基因治疗：美国生物技术投资的风口.pdf

-1- ?????????????????????????????????????????????????? ???????????????????????????????? ?????????????????????????? ????????????????????????? 2006 ???????????????? ???????????????????????????????? ???????????????????????????????? ???????????????????????????????? ?????? ?????????????? FDA?? EMA ???????????????? ?? FDA ??????? ???????? 2014-2015 ??????????????? ???? ???????????????????????????????? ??????? EMA ?? 2012 ?????????? Glybera ?????????????????????????????? ????????????????????????????????? 2013 ???????????? ?????? 6 ?????? IPO?VC ?????????Celgene? Bayer? Pfizer? Sanofi ?????????????????????? ?????????? ??? IPO ? 5 ??????????? ???? ?????? 53% - 595%???????????????????? ????????? ???????????????????? A ???????????????????????? ????????? ???????????????????????????????? ???????????????????????????????? ???????????????????????????????? ???????????????????????? A ??????? ?????????????? ????????????????????????????????????????? BLUE? QURE?CLDN?AGTC ? AAVL?BLUE ?????????????? ???????????????????? ?? FDA ?? ??????? ???????? 3-5 ???????QURE ? Glybera ??????? ????????????????? 2015 ????????CLDN ? ????????????????? ???? MYDICAR ?? FDA ?? ????????AGTC ????????????????????? ???5???????????????? ????????????? AAVL ????????????????????????????? ?????????????????????????????? ??????????????????????????????? 1?????????? --- ?????????????? ??????????????????????????????? ??????????????????????????????? A ? ????????????????????????????????? ????????????????????????????????? ??? 2???????????????????????????????????? ???????? 1972 ?? Fridemann ? Roblin ????? 80 ??? ????????????????? 90 ?????????????? ????????????????????????????????? ?????????????????? 1999 ???? Andrew Gobea ? ????????????? FDA ????????????????? ????????????????????????????????? ??????????????? 2006 ??????????????? ????????????????????????????????? ???? ?? 1?????????????????????? ???? ???????? ???? 1972 Friedmann ? Roblin ???????????? (1) 1984 ??????????????????????????(2) 1990 ??????(ADA)????????? ??? (SCID) FDA ????????????????????????? Ashanti DeSilva ?????????????? ?3? 1992 ADA-SCID ????? Claudio Bordignon ??????????????????? ?????4? 1993 SCID Andrew Gobea ???????????????????? 4 ????? ??????????????????? 1999 ????????????? (OTC-Deficiency) ?? Jesse Gelsinger ??????????????????????? ????????????????FDA ??????????????? ?????????????????????????????? 2002 ????????(Sickle-cell disease) ?? MIT ???????????????????????????? ???(5) 2003 ?? ?? CFDA ?????????? P53 ??????????????? ????? Introgen ???????? 2008 ??????? ??? FDA ? ?? 2006 ??????(chronic granulomatous disease) ??????????????????????(6) ?????????? MicroRNA ????????????????? ????????????????????????????(7) ????(Metastatic melanoma) ?????????(NCI)???????????????????(8) HIV ?? UPenn ???????????????????? 2007 ??????(Leber's Congenital Amaurosis) ????????? Moorfields Eye Hospital ? University College London ????????????????????9? 2009 ????????? (adrenoleukodystrophy) ????????????????????????????????? ??????(10) 2010 ???????(?-thalassaemia) ????? Philippe Leboulch ???????????????? 1 ??????????(11) 2011 ?????????(chronic lymphocytic leukemia) UPenn ?????????????????? T ??????? ???? ???????????? ????? 2013 ?????? ????? 59 ? ????26 ???????? 2012 ?????????(Lipoprotein Lipase Deficiency) UniQure ??????????????? de ???? Glybera ???? ?????Glybera ????????????????????? 2014 HIV UPenn ????????? HIV ???????????(12) ?????????? (inherited retinal dystrophies) ??????Spark Therapeutics????????SPK-PRE65??FDA ???????????????SPK-PRE65 ?? III ????????? 15 ?????????? ??????(chronic heart failure) ?????? Celladon ??????? CYDICAR ?? FDA ?????? ????????CYDICAR ?? II ????????????? 2015 ? ???? 2015 ???????(?-thalassaemia) ?????? BlueBird Bio ???????? LentiGlobin BB305 ?? FDA ??????????????LentiGlobin ???????? ????? 1. Gene therapy for human genetic disease? Science. 1972 Mar 3;175(4025):949-55. 2. Construction and applications of a highly transmissible murine retrovirus shuttle vector. Cell. 1984 37(3): 1053?62 3. T Lymphocyte-Directed Gene Therapy for ADA− SCID: Initial Trial Results After 4 Years. Science 20 October 1995: Vol. 270 no. 5235 pp. 475-480. 4. Gene therapy in peripheral blood lymphocytes and bone marrow for ADA- immunodeficient patients. Science. 1995 Oct 20;270(5235):470-5. 5. Correction of Sickle Cell Disease in Transgenic Mouse Models by Gene Therapy. Science 14 December 2001: Vol. 294 no. 5550 pp. 2368-2371 6. Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nat Med. 2006 Apr;12(4):401-9. Epub 2006 Apr 2. 7. Endogenous microRNA regulation suppresses transgene expression in hematopoietic lineages and enables stable gene transfer. Nature Medicine 12, 585 - 591 (2006) 8. Cancer Regression in Patients After Transfer of Genetically Engineered Lymphocytes. Science. 2006 Oct 6; 314(5796): 126? 129. 9. Safety and Efficacy of Gene Transfer for Leber's Congenital Amaurosis. New England Journal of 。