Sickle Gene Therapies for Sickle

Sickle Gene Gene Therapies for Sickle Cell Anemia: Annotated Bibliography Kohn, D. & Candotti, F. (2009). Gene therapy fulfilling its promise. NEJM 360(5): 518-21. This brief and relatively broad review details a diversity of the advances that have been made in gene therapy since techniques first began to emerge in the latter half of the twentieth century.

A wide variety of different disorders and diseases have been treated and relived if not put into full remission/disappearance through the use of gene therapies, and though such therapies are not the magic bullet that the public often sees them as they do represent a more effective means of addressing many diseases than has been heretofore available. The author focuses on emerging treatments for X-linked SCID Lucarelli G., Gaziev, J., Isgro, a., Sodani, P…. & Andreani, M. (2012).

Allogeneic cellular gene therapy in hemoglobinopathies -- evaluation of hematopoietic SCT in sickle cell anemia. Bone Marrow Transplantation 47: 227-30. This study examined eleven patients suffering from sickle cell anemia and tracked their progress following treatment with stem cell transplantation from an HLA-identical and related donor. One patient in the study died a year following the transplantation, however the remaining ten patients were still free of any sickle cell anemia symptoms five years following the transplantation.

This research confirms that stem cell transplantation from suitable HLA-identical donors is a promising therapy that provides an excellent survival rate and the ability for patients to lead sickle cell-free lives. Morstyn, G. & Sheridan, W. (2006). Cell Therapy. New York: Cambridge University Press. This textbook contains broad yet advanced descriptions of stem cell and certain other genetic therapy techniques that developed in the last several decade providing a state-of-the-art glimpse into certain practices and capabilities.

The authors do not have a specific perspective or viewpoint that they attempt to assert nor do they engage in any primary research themselves, but instead they provide an overview of the science of cell therapy and many of its specific incarnations. While not directly related to sickle cell anemia (at least not wholly so), the information this source contains on cell therapies is highly relevant and useful for foundational knowledge. Papanikolaou, E. & Anagnou, N. (2010). Major Challenges for Gene Therapy of Thalassemia and Sickle Cell Disease.

Current Gene Therapy 10(5): 404-12. Retroviral vectors have been postulated as potentially useful agents in certain gene therapies, yet a variety of problems exist in their use that have hindered research and practical applications. Inefficient gene transfer times and capabilities are noted as especially problematic in retroviral vector use, and these researchers explore other potential vectors noting the specific opportunities and risks or problems of each of the alternatives they identify.

No recommendations for specific therapeutic applications are made, however an abundance of theoretical and research-applicable information is provided that makes the study quite worthwhile. Ray, a., Pearlman, M., Vats, T. & Khatua, S. (2011). Development of ependymoma following allogeneic cord blood transplantation in a sickle cell patient. Neuro-Oncology 13(3): 95-101.

This case study examines the risk of tumor development following the use of cord-blood gene therapies to treat sickle cell anemia following the presentation of a sixteen-year-old male patient with headache and ataxia and found to have a tumor in the posterior fossa. The patient had received a cord blood transfusion at the age of ten, and this is the only instance the authors were aware of in which this secondary malignancy arose following such a transfusion.

Implications for ongoing research into genetic therapies and side effects/later developments are discussed at length. Yannaki, E. & Stamatoyannopoulos, G. (2010). Hematopoietic stem cell mobilization strategies for gene therapy of beta thalassemia and sickle cell disease. Annals of the New York Academy of Sciences 1202: 59-63. Though the clinical trial these two researchers are involved in does not yet have results that are ready for publication, the review of the risks they provide regarding the use of stem cell mobilization with G-CSF in patients with sickle cell is highly useful information.

So, too, is the practice of pre-treating patients with hydroxyurea before administering the stem cell treatment, which the authors describe in detail and which forms the basis of the related clinical trial. Potential reduction of risks appears to be quite promising, though final results from the clinical trial and other supporting evidence will of course be required. Ye, L., Chang, J., Lin, C., Sun, X., Yu, J. & Kan, Y. (2009).

Induced pluripotent stem cells offer new approach to therapy in thalassemia and sickle cell anemia and option in prenatal diagnosis in genetic diseases. Proceedings of the National Academy of Sciences of the United States of America 106(24): 9826-30. This research demonstrated the potential for using cells from amniotic fluid or chorionic villus sampling used in the prenatal diagnosis of a variety of genetic disorders, including sickle cell anemia, to derive induced pluripotent stem cells.

These stem cells can then be used to treat any diagnosed genetic disorder, providing alternatives for parents that receive prenatal diagnoses of significant health issues. This process would also allow for treatment to begin earlier, which has benefits of increased efficacy and reduced damage as well as requiring fewer stem cells than would gene therapies used later in life. Zou, J., Mali, P., Huang, X., Dowey, S. & Cheng, L. (2011). Site-specific gene correction of a point mutation in human iPS cells derived from an adult patient with sickle cell disease.

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