Biochemical Correction of Severe EB by Allo HSCT and "Off-the-shelf" MSCs

MT2009-09: Biochemical Correction of Severe Epidermolysis Bullosa by Allogeneic Stem Cell Transplantation and "Off-the-shelf" Mesenchymal Stem Cells

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.

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.