Rima Adler
National Institutes of Health
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Publication
Featured researches published by Rima Adler.
Nature Medicine | 2008
Thomas R. Bauer; James M. Allen; Mehreen Hai; Laura M. Tuschong; Iram F. Khan; Erik Olson; Rima Adler; Tanya H. Burkholder; Yu Chen Gu; David W. Russell; Dennis D. Hickstein
Recent successes in treating genetic immunodeficiencies have demonstrated the therapeutic potential of stem cell gene therapy. However, the use of gammaretroviral vectors in these trials led to insertional activation of nearby oncogenes and leukemias in some study subjects, prompting studies of modified or alternative vector systems. Here we describe the use of foamy virus vectors to treat canine leukocyte adhesion deficiency (CLAD). Four of five dogs with CLAD that received nonmyeloablative conditioning and infusion of autologous, CD34+ hematopoietic stem cells transduced by a foamy virus vector expressing canine CD18 had complete reversal of the CLAD phenotype, which was sustained more than 2 years after infusion. In vitro assays showed correction of the lymphocyte proliferation and neutrophil adhesion defects that characterize CLAD. There were no genotoxic complications, and integration site analysis showed polyclonality of transduced cells and a decreased risk of integration near oncogenes as compared to gammaretroviral vectors. These results represent the first successful use of a foamy virus vector to treat a genetic disease, to our knowledge, and suggest that foamy virus vectors will be effective in treating human hematopoietic diseases.
Blood | 2009
Yoo-Jin Kim; Yoon-Sang Kim; Andre Larochelle; Gabriel Renaud; Tyra G. Wolfsberg; Rima Adler; Robert E. Donahue; Peiman Hematti; Bum-Kee Hong; Jean Roayaei; Keiko Akagi; Janice M. Riberdy; Arthur W. Nienhuis; Cynthia E. Dunbar; Derek A. Persons
We previously reported that lentiviral vectors derived from the simian immunodeficiency virus (SIV) were efficient at transducing rhesus hematopoietic repopulating cells. To evaluate the persistence of vector-containing and -expressing cells long term, and the safety implications of SIV lentiviral vector-mediated gene transfer, we followed 3 rhesus macaques for more than 4 years after transplantation with transduced CD34+ cells. All 3 animals demonstrated significant vector marking and expression of the GFP transgene in T cells, B cells, and granulocytes, with mean GFP+ levels of 6.7% (range, 3.3%-13.0%), 7.4% (4.2%-13.4%), and 5.6% (3.1%-10.5%), respectively. There was no vector silencing in hematopoietic cells over time. Vector insertion site analysis of granulocytes demonstrated sustained highly polyclonal reconstitution, with no evidence for progression to oligoclonality. A significant number of clones were found to contribute at both 1-year and 3- or 4-year time points. No vector integrations were detected in the MDS1/EVI1 region, in contrast to our previous findings with a gamma-retroviral vector. These data show that lentiviral vectors can mediate stable and efficient long-term expression in the progeny of transduced hematopoietic stem cells, with an integration profile that may be safer than that of standard Moloney murine leukemia virus (MLV)-derived retroviral vectors.
Molecular Therapy | 2010
Stephanie Sellers; Theotonius J. Gomes; Andre Larochelle; Rebecca Lopez; Rima Adler; Allen Krouse; Robert E. Donahue; Richard Childs; Cynthia E. Dunbar
Activation of proto-oncogenes by retroviral insertion is an important issue delaying clinical development of gene therapy. We have reported the nonrandom persistence of hematopoietic clones with vector insertions within the MDS1/EVI1 locus following transplantation of rhesus macaques. We now ask whether prolonged culture of transduced CD34(+) cells before transplantation selects for clones with insertions in the MDS1/EVI11 or other proto-oncogene loci. CD34(+) cells were transduced with standard retroviral vectors for 4 days and then continued in culture for an additional 6 days before transplantation. A 15% of insertions identified in granulocytes 6 months post-transplant were in MDS1/EVI11, significantly increased compared to the frequency in animals transplanted with cells immediately following transduction. MDS1/EVI1 clones became more dominant over time post-transplantation in one animal that was followed long term, accompanied by an increased overall copy number of vector-containing granulocytes, with one MDS1/EVI1 clone eventually accounting for 100% of transduced granulocytes and marrow colony-forming unit (CFU). This vector insertion increased the expression of Evi1 mRNA. There was no overrepresentation of MDS1/EVI1 insertions contributing to lymphoid lineages. Strategies involving prolonged ex vivo expansion of transduced cells may increase the risk of genotoxicity.
Genes, Chromosomes and Cancer | 2009
Lynnsey A. Zweier-Renn; Teresa S. Hawley; Sandra Burkett; Ali Ramezani; Irene Riz; Rima Adler; Dennis D. Hickstein; Robert G. Hawley
Translocations resulting in ectopic expression of the TLX1 homeobox gene (previously known as HOX11) are recurrent events in human T‐cell acute lymphoblastic leukemia (T‐ALL). Transduction of primary murine hematopoietic stem/progenitor cells with retroviral vectors expressing TLX1 readily yields immortalized hematopoietic progenitor cell lines. Understanding the processes involved in TLX1‐mediated cellular immortalization should yield insights into the growth and differentiation pathways altered by TLX1 during the development of T‐ALL. In recent clinical gene therapy trials, hematopoietic clonal dominance or T‐ALL‐like diseases have occurred as a direct consequence of insertional activation of the EVI1, PRDM16 or LMO2 proto‐oncogenes by the retroviral vectors used to deliver the therapeutic genes. Additionally, the generation of murine hematopoietic progenitor cell lines due to retroviral integrations into Evi1 or Prdm16 has also been recently reported. Here, we determined by linker‐mediated nested polymerase chain reaction the integration sites in eight TLX1‐immortalized hematopoietic cell lines. Notably, no common integration site was observed among the cell lines. Moreover, no insertions into the Evi1 or Prdm16 genes were identified although insertion near Lmo2 was observed in one instance. However, neither Lmo2 nor any of the other genes examined surrounding the integration sites showed differential vector‐influenced expression compared to the cell lines lacking such insertions. While we cannot exclude the possibility that insertional side effects transiently provided a selective growth/survival advantage to the hematopoietic progenitor populations, our results unequivocally rule out insertions into Evi1 and Prdm16 as being integral to the TLX1‐initiated immortalization process.
PLOS Biology | 2004
Peiman Hematti; Bum Kee Hong; Cole Ferguson; Rima Adler; Hideki Hanawa; Stephanie Sellers; Ingeborg Holt; Craig E. Eckfeldt; Yugal Sharma; Manfred Schmidt; Christof von Kalle; Derek A. Persons; Eric M. Billings; Catherine M. Verfaillie; Arthur W. Nienhuis; Tyra G. Wolfsberg; Cynthia E. Dunbar; Boris Calmels
Blood | 2005
Boris Calmels; Cole Ferguson; Mikko O. Laukkanen; Rima Adler; Marion Faulhaber; Hyeoung Joon Kim; Stephanie Sellers; Peiman Hematti; Manfred Schmidt; Christof von Kalle; Keiko Akagi; Robert E. Donahue; Cynthia E. Dunbar
Molecular Therapy | 2004
Hans Peter Kiem; Stephanie Sellers; Bobbie Thomasson; Julia C. Morris; John F. Tisdale; Peter A. Horn; Peiman Hematti; Rima Adler; Ken Kuramoto; Boris Calmels; Aylin C. Bonifacino; Christof von Kalle; Manfred Schmidt; Brian P. Sorrentino; Arthur W. Nienhuis; C. Anthony Blau; Robert G. Andrews; Robert E. Donahue; Cynthia E. Dunbar
Ilar Journal | 2009
Thomas R. Bauer; Rima Adler; Dennis D. Hickstein
Molecular Therapy | 2005
Ruth Seggewiss; Stefania Pittaluga; Rima Adler; Cole Ferguson; Elio F. Vanin; Patrick F. Kelly; Robert E. Donahue; Brian P. Sorrentino; Arthur W. Nienhuis; Cynthia E. Dunbar
Blood | 2004
Boris Calmels; Cole Ferguson; Rima Adler; Stephanie Sellers; Mikko O. Laukkanen; Peiman Hematti; Robert E. Donahue; Cynthia E. Dunbar