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Yuet Kan, MD

TitleProfessor
InstitutionUniversity of California San Francisco
DepartmentMedicine
Address513 Parnassus Ave
San Francisco CA 94143
Phone415-476-5841
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    Research Interests: The mechanisms of globin production and exploring novel ways of inserting genes into mammalian cells; investigating newer approaches for fetal diagnosis of genetic disorders.

    Research Summary: The research in our laboratory is focused on the study of two inherited blood diseases; sickle cell anemia and thalassemia. These two diseases constitute the most common genetic diseases in the world and they affect people of African, Mediterranean, Middle East, and Asian origins. At present, treatment mostly consists of treatment of symptoms and complications. Bone marrow or cord blood transfusion can be curative when compatible donors can be found. However, since most of these families have a small number of children, only a minority of patients can be treated by transplantation.

    An effective way of preventing genetic diseases such as sickle cell anemia and thalassemia is by carrier screening, genetic counseling, and prenatal diagnosis. Our laboratory has been involved in prenatal diagnosis from the 1970s. Currently, amniocentesis and chorionic villus sampling is used to obtain DNA for diagnosis. We are investigating the isolation of fetal cells from the mother’s blood for testing so that an invasive procedure to the fetus can be avoided.
    Out laboratory is also investigating gene and cell therapy for treating these conditions. In a thalassemia, the affected fetus usually dies in the third trimester or soon after birth. We have explored in utero gene therapy to treat this condition. Using a mouse model of alpha thalassemia that we have previously made, we introduced to the mouse embryo at the 14th day of gestation a lentiviral vector that contained the human alpha globin gene. Preliminary studies showed that human alpha globin was expressed at moderately levels. Our plan is to see if these vectors can rescue the fetal mouse affected by homozygous a thalassemia.

    The mutations in sickle cell anemia and most clinically important ß thalassemia lie in the ß globin gene. Therefore, the approach to stem cell therapy for both is similar. We first tested embryonic stem cell therapy for a mouse model of sickle cell anemia. We made embryonic stem cells from a sickle cell anemia mouse, corrected the mutation by homologous recombination, differentiated the stem cells into hematopoietic cells and showed that the blood cells made hemoglobin A in additional to hemoglobin S.

    To apply this treatment for the human diseases, it will be necessary to use nuclear transfer in stem cells in order to avoid immunological rejection. However, nuclear transfer to make embryonic stem cell has not been successful in humans. Also, the procedure is complicated, requires egg donors from normal individuals and raises ethical concern. With the description of induced pluripotent stem (iPS) cells, we have now changed to this approach for the treatment of these conditions. Our laboratory has successfully made iPS cells from mouse and human fibroblasts by retroviral delivery of transcription vectors.

    Currently, we are working on correcting mutation in these iPS cells and differentiate them into hematopoietic cells. The future goal to treatment is to take skin cells from patients, differentiate them into iPS cells, correct the mutations by homologous recombination, and differentiate into the hematopoietic cells and re-infuse them into the patients. Since the cells originate from the patients, there would not be immuno-rejection. In order to achieve this goal, several conditions must first be met. First, to convert the skin cell into IPs cell it is necessary to use retrovirus induction. However, integration of retrovirus may disturb vital gene functions. Second, a reliable way of differentiating iPS cells into hematopoietic cells has to be established. We feel strongly that this approach will provide a means for curing these diseases.


    Collapse Research 
    Collapse Research Activities and Funding
    Development of iPS Cells for Treatment of Hemoglobinopathies
    NIH/NIDDK P01DK088760Sep 30, 2011 - Jul 31, 2016
    Role: Principal Investigator
    Northern California Comprehensive Sickle Cell Centers
    NIH U54HL070583Jul 1, 2003 - Mar 31, 2010
    Role: Co-Investigator
    AAV Mediated Angiogenic Therapy for Coronary Disease
    NIH/NHLBI R01HL067969Dec 5, 2002 - Nov 30, 2006
    Role: Principal Investigator
    Gene Therapy for Hemophilia
    NIH U01HL066948Sep 28, 2000 - Aug 31, 2007
    Role: Co-Investigator
    MURINE MODELS TO INVESTIGATE THE HEMATOLOGIC SYSTEM
    NIH/NIDDK P01DK050267Aug 15, 1995 - Jul 31, 2001
    Role: Principal Investigator
    GENE THERAPY STRATEGIES FOR SICKLE CELL DISEASE
    NIH/NHLBI P01HL053762Sep 30, 1994 - Aug 31, 2007
    Role: Principal Investigator
    GENE THERAPY CORE--CYSTIC FIBROSIS &NON-CF GENETIC DIS
    NIH/NIDDK P30DK047766Sep 30, 1993 - Aug 31, 1999
    Role: Principal Investigator
    CENTER OF EXCELLENCE IN MOLECULAR HEMATOLOGY
    NIH/NIDDK P20DK047455Sep 30, 1993 - Aug 31, 1995
    Role: Principal Investigator
    Basic Research in Hematology and Oncology
    NIH/NIDDK T32DK007636May 1, 1984 - Mar 31, 2014
    Role: Co-Principal Investigator
    BASIC RESEARCH IN HEMATOLOGY AND ONCOLOGY
    NIH/NCI T32CA009463May 1, 1984 - Jan 31, 1989
    Role: Principal Investigator
    NORTHERN CALIFORNIA COMPREHENSIVE SICKLE CELL CENTER
    NIH P60HL020985Apr 1, 1978 - Mar 31, 2004
    Role: Co-Investigator
    Abnormal Hemoglobin Synthesis -- Mechanism and Detection
    NIH/NIDDK R01DK016666Aug 1, 1976 - Apr 30, 2007
    Role: Principal Investigator
    ABNORMAL HEMOGLOBIN SYNTHESIS--MECHANISM AND DETECTION
    NIH/NIDDK R37DK016666Aug 1, 1976 - Jul 31, 2002
    Role: Principal Investigator
    ABNORMAL HEMOGLOBIN SYNTHESIS--MECHANISM &DETECTION
    NIH/NIADDK R01AM016666Aug 1, 1976 - Jul 31, 1986
    Role: Principal Investigator
    California National Primate Research Center
    NIH P51RR000169Jun 1, 1975 - Apr 30, 2015
    Role: Co-Investigator

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    Collapse Publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Researchers can login to make corrections and additions, or contact us for help.
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    1. Tan YT, Ye L, Xie F, Beyer AI, Muench MO, Wang J, Chen Z, Liu H, Chen SJ, Kan Y. Respecifying human iPSC-derived blood cells into highly engraftable hematopoietic stem and progenitor cells with a single factor. Proc Natl Acad Sci U S A. 2018 Feb 27; 115(9):2180-2185. PMID: 29386396.
      View in: PubMed
    2. Wang JY, Fang M, Boye A, Wu C, Wu JJ, Ma Y, Hou S, Kan Y, Yang Y. Interaction of microRNA-21/145 and Smad3 domain-specific phosphorylation in hepatocellular carcinoma. Oncotarget. 2017 Oct 17; 8(49):84958-84973. PMID: 29156696.
      View in: PubMed
    3. Ye L, Wang J, Tan Y, Beyer AI, Xie F, Muench MO, Kan Y. Genome editing using CRISPR-Cas9 to create the HPFH genotype in HSPCs: An approach for treating sickle cell disease and ß-thalassemia. Proc Natl Acad Sci U S A. 2016 09 20; 113(38):10661-5. PMID: 27601644.
      View in: PubMed
    4. Xie F, Gong K, Li K, Zhang M, Chang JC, Jiang S, Ye L, Wang J, Tan Y, Kan Y. Reversible Immortalization Enables Seamless Transdifferentiation of Primary Fibroblasts into Other Lineage Cells. Stem Cells Dev. 2016 08 15; 25(16):1243-8. PMID: 27328768; PMCID: PMC4991573 [Available on 08/15/17].
    5. Suzuki S, Sargent RG, Illek B, Fischer H, Esmaeili-Shandiz A, Yezzi MJ, Lee A, Yang Y, Kim S, Renz P, Qi Z, Yu J, Muench MO, Beyer AI, Guimarães AO, Ye L, Chang J, Fine EJ, Cradick TJ, Bao G, Rahdar M, Porteus MH, Shuto T, Kai H, Kan Y, Gruenert DC. TALENs Facilitate Single-step Seamless SDF Correction of F508del CFTR in Airway Epithelial Submucosal Gland Cell-derived CF-iPSCs. Mol Ther Nucleic Acids. 2016 Jan 05; 5:e273. PMID: 26730810; PMCID: PMC5012545.
    6. Al-Sawaf O, Fragoulis A, Rosen C, Keimes N, Liehn EA, Hölzle F, Kan Y, Pufe T, Sönmez TT, Wruck CJ. Nrf2 augments skeletal muscle regeneration after ischaemia-reperfusion injury. J Pathol. 2014 Dec; 234(4):538-47. PMID: 25111334.
      View in: PubMed
    7. Lippross S, Beckmann R, Streubesand N, Ayub F, Tohidnezhad M, Campbell G, Kan Y, Horst F, Sönmez TT, Varoga D, Lichte P, Jahr H, Pufe T, Wruck CJ. Nrf2 deficiency impairs fracture healing in mice. Calcif Tissue Int. 2014 Oct; 95(4):349-61. PMID: 25096517.
      View in: PubMed
    8. Xie F, Ye L, Chang JC, Beyer AI, Wang J, Muench MO, Kan Y. Seamless gene correction of ß-thalassemia mutations in patient-specific iPSCs using CRISPR/Cas9 and piggyBac. Genome Res. 2014 Sep; 24(9):1526-33. PMID: 25096406; PMCID: PMC4158758.
    9. Ye L, Wang J, Beyer AI, Teque F, Cradick TJ, Qi Z, Chang JC, Bao G, Muench MO, Yu J, Levy JA, Kan Y. Seamless modification of wild-type induced pluripotent stem cells to the natural CCR5?32 mutation confers resistance to HIV infection. Proc Natl Acad Sci U S A. 2014 Jul 01; 111(26):9591-6. PMID: 24927590; PMCID: PMC4084478.
    10. Al-Sawaf O, Fragoulis A, Rosen C, Kan Y, Sönmez TT, Pufe T, Wruck CJ. Nrf2 protects against TWEAK-mediated skeletal muscle wasting. Sci Rep. 2014 Jan 10; 4:3625. PMID: 24406502; PMCID: PMC3887379.
    11. Ye L, Muench MO, Fusaki N, Beyer AI, Wang J, Qi Z, Yu J, Kan Y. Blood cell-derived induced pluripotent stem cells free of reprogramming factors generated by Sendai viral vectors. Stem Cells Transl Med. 2013 Aug; 2(8):558-66. PMID: 23847002; PMCID: PMC3726135.
    12. Cao A, Kan Y. The prevention of thalassemia. Cold Spring Harb Perspect Med. 2013 Feb 01; 3(2):a011775. PMID: 23378598; PMCID: PMC3552345.
    13. Tao Z, Chen B, Tan X, Zhao Y, Wang L, Zhu T, Cao K, Yang Z, Kan Y, Su H. Coexpression of VEGF and angiopoietin-1 promotes angiogenesis and cardiomyocyte proliferation reduces apoptosis in porcine myocardial infarction (MI) heart. Proc Natl Acad Sci U S A. 2011 Feb 01; 108(5):2064-9. PMID: 21245320; PMCID: PMC3033313.
    14. Wruck CJ, Fragoulis A, Gurzynski A, Brandenburg LO, Kan Y, Chan K, Hassenpflug J, Freitag-Wolf S, Varoga D, Lippross S, Pufe T. Role of oxidative stress in rheumatoid arthritis: insights from the Nrf2-knockout mice. Ann Rheum Dis. 2011 May; 70(5):844-50. PMID: 21173018.
      View in: PubMed
    15. Ye L, Chang JC, Lin C, Qi Z, Yu J, Kan Y. Generation of induced pluripotent stem cells using site-specific integration with phage integrase. Proc Natl Acad Sci U S A. 2010 Nov 09; 107(45):19467-72. PMID: 20974949; PMCID: PMC2984165.
    16. Kan Y, Chang JC. Molecular diagnosis of hemoglobinopathies and thalassemia. Prenat Diagn. 2010 Jul; 30(7):608-10. PMID: 20572100.
      View in: PubMed
    17. Liu B, Feng D, Lin G, Cao M, Kan Y, Cunha GR, Baskin LS. Signalling molecules involved in mouse bladder smooth muscle cellular differentiation. Int J Dev Biol. 2010; 54(1):175-80. PMID: 20013655; PMCID: PMC2855152.
    18. Pons J, Huang Y, Takagawa J, Arakawa-Hoyt J, Ye J, Grossman W, Kan Y, Su H. Combining angiogenic gene and stem cell therapies for myocardial infarction. J Gene Med. 2009 Sep; 11(9):743-53. PMID: 19554624.
      View in: PubMed
    19. Ye L, Chang JC, Lin C, Sun X, Yu J, Kan Y. Induced pluripotent stem cells offer new approach to therapy in thalassemia and sickle cell anemia and option in prenatal diagnosis in genetic diseases. Proc Natl Acad Sci U S A. 2009 Jun 16; 106(24):9826-30. PMID: 19482945; PMCID: PMC2701047.
    20. Chen PC, Vargas MR, Pani AK, Smeyne RJ, Johnson DA, Kan Y, Johnson JA. Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: Critical role for the astrocyte. Proc Natl Acad Sci U S A. 2009 Feb 24; 106(8):2933-8. PMID: 19196989; PMCID: PMC2650368.
    21. Saeed M, Martin A, Jacquier A, Bucknor M, Saloner D, Do L, Ursell P, Su H, Kan Y, Higgins CB. Permanent coronary artery occlusion: cardiovascular MR imaging is platform for percutaneous transendocardial delivery and assessment of gene therapy in canine model. Radiology. 2008 Nov; 249(2):560-71. PMID: 18780824; PMCID: PMC2657866.
    22. Su H, Takagawa J, Huang Y, Arakawa-Hoyt J, Pons J, Grossman W, Kan Y. Additive effect of AAV-mediated angiopoietin-1 and VEGF expression on the therapy of infarcted heart. Int J Cardiol. 2009 Apr 03; 133(2):191-7. PMID: 18295361; PMCID: PMC2692365.
    23. Ye L, Chang JC, Lu R, Kan Y. High oxygen environment during pregnancy rescues sickle cell anemia mice from prenatal death. Blood Cells Mol Dis. 2008 Jul-Aug; 41(1):67-72. PMID: 18207438.
      View in: PubMed
    24. Zhao X, Sun G, Zhang J, Strong R, Dash PK, Kan Y, Grotta JC, Aronowski J. Transcription factor Nrf2 protects the brain from damage produced by intracerebral hemorrhage. Stroke. 2007 Dec; 38(12):3280-6. PMID: 17962605.
      View in: PubMed
    25. Su H, Kan Y. Adeno-associated viral vector-delivered hypoxia-inducible gene expression in ischemic hearts. Methods Mol Biol. 2007; 366:331-42. PMID: 17568134.
      View in: PubMed
    26. Shen F, Su H, Liu W, Kan Y, Young WL, Yang GY. Recombinant adeno-associated viral vector encoding human VEGF165 induces neomicrovessel formation in the adult mouse brain. Front Biosci. 2006 Sep 01; 11:3190-8. PMID: 16720385.
      View in: PubMed
    27. Kan Y. Yuet Wai Kan, MD: sickle cell and thalassemia pioneer. Interview by Tracy Hampton. JAMA. 2006 Mar 01; 295(9):991. PMID: 16507792.
      View in: PubMed
    28. Chang JC, Ye L, Kan Y. Correction of the sickle cell mutation in embryonic stem cells. Proc Natl Acad Sci U S A. 2006 Jan 24; 103(4):1036-40. PMID: 16407095; PMCID: PMC1326143.
    29. Feng D, Kan Y. The binding of the ubiquitous transcription factor Sp1 at the locus control region represses the expression of beta-like globin genes. Proc Natl Acad Sci U S A. 2005 Jul 12; 102(28):9896-900. PMID: 15998736; PMCID: PMC1174987.
    30. Su H, Joho S, Huang Y, Barcena A, Arakawa-Hoyt J, Grossman W, Kan Y. Adeno-associated viral vector delivers cardiac-specific and hypoxia-inducible VEGF expression in ischemic mouse hearts. Proc Natl Acad Sci U S A. 2004 Nov 16; 101(46):16280-5. PMID: 15534198; PMCID: PMC527136.
    31. Lee JM, Chan K, Kan Y, Johnson JA. Targeted disruption of Nrf2 causes regenerative immune-mediated hemolytic anemia. Proc Natl Acad Sci U S A. 2004 Jun 29; 101(26):9751-6. PMID: 15210949; PMCID: PMC470746.
    32. Ma Q, Kinneer K, Bi Y, Chan JY, Kan Y. Induction of murine NAD(P)H:quinone oxidoreductase by 2,3,7,8-tetrachlorodibenzo-p-dioxin requires the CNC (cap 'n' collar) basic leucine zipper transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2): cross-interaction between AhR (aryl hydrocarbon receptor) and Nrf2 signal transduction. Biochem J. 2004 Jan 01; 377(Pt 1):205-13. PMID: 14510636; PMCID: PMC1223846.
    33. Chang DS, Su H, Tang GL, Brevetti LS, Sarkar R, Wang R, Kan Y, Messina LM. Adeno-associated viral vector-mediated gene transfer of VEGF normalizes skeletal muscle oxygen tension and induces arteriogenesis in ischemic rat hindlimb. Mol Ther. 2003 Jan; 7(1):44-51. PMID: 12573617.
      View in: PubMed
    34. Marini MG, Asunis I, Chan K, Chan JY, Kan Y, Porcu L, Cao A, Moi P. Cloning MafF by recognition site screening with the NFE2 tandem repeat of HS2: analysis of its role in globin and GCSl genes regulation. Blood Cells Mol Dis. 2002 Sep-Oct; 29(2):145-58. PMID: 12490281.
      View in: PubMed
    35. Braun S, Hanselmann C, Gassmann MG, auf dem Keller U, Born-Berclaz C, Chan K, Kan Y, Werner S. Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound. Mol Cell Biol. 2002 Aug; 22(15):5492-505. PMID: 12101242; PMCID: PMC133949.
    36. Su H, Arakawa-Hoyt J, Kan Y. Adeno-associated viral vector-mediated hypoxia response element-regulated gene expression in mouse ischemic heart model. Proc Natl Acad Sci U S A. 2002 Jul 09; 99(14):9480-5. PMID: 12084814; PMCID: PMC123166.