Engraftment of gene–modified umbilical cord blood cells in neonates with adenosine deaminase deficiency

Kohn, Donald B.; Weinberg, Kenneth I.; Nolta, Jan A.; Heiss, Linda N.; Lenarsky, Carl; Crooks, Gay M.; Hanley, Mary Elizabeth; Annett, Geralyn; Brooks, Judith; El-Khoureiy, Anthony; Kim, Lawrence; Wells, Susie; Moen, Robert C.; Bastian, John F.; Williams-Herman, Debora; Elder, Melissa E.; Wara, Diane W.; Bowen, Thomas J.; Hershfield, Michael S.; Mullen, Craig A.; Blaese, R. Michael; Parkman, Robertson

doi:10.1038/nm1095-1017

Cited by 580 publications

(299 citation statements)

References 35 publications

(23 reference statements)

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“…Nested PCR analysis (sensitivity of 1:10 000) performed on peripheral blood mononuclear cells following engraftment and at 3-6 monthly intervals until the present time have been uniformly negative for the vectorderived MDR-1 cDNA sequence. Since levels of transduction in bone marrow (BM) progenitors and CD34 cells have been reported to be higher than in peripheral blood, 6 bone marrow aspirates were obtained from all three patients at 3 months following transplantation. PCR analysis of BM mononuclear cells, CD34 purified cells and progenitor cells was negative for the transgene.…”

Section: Haematological Reconstitution and Follow-upmentioning

confidence: 99%

“…Recent clinical studies employing a variety of transduction pro-tocols, but all using vectors based on Moloney murine leukaemia virus (MoMLV), have reported the long-term detection of proviral DNA in between one in 10 3 and one in 10 4 circulating blood cells. [4][5][6] Transfer of a drug resistance gene such as MDR-1, whose product P-glycoprotein (PGP) is an ATP-dependent membrane efflux transporter for several chemotherapeutic agents, might improve this situation by allowing in vivo selection of transduced cells. In addition, transduction of stem cells with MDR-1 during PBSC transplant for lymphoma might render the patient more resistant to the myelotoxic effects of antilymphoma drugs, many of which are MDR-1 substrates.…”

Section: Introductionmentioning

confidence: 99%

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Feasibility of multidrug resistance (MDR-1) gene transfer in patients undergoing high-dose therapy and peripheral blood stem cell transplantation for lymphoma

et al. 1998

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We have performed a pilot study of MDR-1 gene transfer chain reaction (PCR) for vector-derived MDR-1 cDNA in patients receiving CD34-selected peripheral blood stem sequence in all cases. Analysis of peripheral blood and cell (PBSC) transplant for lymphoma. To ensure minimum bone marrow cells after transplant has, however, shown engraftment thresholds and facilitate CD34 purification, no evidence of in vivo gene transfer with a follow-up of 12, mobilisation of Ͼ2 × 10 6 CD34 cells/kg was a condition for 15 and 18 months. The effect of MDR-1 substrate drugs recruitment. Of 11 patients counselled for study entry, onlyhas not yet been tested as all patients remain in clinical five achieved this target in a single apheresis. In three conand radiological remission of their lymphoma. These senting patients, purified CD34 cells were exposed to results confirm the difficulty of achieving in vivo gene trans-A12M1 MDR-1 retroviral supernatant for 6 h, cryoprefer in human haemopoietic cells and indicate major logisserved then thawed and readministered following ablative tical constraints in PBSC mobilisation in patients with chemotherapy. No delay in engraftment was observed, relapsed and resistant disease in whom initial studies are although one patient received additional back-up cells.appropriate. Gene transfer was demonstrated by polymerase

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Section: Haematological Reconstitution and Follow-upmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Feasibility of multidrug resistance (MDR-1) gene transfer in patients undergoing high-dose therapy and peripheral blood stem cell transplantation for lymphoma

et al. 1998

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“…27 These different lines of evidence indicate that CB cell populations are significantly more primitive and have more in vitro and in vivo proliferative potential than BM or mPB cells. The ability to effectively manipulate and expand CB cells ex vivo offers a significantly improved opportunity for the successful implementation of a number of cell and gene therapy 57 protocols.…”

Section: Discussionmentioning

confidence: 99%

Clinical-scale human umbilical cord blood cell expansion in a novel automated perfusion culture system

Koller

Manchel

Maher

et al. 1998

Bone Marrow Transplant

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Summary:Use of umbilical cord blood (CB) for stem cell transplantation has a number of advantages, but a major disadvantage is the relatively low cell number available. Ex vivo cell expansion has been proposed to overcome this limitation, and this study therefore evaluated the use of perfusion culture systems for CB cell expansion. CB was cryopreserved using standard methods and the thawed unpurified cells were used to initiate small-scale cultures supplemented with PIXY321, flt-3 ligand, and erythropoietin in serum-containing medium. Twelve days of culture resulted in the optimal output from most CB samples. Frequent medium exchange led to significant increases in cell (93%), CFU-GM (82%) and LTC-IC (350%) output as compared with unfed cultures. As the inoculum density was increased from 7.5 ؋ 10 4 per cm 2 to 6.0 ؋ 10 5 per cm 2 , the output of cells, CFU-GM, and LTC-IC increased. Cell and CFU-GM output reached a plateau at 6.0 ؋ 10 5 per cm 2 , whereas LTC-IC output continued to increase up to 1.2 ؋ 10 6 per cm 2 . Because the increase in culture output did not increase linearly with increasing inoculum density, expansion ratios were greatest at 1.5 ؋ 10 5 per cm 2 for cells (6.4-fold) and CFU-GM (192-fold). Despite the lack of adherent stroma, CB cultures expressed mRNA for many growth factors (G-CSF, GM-CSF, IL-1, IL-6, LIF, KL, FL, Tpo, TGF-␤, TNF-␣, and MIP-1␣) that were also found in bone marrow (BM) cultures, with the exception of IL-11 (found only in BM) and IL-3 (found in neither). Culture output was remarkably consistent from 10 CB samples (coefficient of variation 0.3) indicating that the procedure is robust and reproducible. Two commercial serum-free media were evaluated and found to support only approximately 25% of the culture output as compared with serum-containing medium. Implementation of optimal conditions in the clinical scale, automated cell production system (CPS) showed that the process scaled-up well, generating 1.7 ؋ 10 7 CFU-GM (298-fold expansion) from 1.2 ؋ 10 8 thawed viable nucleated CB cells (n = 3). The ability to generate Ͼ Ͼ Ͼ10 7 CFU-GM from Ͻ15 ml of CB within this closed, automated system without the need for extensive cell manipulations

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“…One previous report has appeared in which adenosine deaminase (ADA)-deficient infants with severe combined immune deficiency were transplanted with neonatal blood which had been transduced with a retroviral vector encoding wild-type ADA. 25 However, since it is well documented that ADAexpressing T cells have a competitive growth/survival advantage over non-ADA-expressing cells after transplantation into ADA-deficient recipients, 26 we believed that it was important to confirm these findings using a gene for which no such competitive advantage has been described (ie ASB).…”

Section: Figure 3 Anti-hasb Antibody Titers In Untransplanted and Tramentioning

confidence: 93%

Autologous transplantation of retrovirally transduced bone marrow or neonatal blood cells into cats can lead to long-term engraftment in the absence of myeloablation

et al. 1999

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Autologous transplantation of retrovirally transduced bone required to achieve these results, nor were they dependent marrow (BM) or neonatal blood cells was carried out on on the recipient's age. However, despite the long-term pereight cats (ranging in age from 2 weeks to 12 months) with sistence of transduced cells, the levels of ASB activity in mucopolysaccharidosis type VI (MPS VI). The transducing the transplanted animals was low, and no clinical improvevector contained the full-length cDNA encoding human ments were detected. These data provide evidence for the arylsulfatase B (hASB), the enzymatic activity deficient in long-term persistence of retrovirally transduced feline this lysosomal storage disorder. Following transplantation, hematopoietic cells, and further documentation that the persistence of transduced cells and enzymatic engraftment of transduced cells can be achieved in the expression were monitored for more than 2 years. Five of absence of myeloablation. Consistent with previous bone the cats received no myeloablative preconditioning, two marrow transplantation studies, these results also suggest cats received 370-390 cGy of total body irradiation (TBI), that to achieve clinical improvement of MPS VI, particularly and one cat received 190 cGy TBI. Evidence of transduced in the skeletal system, high-level expression of ASB must cells, as judged by enzymatic activity and PCR detection be achieved in the treated animals and improved techof the provirus, was demonstrated in granulocytes, lymphoniques for targeting the expressed enzyme to specific sites cytes, or BM cells of the treated animals up to 31 months of pathology (eg chondrocytes) must be developed. after transplantation. Radiation preconditioning was not

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Engraftment of gene–modified umbilical cord blood cells in neonates with adenosine deaminase deficiency

Cited by 580 publications

References 35 publications

Feasibility of multidrug resistance (MDR-1) gene transfer in patients undergoing high-dose therapy and peripheral blood stem cell transplantation for lymphoma

Feasibility of multidrug resistance (MDR-1) gene transfer in patients undergoing high-dose therapy and peripheral blood stem cell transplantation for lymphoma

Clinical-scale human umbilical cord blood cell expansion in a novel automated perfusion culture system

Autologous transplantation of retrovirally transduced bone marrow or neonatal blood cells into cats can lead to long-term engraftment in the absence of myeloablation

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