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Bone marrow derived stem cell populations may be capable of reconstituting sufficient collagen type VII that form anchoring fibrils to ameliorate or correct the clinical manifestations of rDEB.
Background.
DEB is a group of heritable mechanobullous skin diseases characterized by skin fragility, blister formation, and scarring. The basement membrane zone (BMZ) is characterized by a paucity or diminutive size of anchoring fibrils. The most severe form of DEB is recessive DEB, characterized by mutilating scarring, blisters (up to 70-80% of the body surface), joint contractures, strictures of the esophagus, corneal erosions, renal disease and aggressive squamous cell carcinoma. Patients with the severe DEB are also affected by profound physical disabilities with social and psychological implications.
Type VII collagen is synthesized and secreted by both human keratinocytes and fibroblasts. It is secreted within the BMZ lying between the epidermis and dermis of skin. It is the anchoring fibrils which are primarily composed of collagen type VII that are responsible for epidermal-dermal adherence. Genetic defects in the type VII collagen gene, designated COL7A1 result in dystrophic EB (DEB, Uitto and Christiano, 1992, 1994).
To assess the beneficial effects of cellular therapy for RDEB, we infused hematopoietic and nonhematopoietic stem cell populations into unconditioned RDEB (Col7a1-/-) mice. The affected mice show all the hallmarks of the disease--extensive blistering, fusion of digits, sublamina densa detachment from underlying dermis, absent of anchoring fibrils and lack of immunostaining of the collagen VII at the BMZ (Heinonen et al., 1999). Affected mice uniformally die within two weeks of birth.
In utero injections of multipotent adult progenitor cells, mesenchymal stem cells, epidermal stem cells, or unmanipulated bone marrow (BM), failed to prevent disease in more than 200 animals with all dying in less than two weeks. In contrast, mice were rescued by a subpopulation of BM cells. These mice were born with evidence of healing blisters and survived for more than 2 months. Surviving animals had evidence of donor cells in the skin with evidence of collagen type VII production and presence of anchoring fibrils in the BMZ. Collectively, these data demonstrate proof-of-principle of that transfer of marrow could provide functional and clinical correction.
This is a open label, single institution, non-randomized phase II study to determine the incidence of detectable donor derived collagen type VII by day 100 after high dose chemotherapy followed by transplantation of allogeneic stem cells from a healthy donor. The primary objective is to determine the incidence of detectable donor derived collagen type VII by day 100.
With additional funds, we will search for more effective, safer cures. For example, our research team will search for better ways of isolating the cells responsible for the correction of EB and enhancing the rate of recovery.
Funds will also be used to expand the breadth of clinical activities to meet all the needs of this unique patient population and support the associated clinical trials.
