SECTION XXIII: NON-MALIGNANT DISORDERS Hematopoietic Cell Transplantation for Nonmalignant Disorders Jakub Tolar,1 Parinda A. Mehta,2 Mark C. Walters3 Hereditary disorders that trace their origin to the hematopoietic stem cell have been targeted for allogeneic therapy and were among the first human diseases cured by successful hematopoietic cell transplantation (HCT). More recently, the possibility of treating nonhematopoietic hereditary disorders in which engraft- ment of hematopoietic cells might ameliorate tissue damage in target organs has also been investigated with encouraging results. As in the malignant hematological disorders, transplantation results have improved over the past 3 decades as a consequence of more refined donor selection and patient risk stratification with modifications to the conditioning regimen. The application of these principles is described in this update about HCT for hereditary marrow failure syndromes and hemoglobin disorders. In addition, a novel indica- tion of HCT for epidermolysis bullosa is presented. Together, these representative disorders illustrate the potential for an expanding role of HCT for nonmalignant disorders. Biol Blood Marrow Transplant 18: S166-S171 (2012) Ó 2012 Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation HEMATOGENOUS CELLS FOR process that integrates the skin cells, skin extracellular EXTRACELLULAR MATRIX DEFICIENCY matrix, and systemic factors—mainly blood cells and EPIDERMOLYSIS BULLOSA cytokines—into dynamic tissue healing. Keratinocytes and dermal fibroblasts express adhesive proteins that One of the most fascinating and daunting chal- ensure the epidermis remains attached to the skin base- lenges of current transplantation biology is to harness ment membrane and to the papillary dermis. Congen- the potential of stem cells for tissue regeneration. ital deficiency of any of at least 15 such proteins results Adoptive transfer of hematopoietic stem cells can, of in a blistering condition called epidermolysis bullosa course, regenerate the lymphohematopoietic system (EB) [1]. Of the multiple forms of EB, the severest are: in the recipients of hematopoietic cell transplantation (HCT), but only recently have we and others obtained recessive dystrophic EB (RDEB) caused by mutations evidence that bone marrow and cord blood transplan- in the collagen type VII (C7) gene (COL7A1), and tation can mediate tissue repair in the largest extrame- junctional EB (JEB) caused by loss-of-function dullary organ—the skin. mutations in one of the three genes (LAMA3, The skin is constantly exposed to environmental in- LAMB3, and LAMC2) that encode one of three chains sults and requires effective repair tools to maintain its in the heterotrimeric protein laminin 332 (L332). protective function. Skin repair is a highly organized C7 and L332 deficiencies result in severe scarring, contractures, and, ultimately, shortened survival— most often because of infections and aggressive squa- From the 1Blood and Marrow Transplantation, University of 2 mous cell carcinoma. Even though suffering is difficult Minnesota Medical School, Minneapolis, Minnesota; Division of Bone Marrow Transplantation and Immune Deficiency, to measure objectively, the painful challenges that Cincinnati Children’s Hospital Medical Center, Cincinnati, individuals with EB endure are extraordinary. EB skin Ohio; and 3Jordan Family Director, Blood and Marrow Trans- can blister with a touch, and the resulting wounds heal plantation Program, Children’s Hospital & Research Center, with mutilating scarring. Their upper alimentary tract Oakland, California. can blister just as easily. Esophageal strictures develop Financial disclosure: See Acknowledgments on page S171. Correspondence and reprint requests: Mark C. Walters, MD, Jordan with aberrant tissue repair, and eating is painful. People Family Director, Blood and Marrow Transplantation Program, with EB are separated from many interactions with their Children’s Hospital & Research Center, Oakland, 747 52nd peers, as most common daily activities are impossible Street, Oakland, CA 94609 (e-mail: [email protected]). Ó for them. Every moment and aspect of their lives is con- 2012 Published by Elsevier Inc. on behalf of American Society for sumed by this debilitating genodermatosis [2]. Blood and Marrow Transplantation 1083-8791/$36.00 Remarkably, stem cell transplantation can amelio- doi:10.1016/j.bbmt.2011.10.023 rate the deficiency of this skin-specific structural S166 Biol Blood Marrow Transplant 18:S166-S171, 2012 HCT for Nonmalignant Disorders S167 protein in an animal model of RDEB [3]. We found nate the early stages of aberrant skin formation in that donor cells at the dermal-epidermal junction pro- development and, in principle, provide an inex- duced C7 in the skin of the RDEB mice. Strikingly, haustible supply of EB patient-specific stem cells paw blisters healed and rudimentary homotrimers of that can be useful for future stem cell gene therapy C7, termed anchoring fibrils, were formed [4]. These strategies [10]. data were supported by the research of others, who Clinical trials in EB illustrate that: demonstrated the positive effect of in utero infusion of bone marrow cells in RDEB and postnatal infusions 1. Translation of laboratory observations in relevant in JEB [5,6]. animal models to a clinically meaningful intervention Based on these proof-of-concept studies in murine is possible within a short period of time (\2 years). models that show the replacement of missing C7 and 2. Further modifications in the use of stem cell trans- skin repair, a first in-human study was initiated in plantation as a durable source of extracellular ma- 2007. After this clinical trial of allogeneic HCT in trix proteins may make this regenerative medicine seven children with RDEB had shown that C7 can in- approach effective in other cutaneous and extra- crease and ameliorate many of the disease manifesta- cutaneous conditions. tions [7], we hypothesized that children with JEB 3. Only by performing the laboratory and clinical ex- could respond favorably to allogeneic transplantation perimentation that contributed to achievement of as well, and that both groups could benefit from coin- the original objectives do we learn about the nature fusion of hematopoietic and mesenchymal stem cells of ‘‘the growing frontier.’’ Thus, only in the context (MSCs) from allogeneic marrow. of new data do previously unanticipated questions To investigate this, we treated eight additional emerge, both biologic, for example, how robust children with RDEB and two children with JEB using must hematogenous engraftment be to significantly allogeneic cotransplantation of hematopoietic and contribute to skin repair?; and ethical, for example, MSCs. Altogether, 17 patients have been treated, how much preliminary data are enough to substan- with survival in 13 and clinical amelioration of the dis- tiate clinical trials in infants with severe phenotype ease in 11. Healthy donor cells from the hematopoietic versus adults with a mild form of the same disease? graft migrated to the injured skin. Simultaneously, In summary, significant biochemical and quality- there has been an increase in the production of C7 of-life benefits can be derived from allogeneic hemato- and L332 and increased skin integrity with reduced poietic and mesenchymal cell transplantation for tendency to blister formation. The results of these tri- RDEB and JEB, conditions characterized by severely als demonstrate that the infusion of allogeneic hemato- compromised wound healing because of the congenital poietic cells can result in substantial clinical benefit [8]. absence of skin structural proteins. These severe Laboratory investigations in EB show that: congenital mechanobullous disorders are unique in 1. Unique among proteins critical to skin integrity, their capacity to illuminate the mechanisms of cross- C7 function depends on extracellular polymeriza- correction of a structural protein deficiency in extracel- tion. This makes RDEB the ideal human skin lular matrix and regeneration of extramedullary tissues condition to explore, and thus illuminate, the by hematogenous cells in disease and injury states. mechanisms of cross-correction of structural pro- tein deficiency in extracellular matrix. 2. Depletion of cells with high proliferative potential HCT FOR CHROMOSOME SENSITIVITY from skin stem cell niches by hyperactive unpro- SYNDROMES ductive tissue repair in EB may facilitate high donor cell engraftment. The empty stem cell niches in EB DNA is continuously damaged by endogenous and skin that are depleted of their own stem cells by exogenous (eg, ionizing radiation) mutagens. Repair of repeated and futile attempts at skin regeneration, DNA damage (DNA double- and single-strand breaks) may serve as permissive ‘‘docking stations’’ for is a complex process carried out by an array of DNA donor cells. Such cells may, in turn, release factors repair pathways (eg, homologous recombination, non- that operate on the host or that may differentiate homologous end-joining). Defects in any of these into cells that directly participate in the wound- repair mechanisms or in telomere maintenance can healing process via release of C7, L332, or other tis- lead to chromosome instability syndromes. The chro- sue repair proteins. Simultaneously, this further mosome instability syndromes mainly manifest as con- supports the idea of EB as a unique model of skin genital bone marrow failure (BMF) syndromes (eg, tissue repair with donor