtgctga 1620 aggagaatgg ccccatggcc tctgaccccc tgtgcctgac ctacagctac ctgagccatg 1680 tggacctggt gaaggacctg aactctggcc tgattggggc cctgctggtg tgcagggagg 1740 gcagcctggc caaggagaag acccagaccc tgcacaagtt catcctgctg tttgctgtgt 1800 ttgatgaggg caagagctgg cactctgaaa ccaagaacag cctgatgcag gacagggatg 1860 ctgcctctgc cagggcctgg cccaagatgc acactgtgaa tggctatgtg aacaggagcc 1920 tgcctggcct gattggctgc cacaggaagt ctgtgtactg gcatgtgatt ggcatgggca 1980 ccacccctga ggtgcacagc atcttcctgg agggccacac cttcctggtc aggaaccaca 2040 ggcaggccag cctggagatc agccccatca ccttcctgac tgcccagacc ctgctgatgg 2100 acctgggcca gttcctgctg ttctgccaca tcagcagcca ccagcatgat ggcatggagg 2160 cctatgtgaa ggtggacagc tgccctgagg agccccagct gaggatgaag aacaatgagg 2220 aggctgagga ctatgatgat gacctgactg actctgagat ggatgtggtg aggtttgatg 2280 atgacaacag ccccagcttc atccagatca ggtctgtggc caagaagcac cccaagacct 2340 gggtgcacta cattgctgct gaggaggagg actgggacta tgcccccctg gtgctggccc 2400 ctgatgacag gagctacaag agccagtacc tgaacaatgg cccccagagg attggcagga 2460 agtacaagaa ggtcaggttc atggcctaca ctgatgaaac cttcaagacc agggaggcca 2520 tccagcatga gtctggcatc ctgggccccc tgctgtatgg ggaggtgggg gacaccctgc 2580 tgatcatctt caagaaccag gccagcaggc cctacaacat ctacccccat ggcatcactg 2640 atgtgaggcc cctgtacagc aggaggctgc ccaagggggt gaagcacctg aaggacttcc 2700 ccatcctgcc tggggagatc ttcaagtaca agtggactgt gactgtggag gatggcccca 2760 ccaagtctga ccccaggtgc ctgaccagat actacagcag ctttgtgaac atggagaggg 2820 acctggcctc tggcctgatt ggccccctgc tgatctgcta caaggagtct gtggaccaga 2880 ggggcaacca gatcatgtct gacaagagga atgtgatcct gttctctgtg tttgatgaga 2940 acaggagctg gtacctgact gagaacatcc agaggttcct gcccaaccct gctggggtgc 3000 agctggagga ccctgagttc caggccagca acatcatgca cagcatcaat ggctatgtgt 3060 ttgacagcct gcagctgtct gtgtgcctgc atgaggtggc ctactggtac atcctgagca 3120 ttggggccca gactgacttc ctgtctgtgt tcttctctgg ctacaccttc aagcacaaga 3180 tggtgtatga ggacaccctg accctgttcc ccttctctgg ggagactgtg ttcatgagca 3240 tggagaaccc tggcctgtgg attctgggct gccacaactc tgacttcagg aacaggggca 3300 tgactgccct gctgaaagtc tccagctgtg acaagaacac tggggactac tatgaggaca 3360 gctatgagga catctctgcc tacctgctga gcaagaacaa tgccattgag cccaggagct 3420 tcagccagaa ccccccagtg ctgaagaggc accagaggga gatcaccagg accaccctgc 3480 agtctgacca ggaggagatt gactatgatg acaccatctc tgtggagatg aagaaggagg 3540 actttgacat ctacgacgag gacgagaacc agagccccag gagcttccag aagaagacca 3600 ggcactactt cattgctgct gtggagaggc tgtgggacta tggcatgagc agcagccccc 3660 atgtgctgag gaacagggcc cagtctggct ctgtgcccca gttcaagaag gtggtgttcc 3720 aggagttcac tgatggcagc ttcacccagc ccctgtacag aggggagctg aatgagcacc 3780 tgggcctgct gggcccctac atcagggctg aggtggagga caacatcatg gtgaccttca 3840 ggaaccaggc cagcaggccc tacagcttct acagcagcct gatcagctat gaggaggacc 3900 agaggcaggg ggctgagccc aggaagaact ttgtgaagcc caatgaaacc aagacctact 3960 tctggaaggt gcagcaccac atggccccca ccaaggatga gtttgactgc aaggcctggg 4020 cctacttctc tgatgtggac ctggagaagg atgtgcactc tggcctgatt ggccccctgc 4080 tggtgtgcca caccaacacc ctgaaccctg cccatggcag gcaggtgact gtgcaggagt 4140 ttgccctgtt cttcaccatc tttgatgaaa ccaagagctg gtacttcact gagaacatgg 4200 agaggaactg cagggccccc tgcaacatcc agatggagga ccccaccttc aaggagaact 4260 acaggttcca tgccatcaat ggctacatca tggacaccct gcctggcctg gtgatggccc 4320 aggaccagag gatcaggtgg tacctgctga gcatgggcag caatgagaac atccacagca 4380 tccacttctc tggccatgtg ttcactgtga ggaagaagga ggagtacaag atggccctgt 4440 acaacctgta ccctggggtg tttgagactg tggagatgct gcccagcaag gctggcatct 4500 ggagggtgga gtgcctgatt ggggagcacc tgcatgctgg catgagcacc ctgttcctgg 4560 tgtacagcaa caagtgccag acccccctgg gcatggcctc tggccacatc agggacttcc 4620 agatcactgc ctctggccag tatggccagt gggcccccaa gctggccagg ctgcactact 4680 ctggcagcat caatgcctgg agcaccaagg agcccttcag ctggatcaag gtggacctgc 4740 tggcccccat gatcatccat ggcatcaaga cccagggggc caggcagaag ttcagcagcc 4800 tgtacatcag ccagttcatc atcatgtaca gcctggatgg caagaagtgg cagacctaca 4860 ggggcaacag cactggcacc ctgatggtgt tctttggcaa tgtggacagc tctggcatca 4920 agcacaacat cttcaacccc cccatcattg ccagatacat caggctgcac cccacccact 4980 acagcatcag gagcaccctg aggatggagc tgatgggctg tgacctgaac agctgcagca 5040 tgcccctggg catggagagc aaggccatct ctgatgccca gatcactgcc agcagctact 5100 tcaccaacat gtttgccacc tggagcccca gcaaggccag gctgcacctg cagggcagga 5160 gcaatgcctg gaggccccag gtcaacaacc ccaaggagtg gctgcaggtg gacttccaga 5220 agaccatgaa ggtgactggg gtgaccaccc agggggtgaa gagcctgctg accagcatgt 5280 atgtgaagga gttcctgatc agcagcagcc aggatggcca ccagtggacc ctgttcttcc 5340 agaatggcaa ggtgaaggtg ttccagggca accaggacag cttcacccct gtggtgaaca 5400 gcctggaccc ccccctgctg accagatacc tgaggattca cccccagagc tgggtgcacc 5460 agattgccct gaggatggag gtgctgggct gtgaggccca ggacctgtac tgacctcgag 5520 gtgtgccttc tagttgccag ccatctgttg tttgcccctc ccccgtgcct tccttgaccc 5580 tggaaggtgc cactcccact gtcctttcct aataaaatga ggaaattgca tcgcattgtc 5640 tgagtaggtg tcattctatt ctggggggtg gggtggggca ggacagcaag ggggaggatt 5700 gggaagacaa tagcaggcat gctggggatg cggtgggctc tatgggcacg tggcggccgc 5760 aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg 5820 ccgggcgacc aaaggtcgcc cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc 5880 gagcgcgcag agagggagtg gccaa 5905 <210> 40 <211> 5355 <212> DNA <213> Adeno-Associated Virus 2 <400> 40 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ttttcgactg tttgctgttt 180 gctgcttgca atgtttgccc attttaggga catgtttgct gtttgctgct tgcaatgttt 240 gcccatttta gggacatgtt tgctgtttgc tgcttgcaat gtttgcccat tttagggaca 300 tgtttgctgt ttgctgcttg caatgtttgc ccattttagg gacaacgcga aacgtcgact 360 ggacacagga cgctgtggtt tctgagccag ggggcgactc agatcccagc cagtggactt 420 agcccctgtt tgctcctccg ataactgggg tgaccttggt taatattcac cagcagcctc 480 ccccgttgcc cctctggatc cactgcttaa atacggacga ggacagggcc ctgtctcctc 540 agcttcaggc accaccactg acctgggaca gtgaatcgcg atcgccacca tgcagattga 600 gctgagcacc tgcttcttcc tgtgcctgct gaggttctgc ttctctgcca ccaggagata 660 ctacctgggg gctgtggagc tgagctggga ctacatgcag tctgacctgg gggagctgcc 720 tgtggatgcc aggttccccc ccagagtgcc caagagcttc cccttcaaca cctctgtggt 780 gtacaagaag accctgtttg tggagttcac tgaccacctg ttcaacattg ccaagcccag 840 gcccccctgg atgggcctgc tgggccccac catccaggct gaggtgtatg acactgtggt 900 gatcaccctg aagaacatgg ccagccaccc tgtgagcctg catgctgtgg gggtgagcta 960 ctggaaggcc tctgaggggg ctgagtatga tgaccagacc agccagaggg agaaggagga 1020 tgacaaggtg ttccctgggg gcagccacac ctatgtgtgg caggtgctga aggagaatgg 1080 ccccatggcc tctgaccccc tgtgcctgac ctacagctac ctgagccatg tggacctggt 1140 gaaggacctg aactctggcc tgattggggc cctgctggtg tgcagggagg gcagcctggc 1200 caaggagaag acccagaccc tgcacaagtt catcctgctg tttgctgtgt ttgatgaggg 1260 caagagctgg cactctgaaa ccaagaacag cctgatgcag gacagggatg ctgcctctgc 1320 cagggcctgg cccaagatgc acactgtgaa tggctatgtg aacaggagcc tgcctggcct 1380 gattggctgc cacaggaagt ctgtgtactg gcatgtgatt ggcatgggca ccacccctga 1440 ggtgcacagc atcttcctgg agggccacac cttcctggtc aggaaccaca ggcaggccag 1500 cctggagatc agccccatca ccttcctgac tgcccagacc ctgctgatgg acctgggcca 1560 gttcctgctg ttctgccaca tcagcagcca ccagcatgat ggcatggagg cctatgtgaa 1620 ggtggacagc tgccctgagg agccccagct gaggatgaag aacaatgagg aggctgagga 1680 ctatgatgat gacctgactg actctgagat ggatgtggtg aggtttgatg atgacaacag 1740 ccccagcttc atccagatca ggtctgtggc caagaagcac cccaagacct gggtgcacta 1800 cattgctgct gaggaggagg actgggacta tgcccccctg gtgctggccc ctgatgacag 1860 gagctacaag agccagtacc tgaacaatgg cccccagagg attggcagga agtacaagaa 1920 ggtcaggttc atggcctaca ctgatgaaac cttcaagacc agggaggcca tccagcatga 1980 gtctggcatc ctgggccccc tgctgtatgg ggaggtgggg gacaccctgc tgatcatctt 2040 caagaaccag gccagcaggc cctacaacat ctacccccat ggcatcactg atgtgaggcc 2100 cctgtacagc aggaggctgc ccaagggggt gaagcacctg aaggacttcc ccatcctgcc 2160 tggggagatc ttcaagtaca agtggactgt gactgtggag gatggcccca ccaagtctga 2220 ccccaggtgc ctgaccagat actacagcag ctttgtgaac atggagaggg acctggcctc 2280 tggcctgatt ggccccctgc tgatctgcta caaggagtct gtggaccaga ggggcaacca 2340 gatcatgtct gacaagagga atgtgatcct gttctctgtg tttgatgaga acaggagctg 2400 gtacctgact gagaacatcc agaggttcct gcccaaccct gctggggtgc agctggagga 2460 ccctgagttc caggccagca acatcatgca cagcatcaat ggctatgtgt ttgacagcct 2520 gcagctgtct gtgtgcctgc atgaggtggc ctactggtac atcctgagca ttggggccca 2580 gactgacttc ctgtctgtgt tcttctctgg ctacaccttc aagcacaaga tggtgtatga 2640 ggacaccctg accctgttcc ccttctctgg ggagactgtg ttcatgagca tggagaaccc 2700 tggcctgtgg attctgggct gccacaactc tgacttcagg aacaggggca tgactgccct 2760 gctgaaagtc tccagctgtg acaagaacac tggggactac tatgaggaca gctatgagga 2820 catctctgcc tacctgctga gcaagaacaa tgccattgag cccaggagct tcagccagaa 2880 ccccccagtg ctgaagaggc accagaggga gatcaccagg accaccctgc agtctgacca 2940 ggaggagatt gactatgatg acaccatctc tgtggagatg aagaaggagg actttgacat 3000 ctacgacgag gacgagaacc agagccccag gagcttccag aagaagacca ggcactactt 3060 cattgctgct gtggagaggc tgtgggacta tggcatgagc agcagccccc atgtgctgag 3120 gaacagggcc cagtctggct ctgtgcccca gttcaagaag gtggtgttcc aggagttcac 3180 tgatggcagc ttcacccagc ccctgtacag aggggagctg aatgagcacc tgggcctgct 3240 gggcccctac atcagggctg aggtggagga caacatcatg gtgaccttca ggaaccaggc 3300 cagcaggccc tacagcttct acagcagcct gatcagctat gaggaggacc agaggcaggg 3360 ggctgagccc aggaagaact ttgtgaagcc caatgaaacc aagacctact tctggaaggt 3420 gcagcaccac atggccccca ccaaggatga gtttgactgc aaggcctggg cctacttctc 3480 tgatgtggac ctggagaagg atgtgcactc tggcctgatt ggccccctgc tggtgtgcca 3540 caccaacacc ctgaaccctg cccatggcag gcaggtgact gtgcaggagt ttgccctgtt 3600 cttcaccatc tttgatgaaa ccaagagctg gtacttcact gagaacatgg agaggaactg 3660 cagggccccc tgcaacatcc agatggagga ccccaccttc aaggagaact acaggttcca 3720 tgccatcaat ggctacatca tggacaccct gcctggcctg gtgatggccc aggaccagag 3780 gatcaggtgg tacctgctga gcatgggcag caatgagaac atccacagca tccacttctc 3840 tggccatgtg ttcactgtga ggaagaagga ggagtacaag atggccctgt acaacctgta 3900 ccctggggtg tttgagactg tggagatgct gcccagcaag gctggcatct ggagggtgga 3960 gtgcctgatt ggggagcacc tgcatgctgg catgagcacc ctgttcctgg tgtacagcaa 4020 caagtgccag acccccctgg gcatggcctc tggccacatc agggacttcc agatcactgc 4080 ctctggccag tatggccagt gggcccccaa gctggccagg ctgcactact ctggcagcat 4140 caatgcctgg agcaccaagg agcccttcag ctggatcaag gtggacctgc tggcccccat 4200 gatcatccat ggcatcaaga cccagggggc caggcagaag ttcagcagcc tgtacatcag 4260 ccagttcatc atcatgtaca gcctggatgg caagaagtgg cagacctaca ggggcaacag 4320 cactggcacc ctgatggtgt tctttggcaa tgtggacagc tctggcatca agcacaacat 4380 cttcaacccc cccatcattg ccagatacat caggctgcac cccacccact acagcatcag 4440 gagcaccctg aggatggagc tgatgggctg tgacctgaac agctgcagca tgcccctggg 4500 catggagagc aaggccatct ctgatgccca gatcactgcc agcagctact tcaccaacat 4560 gtttgccacc tggagcccca gcaaggccag gctgcacctg cagggcagga gcaatgcctg 4620 gaggccccag gtcaacaacc ccaaggagtg gctgcaggtg gacttccaga agaccatgaa 4680 ggtgactggg gtgaccaccc agggggtgaa gagcctgctg accagcatgt atgtgaagga 4740 gttcctgatc agcagcagcc aggatggcca ccagtggacc ctgttcttcc agaatggcaa 4800 ggtgaaggtg ttccagggca accaggacag cttcacccct gtggtgaaca gcctggaccc 4860 ccccctgctg accagatacc tgaggattca cccccagagc tgggtgcacc agattgccct 4920 gaggatggag gtgctgggct gtgaggccca ggacctgtac tgacctcgag gtgtgccttc 4980 tagttgccag ccatctgttg tttgcccctc ccccgtgcct tccttgaccc tggaaggtgc 5040 cactcccact gtcctttcct aataaaatga ggaaattgca tcgcattgtc tgagtaggtg 5100 tcattctatt ctggggggtg gggtggggca ggacagcaag ggggaggatt gggaagacaa 5160 tagcaggcat gctggggatg cggtgggctc tatgggcacg tggcggccgc aggaacccct 5220 agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc 5280 aaaggtcgcc cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc gagcgcgcag 5340 agagggagtg gccaa 5355 <210> 41 <211> 5618 <212> DNA <213> Adeno-Associated Virus 2 <400> 41 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ttttcgacca gagaggtctc 180 tgacctctgc cccagctcca aggtcagcag gcagggaggg ctgtgtgttt gctgtttgct 240 gcttgcaatg tttgcccatt ttagggacat gagtaggctg aagtttgttc agtgtggact 300 tcagaggcag cacacaaaca gccagagagg tctctgacct ctgccccagc tccaaggtca 360 gcaggcaggg agggctgtgt gtttgctgtt tgctgcttgc aatgtttgcc cattttaggg 420 acatgagtag gctgaagttt gttcagtgtg gacttcagag gcagcacaca aacagccaga 480 gaggtctctg acctctgccc cagctccaag gtcagcaggc agggagggct gtgtgtttgc 540 tgtttgctgc ttgcaatgtt tgcccatttt agggacatga gtaggctgaa gtttgttcag 600 tgtggacttc agaggcagca cacaaacagc cagagaggtc tctgacctct gccccagctc 660 caaggtcagc aggcagggag ggctgtgtgt ttgctgtttg ctgcttgcaa tgtttgccca 720 ttttagggac atgagtaggc tgaagtttgt tcagtgtgga cttcagaggc agcacacaaa 780 cagcacgcga aacgtcgact ggacacagga cgctgtggtt tctgagccag ggggcgactc 840 agatcccagc cagtggactt agcccctgtt tgctcctccg ataactgggg tgaccttggt 900 taatattcac cagcagcctc ccccgttgcc cctctggatc cactgcttaa atacggacga 960 ggacagggcc ctgtctcctc agcttcaggc accaccactg acctgggaca gtgaatcgcg 1020 atcgccacca tgcagattga gctgagcacc tgcttcttcc tgtgcctgct gaggttctgc 1080 ttctctgcca ccaggagata ctacctgggg gctgtggagc tgagctggga ctacatgcag 1140 tctgacctgg gggagctgcc tgtggatgcc aggttccccc ccagagtgcc caagagcttc 1200 cccttcaaca cctctgtggt gtacaagaag accctgtttg tggagttcac tgaccacctg 1260 ttcaacattg ccaagcccag gcccccctgg atgggcctgc tgggccccac catccaggct 1320 gaggtgtatg acactgtggt gatcaccctg aagaacatgg ccagccaccc tgtgagcctg 1380 catgctgtgg gggtgagcta ctggaaggcc tctgaggggg ctgagtatga tgaccagacc 1440 agccagaggg agaaggagga tgacaaggtg ttccctgggg gcagccacac ctatgtgtgg 1500 caggtgctga aggagaatgg ccccatggcc tctgaccccc tgtgcctgac ctacagctac 1560 ctgagccatg tggacctggt gaaggacctg aactctggcc tgattggggc cctgctggtg 1620 tgcagggagg gcagcctggc caaggagaag acccagaccc tgcacaagtt catcctgctg 1680 tttgctgtgt ttgatgaggg caagagctgg cactctgaaa ccaagaacag cctgatgcag 1740 gacagggatg ctgcctctgc cagggcctgg cccaagatgc acactgtgaa tggctatgtg 1800 aacaggagcc tgcctggcct gattggctgc cacaggaagt ctgtgtactg gcatgtgatt 1860 ggcatgggca ccacccctga ggtgcacagc atcttcctgg agggccacac cttcctggtc 1920 aggaaccaca ggcaggccag cctggagatc agccccatca ccttcctgac tgcccagacc 1980 ctgctgatgg acctgggcca gttcctgctg ttctgccaca tcagcagcca ccagcatgat 2040 ggcatggagg cctatgtgaa ggtggacagc tgccctgagg agccccagct gaggatgaag 2100 aacaatgagg aggctgagga ctatgatgat gacctgactg actctgagat ggatgtggtg 2160 aggtttgatg atgacaacag ccccagcttc atccagatca ggtctgtggc caagaagcac 2220 cccaagacct gggtgcacta cattgctgct gaggaggagg actgggacta tgcccccctg 2280 gtgctggccc ctgatgacag gagctacaag agccagtacc tgaacaatgg cccccagagg 2340 attggcagga agtacaagaa ggtcaggttc atggcctaca ctgatgaaac cttcaagacc 2400 agggaggcca tccagcatga gtctggcatc ctgggccccc tgctgtatgg ggaggtgggg 2460 gacaccctgc tgatcatctt caagaaccag gccagcaggc cctacaacat ctacccccat 2520 ggcatcactg atgtgaggcc cctgtacagc aggaggctgc ccaagggggt gaagcacctg 2580 aaggacttcc ccatcctgcc tggggagatc ttcaagtaca agtggactgt gactgtggag 2640 gatggcccca ccaagtctga ccccaggtgc ctgaccagat actacagcag ctttgtgaac 2700 atggagaggg acctggcctc tggcctgatt ggccccctgc tgatctgcta caaggagtct 2760 gtggaccaga ggggcaacca gatcatgtct gacaagagga atgtgatcct gttctctgtg 2820 tttgatgaga acaggagctg gtacctgact gagaacatcc agaggttcct gcccaaccct 2880 gctggggtgc agctggagga ccctgagttc caggccagca acatcatgca cagcatcaat 2940 ggctatgtgt ttgacagcct gcagctgtct gtgtgcctgc atgaggtggc ctactggtac 3000 atcctgagca ttggggccca gactgacttc ctgtctgtgt tcttctctgg ctacaccttc 3060 aagcacaaga tggtgtatga ggacaccctg accctgttcc ccttctctgg ggagactgtg 3120 ttcatgagca tggagaaccc tggcctgtgg attctgggct gccacaactc tgacttcagg 3180 aacaggggca tgactgccct gctgaaagtc tccagctgtg acaagaacac tggggactac 3240 tatgaggaca gctatgagga catctctgcc tacctgctga gcaagaacaa tgccattgag 3300 cccaggagct tcagccagaa ccccccagtg ctgaagaggc accagaggga gatcaccagg 3360 accaccctgc agtctgacca ggaggagatt gactatgatg acaccatctc tgtggagatg 3420 aagaaggagg actttgacat ctacgacgag gacgagaacc agagccccag gagcttccag 3480 aagaagacca ggcactactt cattgctgct gtggagaggc tgtgggacta tggcatgagc 3540 agcagccccc atgtgctgag gaacagggcc cagtctggct ctgtgcccca gttcaagaag 3600 gtggtgttcc aggagttcac tgatggcagc ttcacccagc ccctgtacag aggggagctg 3660 aatgagcacc tgggcctgct gggcccctac atcagggctg aggtggagga caacatcatg 3720 gtgaccttca ggaaccaggc cagcaggccc tacagcttct acagcagcct gatcagctat 3780 gaggaggacc agaggcaggg ggctgagccc aggaagaact ttgtgaagcc caatgaaacc 3840 aagacctact tctggaaggt gcagcaccac atggccccca ccaaggatga gtttgactgc 3900 aaggcctggg cctacttctc tgatgtggac ctggagaagg atgtgcactc tggcctgatt 3960 ggccccctgc tggtgtgcca caccaacacc ctgaaccctg cccatggcag gcaggtgact 4020 gtgcaggagt ttgccctgtt cttcaccatc tttgatgaaa ccaagagctg gtacttcact 4080 gagaacatgg agaggaactg cagggccccc tgcaacatcc agatggagga ccccaccttc 4140 aaggagaact acaggttcca tgccatcaat ggctacatca tggacaccct gcctggcctg 4200 gtgatggccc aggaccagag gatcaggtgg tacctgctga gcatgggcag caatgagaac 4260 atccacagca tccacttctc tggccatgtg ttcactgtga ggaagaagga ggagtacaag 4320 atggccctgt acaacctgta ccctggggtg tttgagactg tggagatgct gcccagcaag 4380 gctggcatct ggagggtgga gtgcctgatt ggggagcacc tgcatgctgg catgagcacc 4440 ctgttcctgg tgtacagcaa caagtgccag acccccctgg gcatggcctc tggccacatc 4500 agggacttcc agatcactgc ctctggccag tatggccagt gggcccccaa gctggccagg 4560 ctgcactact ctggcagcat caatgcctgg agcaccaagg agcccttcag ctggatcaag 4620 gtggacctgc tggcccccat gatcatccat ggcatcaaga cccagggggc caggcagaag 4680 ttcagcagcc tgtacatcag ccagttcatc atcatgtaca gcctggatgg caagaagtgg 4740 cagacctaca ggggcaacag cactggcacc ctgatggtgt tctttggcaa tgtggacagc 4800 tctggcatca agcacaacat cttcaacccc cccatcattg ccagatacat caggctgcac 4860 cccacccact acagcatcag gagcaccctg aggatggagc tgatgggctg tgacctgaac 4920 agctgcagca tgcccctggg catggagagc aaggccatct ctgatgccca gatcactgcc 4980 agcagctact tcaccaacat gtttgccacc tggagcccca gcaaggccag gctgcacctg 5040 cagggcagga gcaatgcctg gaggccccag gtcaacaacc ccaaggagtg gctgcaggtg 5100 gacttccaga agaccatgaa ggtgactggg gtgaccaccc agggggtgaa gagcctgctg 5160 accagcatgt atgtgaagga gttcctgatc agcagcagcc aggatggcca ccagtggacc 5220 ctgttcttcc agaatggcaa ggtgaaggtg ttccagggca accaggacag cttcacccct 5280 gtggtgaaca gcctggaccc ccccctgctg accagatacc tgaggattca cccccagagc 5340 tgggtgcacc agattgccct gaggatggag gtgctgggct gtgaggccca ggacctgtac 5400 tgacctcgag gaataaagga aatttatttt cattgcaata gtgtgttggt tttttgtgtc 5460 acgtggcggc cgcaggaacc cctagtgatg gagttggcca ctccctctct gcgcgctcgc 5520 tcgctcactg aggccgggcg accaaaggtc gcccgacgcc cgggctttgc ccgggcggcc 5580 tcagtgagcg agcgagcgcg cagagaggga gtggccaa 5618 <210> 42 <211> 5993 <212> DNA <213> Adeno-Associated Virus 2 <400> 42 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg tttaaacgtc gacaggttaa 180 tttttaaaaa gcagtcaaaa gtccaagtgg cccttggcag catttactct ctctgtttgc 240 tctggttaat aatctcagga gcacaaacat tcctggaggc aggagaagaa atcaacatcc 300 tggacttatc ctctgggcct ctccccaccc ccaggagagg ctcaggttaa tttttaaaaa 360 gcagtcaaaa gtccaagtgg cccttggcag catttactct ctctgtttgc tctggttaat 420 aatctcagga gcacaaacat tcctggaggc aggagaagaa atcaacatcc tggacttatc 480 ctctgggcct ctccccaccc ccaggagagg ctgtcgactg gacacaggac gctgtggttt 540 ctgagccagg gggcgactca gatcccagcc agtggactta gcccctgttt gctcctccga 600 taactggggt gaccttggtt aatattcacc agcagcctcc cccgttgccc ctctggatcc 660 actgcttaaa tacggacgag gacagggccc tgtctcctca gcttcaggca ccaccactga 720 cctgggacag tgaatcgcga tcgccaccat gcagattgag ctgagcacct gcttcttcct 780 gtgcctgctg aggttctgct tctctgccac caggagatac tacctggggg ctgtggagct 840 gagctgggac tacatgcagt ctgacctggg ggagctgcct gtggatgcca ggttcccccc 900 cagagtgccc aagagcttcc ccttcaacac ctctgtggtg tacaagaaga ccctgtttgt 960 ggagttcact gaccacctgt tcaacattgc caagcccagg cccccctgga tgggcctgct 1020 gggccccacc atccaggctg aggtgtatga cactgtggtg atcaccctga agaacatggc 1080 cagccaccct gtgagcctgc atgctgtggg ggtgagctac tggaaggcct ctgagggggc 1140 tgagtatgat gaccagacca gccagaggga gaaggaggat gacaaggtgt tccctggggg 1200 cagccacacc tatgtgtggc aggtgctgaa ggagaatggc cccatggcct ctgaccccct 1260 gtgcctgacc tacagctacc tgagccatgt ggacctggtg aaggacctga actctggcct 1320 gattggggcc ctgctggtgt gcagggaggg cagcctggcc aaggagaaga cccagaccct 1380 gcacaagttc atcctgctgt ttgctgtgtt tgatgagggc aagagctggc actctgaaac 1440 caagaacagc ctgatgcagg acagggatgc tgcctctgcc agggcctggc ccaagatgca 1500 cactgtgaat ggctatgtga acaggagcct gcctggcctg attggctgcc acaggaagtc 1560 tgtgtactgg catgtgattg gcatgggcac cacccctgag gtgcacagca tcttcctgga 1620 gggccacacc ttcctggtca ggaaccacag gcaggccagc ctggagatca gccccatcac 1680 cttcctgact gcccagaccc tgctgatgga cctgggccag ttcctgctgt tctgccacat 1740 cagcagccac cagcatgatg gcatggaggc ctatgtgaag gtggacagct gccctgagga 1800 gccccagctg aggatgaaga acaatgagga ggctgaggac tatgatgatg acctgactga 1860 ctctgagatg gatgtggtga ggtttgatga tgacaacagc cccagcttca tccagatcag 1920 gtctgtggcc aagaagcacc ccaagacctg ggtgcactac attgctgctg aggaggagga 1980 ctgggactat gcccccctgg tgctggcccc tgatgacagg agctacaaga gccagtacct 2040 gaacaatggc ccccagagga ttggcaggaa gtacaagaag gtcaggttca tggcctacac 2100 tgatgaaacc ttcaagacca gggaggccat ccagcatgag tctggcatcc tgggccccct 2160 gctgtatggg gaggtggggg acaccctgct gatcatcttc aagaaccagg ccagcaggcc 2220 ctacaacatc tacccccatg gcatcactga tgtgaggccc ctgtacagca ggaggctgcc 2280 caagggggtg aagcacctga aggacttccc catcctgcct ggggagatct tcaagtacaa 2340 gtggactgtg actgtggagg atggccccac caagtctgac cccaggtgcc tgaccagata 2400 ctacagcagc tttgtgaaca tggagaggga cctggcctct ggcctgattg gccccctgct 2460 gatctgctac aaggagtctg tggaccagag gggcaaccag atcatgtctg acaagaggaa 2520 tgtgatcctg ttctctgtgt ttgatgagaa caggagctgg tacctgactg agaacatcca 2580 gaggttcctg cccaaccctg ctggggtgca gctggaggac cctgagttcc aggccagcaa 2640 catcatgcac agcatcaatg gctatgtgtt tgacagcctg cagctgtctg tgtgcctgca 2700 tgaggtggcc tactggtaca tcctgagcat tggggcccag actgacttcc tgtctgtgtt 2760 cttctctggc tacaccttca agcacaagat ggtgtatgag gacaccctga ccctgttccc 2820 cttctctggg gagactgtgt tcatgagcat ggagaaccct ggcctgtgga ttctgggctg 2880 ccacaactct gacttcagga acaggggcat gactgccctg ctgaaagtct ccagctgtga 2940 caagaacact ggggactact atgaggacag ctatgaggac atctctgcct acctgctgag 3000 caagaacaat gccattgagc ccaggagctt cagccagaac cccccagtgc tgaagaggca 3060 ccagagggag atcaccagga ccaccctgca gtctgaccag gaggagattg actatgatga 3120 caccatctct gtggagatga agaaggagga ctttgacatc tacgacgagg acgagaacca 3180 gagccccagg agcttccaga agaagaccag gcactacttc attgctgctg tggagaggct 3240 gtgggactat ggcatgagca gcagccccca tgtgctgagg aacagggccc agtctggctc 3300 tgtgccccag ttcaagaagg tggtgttcca ggagttcact gatggcagct tcacccagcc 3360 cctgtacaga ggggagctga atgagcacct gggcctgctg ggcccctaca tcagggctga 3420 ggtggaggac aacatcatgg tgaccttcag gaaccaggcc agcaggccct acagcttcta 3480 cagcagcctg atcagctatg aggaggacca gaggcagggg gctgagccca ggaagaactt 3540 tgtgaagccc aatgaaacca agacctactt ctggaaggtg cagcaccaca tggcccccac 3600 caaggatgag tttgactgca aggcctgggc ctacttctct gatgtggacc tggagaagga 3660 tgtgcactct ggcctgattg gccccctgct ggtgtgccac accaacaccc tgaaccctgc 3720 ccatggcagg caggtgactg tgcaggagtt tgccctgttc ttcaccatct ttgatgaaac 3780 caagagctgg tacttcactg agaacatgga gaggaactgc agggccccct gcaacatcca 3840 gatggaggac cccaccttca aggagaacta caggttccat gccatcaatg gctacatcat 3900 ggacaccctg cctggcctgg tgatggccca ggaccagagg atcaggtggt acctgctgag 3960 catgggcagc aatgagaaca tccacagcat ccacttctct ggccatgtgt tcactgtgag 4020 gaagaaggag gagtacaaga tggccctgta caacctgtac cctggggtgt ttgagactgt 4080 ggagatgctg cccagcaagg ctggcatctg gagggtggag tgcctgattg gggagcacct 4140 gcatgctggc atgagcaccc tgttcctggt gtacagcaac aagtgccaga cccccctggg 4200 catggcctct ggccacatca gggacttcca gatcactgcc tctggccagt atggccagtg 4260 ggcccccaag ctggccaggc tgcactactc tggcagcatc aatgcctgga gcaccaagga 4320 gcccttcagc tggatcaagg tggacctgct ggcccccatg atcatccatg gcatcaagac 4380 ccagggggcc aggcagaagt tcagcagcct gtacatcagc cagttcatca tcatgtacag 4440 cctggatggc aagaagtggc agacctacag gggcaacagc actggcaccc tgatggtgtt 4500 ctttggcaat gtggacagct ctggcatcaa gcacaacatc ttcaaccccc ccatcattgc 4560 cagatacatc aggctgcacc ccacccacta cagcatcagg agcaccctga ggatggagct 4620 gatgggctgt gacctgaaca gctgcagcat gcccctgggc atggagagca aggccatctc 4680 tgatgcccag atcactgcca gcagctactt caccaacatg tttgccacct ggagccccag 4740 caaggccagg ctgcacctgc agggcaggag caatgcctgg aggccccagg tcaacaaccc 4800 caaggagtgg ctgcaggtgg acttccagaa gaccatgaag gtgactgggg tgaccaccca 4860 gggggtgaag agcctgctga ccagcatgta tgtgaaggag ttcctgatca gcagcagcca 4920 ggatggccac cagtggaccc tgttcttcca gaatggcaag gtgaaggtgt tccagggcaa 4980 ccaggacagc ttcacccctg tggtgaacag cctggacccc cccctgctga ccagatacct 5040 gaggattcac ccccagagct gggtgcacca gattgccctg aggatggagg tgctgggctg 5100 tgaggcccag gacctgtact gacctcgagg aataaaggaa atttattttc attgcaatag 5160 tgtgttggtt ttttgtgtca cgtgccctct cacactacct aaaccacgcc aggacaacct 5220 ctgctcctct ccaccgaaat tccaaggggt cgagtggatg ttggaggtgg catgggccca 5280 gagaggtctc tgacctctgc cccagctcca aggtcagcag gcagggaggg ctgtgtgttt 5340 gctgtttgct gcttgcaatg tttgcccatt ttagggacat gagtaggctg aagtttgttc 5400 agtgtggact tcagaggcag cacacaaaca gctgctggag gatgggaact gaggggttgg 5460 aagggggcag ggtgagccca gaaactcctg tgtgcctctg agcctgcagc cctctcacac 5520 tacctaaacc acgccaggac aacctctgct cctctccacc gaaattccaa ggggtcgagt 5580 ggatgttgga ggtggcatgg gcccagagag gtctctgacc tctgccccag ctccaaggtc 5640 agcaggcagg gagggctgtg tgtttgctgt ttgctgcttg caatgtttgc ccattttagg 5700 gacatgagta ggctgaagtt tgttcagtgt ggacttcaga ggcagcacac aaacagctgc 5760 tggaggatgg gaactgaggg gttggaaggg ggcagggtga gcccagaaac tcctgtgtgc 5820 ctctgagcct gcagcacgtg gcggccgcag gaacccctag tgatggagtt ggccactccc 5880 tctctgcgcg ctcgctcgct cactgaggcc gggcgaccaa aggtcgcccg acgcccgggc 5940 tttgcccggg cggcctcagt gagcgagcga gcgcgcagag agggagtggc caa 5993 <210> 43 <211> 5337 <212> DNA <213> Adeno-Associated Virus 2 <400> 43 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg tttaaacgtc gacaggttaa 180 tttttaaaaa gcagtcaaaa gtccaagtgg cccttggcag catttactct ctctgtttgc 240 tctggttaat aatctcagga gcacaaacat tcctggaggc aggagaagaa atcaacatcc 300 tggacttatc ctctgggcct ctccccaccc ccaggagagg ctcaggttaa tttttaaaaa 360 gcagtcaaaa gtccaagtgg cccttggcag catttactct ctctgtttgc tctggttaat 420 aatctcagga gcacaaacat tcctggaggc aggagaagaa atcaacatcc tggacttatc 480 ctctgggcct ctccccaccc ccaggagagg ctgtcgactg gacacaggac gctgtggttt 540 ctgagccagg gggcgactca gatcccagcc agtggactta gcccctgttt gctcctccga 600 taactggggt gaccttggtt aatattcacc agcagcctcc cccgttgccc ctctggatcc 660 actgcttaaa tacggacgag gacagggccc tgtctcctca gcttcaggca ccaccactga 720 cctgggacag tgaatcgcga tcgccaccat gcagattgag ctgagcacct gcttcttcct 780 gtgcctgctg aggttctgct tctctgccac caggagatac tacctggggg ctgtggagct 840 gagctgggac tacatgcagt ctgacctggg ggagctgcct gtggatgcca ggttcccccc 900 cagagtgccc aagagcttcc ccttcaacac ctctgtggtg tacaagaaga ccctgtttgt 960 ggagttcact gaccacctgt tcaacattgc caagcccagg cccccctgga tgggcctgct 1020 gggccccacc atccaggctg aggtgtatga cactgtggtg atcaccctga agaacatggc 1080 cagccaccct gtgagcctgc atgctgtggg ggtgagctac tggaaggcct ctgagggggc 1140 tgagtatgat gaccagacca gccagaggga gaaggaggat gacaaggtgt tccctggggg 1200 cagccacacc tatgtgtggc aggtgctgaa ggagaatggc cccatggcct ctgaccccct 1260 gtgcctgacc tacagctacc tgagccatgt ggacctggtg aaggacctga actctggcct 1320 gattggggcc ctgctggtgt gcagggaggg cagcctggcc aaggagaaga cccagaccct 1380 gcacaagttc atcctgctgt ttgctgtgtt tgatgagggc aagagctggc actctgaaac 1440 caagaacagc ctgatgcagg acagggatgc tgcctctgcc agggcctggc ccaagatgca 1500 cactgtgaat ggctatgtga acaggagcct gcctggcctg attggctgcc acaggaagtc 1560 tgtgtactgg catgtgattg gcatgggcac cacccctgag gtgcacagca tcttcctgga 1620 gggccacacc ttcctggtca ggaaccacag gcaggccagc ctggagatca gccccatcac 1680 cttcctgact gcccagaccc tgctgatgga cctgggccag ttcctgctgt tctgccacat 1740 cagcagccac cagcatgatg gcatggaggc ctatgtgaag gtggacagct gccctgagga 1800 gccccagctg aggatgaaga acaatgagga ggctgaggac tatgatgatg acctgactga 1860 ctctgagatg gatgtggtga ggtttgatga tgacaacagc cccagcttca tccagatcag 1920 gtctgtggcc aagaagcacc ccaagacctg ggtgcactac attgctgctg aggaggagga 1980 ctgggactat gcccccctgg tgctggcccc tgatgacagg agctacaaga gccagtacct 2040 gaacaatggc ccccagagga ttggcaggaa gtacaagaag gtcaggttca tggcctacac 2100 tgatgaaacc ttcaagacca gggaggccat ccagcatgag tctggcatcc tgggccccct 2160 gctgtatggg gaggtggggg acaccctgct gatcatcttc aagaaccagg ccagcaggcc 2220 ctacaacatc tacccccatg gcatcactga tgtgaggccc ctgtacagca ggaggctgcc 2280 caagggggtg aagcacctga aggacttccc catcctgcct ggggagatct tcaagtacaa 2340 gtggactgtg actgtggagg atggccccac caagtctgac cccaggtgcc tgaccagata 2400 ctacagcagc tttgtgaaca tggagaggga cctggcctct ggcctgattg gccccctgct 2460 gatctgctac aaggagtctg tggaccagag gggcaaccag atcatgtctg acaagaggaa 2520 tgtgatcctg ttctctgtgt ttgatgagaa caggagctgg tacctgactg agaacatcca 2580 gaggttcctg cccaaccctg ctggggtgca gctggaggac cctgagttcc aggccagcaa 2640 catcatgcac agcatcaatg gctatgtgtt tgacagcctg cagctgtctg tgtgcctgca 2700 tgaggtggcc tactggtaca tcctgagcat tggggcccag actgacttcc tgtctgtgtt 2760 cttctctggc tacaccttca agcacaagat ggtgtatgag gacaccctga ccctgttccc 2820 cttctctggg gagactgtgt tcatgagcat ggagaaccct ggcctgtgga ttctgggctg 2880 ccacaactct gacttcagga acaggggcat gactgccctg ctgaaagtct ccagctgtga 2940 caagaacact ggggactact atgaggacag ctatgaggac atctctgcct acctgctgag 3000 caagaacaat gccattgagc ccaggagctt cagccagaac cccccagtgc tgaagaggca 3060 ccagagggag atcaccagga ccaccctgca gtctgaccag gaggagattg actatgatga 3120 caccatctct gtggagatga agaaggagga ctttgacatc tacgacgagg acgagaacca 3180 gagccccagg agcttccaga agaagaccag gcactacttc attgctgctg tggagaggct 3240 gtgggactat ggcatgagca gcagccccca tgtgctgagg aacagggccc agtctggctc 3300 tgtgccccag ttcaagaagg tggtgttcca ggagttcact gatggcagct tcacccagcc 3360 cctgtacaga ggggagctga atgagcacct gggcctgctg ggcccctaca tcagggctga 3420 ggtggaggac aacatcatgg tgaccttcag gaaccaggcc agcaggccct acagcttcta 3480 cagcagcctg atcagctatg aggaggacca gaggcagggg gctgagccca ggaagaactt 3540 tgtgaagccc aatgaaacca agacctactt ctggaaggtg cagcaccaca tggcccccac 3600 caaggatgag tttgactgca aggcctgggc ctacttctct gatgtggacc tggagaagga 3660 tgtgcactct ggcctgattg gccccctgct ggtgtgccac accaacaccc tgaaccctgc 3720 ccatggcagg caggtgactg tgcaggagtt tgccctgttc ttcaccatct ttgatgaaac 3780 caagagctgg tacttcactg agaacatgga gaggaactgc agggccccct gcaacatcca 3840 gatggaggac cccaccttca aggagaacta caggttccat gccatcaatg gctacatcat 3900 ggacaccctg cctggcctgg tgatggccca ggaccagagg atcaggtggt acctgctgag 3960 catgggcagc aatgagaaca tccacagcat ccacttctct ggccatgtgt tcactgtgag 4020 gaagaaggag gagtacaaga tggccctgta caacctgtac cctggggtgt ttgagactgt 4080 ggagatgctg cccagcaagg ctggcatctg gagggtggag tgcctgattg gggagcacct 4140 gcatgctggc atgagcaccc tgttcctggt gtacagcaac aagtgccaga cccccctggg 4200 catggcctct ggccacatca gggacttcca gatcactgcc tctggccagt atggccagtg 4260 ggcccccaag ctggccaggc tgcactactc tggcagcatc aatgcctgga gcaccaagga 4320 gcccttcagc tggatcaagg tggacctgct ggcccccatg atcatccatg gcatcaagac 4380 ccagggggcc aggcagaagt tcagcagcct gtacatcagc cagttcatca tcatgtacag 4440 cctggatggc aagaagtggc agacctacag gggcaacagc actggcaccc tgatggtgtt 4500 ctttggcaat gtggacagct ctggcatcaa gcacaacatc ttcaaccccc ccatcattgc 4560 cagatacatc aggctgcacc ccacccacta cagcatcagg agcaccctga ggatggagct 4620 gatgggctgt gacctgaaca gctgcagcat gcccctgggc atggagagca aggccatctc 4680 tgatgcccag atcactgcca gcagctactt caccaacatg tttgccacct ggagccccag 4740 caaggccagg ctgcacctgc agggcaggag caatgcctgg aggccccagg tcaacaaccc 4800 caaggagtgg ctgcaggtgg acttccagaa gaccatgaag gtgactgggg tgaccaccca 4860 gggggtgaag agcctgctga ccagcatgta tgtgaaggag ttcctgatca gcagcagcca 4920 ggatggccac cagtggaccc tgttcttcca gaatggcaag gtgaaggtgt tccagggcaa 4980 ccaggacagc ttcacccctg tggtgaacag cctggacccc cccctgctga ccagatacct 5040 gaggattcac ccccagagct gggtgcacca gattgccctg aggatggagg tgctgggctg 5100 tgaggcccag gacctgtact gacctcgagg aataaaggaa atttattttc attgcaatag 5160 tgtgttggtt ttttgtgtca cgtggcggcc gcaggaaccc ctagtgatgg agttggccac 5220 tccctctctg cgcgctcgct cgctcactga ggccgggcga ccaaaggtcg cccgacgccc 5280 gggctttgcc cgggcggcct cagtgagcga gcgagcgcgc agagagggag tggccaa 5337 <210> 44 <211> 5542 <212> DNA <213> Adeno-Associated Virus 2 <400> 44 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg tttaaacgtc gacaggttaa 180 tttttaaaaa gcagtcaaaa gtccaagtgg cccttggcag catttactct ctctgtttgc 240 tctggttaat aatctcagga gcacaaacat tcctggaggc aggagaagaa atcaacatcc 300 tggacttatc ctctgggcct ctccccaccc ccaggagagg ctcaggttaa tttttaaaaa 360 gcagtcaaaa gtccaagtgg cccttggcag catttactct ctctgtttgc tctggttaat 420 aatctcagga gcacaaacat tcctggaggc aggagaagaa atcaacatcc tggacttatc 480 ctctgggcct ctccccaccc ccaggagagg ctgtcgactg gacacaggac gctgtggttt 540 ctgagccagg gggcgactca gatcccagcc agtggactta gcccctgttt gctcctccga 600 taactggggt gaccttggtt aatattcacc agcagcctcc cccgttgccc ctctggatcc 660 actgcttaaa tacggacgag gacagggccc tgtctcctca gcttcaggca ccaccactga 720 cctgggacag tgaatcgtaa gtatgccttt cactgcgaga ggttctggag aggcttctga 780 gctccccatg gcccaggcag gcagcaggtc tggggcagga ggggggttgt ggagtgcctt 840 gactcggggc ctggcccccc catctctgtc ttgcaggaca attgccgtct tctgtctcgt 900 ggggcatcct cctgctggca ggcctgtgct gcctggtccc tgcgatcgcc accatgcaga 960 ttgagctgag cacctgcttc ttcctgtgcc tgctgaggtt ctgcttctct gccaccagga 1020 gatactacct gggggctgtg gagctgagct gggactacat gcagtctgac ctgggggagc 1080 tgcctgtgga tgccaggttc ccccccagag tgcccaagag cttccccttc aacacctctg 1140 tggtgtacaa gaagaccctg tttgtggagt tcactgacca cctgttcaac attgccaagc 1200 ccaggccccc ctggatgggc ctgctgggcc ccaccatcca ggctgaggtg tatgacactg 1260 tggtgatcac cctgaagaac atggccagcc accctgtgag cctgcatgct gtgggggtga 1320 gctactggaa ggcctctgag ggggctgagt atgatgacca gaccagccag agggagaagg 1380 aggatgacaa ggtgttccct gggggcagcc acacctatgt gtggcaggtg ctgaaggaga 1440 atggccccat ggcctctgac cccctgtgcc tgacctacag ctacctgagc catgtggacc 1500 tggtgaagga cctgaactct ggcctgattg gggccctgct ggtgtgcagg gagggcagcc 1560 tggccaagga gaagacccag accctgcaca agttcatcct gctgtttgct gtgtttgatg 1620 agggcaagag ctggcactct gaaaccaaga acagcctgat gcaggacagg gatgctgcct 1680 ctgccagggc ctggcccaag atgcacactg tgaatggcta tgtgaacagg agcctgcctg 1740 gcctgattgg ctgccacagg aagtctgtgt actggcatgt gattggcatg ggcaccaccc 1800 ctgaggtgca cagcatcttc ctggagggcc acaccttcct ggtcaggaac cacaggcagg 1860 ccagcctgga gatcagcccc atcaccttcc tgactgccca gaccctgctg atggacctgg 1920 gccagttcct gctgttctgc cacatcagca gccaccagca tgatggcatg gaggcctatg 1980 tgaaggtgga cagctgccct gaggagcccc agctgaggat gaagaacaat gaggaggctg 2040 aggactatga tgatgacctg actgactctg agatggatgt ggtgaggttt gatgatgaca 2100 acagccccag cttcatccag atcaggtctg tggccaagaa gcaccccaag acctgggtgc 2160 actacattgc tgctgaggag gaggactggg actatgcccc cctggtgctg gcccctgatg 2220 acaggagcta caagagccag tacctgaaca atggccccca gaggattggc aggaagtaca 2280 agaaggtcag gttcatggcc tacactgatg aaaccttcaa gaccagggag gccatccagc 2340 atgagtctgg catcctgggc cccctgctgt atggggaggt gggggacacc ctgctgatca 2400 tcttcaagaa ccaggccagc aggccctaca acatctaccc ccatggcatc actgatgtga 2460 ggcccctgta cagcaggagg ctgcccaagg gggtgaagca cctgaaggac ttccccatcc 2520 tgcctgggga gatcttcaag tacaagtgga ctgtgactgt ggaggatggc cccaccaagt 2580 ctgaccccag gtgcctgacc agatactaca gcagctttgt gaacatggag agggacctgg 2640 cctctggcct gattggcccc ctgctgatct gctacaagga gtctgtggac cagaggggca 2700 accagatcat gtctgacaag aggaatgtga tcctgttctc tgtgtttgat gagaacagga 2760 gctggtacct gactgagaac atccagaggt tcctgcccaa ccctgctggg gtgcagctgg 2820 aggaccctga gttccaggcc agcaacatca tgcacagcat caatggctat gtgtttgaca 2880 gcctgcagct gtctgtgtgc ctgcatgagg tggcctactg gtacatcctg agcattgggg 2940 cccagactga cttcctgtct gtgttcttct ctggctacac cttcaagcac aagatggtgt 3000 atgaggacac cctgaccctg ttccccttct ctggggagac tgtgttcatg agcatggaga 3060 accctggcct gtggattctg ggctgccaca actctgactt caggaacagg ggcatgactg 3120 ccctgctgaa agtctccagc tgtgacaaga acactgggga ctactatgag gacagctatg 3180 aggacatctc tgcctacctg ctgagcaaga acaatgccat tgagcccagg agcttcagcc 3240 agaacccccc agtgctgaag aggcaccaga gggagatcac caggaccacc ctgcagtctg 3300 accaggagga gattgactat gatgacacca tctctgtgga gatgaagaag gaggactttg 3360 acatctacga cgaggacgag aaccagagcc ccaggagctt ccagaagaag accaggcact 3420 acttcattgc tgctgtggag aggctgtggg actatggcat gagcagcagc ccccatgtgc 3480 tgaggaacag ggcccagtct ggctctgtgc cccagttcaa gaaggtggtg ttccaggagt 3540 tcactgatgg cagcttcacc cagcccctgt acagagggga gctgaatgag cacctgggcc 3600 tgctgggccc ctacatcagg gctgaggtgg aggacaacat catggtgacc ttcaggaacc 3660 aggccagcag gccctacagc ttctacagca gcctgatcag ctatgaggag gaccagaggc 3720 agggggctga gcccaggaag aactttgtga agcccaatga aaccaagacc tacttctgga 3780 aggtgcagca ccacatggcc cccaccaagg atgagtttga ctgcaaggcc tgggcctact 3840 tctctgatgt ggacctggag aaggatgtgc actctggcct gattggcccc ctgctggtgt 3900 gccacaccaa caccctgaac cctgcccatg gcaggcaggt gactgtgcag gagtttgccc 3960 tgttcttcac catctttgat gaaaccaaga gctggtactt cactgagaac atggagagga 4020 actgcagggc cccctgcaac atccagatgg aggaccccac cttcaaggag aactacaggt 4080 tccatgccat caatggctac atcatggaca ccctgcctgg cctggtgatg gcccaggacc 4140 agaggatcag gtggtacctg ctgagcatgg gcagcaatga gaacatccac agcatccact 4200 tctctggcca tgtgttcact gtgaggaaga aggaggagta caagatggcc ctgtacaacc 4260 tgtaccctgg ggtgtttgag actgtggaga tgctgcccag caaggctggc atctggaggg 4320 tggagtgcct gattggggag cacctgcatg ctggcatgag caccctgttc ctggtgtaca 4380 gcaacaagtg ccagaccccc ctgggcatgg cctctggcca catcagggac ttccagatca 4440 ctgcctctgg ccagtatggc cagtgggccc ccaagctggc caggctgcac tactctggca 4500 gcatcaatgc ctggagcacc aaggagccct tcagctggat caaggtggac ctgctggccc 4560 ccatgatcat ccatggcatc aagacccagg gggccaggca gaagttcagc agcctgtaca 4620 tcagccagtt catcatcatg tacagcctgg atggcaagaa gtggcagacc tacaggggca 4680 acagcactgg caccctgatg gtgttctttg gcaatgtgga cagctctggc atcaagcaca 4740 acatcttcaa cccccccatc attgccagat acatcaggct gcaccccacc cactacagca 4800 tcaggagcac cctgaggatg gagctgatgg gctgtgacct gaacagctgc agcatgcccc 4860 tgggcatgga gagcaaggcc atctctgatg cccagatcac tgccagcagc tacttcacca 4920 acatgtttgc cacctggagc cccagcaagg ccaggctgca cctgcagggc aggagcaatg 4980 cctggaggcc ccaggtcaac aaccccaagg agtggctgca ggtggacttc cagaagacca 5040 tgaaggtgac tggggtgacc acccaggggg tgaagagcct gctgaccagc atgtatgtga 5100 aggagttcct gatcagcagc agccaggatg gccaccagtg gaccctgttc ttccagaatg 5160 gcaaggtgaa ggtgttccag ggcaaccagg acagcttcac ccctgtggtg aacagcctgg 5220 acccccccct gctgaccaga tacctgagga ttcaccccca gagctgggtg caccagattg 5280 ccctgaggat ggaggtgctg ggctgtgagg cccaggacct gtactgacct cgaggaataa 5340 aggaaattta ttttcattgc aatagtgtgt tggttttttg tgtcacgtgg cggccgcagg 5400 aacccctagt gatggagttg gccactccct ctctgcgcgc tcgctcgctc actgaggccg 5460 ggcgaccaaa ggtcgcccga cgcccgggct ttgcccgggc ggcctcagtg agcgagcgag 5520 cgcgcagaga gggagtggcc aa 5542 <210> 45 <211> 5126 <212> DNA <213> Adeno-Associated Virus 2 <400> 45 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgcggc cgcacgcgtg ggaggctgct ggtgaatatt 180 aaccaaggtc accccagtta tcggaggagc aaacaggggc taagtccacg gggaggctgc 240 tggtgaatat taaccaaggt caccccagtt atcggaggag caaacagggg ctaagtccac 300 ggtcgactgg acacaggacg ctgtggtttc tgagccaggg ggcgactcag atcccagcca 360 gtggacttag cccctgtttg ctcctccgat aactggggtg accttggtta atattcacca 420 gcagcctccc ccgttgcccc tctggatcca ctgcttaaat acggacgagg acagggccct 480 gtctcctcag cttcaggcac caccactgac ctgggacagt gaatcgcgat cgccaccatg 540 cagattgagc tgagcacctg cttcttcctg tgcctgctga ggttctgctt ctctgccacc 600 aggagatact acctgggggc tgtggagctg agctgggact acatgcagtc tgacctgggg 660 gagctgcctg tggatgccag gttccccccc agagtgccca agagcttccc cttcaacacc 720 tctgtggtgt acaagaagac cctgtttgtg gagttcactg accacctgtt caacattgcc 780 aagcccaggc ccccctggat gggcctgctg ggccccacca tccaggctga ggtgtatgac 840 actgtggtga tcaccctgaa gaacatggcc agccaccctg tgagcctgca tgctgtgggg 900 gtgagctact ggaaggcctc tgagggggct gagtatgatg accagaccag ccagagggag 960 aaggaggatg acaaggtgtt ccctgggggc agccacacct atgtgtggca ggtgctgaag 1020 gagaatggcc ccatggcctc tgaccccctg tgcctgacct acagctacct gagccatgtg 1080 gacctggtga aggacctgaa ctctggcctg attggggccc tgctggtgtg cagggagggc 1140 agcctggcca aggagaagac ccagaccctg cacaagttca tcctgctgtt tgctgtgttt 1200 gatgagggca agagctggca ctctgaaacc aagaacagcc tgatgcagga cagggatgct 1260 gcctctgcca gggcctggcc caagatgcac actgtgaatg gctatgtgaa caggagcctg 1320 cctggcctga ttggctgcca caggaagtct gtgtactggc atgtgattgg catgggcacc 1380 acccctgagg tgcacagcat cttcctggag ggccacacct tcctggtcag gaaccacagg 1440 caggccagcc tggagatcag ccccatcacc ttcctgactg cccagaccct gctgatggac 1500 ctgggccagt tcctgctgtt ctgccacatc agcagccacc agcatgatgg catggaggcc 1560 tatgtgaagg tggacagctg ccctgaggag ccccagctga ggatgaagaa caatgaggag 1620 gctgaggact atgatgatga cctgactgac tctgagatgg atgtggtgag gtttgatgat 1680 gacaacagcc ccagcttcat ccagatcagg tctgtggcca agaagcaccc caagacctgg 1740 gtgcactaca ttgctgctga ggaggaggac tgggactatg cccccctggt gctggcccct 1800 gatgacagga gctacaagag ccagtacctg aacaatggcc cccagaggat tggcaggaag 1860 tacaagaagg tcaggttcat ggcctacact gatgaaacct tcaagaccag ggaggccatc 1920 cagcatgagt ctggcatcct gggccccctg ctgtatgggg aggtggggga caccctgctg 1980 atcatcttca agaaccaggc cagcaggccc tacaacatct acccccatgg catcactgat 2040 gtgaggcccc tgtacagcag gaggctgccc aagggggtga agcacctgaa ggacttcccc 2100 atcctgcctg gggagatctt caagtacaag tggactgtga ctgtggagga tggccccacc 2160 aagtctgacc ccaggtgcct gaccagatac tacagcagct ttgtgaacat ggagagggac 2220 ctggcctctg gcctgattgg ccccctgctg atctgctaca aggagtctgt ggaccagagg 2280 ggcaaccaga tcatgtctga caagaggaat gtgatcctgt tctctgtgtt tgatgagaac 2340 aggagctggt acctgactga gaacatccag aggttcctgc ccaaccctgc tggggtgcag 2400 ctggaggacc ctgagttcca ggccagcaac atcatgcaca gcatcaatgg ctatgtgttt 2460 gacagcctgc agctgtctgt gtgcctgcat gaggtggcct actggtacat cctgagcatt 2520 ggggcccaga ctgacttcct gtctgtgttc ttctctggct acaccttcaa gcacaagatg 2580 gtgtatgagg acaccctgac cctgttcccc ttctctgggg agactgtgtt catgagcatg 2640 gagaaccctg gcctgtggat tctgggctgc cacaactctg acttcaggaa caggggcatg 2700 actgccctgc tgaaagtctc cagctgtgac aagaacactg gggactacta tgaggacagc 2760 tatgaggaca tctctgccta cctgctgagc aagaacaatg ccattgagcc caggagcttc 2820 agccagaacc ccccagtgct gaagaggcac cagagggaga tcaccaggac caccctgcag 2880 tctgaccagg aggagattga ctatgatgac accatctctg tggagatgaa gaaggaggac 2940 tttgacatct acgacgagga cgagaaccag agccccagga gcttccagaa gaagaccagg 3000 cactacttca ttgctgctgt ggagaggctg tgggactatg gcatgagcag cagcccccat 3060 gtgctgagga acagggccca gtctggctct gtgccccagt tcaagaaggt ggtgttccag 3120 gagttcactg atggcagctt cacccagccc ctgtacagag gggagctgaa tgagcacctg 3180 ggcctgctgg gcccctacat cagggctgag gtggaggaca acatcatggt gaccttcagg 3240 aaccaggcca gcaggcccta cagcttctac agcagcctga tcagctatga ggaggaccag 3300 aggcaggggg ctgagcccag gaagaacttt gtgaagccca atgaaaccaa gacctacttc 3360 tggaaggtgc agcaccacat ggcccccacc aaggatgagt ttgactgcaa ggcctgggcc 3420 tacttctctg atgtggacct ggagaaggat gtgcactctg gcctgattgg ccccctgctg 3480 gtgtgccaca ccaacaccct gaaccctgcc catggcaggc aggtgactgt gcaggagttt 3540 gccctgttct tcaccatctt tgatgaaacc aagagctggt acttcactga gaacatggag 3600 aggaactgca gggccccctg caacatccag atggaggacc ccaccttcaa ggagaactac 3660 aggttccatg ccatcaatgg ctacatcatg gacaccctgc ctggcctggt gatggcccag 3720 gaccagagga tcaggtggta cctgctgagc atgggcagca atgagaacat ccacagcatc 3780 cacttctctg gccatgtgtt cactgtgagg aagaaggagg agtacaagat ggccctgtac 3840 aacctgtacc ctggggtgtt tgagactgtg gagatgctgc ccagcaaggc tggcatctgg 3900 agggtggagt gcctgattgg ggagcacctg catgctggca tgagcaccct gttcctggtg 3960 tacagcaaca agtgccagac ccccctgggc atggcctctg gccacatcag ggacttccag 4020 atcactgcct ctggccagta tggccagtgg gcccccaagc tggccaggct gcactactct 4080 ggcagcatca atgcctggag caccaaggag cccttcagct ggatcaaggt ggacctgctg 4140 gcccccatga tcatccatgg catcaagacc cagggggcca ggcagaagtt cagcagcctg 4200 tacatcagcc agttcatcat catgtacagc ctggatggca agaagtggca gacctacagg 4260 ggcaacagca ctggcaccct gatggtgttc tttggcaatg tggacagctc tggcatcaag 4320 cacaacatct tcaacccccc catcattgcc agatacatca ggctgcaccc cacccactac 4380 agcatcagga gcaccctgag gatggagctg atgggctgtg acctgaacag ctgcagcatg 4440 cccctgggca tggagagcaa ggccatctct gatgcccaga tcactgccag cagctacttc 4500 accaacatgt ttgccacctg gagccccagc aaggccaggc tgcacctgca gggcaggagc 4560 aatgcctgga ggccccaggt caacaacccc aaggagtggc tgcaggtgga cttccagaag 4620 accatgaagg tgactggggt gaccacccag ggggtgaaga gcctgctgac cagcatgtat 4680 gtgaaggagt tcctgatcag cagcagccag gatggccacc agtggaccct gttcttccag 4740 aatggcaagg tgaaggtgtt ccagggcaac caggacagct tcacccctgt ggtgaacagc 4800 ctggaccccc ccctgctgac cagatacctg aggattcacc cccagagctg ggtgcaccag 4860 attgccctga ggatggaggt gctgggctgt gaggcccagg acctgtactg acctcgagga 4920 ataaaggaaa tttattttca ttgcaatagt gtgttggttt tttgtgtcac gtggcggccg 4980 caggaacccc tagtgatgga gttggccact ccctctctgc gcgctcgctc gctcactgag 5040 gccgggcgac caaaggtcgc ccgacgcccg ggctttgccc gggcggcctc agtgagcgag 5100 cgagcgcgca gagagggagt ggccaa 5126

Claims (8)

  1. AAV2 5’ 역전된 말단 반복 (ITR), 간-특이적 전사 조절 영역, 코돈-최적화된 기능적 활성 FVIII 코딩 영역, 임의로 하나 이상의 인트론, 폴리아데닐화 서열, 및 AAV2 3’ ITR을 포함하는 핵산을 포함하는 아데노-관련된 바이러스 (AAV) 인자 VIII (FVIII) 벡터.
  2. 제1항에 있어서, 상기 핵산은 하기로 구성된 군으로부터 선택된 뉴클레오타이드 서열을 포함하는, AAV FVIII 벡터:
    i. 서열번호 1에서 제시된 프로토 1 서열,
    ii. 서열번호 2에서 제시된 프로토 1S 서열,
    iii. 서열번호 3에서 제시된 프로토 2S 서열,
    iv. 서열번호 4에서 제시된 프로토 3S 서열,
    v. 서열번호 5에서 제시된 프로토 4 서열,
    vi. 서열번호 6에서 제시된 프로토 5 서열,
    vii. 서열번호 7에서 제시된 프로토 6 서열,
    viii. 서열번호 8에서 제시된 프로토 7 서열,
    ix. 서열번호 9에서 제시된 작제물 100ATG 서열,
    x. 서열번호 10에서 제시된 작제물 100ATG bGH poly A 서열,
    xi. 서열번호 11에서 제시된 작제물 100ATG 짧은 bGH polyA 서열,
    xii. 서열번호 12에서 제시된 작제물 103ATG 서열,
    xiii. 서열번호 13에서 제시된 작제물 103ATG 짧은 bGH poly A 서열,
    xiv. 서열번호 14에서 제시된 작제물 105ATG bGH poly A 서열,
    xv. 서열번호 15에서 제시된 작제물 DC172ATG FVIII 서열,
    xvi. 서열번호 16에서 제시된 작제물 DC172 ATG FVIII hAAT 서열,
    xvii. 서열번호 17에서 제시된 작제물 DC172 2xHCR ATG FVIII 서열,
    xviii. 서열번호 18에서 제시된 작제물 DC172 2xHCR ATG FVIII hAAT 서열,
    xix. 서열번호 19에서 제시된 작제물 2x 세르핀A hAAT ATG FVIII 서열,
    xx. 서열번호 20에서 제시된 작제물 2x 세르핀A hAAT ATG FVIII 2x μ-글로불린 인핸서 서열,
    xxi. 서열번호 21에서 제시된 작제물 100ATG 짧은 polyA 2x μ-글로불린 인핸서 서열,
    xxii. 서열번호 22에서 제시된 작제물 인자 VIII-BMN001 서열,
    xxiii. 서열번호 23에서 제시된 작제물 인자 VIII-BMN002 서열,
    xxiv. 서열번호 24에서 제시된 작제물 99 서열,
    xxv. 서열번호 25에서 제시된 작제물 100 서열,
    xxvi. 서열번호 26에서 제시된 작제물 100 역방향 서열,
    xxvii. 서열번호 27에서 제시된 작제물 100AT 서열,
    xxviii. 서열번호 28에서 제시된 작제물 100AT 2x MG 서열,
    xxix. 서열번호 29에서 제시된 작제물 100AT 2x MG polyA 서열,
    xxx. 서열번호 30에서 제시된 작제물 100AT 2x MG (역) bGH polyA 서열,
    xxxi. 서열번호 31에서 제시된 작제물 100 bGH polyA 서열,
    xxxii. 서열번호 32에서 제시된 작제물 100-400 서열,
    xxxiii. 서열번호 33에서 제시된 작제물 101 서열,
    xxxiv. 서열번호 34에서 제시된 작제물 102 서열,
    xxxv. 서열번호 35에서 제시된 작제물 103 서열,
    xxxvi. 서열번호 36에서 제시된 작제물 103 역방향 서열,
    xxxvii. 서열번호 37에서 제시된 작제물 103AT 서열,
    xxxviii. 서열번호 38에서 제시된 작제물 103AT 2x MG 서열,
    xxxix. 서열번호 39에서 제시된 작제물 103AT 2x MG polyA 서열,
    xl. 서열번호 40에서 제시된 작제물 103 bGH polyA 서열,
    xli. 서열번호 41에서 제시된 작제물 104 서열,
    xlii. 서열번호 42에서 제시된 작제물 105 서열,
    xliii. 서열번호 43에서 제시된 작제물 106 서열,
    xliv. 서열번호 44에서 제시된 작제물 106AT 서열, 및
    xlv. 서열번호 45에서 제시된 작제물 2x 세르핀 A hAAT 서열.
  3. 하기의 단계들을 포함하는, 재조합 아데노-관련된 바이러스 (AAV) 입자를 생산하는 방법:
    A) 제1항 또는 제2항의 AAV 벡터로 형질감염된 세포를 배양하는 단계; 및
    B) 재조합 AAV 입자를 상기 형질감염된 세포의 상청액으로부터 회수하는 단계.
  4. 제1항 또는 제2항의 바이러스 벡터를 포함하는 바이러스 입자.
  5. 제1항 또는 제2항의 바이러스 벡터를 포함하는 세포.
  6. 혈우병 A를 앓고 있는 환자를 치료하는 방법으로서, 상기 환자에게 유효량의 제1항 또는 제2항의 AAV FVIII 벡터를 투여하는 것을 포함하는, 방법.
  7. 혈우병 A의 치료용 약제의 제조를 위한, 제1항 또는 제2항의 AAV FVIII 벡터의 용도.
  8. 혈우병 A를 치료하기 위한, 제1항 또는 제2항의 AAV FVIII 벡터를 포함하는 조성물.
KR1020167009492A 2013-09-12 2014-09-10 아데노-관련된 바이러스 인자 viii 벡터 KR102484396B1 (ko)

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Families Citing this family (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB201210357D0 (en) 2012-06-12 2012-07-25 Ucl Business Plc Factor VIII sequences
PL3044231T3 (pl) 2013-09-12 2021-01-11 Biomarin Pharmaceutical Inc. Wektory aav zawierające gen kodujący czynnik viii
BR112017009497A2 (pt) 2014-11-05 2018-02-06 Voyager Therapeutics, Inc. polinucleotídeos de aadc para o tratamento da doença de parkinson
GB201420139D0 (en) 2014-11-12 2014-12-24 Ucl Business Plc Factor IX gene therapy
WO2016146757A1 (en) * 2015-03-17 2016-09-22 Vrije Universiteit Brussel Optimized liver-specific expression systems for fviii and fix
TWI707951B (zh) * 2015-04-08 2020-10-21 美商健臻公司 過大腺相關載體之製造
EP3626274A3 (en) * 2015-04-16 2020-06-17 Emory University Recombinant promoters and vectors for protein expression in liver and use thereof
IL257939B2 (en) * 2015-09-24 2023-03-01 Biomarin Pharm Inc Adeno-associated virus factor 8 vectors, associated virus particles, and medicinal formulations comprising the same
BR112018008519A2 (pt) * 2015-10-28 2018-11-06 Sangamo Therapeutics Inc construtos específicos de fígado, cassetes de expressão de fator viii e métodos de uso dos mesmos
PE20231949A1 (es) * 2015-10-30 2023-12-05 Spark Therapeutics Inc VARIANTES DEL FACTOR VIII REDUCIDO CON CpG, COMPOSICIONES Y METODOS Y USOS PARA EL TRATAMIENTO DE TRASTORNOS DE LA HEMOSTASIA
JP6695426B2 (ja) * 2015-11-13 2020-05-20 バクスアルタ インコーポレイテッド 組換えｆｖｉｉｉ変異型をコードする血友病ａ遺伝子治療用高発現ウイルスベクター
KR20230008256A (ko) * 2015-11-13 2023-01-13 다케다 야쿠힌 고교 가부시키가이샤 A형 혈우병의 유전자 요법을 위한 증가된 발현을 갖는 재조합 fviii 변이체를 인코딩하는 바이러스 벡터
TWI791433B (zh) * 2016-04-15 2023-02-11 賓州大學委員會 治療ａ型血友病之基因治療
KR102450255B1 (ko) * 2016-05-25 2022-10-04 론자 휴스턴 아이엔씨. 폴리디알릴 디알킬암모늄 염을 이용한 아데노-관련 바이러스의 분리방법
JP6994018B2 (ja) 2016-07-26 2022-01-14 バイオマリン ファーマシューティカル インコーポレイテッド 新規アデノ随伴ウイルスキャプシドタンパク質
JOP20190269A1 (ar) 2017-06-15 2019-11-20 Voyager Therapeutics Inc بولي نوكليوتيدات aadc لعلاج مرض باركنسون
CN111163796A (zh) * 2017-08-01 2020-05-15 星火治疗有限公司 因子viii(fviii)基因治疗方法
CN113164762A (zh) 2018-05-09 2021-07-23 生物马林药物股份有限公司 苯丙酮尿症的治疗方法
TW202005978A (zh) 2018-05-14 2020-02-01 美商拜奧馬林製藥公司 新穎肝靶向腺相關病毒載體
TW202016298A (zh) 2018-05-14 2020-05-01 美商拜奧馬林製藥公司 Aav 載體於幼年受試者中之穩定表現
CA3106590A1 (en) 2018-07-16 2020-01-23 Baxalta Incorporated Gene therapy of hemophilia a using viral vectors encoding recombinant fviii variants with increased expression
WO2020020475A1 (en) * 2018-07-27 2020-01-30 Zentrum Für Forschungsförderung In Der Pädiatrie Gmbh Improved concepts for the treatment of genetic disorders with high-capacity plal-generated gold nanoparticles
US10842885B2 (en) 2018-08-20 2020-11-24 Ucl Business Ltd Factor IX encoding nucleotides
SG11202103614RA (en) * 2018-10-12 2021-05-28 Genzyme Corp Generation of improved human pah for treatment of severe pku by liver-directed gene replacement therapy
CA3127065A1 (en) * 2019-01-16 2020-07-23 Baxalta Incorporated Viral vectors encoding recombinant fviii variants with increased expression for gene therapy of hemophilia a
AU2020221340A1 (en) 2019-02-15 2021-09-16 Bayer Healthcare Llc Gene editing for hemophilia A with improved Factor VIII expression
WO2020186207A2 (en) * 2019-03-13 2020-09-17 Generation Bio Co. Non-viral dna vectors and uses thereof for expressing fviii therapeutics
JP6831943B1 (ja) 2019-10-24 2021-02-17 三ツ星ベルト株式会社 摩擦伝動ベルトおよびその製造方法
JP2023501263A (ja) * 2019-11-01 2023-01-18 フリーライン セラピューティクス リミテッド 第ｖｉｉｉ因子ポリペプチド
CN114981299A (zh) 2019-12-12 2022-08-30 武田药品工业株式会社 使用编码具有增加的表达的重组fviii变体的病毒载体的a型血友病的基因疗法
WO2021236908A2 (en) 2020-05-20 2021-11-25 Biomarin Pharmaceutical Inc. Use of regulatory proteins for the production of adeno-associated virus
WO2022094461A1 (en) 2020-11-02 2022-05-05 Biomarin Pharmaceutical Inc. Process for enriching adeno-associated virus
JP2024527252A (ja) 2021-06-14 2024-07-24 武田薬品工業株式会社 発現の増加した組み換えｆｖｉｉｉバリアントをコードするウイルスベクターを用いた、血友病ａの遺伝子療法
JP2023002483A (ja) * 2021-06-22 2023-01-10 ファイザー・インク 昆虫細胞におけるアデノ随伴ウイルスベクターの産生
AU2022317647A1 (en) * 2021-07-28 2024-01-25 Biomarin Pharmaceutical Inc. Large scale adeno-associated virus production systems
KR20240049332A (ko) * 2021-08-23 2024-04-16 바이오버라티브 테라퓨틱스 인크. 최적화된 인자 viii 유전자
WO2023036054A2 (en) * 2021-09-08 2023-03-16 Inspirar Limited Composition and method for treating hemophilia
WO2023135273A2 (en) 2022-01-14 2023-07-20 Anjarium Biosciences Ag Compositions of dna molecules encoding factor viii, methods of making thereof, and methods of use thereof
AR128760A1 (es) * 2022-03-11 2024-06-12 Homology Medicines Inc Vectores de expresión con promotores dobles bidireccionales y sus usos
WO2023205300A2 (en) * 2022-04-20 2023-10-26 Asklepios Biopharmaceutical, Inc. Therapeutic adeno-associated virus using codon optimized nucleic acid encoding factor viii
WO2024064856A1 (en) 2022-09-22 2024-03-28 Biomarin Pharmaceutical Inc. Treatment of cardiomyopathy with aav gene therapy vectors
TW202421788A (zh) 2022-09-22 2024-06-01 美商拜奧馬林製藥公司 用ａａｖ基因療法載體治療致心律不整性心肌病
CN115948408A (zh) * 2022-09-23 2023-04-11 上海信致医药科技有限公司 改进的人凝血因子viii基因表达盒及其应用
WO2024074143A1 (en) * 2022-10-08 2024-04-11 Lingyi Biotech Co., Ltd. Construct for enhancing gene expression
CN116555266A (zh) * 2023-06-09 2023-08-08 呈诺再生医学科技(北京)有限公司 肝脏特异性表达的重组启动子和载体及其在肝脏相关疾病治疗中的应用
CN118064436B (zh) * 2024-04-18 2024-07-26 上海凌医生物科技有限公司 一种增强基因表达的嵌合启动子

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011005968A1 (en) * 2009-07-08 2011-01-13 Ucl Business Plc Codon-optimized factor vi i i variants and synthetic liver-specific promoter

Family Cites Families (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4745051A (en) 1983-05-27 1988-05-17 The Texas A&M University System Method for producing a recombinant baculovirus expression vector
DE3485810T2 (de) 1983-05-27 1992-12-10 Texas A & M University Syst Verfahren zur herstellung eines rekombinanten baculovirus-expressionsvektors.
DK518384A (da) 1984-01-31 1985-07-01 Idaho Res Found Vektor til fremstilling af et gen-produkt i insektceller, fremgangsmaade til dens fremstilling samt dens anvendelse
RU2219241C2 (ru) * 1993-07-13 2003-12-20 Рон-Пуленк Роре С.А. Дефектный рекомбинантный аденовирусный вектор (варианты)
US6204059B1 (en) 1994-06-30 2001-03-20 University Of Pittsburgh AAV capsid vehicles for molecular transfer
WO1998009524A1 (en) 1996-09-06 1998-03-12 Chiron Corporation Methods and compositions for liver specific delivery of therapeutic molecules using recombinant aav vectors
AU5689699A (en) * 1998-08-24 2000-03-14 Uab Research Foundation Methods of producing high titer recombinant adeno-associated virus
US6221349B1 (en) 1998-10-20 2001-04-24 Avigen, Inc. Adeno-associated vectors for expression of factor VIII by target cells
US6200560B1 (en) 1998-10-20 2001-03-13 Avigen, Inc. Adeno-associated virus vectors for expression of factor VIII by target cells
US6723551B2 (en) 2001-11-09 2004-04-20 The United States Of America As Represented By The Department Of Health And Human Services Production of adeno-associated virus in insect cells
WO2003074714A1 (en) 2002-03-05 2003-09-12 Stichting Voor De Technische Wetenschappen Baculovirus expression system
ATE549037T1 (de) 2004-09-22 2012-03-15 St Jude Childrens Res Hospital Verbesserte expression von faktor-ix in gentherapie-vektoren
CN1286981C (zh) * 2004-11-30 2006-11-29 华中科技大学同济医学院附属同济医院 表达人类cyp2j2反义基因的重组腺相关病毒及其制备方法
EP1739179A1 (en) * 2005-06-30 2007-01-03 Octapharma AG Serum-free stable transfection and production of recombinant human proteins in human cell lines
US7943374B2 (en) * 2005-08-21 2011-05-17 Markus Hildinger Super-size adeno-associated viral vector harboring a recombinant genome larger than 5.7 kb
US7943379B2 (en) 2008-04-30 2011-05-17 Nationwide Children's Hospital, Inc. Production of rAAV in vero cells using particular adenovirus helpers
JP6029674B2 (ja) * 2011-10-18 2016-11-24 ツェー・エス・エル・ベーリング・ゲー・エム・ベー・ハー 第ｖｉｉｉ因子のバイオアベイラビリティを改善するための、硫酸化グリコサミノグリカン及びヒアルロニダーゼの組み合わせ使用
CN103215308B (zh) * 2013-02-01 2015-12-23 中国科学院苏州生物医学工程技术研究所 表达重组人fviii的整合质粒、细胞株及其构建方法和应用
PL3044231T3 (pl) 2013-09-12 2021-01-11 Biomarin Pharmaceutical Inc. Wektory aav zawierające gen kodujący czynnik viii

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011005968A1 (en) * 2009-07-08 2011-01-13 Ucl Business Plc Codon-optimized factor vi i i variants and synthetic liver-specific promoter
US20130024960A1 (en) * 2009-07-08 2013-01-24 Ucl Business Plc Optimised coding sequence and promoter

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Blood, Vol. 121, No, 7, pp3335-3344(2013). *
MT568995.1(GenBank #) *

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