biochemical correction of severe eb by allo hsct and "off-the-shelf" mscs

Conditions: Epidermolysis Bullosa

Summary: this is an open-label, single institution, phase ii study in patients with epidermolysis bullosa (eb). the underlying hypothesis is that the infusion of bone marrow or umbilical cord blood from a healthy unaffected donor will correct the collagen, laminin, integrin, or plakin deficiency and reduce the skin fragility characteristic of severe forms of eb. a secondary hypothesis is that mesenchymal stem cells from a healthy donor will enhance the safety and efficacy of the allogeneic hematopoietic stem cell transplant as well as serve as a source of renewable cells for the treatment of focal areas of residual blistering.

the primary objective of this study is to estimate the event-free survival rate by 1 year post-transplant with an event defined as a death or failure to have a demonstrable increase in collagen, laminin, integrin, keratin or plakin deposition by 1 year post-transplant or other biochemical, structural or physical measure of improvement. the secondary objectives of this study are to i) determine the incidence of transplant-related mortality (trm) at 180 days; ii) describe the pattern of biochemical improvement as measured by an increase in protein expression (collagen, laminin, integrin, keratin or plakin) and related structural and physical changes; iii) describe health quality of life at day 365 and 730 as compared to pretreatment results; iv) describe the pattern and durability of hsc and third party msc engraftment in the skin; v) determine the probability of survival at 1 year. patients with severe epidermolysis bullosa will be screened to meet the eligibility requirements, related or unrelated donor marrow or ucb will be infused, and subjects will be followed for a minimum of 5 years after stem cell transplant. a target accrual of 75 subjects over 5 years will be recruited to the study.

Eligibility criteria:
inclusion criteria: * diagnosis of severe form of epidermolysis bullosa (eb) characterized by collagen, laminin, integrin, keratin or plakin deficiency. assessment criteria for severe eb: * documented collagen, laminin, integrin, keratin or plakin deficiency (by immunofluorescence staining with protein specific antibodies or western blotting and by mutation analysis) * adequate organ function criteria * renal: glomerular filtration rate within normal range for age * hepatic: bilirubin, aspartate aminotransferase/alanine aminotransferase (ast/alt), alkaline phosphatase (alp) \< 5 x upper limit of normal * pulmonary: adequate pulmonary function in the opinion of the enrolling investigator * cardiac: left ventricular ejection fraction ≥ 45%, normal electrocardiogram (ekg) or approved by cardiology for transplant. * available healthy hsc donor (order of preference) * related donor (marrow or ucb) * hla-a, b, c, drb1 genotypic identical (sibling) donor * hla-a, b, c, drb1 phenotypic identical donor * 7/8 hla matched donor at hla-a, b, c, drb1 * unrelated donor * marrow * hla-a, b, c, drb1 phenotypic identical donor * 7/8 hla matched donor at hla-a, b, c, drb1 * ucb * hla-a, b (antigen level) and drb1 (allele level) matched donor * 5/6 hla matched donor at hla-a, b, drb1 * 4/6 hla matched donor at hla-a, b, drb1 * voluntary written consent absence of exclusion criteria: * active systemic infection at time of transplantation (including active infection with aspergillus or other mold within 30 days). * history of human immunodeficiency virus (hiv) infection * evidence of squamous cell carcinoma * donor has eb * pregnancy females of child-bearing age must have a documented negative pregnancy test and agree to use contraception as a condition for enrollment.