Drug screening libraries support from the Agency for Healthcare Research Quality 5K08 HS014739

Drug screening libraries support from the Agency for Healthcare Research Quality 5K08 HS014739. The funding organizations had no involvement in the conduct of this study or the decision to submit this manuscript for publication. Acknowledgements The authors would like to thank the anonymous reviewers for providing helpful feedback that has significantly improved this manuscript.Genetic blood cell diseases, such as primary immune deficiencies, hemoglobinopathies, and lysosomal storage and metabolic diseases, may be nattokinase treated by transplantation of hematopoietic stem cells from a healthy allogeneic donor to the affected patient. Gene therapy using gene correction of autologous HSC is under development to treat these genetic blood cell diseases. Ideally, gene therapy will achieve equivalent clinical benefits for patients with these disorders, but with no risks for graft versus host disease, which can be a significant cause of morbidity and mortality with allogeneic HSC transplants. Initial gene therapy efforts using HSC did not administer cytoreductive conditioning to avoid the potential toxicities when benefits were unproven.
However, in these early studies, essentially no clinical benefits were achieved and only extremely low levels of engrafted gene high throughput chemical screening corrected HSC were found. An important exception has been in trials for X linked severe combined immune deficiency where the potent selective expansion of gene corrected T lymphocytes allowed immune reconstitution to occur,4,5 although engraftment of gene corrected HSC may not have occurred based on the absence of transduced myeloid cells beyond 1 year.6 Aiuti et al.7,8 advanced the field by using a nonmyeloablative regimen of daunorubicin busulfan as cytoreductive conditioning prior to gene therapy for patients with adenosine deaminase deficient severe combined immune deficiency. By administering 4 mg/kg of busulfan, approximately one fourth of the standard clinical dosage for full cytoablation of 16 mg/kg typically used, these authors achieved much higher levels of engraftment of gene corrected HSC than previously observed, providing therapeutic benefits to the patients with essentially no clinical toxicity except transient myelosuppression.
Immune responses to transgene products may be a major factor limiting the successful replacement of missing gene products by gene therapy for genetic diseases. Immune responses to the transgene product, which is foreign in patients who congenitally lack expression of the protein, may lead to rejection of the transduced cells and loss of efficacy. The successful gene therapy in severe combined immune deficiency patients may, in part, reflect the inherent absence of immune responsiveness in the recipientsthat could reject the gene corrected cells. For most other genetic disorders considered for gene therapy, the recipients will have relatively normal immune function and may react immunologically against the transgene product, the vector, or excipients.9,10 While moderate dosages of chemotherapeutic agents such as busulfan or melphalan may increase the engraftment of gene modified HSC, they are not significantly immune suppressive and thus do not abrogate immune responses to the transgene products. For these patients, it may be necessary to impose both myelosuppression as well as immune.

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