John E Wagner

Indiana Blood and Marrow Transplantation, Indianapolis, Indiana, United States

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Publications (189)1644.93 Total impact

  • Jakub Tolar, John E Wagner
    New England Journal of Medicine 01/2015; 372(4):382-4. · 54.42 Impact Factor
  • John E Wagner, Mary Eapen, Joanne Kurtzberg
    New England Journal of Medicine 01/2015; 372(3):288. · 54.42 Impact Factor
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    ABSTRACT: Fanconi anemia (FA) is an inherited DNA repair disorder associated with short stature and bone marrow failure usually requiring hematopoietic cell transplant (HCT). While low bone mineral density (BMD) has been reported in leukemia patients after HCT, little is known about BMD in FA children after HCT (FA HCT). This study's goals were to compare BMD in FA HCT to BMD in healthy controls, and in children who received HCT for hematologic malignancy (Cancer HCT), and to test for associations between BMD and risk factors for bone loss. This cross-sectional study included 20 FA HCT, 13 Cancer HCT, and 90 healthy controls, age-matched and <18 years old at evaluation. BMD Z-scores for total body (TBMD) and lumbar spine (LBMD) were measured by dual energy x-ray absorptiometry and adjusted for height-for-age Z-score (HAZ). FA HCT had lower mean TBMDHAZ Z-score (by 0.8 SD) and higher fraction with Z-score ≤ -1 than healthy controls (42% vs. 11%). No LBMD deficits were detected. FA HCT and Cancer HCT groups did not differ significantly in TBMD or LBMD Z-scores. In FA HCT patients, lower BMI and lower percent fat were associated with lower BMD. This study highlights the importance of monitoring BMD to optimize bone health in FA patients. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 01/2015; · 3.15 Impact Factor
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    ABSTRACT: Genome engineering with designer nucleases is a rapidly progressing field, and the ability to correct human gene mutations in situ is highly desirable. We employed fibroblasts derived from a patient with Fanconi anemia as a model to test the ability of the clustered regularly interspaced short palindromic repeats/Cas9 nuclease system to mediate gene correction. We show that the Cas9 nuclease and nickase each resulted in gene correction, but the nickase, due to its ability to preferentially mediate homology-directed repair, resulted in a higher frequency of corrected clonal isolates. To assess the off-target effects, we used both a predictive software platform to identify intragenic sequences of homology as well as a genome-wide screen utilizing linear amplification-mediated PCR. We observed no off-target activity and show RNA-guided endonuclease candidate sites that do not possess low sequence complexity function in a highly specific manner. Collectively, we provide proof of principle for precision genome editing in Fanconi anemia, a DNA repair-deficient human disorder.
    Human Gene Therapy 12/2014; · 3.62 Impact Factor
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    ABSTRACT: The use of umbilical cord blood (UCB) as an alternative haematopoietic cell source in lieu of bone marrow for haematopoietic reconstitution is increasingly becoming a mainstay treatment for both malignant and nonmalignant diseases, as most individuals will have at least one available, suitably HLA-matched unit of blood. The principal limitation of UCB is the low and finite number of haematopoietic stem and progenitor cells (HSPC) relative to the number found in a typical bone marrow or mobilized peripheral blood allograft, which leads to prolonged engraftment times. In an attempt to overcome this obstacle, strategies that are often based on native processes occurring in the bone marrow microenvironment or 'niche' have been developed with the goal of accelerating UCB engraftment. In broad terms, the two main approaches have been either to expand UCB HSPC ex vivo before transplantation, or to modulate HSPC functionality to increase the efficiency of HSPC homing to the bone marrow niche after transplant both of which enhance the biological activities of the engrafted HSPC. Several early phase clinical trials of these approaches have reported promising results.
    Nature Reviews Clinical Oncology 12/2014; · 15.03 Impact Factor
  • Transfusion 11/2014; · 3.57 Impact Factor
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    ABSTRACT: Umbilical-cord blood has been used as the source of hematopoietic stem cells in an estimated 30,000 transplants. The limited number of hematopoietic cells in a single cord-blood unit prevents its use in recipients with larger body mass and results in delayed hematopoietic recovery and higher mortality. Therefore, we hypothesized that the greater numbers of hematopoietic cells in two units of cord blood would be associated with improved outcomes after transplantation.
    New England Journal of Medicine 10/2014; 371(18):1685-94. · 54.42 Impact Factor
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    ABSTRACT: Certain mitochondrial haplotypes (mthaps) are associated with disease, possibly through differences in oxidative phosphorylation and/or immunosurveillance. We explored whether mthaps are associated with allogeneic HCT outcomes. Recipient (n=437) and donor (n=327) DNA was genotyped for common European mthaps (H, J, U, T, Z, K, V, X, I, W, K2). HCT outcomes for mthap matched siblings (n=198), all recipients, and all donors were modeled using relative risks (RR) and 95% confidence intervals and compared to mthap H, the most common. Siblings with I and V were significantly more likely to die within 5 years (RR=3.0;1.2-7.9 and 4.6;1.8-12.3, respectively). W siblings experienced higher aGVHD II-IV events (RR=2.1;1.1-2.4) with no events for K or K2. Similar results were observed for all recipients combined, although J recipients experienced lower GVHD and higher relapse. Patients with I donors had a 2.7 fold (1.2-6.2) increased risk of death in five years, while few patients with K2 or W donors died. No patients with K2 donors and few patients with U donors relapsed. Mthap may be an important consideration in HCT outcomes, although validation and functional studies are needed. If confirmed, it may be feasible to select donors based on mthap to increase positive or decrease negative outcomes.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 10/2014; · 3.15 Impact Factor
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    ABSTRACT: Fanconi anemia (FA) is a rare recessive disease resulting from mutations in one of at least 16 different genes. Mutation types and phenotypic manifestations of FA are highly heterogeneous and influence the clinical management of the disease. We analyzed 202 FA families for large deletions, using high-resolution Comparative Genome Hybridization arrays (arrayCGH), Single Nucleotide Polymorphism arrays (SNParrays) and DNA sequencing. We found pathogenic deletions in 88 FANCA, seven FANCC, two FANCD2, and one FANCB families. We find 35% of FA families carry large deletions, accounting for 18% of all FA pathogenic variants. Cloning and sequencing across the deletion breakpoints revealed that 52 FANCA deletion ends, and one FANCC deletion end extended beyond the gene boundaries, potentially affecting neighboring genes with phenotypic consequences. Seventy-five percent of the FANCA deletions are Alu-Alu mediated, predominantly by AluY elements, and appear to be caused by Non-Allelic Homologous Recombination. Individual Alu hotspots were identified. Defining the haplotypes of four FANCA deletions shared by multiple families revealed that three share a common ancestry. Knowing the exact molecular changes that lead to the disease may be critical for a better understanding of the FA phenotype, and to gain insight into the mechanisms driving these pathogenic deletion variants.This article is protected by copyright. All rights reserved
    Human Mutation 08/2014; · 5.05 Impact Factor
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    ABSTRACT: NK cell efficacy correlates with in vivo proliferation and we hypothesize that NK cell product manipulations may optimize this endpoint. Xenotransplantation was used to compare GMP grade freshly activated NK cells (FA-NK) and ex vivo expanded NK cells (Ex-NK). Cells were infused into NSG mice followed by IL-2, IL-15, or no cytokines. Evaluation of blood, spleen and marrow showed that persistence and expansion was cytokine dependent, IL-15 being superior to IL-2. Cryopreservation and immediate infusion resulted in less cytotoxicity and fewer NK cells in vivo and this could be rescued in FA-NK by overnight culture and testing the next day. Marked differences in the kinetics and homing of FA-NK versus Ex-NK were apparent: FA-NK cells preferentially homed to spleen, and persisted longer after cytokine withdrawal. These data would suggest that cryopreservation of FA-NK and Ex-NK is detrimental and that culture conditions profoundly affect homing, persistence and expansion of NK cells in vivo. The NSG mouse model is an adjuvant to in vitro assays prior to clinical testing.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 05/2014; · 3.15 Impact Factor
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    ABSTRACT: Donor-derived myelodysplastic syndrome/acute leukaemia (DD-MDS/AL) is a rare life-threatening complication of allogeneic haematopoietic stem cell (HSC) transplantation. However, it is unknown whether the risk differs by HSC source. Therefore, we evaluated the incidence of DD-MDS/AL in 2390 engrafted patients. With a median follow-up of 7·1 years (1-20·8), the incidence of DD-MDS/AL was 0·53% (95% confidence interval (CI), 0·01-1·41%], 0·56% (95%CI, 0·01-1·36%) and 0·56% (95%CI, 0·01-1·10%) in recipients of bone marrow (n = 1117), peripheral blood (n = 489) and umbilical cord blood (UCB, n = 784), respectively. While follow-up is shorter in recipients of UCB and peripheral blood, incidence of DD-MDS/AL is, thus far, similar between HSC sources.
    British Journal of Haematology 03/2014; · 4.94 Impact Factor
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    ABSTRACT: Recognizing the challenges faced by researchers and clinicians working in the field of cellular therapy, the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, established the Production Assistance for Cellular Therapies (PACT) program in 2003 and expanded it in 2010. The PACT program provides both clinical product manufacturing support that furthers the mission of NHLBI in the areas of cardiac, lung, and blood diseases and broad support of translational development across all disease areas to serve the entire cell therapy community. The program also provides access to expertise in project management, regulatory affairs, and quality assurance and control. Education initiatives include webinars, cell processing facility-hosted workshops, national workshops, and active participation and leadership within the cell therapy community through collaboration with other cell therapy organizations and academia. So far, over 650 PACT-manufactured cell therapy products have been administered in 32 clinical trials for a range of illnesses and diseases such as acute myocardial infarction, sickle cell disease, and graft-versus-host disease.
    Clinical and Translational Science 03/2014; · 2.33 Impact Factor
  • Biology of Blood and Marrow Transplantation 02/2014; 20(2):S28–S29. · 3.35 Impact Factor
  • Pediatric Blood & Cancer 12/2013; 61(6). · 2.35 Impact Factor
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    ABSTRACT: Allogeneic hematopoietic stem cell transplantation (HSCT) for patients with a hemoglobinopathy can be curative but is limited by donor availability. While positive results are frequently observed in those with a HLA matched sibling donor, the use of unrelated donors has been complicated by poor engraftment, excessive regimen-related toxicity and graft-versus-host disease (GVHD). As a potential strategy to address these obstacles, a pilot study was designed that incorporated both a reduced intensity conditioning (RIC) and mesenchymal stromal cells (MSCs). Six patients were enrolled including four with high risk Sickle Cell Disease (SCD) and two with transfusion dependent thalassemia major. Conditioning consisted of Fludarabine (150mg/m2), Melphalan (140mg/m2), and Alemtuzumab (60mg for patients weighing >30kg and 0.9mg/kg for patients weighing <30kg). Two patients received a HLA 7/8 allele matched bone marrow and four received 4-5/6 HLA matched umbilical cord blood (UCB) as the source of HSCs. MSCs were of bone marrow origin and derived from a parent in one patient and unrelated third party donor in the remaining five patients. GVHD prophylaxis consisted of cyclosporine A (CSA) and mycophenolate mofetil (MMF). One patient had neutropenic graft failure, two had autologous hematopoietic recovery and three had hematopoietic recovery with complete chimerism. The two SCD patients with autologous hematopoietic recovery are alive. The remaining four died either from opportunistic infection, GVHD, or intracranial hemorrhage. While there was no infusion-related toxicity, the co-transplantation of MSCs was not sufficient for reliable engraftment in patients with advanced hemoglobinopathy. While poor engraftment has been observed in nearly all such trials to date in this patient population, there was no evidence to suggest that MSC had any positive impact on engraftment. Due to lack of improved engraftment and unacceptably high transplant-related mortality, the study was prematurely terminated. Further investigations into understanding the mechanisms of graft resistance and development of strategies to overcome this barrier are needed to move this field forward.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 12/2013; · 3.15 Impact Factor
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    ABSTRACT: Spontaneous reversion of disease-causing mutations has been observed in some genetic disorders. In our clinical observations of severe generalized recessive dystrophic epidermolysis bullosa (RDEB), a currently incurable blistering genodermatosis caused by loss-of-function mutations in COL7A1 that results in a deficit of type VII collagen (C7), we have observed patches of healthy-appearing skin on some individuals. When biopsied, this skin revealed somatic mosaicism resulting from the self-correction of C7 deficiency. We believe this source of cells could represent an opportunity for translational "natural" gene therapy. We show that revertant RDEB keratinocytes expressing functional C7 can be reprogrammed into induced pluripotent stem cells (iPSCs) and that self-corrected RDEB iPSCs can be induced to differentiate into either epidermal or hematopoietic cell populations. Our results give proof in principle that an inexhaustible supply of functional patient-specific revertant cells can be obtained-potentially relevant to local wound therapy and systemic hematopoietic cell transplantation. This technology may also avoid some of the major limitations of other cell therapy strategies, eg, immune rejection and insertional mutagenesis, which are associated with viral- and non-viral-mediated gene therapy. We believe this approach should be the starting point for autologous cellular therapies using "natural" gene therapy in RDEB and other diseases.Journal of Investigative Dermatology accepted article preview online, 6 December 2013. doi:10.1038/jid.2013.523.
    Journal of Investigative Dermatology 12/2013; · 6.19 Impact Factor
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    ABSTRACT: Acute graft-versus-host disease (aGVHD) occurs in 40-60% of recipients of partially matched umbilical cord blood transplantation (UCB). In a phase I study, adoptive transfer of expanded CD4+CD25+Foxp3+ natural regulatory T cells (nTregs) resulted in a reduced incidence of grade II-IV GVHD. To investigate potential mechanisms responsible for the reduced GVHD risk, we analyzed peripheral blood mononuclear cell (PBMC) mRNA expression of a tolerance gene set previously identified in operational tolerant kidney transplant recipients, comparing healthy controls to patients who received no nTregs or nTregs with and without GVHD. Samples from patients receiving nTregs regardless of GVHD showed increased Foxp3, but also B cell related tolerance marker expression. This correlated with early B cell recovery, predominately of naïve B cells, and nearly normal T cell reconstitution. CD8+ T cells showed reduced signs of activation (HLA-DR+ expression) in comparison to conventionally treated patients developing GVHD. In contrast, patients with GVHD had significantly increased whereas nTreg-treated patients without GVHD had reduced TLR5 mRNA expression. We identified Lin-HLADR-CD33+CD16+ cells and CD14++CD16- monocytes as main TLR5 producers especially in samples of conventionally treated patients developing GVHD. Together, these data reveal interesting similarities and differences between tolerant organ and nTreg-treated hematopoietic stem cell transplant recipients.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 10/2013; · 3.15 Impact Factor
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    ABSTRACT: Acute leukaemia or advanced myelodysplastic syndrome (MDS ≥ 5% blasts) in Fanconi anaemia (FA) patients is associated with a poor prognosis. We report 21 FA patients with acute leukaemia or advanced MDS who underwent haematopoietic cell transplantation (HCT) at the University of Minnesota between 1988 and 2011. Six patients had biallelic BRCA2 mutations. Eight patients received pre-transplant cytoreduction, with 3 achieving complete remission. HCT donor source included human leucocyte antigen-matched sibling (n = 2) or alternative donors (n = 19). Neutrophil engraftment was 95% for the entire cohort, and the incidence of acute graft-versus-host disease was 19%. 5-year overall survival (OS) was 33%, with a relapse rate of 24%, with similar OS in patients with biallelic BRCA2 mutations. Our study supports the use of HCT in the treatment of FA patients with acute leukaemia or advanced MDS, however, the role of chemotherapy prior to HCT remains unclear for this population. FA patients with biallelic BRCA2 are unique and may benefit from higher dose chemotherapy relative to other complementation groups.
    British Journal of Haematology 10/2013; · 4.94 Impact Factor
  • Jakub Tolar, John E Wagner
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    ABSTRACT: Contrary to the prevailing professional opinion of the past few decades, recent experimental and clinical data support the fact that protein replacement therapy by allogeneic blood and marrow transplantation is not limited to freely diffusible molecules such as enzymes, but also large structural proteins such as collagens. A prime example is the cross-correction of type VII collagen deficiency in generalised severe recessive dystrophic epidermolysis bullosa, in which blood and marrow transplantation can attenuate the mucocutaneous manifestations of the disease and improve patients' quality of life. Although allogeneic blood and marrow transplantation can improve the integrity of the skin and mucous membranes, today's accomplishments are only the first steps on the long pathway to cure. Future strategies will be built on the lessons learned from these first transplant studies.
    The Lancet 10/2013; 382(9899):1214-1223. · 39.21 Impact Factor
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    ABSTRACT: We compared the clinical outcomes of adults with acute leukemia that received single-unit umbilical cord blood transplantation (sUCBT) after conditioning with a busulfan/antithymocyte globulin (BU-ATG)-based regimen at University Hospital La Fe (n=102) or double-unit UCBT (dUCBT) after conditioning with a total body irradiation (TBI)-based regimen at the University of Minnesota (n=91). Non-relapse mortality, relapse and disease-free survival (DFS) were similar in the two groups. Multivariate analyses, showed more rapid neutrophil (HR 0.6; 95% CI 0.45 - 0.80; p = 0.0006) and platelet recovery (HR 0.59; 95% CI 0.43 - 0.83; p = 0.002) after the BU-ATG-based conditioning and sUCBT. While there was a lower risk of acute GVHD grade II-IV (HR 2.81; 95% CI 1.75 - 4.35; p < 0.001) after BU-ATG and sUCBT, the incidences of grade III-IV acute and chronic GVHD were similar between the two groups. Regarding disease-specific outcomes, DFS in both acute myeloid leukemia and acute lymphoblastic leukemia (ALL) patients were not significantly different; however, a significantly lower relapse rate was found in patients with ALL treated with TBI and dUCBT (HR 0.3; 95% CI 0.12 - 0.84; p = 0.02). In the context these specific treatment platforms our study demonstrates that sUCB and dUCBT offer similar outcomes.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 09/2013; · 3.15 Impact Factor

Publication Stats

10k Citations
1,644.93 Total Impact Points

Institutions

  • 2005–2014
    • Indiana Blood and Marrow Transplantation
      Indianapolis, Indiana, United States
    • Texas Transplant Institute
      San Antonio, Texas, United States
  • 1995–2014
    • University of Minnesota Duluth
      • Medical School
      Duluth, Minnesota, United States
  • 2013
    • Charité Universitätsmedizin Berlin
      • Institute of Medical Immunology
      Berlín, Berlin, Germany
    • Children's Hospitals and Clinics of Minnesota
      Minneapolis, Minnesota, United States
    • Blood Systems Research Institute
      San Francisco, California, United States
  • 1997–2011
    • University of Minnesota Twin Cities
      • • Department of Pediatrics
      • • Department of Medicine
      • • Division of Hematology, Oncology and Transplantation
      • • Division of Pediatric Blood and Marrow Transplantation (BMT)
      Minneapolis, MN, United States
  • 2008–2010
    • University of Minnesota Medical Center, Fairview
      Minneapolis, Minnesota, United States
  • 2005–2010
    • Medical College of Wisconsin
      • Center for International Blood & Marrow Transplant Research
      International Falls, MN, United States
  • 2009
    • Memorial Sloan-Kettering Cancer Center
      New York City, New York, United States
  • 2006–2008
    • Duke University Medical Center
      Durham, North Carolina, United States
    • Children's Hospital Los Angeles
      • Division of Bone Marrow Transplant/Research Immunology
      Los Angeles, California, United States
  • 2002
    • Cincinnati Children's Hospital Medical Center
      Cincinnati, Ohio, United States
  • 2001
    • Case Western Reserve University
      • School of Medicine
      Cleveland, OH, United States