Amanda Days

Professor Janet Rinehart-Kim

Genetics BIOL 294

9/30/2022

“Writing Assignment 3”

            This peer-reviewed article is centered around the topic of Wiskott-Aldrich Syndrome (WAS) which is associated with thrombocytopenia, eczema, and autoimmunity. In this study, two patients were treated with stem cells, after which they had improvements in their conditions.

            The WAS protein is a regulator for actin polymerization in hematopoietic cells which affects cell signaling, movement, and immunological processes. Some of the defects resulting from the mutations in the WAS protein include the dysfunction of T and B cells. The disease is an X-linked recessive primary immunodeficiency disorder that was found to be able to be treated with the transfusion of genetically modified hematopoietic stem cells (HSC). This treatment was able to improve the patient’s conditions and is currently the only treatment for this disorder.

            The method used in this study was approved by the local authorities and was able to include patients twelve months and older that have severe cases of WAS and no indication of malignant cells prior to therapy. The two patients selected for this study were two boys, 3 years of age, that a sufficient number of CS34+ cells from bone marrow and that had written consent from their parents. Patient 1 had a splice mutation in WAS, IVS6+1, which resulted in hematoma and petechiae at birth and colitis, eczema, anemia, and reoccurring infections after 1 year of age. Patient 2 had a mutation in WAS (c. G257A, p. Arg86His), which resulted in him having thrombocytopenia and hemorrhagic diathesis at birth and eczema, salmonella septicemia, and upper respiratory tract infections soon after. To treat these conditions, autologous CD34+ HSCs were collected by leukapheresis which were transduced with WASP-expressing retroviral vectors which were then reinfused into the patients after they were given busulfan two days before. The main side effects of this therapy were myelosuppression and partial alopecia.

            The results of this treatment were that WASP-positive cells in various groups were detected on flow cytometry, overall, the WASP-positive cells showed an increase in number or continued to stay at stable levels. Polymerase-chain-reaction (PCR) was used to detect the change in these cells and was used to analyze colony forming units in both patients. Other improvements were in WASP expression that allowed the capacity for rearrangement of cytoskeleton in myeloid cells and regeneration in T-cell proliferative responses. Both patients had an increase in B-cells and were able to be immunized twelve months later, both developing antibodies to tetanus, diphtheria and haemophilus influenzae. Patient 1 had undergone a splenectomy earlier which might have been the cause of an inability to increase his B-cell count, making him more susceptible to infections. Except for patient one’s case of meningitis two years after therapy, both patients had far less infections and autoimmunity in both patients had disappeared including many of their other symptoms.

Citation:

Boztug K, et al. Stem-cell gene therapy for the Wiskott-Aldrich syndrome. N Engl J Med. (2010 Nov 11) https://doi.org/10.1056%2FNEJMoa1003548