Yuet Kan, MD
Professor Emeritus
Medicine
School of Medicine

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.

• Salvianolic acid B protects against acute and chronic liver injury by inhibiting Smad2C/L phosphorylation.
  Experimental and therapeutic medicine 2021 Tao XM, Li D, Zhang C, Wen GH, Wu C, Xu YY, Kan Y, Lu WP, Ding HY, Yang Y
• Induction of therapeutic levels of HbF in genome-edited primary β0 39-thalassaemia haematopoietic stem and progenitor cells.
  British journal of haematology 2020 Mingoia M, Caria CA, Ye L, Asunis I, Marongiu MF, Manunza L, Sollaino MC, Wang J, Cabriolu A, Kurita R, Nakamura Y, Cucca F, Kan YW, Marini MG, Moi P
• Genetically-edited induced pluripotent stem cells derived from HIV-1-infected patients on therapy can give rise to immune cells resistant to HIV-1 infection.
  AIDS (London, England) 2020 Teque F, Ye L, Xie F, Wang J, Morvan MG, Kan YW, Levy JA
• Biochar as simultaneous shelter, adsorbent, pH buffer, and substrate of Pseudomonas citronellolis to promote biodegradation of high concentrations of phenol in wastewater.
  Water research 2020 Zhao L, Xiao D, Liu Y, Xu H, Nan H, Li D, Kan Y, Cao X
• CRISPR/Cas9-mediated gene deletion efficiently retards the progression of Philadelphia-positive acute lymphoblastic leukemia in a p210 BCR-ABL1T315I mutation mouse model.
  Haematologica 2019 Tan YT, Ye L, Xie F, Wang J, Müschen M, Chen SJ, Kan YW, Liu H
• Infiltration behavior of heavy metals in runoff through soil amended with biochar as bulking agent.
  Environmental pollution (Barking, Essex : 1987) 2019 Zhao L, Nan H, Kan Y, Xu X, Qiu H, Cao X
• Respecifying human iPSC-derived blood cells into highly engraftable hematopoietic stem and progenitor cells with a single factor.
  Proceedings of the National Academy of Sciences of the United States of America 2018 Tan YT, Ye L, Xie F, Beyer AI, Muench MO, Wang J, Chen Z, Liu H, Chen SJ, Kan YW
• Interaction of microRNA-21/145 and Smad3 domain-specific phosphorylation in hepatocellular carcinoma.
  Oncotarget 2017 Wang JY, Fang M, Boye A, Wu C, Wu JJ, Ma Y, Hou S, Kan Y, Yang Y
• Role of Inherent Inorganic Constituents in SO2 Sorption Ability of Biochars Derived from Three Biomass Wastes.
  Environmental science & technology 2016 Xu X, Huang D, Zhao L, Kan Y, Cao X
• Genome editing using CRISPR-Cas9 to create the HPFH genotype in HSPCs: An approach for treating sickle cell disease and β-thalassemia.
  Proceedings of the National Academy of Sciences of the United States of America 2016 Ye L, Wang J, Tan Y, Beyer AI, Xie F, Muench MO, Kan YW
• Reversible Immortalization Enables Seamless Transdifferentiation of Primary Fibroblasts into Other Lineage Cells.
  Stem cells and development 2016 Xie F, Gong K, Li K, Zhang M, Chang JC, Jiang S, Ye L, Wang J, Tan Y, Kan YW
• Chemical transformation of CO2 during its capture by waste biomass derived biochars.
  Environmental pollution (Barking, Essex : 1987) 2016 Xu X, Kan Y, Zhao L, Cao X
• TALENs Facilitate Single-step Seamless SDF Correction of F508del CFTR in Airway Epithelial Submucosal Gland Cell-derived CF-iPSCs.
  Molecular therapy. Nucleic acids 2016 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…
• Phosphorus-assisted biomass thermal conversion: reducing carbon loss and improving biochar stability.
  PloS one 2014 Zhao L, Cao X, Zheng W, Kan Y
• Nrf2 augments skeletal muscle regeneration after ischaemia-reperfusion injury.
  The Journal of pathology 2014 Al-Sawaf O, Fragoulis A, Rosen C, Keimes N, Liehn EA, Hölzle F, Kan YW, Pufe T, Sönmez TT, Wruck CJ
• Nrf2 deficiency impairs fracture healing in mice.
  Calcified tissue international 2014 Lippross S, Beckmann R, Streubesand N, Ayub F, Tohidnezhad M, Campbell G, Kan YW, Horst F, Sönmez TT, Varoga D, Lichte P, Jahr H, Pufe T, Wruck CJ
• Seamless gene correction of β-thalassemia mutations in patient-specific iPSCs using CRISPR/Cas9 and piggyBac.
  Genome research 2014 Xie F, Ye L, Chang JC, Beyer AI, Wang J, Muench MO, Kan YW
• Seamless modification of wild-type induced pluripotent stem cells to the natural CCR5Δ32 mutation confers resistance to HIV infection.
  Proceedings of the National Academy of Sciences of the United States of America 2014 Ye L, Wang J, Beyer AI, Teque F, Cradick TJ, Qi Z, Chang JC, Bao G, Muench MO, Yu J, Levy JA, Kan YW
• Nrf2 protects against TWEAK-mediated skeletal muscle wasting.
  Scientific reports 2014 Al-Sawaf O, Fragoulis A, Rosen C, Kan YW, Sönmez TT, Pufe T, Wruck CJ
• Blood cell-derived induced pluripotent stem cells free of reprogramming factors generated by Sendai viral vectors.
  Stem cells translational medicine 2013 Ye L, Muench MO, Fusaki N, Beyer AI, Wang J, Qi Z, Yu J, Kan YW
• The prevention of thalassemia.
  Cold Spring Harbor perspectives in medicine 2013 Cao A, Kan YW
• Coexpression of VEGF and angiopoietin-1 promotes angiogenesis and cardiomyocyte proliferation reduces apoptosis in porcine myocardial infarction (MI) heart.
  Proceedings of the National Academy of Sciences of the United States of America 2011 Tao Z, Chen B, Tan X, Zhao Y, Wang L, Zhu T, Cao K, Yang Z, Kan YW, Su H
• Role of oxidative stress in rheumatoid arthritis: insights from the Nrf2-knockout mice.
  Annals of the rheumatic diseases 2010 Wruck CJ, Fragoulis A, Gurzynski A, Brandenburg LO, Kan YW, Chan K, Hassenpflug J, Freitag-Wolf S, Varoga D, Lippross S, Pufe T
• Nrf2 induces interleukin-6 (IL-6) expression via an antioxidant response element within the IL-6 promoter.
  The Journal of biological chemistry 2010 Wruck CJ, Streetz K, Pavic G, Götz ME, Tohidnezhad M, Brandenburg LO, Varoga D, Eickelberg O, Herdegen T, Trautwein C, Cha K, Kan YW, Pufe T
• Generation of induced pluripotent stem cells using site-specific integration with phage integrase.
  Proceedings of the National Academy of Sciences of the United States of America 2010 Ye L, Chang JC, Lin C, Qi Z, Yu J, Kan YW
• Molecular diagnosis of hemoglobinopathies and thalassemia.
  Prenatal diagnosis 2010 Kan YW, Chang JC
• Signalling molecules involved in mouse bladder smooth muscle cellular differentiation.
  The International journal of developmental biology 2010 Liu B, Feng D, Lin G, Cao M, Kan YW, Cunha GR, Baskin LS
• Combining angiogenic gene and stem cell therapies for myocardial infarction.
  The journal of gene medicine 2009 Pons J, Huang Y, Takagawa J, Arakawa-Hoyt J, Ye J, Grossman W, Kan YW, Su H
• Induced pluripotent stem cells offer new approach to therapy in thalassemia and sickle cell anemia and option in prenatal diagnosis in genetic diseases.
  Proceedings of the National Academy of Sciences of the United States of America 2009 Ye L, Chang JC, Lin C, Sun X, Yu J, Kan YW
• Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: Critical role for the astrocyte.
  Proceedings of the National Academy of Sciences of the United States of America 2009 Chen PC, Vargas MR, Pani AK, Smeyne RJ, Johnson DA, Kan YW, Johnson JA
• Permanent coronary artery occlusion: cardiovascular MR imaging is platform for percutaneous transendocardial delivery and assessment of gene therapy in canine model.
  Radiology 2008 Saeed M, Martin A, Jacquier A, Bucknor M, Saloner D, Do L, Ursell P, Su H, Kan YW, Higgins CB
• Additive effect of AAV-mediated angiopoietin-1 and VEGF expression on the therapy of infarcted heart.
  International journal of cardiology 2008 Su H, Takagawa J, Huang Y, Arakawa-Hoyt J, Pons J, Grossman W, Kan YW
• High oxygen environment during pregnancy rescues sickle cell anemia mice from prenatal death.
  Blood cells, molecules & diseases 2008 Ye L, Chang JC, Lu R, Kan YW
• Transcription factor Nrf2 protects the brain from damage produced by intracerebral hemorrhage.
  Stroke 2007 Zhao X, Sun G, Zhang J, Strong R, Dash PK, Kan YW, Grotta JC, Aronowski J
• Adeno-associated viral vector-delivered hypoxia-inducible gene expression in ischemic hearts.
  Methods in molecular biology (Clifton, N.J.) 2007 Su H, Kan YW
• Recombinant adeno-associated viral vector encoding human VEGF165 induces neomicrovessel formation in the adult mouse brain.
  Frontiers in bioscience : a journal and virtual library 2006 Shen F, Su H, Liu W, Kan YW, Young WL, Yang GY
• Yuet Wai Kan, MD: sickle cell and thalassemia pioneer. Interview by Tracy Hampton.
  JAMA 2006 Kan YW
• Correction of the sickle cell mutation in embryonic stem cells.
  Proceedings of the National Academy of Sciences of the United States of America 2006 Chang JC, Ye L, Kan YW
• The binding of the ubiquitous transcription factor Sp1 at the locus control region represses the expression of beta-like globin genes.
  Proceedings of the National Academy of Sciences of the United States of America 2005 Feng D, Kan YW
• Adeno-associated viral vector delivers cardiac-specific and hypoxia-inducible VEGF expression in ischemic mouse hearts.
  Proceedings of the National Academy of Sciences of the United States of America 2004 Su H, Joho S, Huang Y, Barcena A, Arakawa-Hoyt J, Grossman W, Kan YW
• Targeted disruption of Nrf2 causes regenerative immune-mediated hemolytic anemia.
  Proceedings of the National Academy of Sciences of the United States of America 2004 Lee JM, Chan K, Kan YW, Johnson JA
• 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.
  The Biochemical journal 2004 Ma Q, Kinneer K, Bi Y, Chan JY, Kan YW
• Adeno-associated viral vector-mediated gene transfer of VEGF normalizes skeletal muscle oxygen tension and induces arteriogenesis in ischemic rat hindlimb.
  Molecular therapy : the journal of the American Society of Gene Therapy 2003 Chang DS, Su H, Tang GL, Brevetti LS, Sarkar R, Wang R, Kan YW, Messina LM
• 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, molecules & diseases 2002 Marini MG, Asunis I, Chan K, Chan JY, Kan YW, Porcu L, Cao A, Moi P
• Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound.
  Molecular and cellular biology 2002 Braun S, Hanselmann C, Gassmann MG, auf dem Keller U, Born-Berclaz C, Chan K, Kan YW, Werner S
• Adeno-associated viral vector-mediated hypoxia response element-regulated gene expression in mouse ischemic heart model.
  Proceedings of the National Academy of Sciences of the United States of America 2002 Su H, Arakawa-Hoyt J, Kan YW