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Title: Manipulation of haemopoietic stem cells for clinical use
Author: Johnson, Roderick
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1998
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I have examined three specific aspects of the manipulation of haemopoietic stem cells with the aim of generating clinically useful therapeutic products. A disease-specific mobilisation procedure was studied in patients with CML in an attempt to collect mainly normal progenitors for subsequent transplantation. This in vivo purging strategy relies on the differential mobilisation of Ph+ve/Ph-ve stem cells following myelosuppression. The Hydroxyurea/G-SF regimen used is markedly less toxic than existing methods and the results compared favourably with 28% of the harvests entirely Ph-ve and 56% showing a major response. Cytogenetic responses have been demonstrated post transplant in some patients. Clinical scale ex vivo tumour purging was performed in myeloma patients by CD34 selection using an immunoaffinity column (CeprateTM). This procedure can effect a 3-4 log tumour reduction and also yields cells suitable for further laboratory manipulation. I wished to confirm that the method was clinically acceptable. All but one patient achieved an adequate CD34+ve cell dose for transplant post selection and engraftment was normal, confirming the safety and efficacy of the approach. Genetic modification of peripheral blood stem cells was achieved using a retroviral construct (CD59-TM) capable of ameliorating the complement sensitivity in PNH. This was used successfully to transduce CFU-GM and BFU-E in peripheral blood and stem cell harvests from patients with haematological malignancy. In PNH, the most primitive peripheral blood stem cells are of normal phenotype which has prompted suggestions in some authors that they might be collected and used for autologous transplantation. I have shown however, that G-CSF mobilises mainly cells of PNH phenotype in these patients. This combined with the observation that the overall progenitor numbers in these hypoplastic patients are low suggests that the prospects for autografting or gene therapy are poor in this disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available