Karin Gaensler, MD
Professor
Medicine
School of Medicine

My laboratory has focused on the development of gene transfer and stem cell transplantation approaches for the treatment of hematologic disorders, with a current focus on the development of immunotherapeutic approaches to treat minimal residual disease (MRD) in older patients with acute myelogenous leukemia (AML). There is a major clinical unmet need for effective and safe therapies to increase progression-free and overall survival in older individuals with leukemia whose prognosis is grim. Compelling evidence for the efficacy of immunotherapy in eliminating minimal residual disease (MRD) is provided by the superior outcomes of allogeneic hematopoietic stem cell transplants (HSCT) due to graft vs leukemia (GVL) effects. However, patients > 60 yo are often ineligible for allo-HSCT. Two vaccine approaches are being developed as part of a collaborative consortium at UCSF, UCLA, UC Davis, and King’s College, London. Our vaccine project focuses on genetic engineering of autologous whole cell AML vaccines to express CD80, and IL-15, and IL-15 Receptor alpha (IL-15Rα). The leukemia-specific cytolytic activity stimulated by engineered, irradiated AML cell vaccines expressing IL-15/IL-15Ra/CD80 was tested in the murine 32Dp210 myeloid leukemia model that recapitulates many features of human AML. Proof of concept (POC) studies showed that treatment of leukemia-bearing hosts induced superior anti-leukemic immunity when compared with vaccines expressing either CD80, or IL15-IL15Rα alone and eradicated leukemia 80% in leukemic mice an effect mediated by CD8+ T cells. (Shi, Y. et al (2018)). Based on these proof of concept studies we received a Catalyst award through the CTSI at UCSF, a Translational Research Program grant from the Leukemia and Lymphoma Society in 2017, and a CIRM Translational-1 grant in 2018 to pursue non-overlapping studies with cGMP reagents supporting submission of a Pre-IND package to the FDA. Most recently, we were awarded a CIRM CLIN 1 grant (12/2022)to pursue IND enabling studies. These studies are being pursued as part of a collaborative consortium with investigators at UCSF (M. Rosenblum, L. Damon, A. Nambiar, A.Combes and K. Ganapathi), UCLA (Donald Kohn), and King's College London (Farzin Farzaneh).

• IL-15/IL-15Rα/CD80-expressing AML cell vaccines eradicate minimal residual disease in leukemic mice.
  Blood advances 2018 Shi Y, Dincheva-Vogel L, Ayemoba CE, Fung JP, Bergamaschi C, Pavlakis GN, Farzaneh F, Gaensler KML
• Myelodysplastic Syndromes, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology.
  Journal of the National Comprehensive Cancer Network : JNCCN 2017 Greenberg PL, Stone RM, Al-Kali A, Barta SK, Bejar R, Bennett JM, Carraway H, De Castro CM, Deeg HJ, DeZern AE, Fathi AT, Frankfurt O, Gaensler K, Garcia-Manero G, Griffiths EA, Head D, Horsfall R, …
• Quantification of Acute Lymphoblastic Leukemia Clonotypes in Leukapheresed Peripheral Blood Progenitor Cells Predicts Relapse Risk after Autologous Hematopoietic Stem Cell Transplantation.
  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 2016 Mannis GN, Martin TG, Damon LE, Andreadis C, Olin RL, Kong KA, Faham M, Hwang J, Ai WZ, Gaensler KML, Sayre PH, Wolf JL, Logan AC
• Long-term outcomes of patients with intermediate-risk acute myeloid leukemia treated with autologous hematopoietic cell transplant in first complete remission.
  Leukemia & lymphoma 2016 Mannis GN, Martin TG, Damon LE, Logan AC, Olin RL, Flanders MD, Ai WZ, Gaensler KM, Kaplan LD, Sayre PH, Smith CC, Wolf JL, Andreadis C
• Nitric Oxide-cGMP Signaling Stimulates Erythropoiesis through Multiple Lineage-Specific Transcription Factors: Clinical Implications and a Novel Target for Erythropoiesis.
  PloS one 2016 Ikuta T, Sellak H, Odo N, Adekile AD, Gaensler KM
• An Orthogonal Array Optimization of Lipid-like Nanoparticles for mRNA Delivery in Vivo.
  Nano letters 2015 Li B, Luo X, Deng B, Wang J, McComb DW, Shi Y, Gaensler KM, Tan X, Dunn AL, Kerlin BA, Dong Y
• The combined molecular adjuvant CASAC enhances the CD8+ T cell response to a tumor-associated self-antigen in aged, immunosenescent mice.
  Immunity & ageing : I & A 2015 Tye GJ, Ioannou K, Amofah E, Quartey-Papafio R, Westrop SJ, Krishnamurthy P, Noble A, Harrison PM, Gaensler KML, Barber LD, Farzaneh F
• Myelodysplastic syndromes, version 2.2015.
  Journal of the National Comprehensive Cancer Network : JNCCN 2015 Greenberg PL, Stone RM, Bejar R, Bennett JM, Bloomfield CD, Borate U, De Castro CM, Deeg HJ, DeZern AE, Fathi AT, Frankfurt O, Gaensler K, Garcia-Manero G, Griffiths EA, Head D, Klimek V, Komrokji R, …
• A phase I study of targeted, dose-escalated intravenous busulfan in combination with etoposide as myeloablative therapy for autologous stem cell transplantation in acute myeloid leukemia.
  Clinical lymphoma, myeloma & leukemia 2015 Mannis GN, Andreadis C, Logan AC, Damon LE, Benet LZ, Ai WZ, Gaensler KM, Kaplan LD, Koplowicz YB, Linker CA, Olin RL, Sayre PH, Smith CC, Sudhindra A, Venstrom JM, Wolf JL, Martin TG
• Promoterless gene targeting without nucleases ameliorates haemophilia B in mice.
  Nature 2014 Barzel A, Paulk NK, Shi Y, Huang Y, Chu K, Zhang F, Valdmanis PN, Spector LP, Porteus MH, Gaensler KM, Kay MA
• Delayed hematopoietic recovery after auto-SCT in patients receiving arsenic trioxide-based therapy for acute promyelocytic leukemia: a multi-center analysis.
  Bone marrow transplantation 2014 Mannis GN, Logan AC, Leavitt AD, Yanada M, Hwang J, Olin RL, Damon LE, Andreadis C, Ai WZ, Gaensler KM, Greene CC, Gupta NK, Kaplan LD, Mahindra A, Miyazaki Y, Naoe T, Ohtake S, Sayre PH, Smith CC, …
• Hematopoietic cell transplantation comorbidity index (HCT-CI) is predictive of adverse events and overall survival in older allogeneic transplant recipients.
  Journal of geriatric oncology 2014 Keller JW, Andreadis C, Damon LE, Kaplan LD, Martin TG, Wolf JL, Ai WZ, Venstrom JM, Smith CC, Gaensler KM, Hwang J, Olin RL
• Role of antigen-specific regulatory CD4+CD25+ T cells in tolerance induction after neonatal IP administration of AAV-hF.IX.
  Gene therapy 2013 Shi Y, Falahati R, Zhang J, Flebbe-Rehwaldt L, Gaensler KM
• Early Chk1 phosphorylation is driven by temozolomide-induced, DNA double strand break- and mismatch repair-independent DNA damage.
  PloS one 2013 Ito M, Ohba S, Gaensler K, Ronen SM, Mukherjee J, Pieper RO
• Chemoselection of allogeneic HSC after murine neonatal transplantation without myeloablation or post-transplant immunosuppression.
  Molecular therapy : the journal of the American Society of Gene Therapy 2012 Falahati R, Zhang J, Flebbe-Rehwaldt L, Shi Y, Gerson SL, Gaensler KM
• MicroRNA-181a* Targets Nanog in a Subpopulation of CD34(+) Cells Isolated From Peripheral Blood.
  Molecular therapy. Nucleic acids 2012 Mintz PJ, Sætrom P, Reebye V, Lundbæk MB, Lao K, Rossi JJ, Gaensler KM, Kasahara N, Nicholls JP, Jensen S, Haoudi A, Emara MM, Gordon MY, Habib NA
• Transcription factors KLF1 and KLF2 positively regulate embryonic and fetal beta-globin genes through direct promoter binding.
  The Journal of biological chemistry 2011 Alhashem YN, Vinjamur DS, Basu M, Klingmüller U, Gaensler KM, Lloyd JA
• Suppression of HLA expression by lentivirus-mediated gene transfer of siRNA cassettes and in vivo chemoselection to enhance hematopoietic stem cell transplantation.
  Immunologic research 2009 Hacke K, Falahati R, Flebbe-Rehwaldt L, Kasahara N, Gaensler KM
• Impact of intensive PBSC mobilization therapy on outcomes following auto-SCT for non-Hodgkin's lymphoma.
  Bone marrow transplantation 2008 Damon L, Damon LE, Gaensler K, Kaplan L, Martin T, Rubenstein J, Linker C
• A mechanism for Ikaros regulation of human globin gene switching.
  British journal of haematology 2008 Keys JR, Tallack MR, Zhan Y, Papathanasiou P, Goodnow CC, Gaensler KM, Crossley M, Dekker J, Perkins AC
• Methyl binding domain protein 2 mediates gamma-globin gene silencing in adult human betaYAC transgenic mice.
  Proceedings of the National Academy of Sciences of the United States of America 2006 Rupon JW, Wang SZ, Gaensler K, Lloyd J, Ginder GD
• KLF2 is essential for primitive erythropoiesis and regulates the human and murine embryonic beta-like globin genes in vivo.
  Blood 2005 Basu P, Morris PE, Haar JL, Wani MA, Lingrel JB, Gaensler KM, Lloyd JA
• Comparison of gene expression after intraperitoneal delivery of AAV2 or AAV5 in utero.
  Molecular therapy : the journal of the American Society of Gene Therapy 2003 Lipshutz GS, Titre D, Brindle M, Bisconte AR, Contag CH, Gaensler KM
• Sequences in the (A)gamma-delta intergenic region are not required for stage-specific regulation of the human beta-globin gene locus.
  Proceedings of the National Academy of Sciences of the United States of America 2003 Gaensler KM, Zhang Z, Lin C, Yang S, Hardt K, Flebbe-Rehwaldt L
• In utero delivery of adeno-associated viral vectors: intraperitoneal gene transfer produces long-term expression.
  Molecular therapy : the journal of the American Society of Gene Therapy 2001 Lipshutz GS, Gruber CA, Hardy J, Contag CH, Gaensler KM
• Reexpression following readministration of an adenoviral vector in adult mice after initial in utero adenoviral administration.
  Molecular therapy : the journal of the American Society of Gene Therapy 2000 Lipshutz GS, Flebbe-Rehwaldt L, Gaensler KM
• Therapeutic haemoglobin synthesis in beta-thalassaemic mice expressing lentivirus-encoded human beta-globin.
  Nature 2000 May C, Rivella S, Callegari J, Heller G, Gaensler KM, Luzzatto L, Sadelain M
• Fetal gene transfer by transuterine injection of cationic liposome-DNA complexes.
  Nature biotechnology 1999 Gaensler KM, Tu G, Bruch S, Liggitt D, Lipshutz GS, Metkus A, Harrison M, Heath TD, Debs RJ
• Short-term correction of factor VIII deficiency in a murine model of hemophilia A after delivery of adenovirus murine factor VIII in utero.
  Proceedings of the National Academy of Sciences of the United States of America 1999 Lipshutz GS, Sarkar R, Flebbe-Rehwaldt L, Kazazian H, Gaensler KM
• Adenovirus-mediated gene transfer to the peritoneum and hepatic parenchyma of fetal mice in utero.
  Surgery 1999 Lipshutz GS, Flebbe-Rehwaldt L, Gaensler KM
• Adenovirus-mediated gene transfer in the midgestation fetal mouse.
  The Journal of surgical research 1999 Lipshutz GS, Flebbe-Rehwaldt L, Gaensler KM
• Transgenic knockout mice exclusively expressing human hemoglobin S after transfer of a 240-kb betas-globin yeast artificial chromosome: A mouse model of sickle cell anemia.
  Proceedings of the National Academy of Sciences of the United States of America 1998 Chang JC, Lu R, Lin C, Xu SM, Kan YW, Porcu S, Carlson E, Kitamura M, Yang S, Flebbe-Rehwaldt L, Gaensler KM
• The human beta globin locus introduced by YAC transfer exhibits a specific and reproducible pattern of developmental regulation in transgenic mice.
  Blood 1997 Porcu S, Kitamura M, Witkowska E, Zhang Z, Mutero A, Lin C, Chang J, Gaensler KM
• Silencing of human fetal globin expression is impaired in the absence of the adult beta-globin gene activator protein EKLF.
  Proceedings of the National Academy of Sciences of the United States of America 1996 Perkins AC, Gaensler KM, Orkin SH
• Cationic liposome-mediated intravenous gene delivery.
  The Journal of biological chemistry 1995 Liu Y, Liggitt D, Zhong W, Tu G, Gaensler K, Debs R
• Germ-line transmission and developmental regulation of a 150-kb yeast artificial chromosome containing the human beta-globin locus in transgenic mice.
  Proceedings of the National Academy of Sciences of the United States of America 1993 Gaensler KM, Kitamura M, Kan YW
• Aerosol gene delivery in vivo.
  Proceedings of the National Academy of Sciences of the United States of America 1992 Stribling R, Brunette E, Liggitt D, Gaensler K, Debs R
• Prolonged transgene expression in rodent lung cells.
  American journal of respiratory cell and molecular biology 1992 Debs R, Pian M, Gaensler K, Clements J, Friend DS, Dobbs L
• Physical mapping of yeast artificial chromosomes containing sequences from the human beta-globin gene region.
  Genomics 1991 Gaensler KM, Burmeister M, Brownstein BH, Taillon-Miller P, Myers RM
• Genetic and biochemical analysis of the mouse beta-major globin promoter.
  Progress in clinical and biological research 1989 Myers RM, Cowie A, Stuve L, Hartzog G, Gaensler K