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Autologous stem cell transplantation with the gene modified collagen VII under the control of the promoter Scavanger for treating dystrophic epidermolysis bullosa

Grant number: 12/09627-3
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): September 01, 2012
Effective date (End): December 31, 2015
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:Sang Won Han
Grantee:Priscila Keiko Matsumoto Martin
Host Institution: Centro de Terapia Celular e Molecular. Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Associated scholarship(s):12/21686-5 - Autologous hematopoietic stem cells transplantation for expression of collagen vii using the scavenger promoter and sleeping beauty system, BE.EP.DR


Recessive dystrophic epidermolysis bullosa (REBD) is a disease caused by the absence of type VII collagen in the skin of patients which provides a series of bubbles brought about by trauma, and wounds and inflammatory processes throughout the body, both internally and externally. Other minor problems are common in patients with REBD: contraction joints, hands and feet deformities, malnutrition, growth retardation, severe dental problems and the appearance of squamous cell carcinoma in more advanced stages of disease. As patients suffering exclusively REBD deficiency of collagen VII, the logical solution would be to provide the protein in the skin/epithelium continually throughout their lives, but how this solution can become a reality?A major obstacle to the REBD gene therapy is that the genetic modification is widespread throughout the cells of the patient. Fix all the skin cells in addition to being impractical, implies the need for systemic expression of collagen. However, production of the protein collagen VII current could cause a number of inflammatory effects in various organs due to activation of platelets and fibronectin. Thus, it is desirable that the expression of collagen VII is specific to the skin and in a controlled manner as it occurs naturally in the body.Our proposal is to use stem cells from bone marrow modified to express the COL7A1 gene under the control of promoters in combination with macrophages therapy in situ using fibroblasts modified with the COL7A1 gene constitutive promoters through the skin. Thus, it is expected that expression of collagen VII occurs specifically in the skin and epithelia, suffering from chronic inflammation due to the formation of bubbles and attract macrophages to this location, throughout the lifetime and when inflammation is active. For this work become easier to bring to the clinical stage on the future, the vectors are drawn at the base of plasmid vectors with Sleeping Beauty. Although there are several studies on bone marrow transplantation for treatment of various diseases, our proposal to modify these cells to express a therapeutic gene in a specific location and condition is unprecedented, and could be translated into other pathologies.

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