Retroviral Mediated Transfer of the cDNA for Human Glucocerebrosidase into Hematopoietic Stem Cells of Patients with Gaucher Disease. A Phase I Study. National Institutes of Health, Bethesda, Maryland

PURPOSE A phase I trial that evaluated for extrahematopoietic toxicity was conducted with iodine-131 (131I) labeled monoclonal antibody (MAb) CC49. Correlative studies included pharmacokinetic and biodistribution analyses, estimates of absorbed radiation dose, and measurement of human antimonoclonal antibodies (HAMA). PATIENTS AND METHODS After collection and cryopreservation of hematopoietic stem cells, 15 patients with gastrointestinal cancers were administered a tracer dose of 131I-MAb CC49. Within 5 to 6 days, 14 patients (two to three per activity level) underwent a single treatment with 131I-MAb CC49 (50, 100, 150, 200, 250, and 300 mCi/m2). Biodistribution was determined using planar and single photon emission computer tomographic (SPECT) imaging. Pharmacokinetic studies were performed by measuring radioactivity in serial blood samples. In some patients, biopsies of metastases and related normal tissues were obtained for radioactivity measurements. Radiation dosimetry estimates were calculated using available biodistribution, pharmacokinetic, and tissue biopsy data. Toxicity was evaluated using the National Cancer Institute (NCI) Common Toxicity Criteria. RESULTS No dose-limiting extrahematopoietic toxicity was identified. Twelve patients experienced grade IV myelosuppression and met criteria for infusion of hematopoietic stem cells. Radioimmunolocalization was excellent. The T1/2 for 131I-MAb CC49 after diagnostic and therapeutic administration was 39.7 +/- 10.4 and 46.1 +/- 10.6 hours, respectively. The percent injected dose per killigram of tumor ranged from 0.2 to 2.1. Absorbed radiation dose in metastatic tumor sites ranged from 630 to 3300 cGy. CONCLUSION Although extrahematopoietic dose-limiting toxicity was neither observed or predicted, suboptimal absorbed dose estimates suggested that further escalation of 131I-MAb CC49 would not be useful. Future studies should focus on the use of radionuclides with high energy beta emissions, such as yttrium 90, and on strategies to optimize access of antibody to target antigens.

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High levels of human glucocerebrosidase activity in macrophages of long- term reconstituted mice after retroviral infection of hematopoietic stem cells

Blood ◽

10.1182/blood.v80.2.331.bloodjournal802331 ◽

1992 ◽

Vol 80 (2) ◽

pp. 331-336 ◽

Cited By ~ 1

Author(s):

PH Correll ◽

S Colilla ◽

HP Dave ◽

S Karlsson

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Messenger Rna ◽

Gaucher Disease ◽

Leukemia Virus ◽

Immunohistochemical Analysis ◽

Target Tissue ◽

Retroviral Infection ◽

Hematopoietic Stem

Gaucher disease is a leading candidate for somatic gene therapy using bone marrow (BM) cells as target tissue. Towards this end, we have constructed a retroviral vector (LG) in which the human glucocerebrosidase (GC) cDNA is driven by the Moloney murine leukemia virus (MoMLV) long terminal repeat (LTR). Day 12 to 14 colony-forming unit-spleen progenitor cells were infected by the LG virus with a 100% efficiency, and GC messenger RNA (mRNA) and protein were detected in the progeny of these cells. Tissues from long-term reconstituted mice analyzed 8 months posttransplantation with LG-infected BM contained the intact provirus at greater than 1 copy per cell, indicating effective infection of hematopoietic stem cells. Human GC mRNA generated by the viral LTR was detected in macrophages as well as other hematopoietic cells. Enzyme activity was increased fivefold and twofold in macrophages from BM and spleen, respectively, and could be precipitated with an antibody specific for human GC. Immunohistochemical analysis detected the human GC protein in 81% of the macrophages from five recipient mice. These data indicate that, after transduction of hematopoietic stem cells, the LG vector is capable of directing expression of human GC in the majority of macrophages from long-term reconstituted mice and producing enzyme levels comparable with endogenous mouse activity, suggesting that this virus may be useful in the treatment of Gaucher disease.

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Early Results of a Phase I/ II Study of Gene Therapy for β-Thalassemia Major Via Transplantation of Autologous Hematopoietic Stem Cells Transduced Ex-Vivo with a Lentiviral βAT87Q -Globin Vector

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2014.11.018 ◽

2015 ◽

Vol 21 (2) ◽

pp. S28-S29 ◽

Cited By ~ 1

Author(s):

Sandeep Soni ◽

Alexis A. Thompson ◽

Mark Walters ◽

Philippe Leboulch ◽

Marina Cavazzana

Keyword(s):

Stem Cells ◽

Gene Therapy ◽

Phase I ◽

Hematopoietic Stem Cells ◽

Ex Vivo ◽

Thalassemia Major ◽

Hematopoietic Stem ◽

Early Results

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Phase I/II Trial of StemRegenin-1 Expanded Umbilical Cord Blood Hematopoietic Stem Cells Supports Testing as a Stand-Alone Graft

Cell Stem Cell ◽

10.1016/j.stem.2015.10.004 ◽

2016 ◽

Vol 18 (1) ◽

pp. 144-155 ◽

Cited By ~ 156

Author(s):

John E. Wagner ◽

Claudio G. Brunstein ◽

Anthony E. Boitano ◽

Todd E. DeFor ◽

David McKenna ◽

...

Keyword(s):

Stem Cells ◽

Phase I ◽

Hematopoietic Stem Cells ◽

Cord Blood ◽

Umbilical Cord ◽

Umbilical Cord Blood ◽

Hematopoietic Stem

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GMP Compliant Expansion of Hematopoietic Stem Cells (CD34+) Selected from Cord Blood for a Phase I Cell Therapy Trial

Animal Cell Technology: From Target to Market ◽

10.1007/978-94-010-0369-8_123 ◽

2001 ◽

pp. 517-522

Author(s):

B. Schröder ◽

C. Fahr ◽

G. Bug ◽

T. Roßmanith ◽

H. Merget-Millitzer

Keyword(s):

Stem Cells ◽

Cell Therapy ◽

Phase I ◽

Hematopoietic Stem Cells ◽

Cord Blood ◽

Hematopoietic Stem ◽

Therapy Trial

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High levels of human glucocerebrosidase activity in macrophages of long- term reconstituted mice after retroviral infection of hematopoietic stem cells

Blood ◽

10.1182/blood.v80.2.331.331 ◽

1992 ◽

Vol 80 (2) ◽

pp. 331-336 ◽

Cited By ~ 55

Author(s):

PH Correll ◽

S Colilla ◽

HP Dave ◽

S Karlsson

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Messenger Rna ◽

Gaucher Disease ◽

Leukemia Virus ◽

Immunohistochemical Analysis ◽

Target Tissue ◽

Retroviral Infection ◽

Hematopoietic Stem

Abstract Gaucher disease is a leading candidate for somatic gene therapy using bone marrow (BM) cells as target tissue. Towards this end, we have constructed a retroviral vector (LG) in which the human glucocerebrosidase (GC) cDNA is driven by the Moloney murine leukemia virus (MoMLV) long terminal repeat (LTR). Day 12 to 14 colony-forming unit-spleen progenitor cells were infected by the LG virus with a 100% efficiency, and GC messenger RNA (mRNA) and protein were detected in the progeny of these cells. Tissues from long-term reconstituted mice analyzed 8 months posttransplantation with LG-infected BM contained the intact provirus at greater than 1 copy per cell, indicating effective infection of hematopoietic stem cells. Human GC mRNA generated by the viral LTR was detected in macrophages as well as other hematopoietic cells. Enzyme activity was increased fivefold and twofold in macrophages from BM and spleen, respectively, and could be precipitated with an antibody specific for human GC. Immunohistochemical analysis detected the human GC protein in 81% of the macrophages from five recipient mice. These data indicate that, after transduction of hematopoietic stem cells, the LG vector is capable of directing expression of human GC in the majority of macrophages from long-term reconstituted mice and producing enzyme levels comparable with endogenous mouse activity, suggesting that this virus may be useful in the treatment of Gaucher disease.

Download Full-text