Neonatal bone marrow transplantation of ADA-deficient SCID mice results in immunologic reconstitution despite low levels of engraftment and an absence of selective donor T lymphoid expansion

Carbonaro, Denise A.; Jin, Xiangyang; Cotoi, Daniel; Mi, Tiejuan; Yu, Xiao; Skelton, Dianne C.; Dorey, Frederick J.; Kellems, Rodney E.; Blackburn, Michael R.; Kohn, Donald B.

doi:10.1182/blood-2007-08-103663

Cited by 23 publications

(26 citation statements)

References 26 publications

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“…When engraftment of oc/oc mice was compared with control mice, there was no significant difference, indicating that there is no homing or engraftment advantage for normal cells in the osteopetrotic marrow compared to WT marrow. Our engraftment data are highly compatible with those observed in a study of successful nonablative transplantation of neonatal mice with mucopolysaccharidosis VII (MPS VII or Sly disease in humans), (24) as well as with those seen in two murine models of SCID (25) (see below).…”

Section: Discussionsupporting

confidence: 86%

“…However, somewhat surprisingly, Kohn and colleagues found in a mouse-model of ADA-SCID that there was no evidence of selective expansion after nonablative SCT. (25) This was therefore in contrast to the human situation and also to the mouse model of X-linked SCID, in which a clear expansion of T-lymphocytes was seen. (1,25) With this background, we wanted to determine if there was any evidence of selective expansion of the osteoclast lineage in the oc/oc mouse model after nonablative SCT.…”

Section: Discussionmentioning

confidence: 83%

“…(25) This was therefore in contrast to the human situation and also to the mouse model of X-linked SCID, in which a clear expansion of T-lymphocytes was seen. (1,25) With this background, we wanted to determine if there was any evidence of selective expansion of the osteoclast lineage in the oc/oc mouse model after nonablative SCT. However, when comparing the frequency of donor-derived cells in the dynamic 18-to 20-day period after transplantation, there was no difference between oc/oc and control mice in the frequency of GFP þ cells in the preosteoclast CD11b/Gr1 low cell population in peripheral blood, spleen, or bone marrow, indicating that increased recruitment of cells to the osteoclast lineage is not the driving force behind the rapid reversal of osteopetrosis.…”

Section: Discussionmentioning

confidence: 83%

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Nonablative neonatal bone marrow transplantation rapidly reverses severe murine osteopetrosis despite low-level engraftment and lack of selective expansion of the osteoclastic lineage

Flores

Vries

Moscatelli

et al. 2010

Journal of Bone and Mineral Research

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Infantile malignant osteopetrosis (IMO) is caused by lack of functional osteoclasts leading to skeletal abnormalities, blindness owing to compression of the optic nerves, bone marrow (BM) failure, and early death. In most patients, TCIRG1, a proton pump subunit essential for bone resorption, is mutated. oc/oc mice represent a model for IMO owing to a deletion in Tcirg1 and die around 4 weeks of age. To determine if hematopoietic stem cell transplantation without prior conditioning can reverse osteopetrosis, neonatal mice were transplanted intravenously with lineage-depleted BM cells. More than 85% of oc/oc mice transplanted with 5 Â 10 6 cells survived long term with an engraftment of 3% to 5% in peripheral blood (PB). At 3 weeks, engraftment in the BM was 1% to 2%, but the cellularity had increased 60-fold compared with untreated oc/oc mice, and RANKL and macrophage colony-stimulating factor (M-CSF) expression in the BM was normalized. Histopathology and micro-computed tomography revealed almost complete reversal of osteopetrosis after 4 weeks. In vitro studies showed that bone resorption by osteoclasts from transplanted oc/oc mice was 14% of transplanted controls, and immunofluorescence microscopy revealed that resorption was mainly associated with osteoclasts of donor origin. Lineage analysis of BM, PB, and spleen did not provide any evidence for selective recruitment of cells to the osteoclastic lineage. The vision also was preserved in transplanted oc/oc mice, as determined by a visual tracking drum test. In summary, nonablative neonatal transplantation leading to engraftment of only a small fraction of normal cells rapidly reverses severe osteopetrosis in the oc/oc mouse model. ß

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 83%

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Nonablative neonatal bone marrow transplantation rapidly reverses severe murine osteopetrosis despite low-level engraftment and lack of selective expansion of the osteoclastic lineage

Flores

Vries

Moscatelli

et al. 2010

Journal of Bone and Mineral Research

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“…Nevertheless, safety monitoring should be continued to be strictly implemented long term in all patients, according to guidelines of regulatory agencies. The development of selfinactivating vectors, such as lentiviral vectors, 51,52 might further improve the safety of this approach.…”

Section: Org Frommentioning

confidence: 99%

How I treat ADA deficiency

Gaspar

Aiuti

Porta

et al. 2009

Blood

193

208

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Adenosine deaminase deficiency is a disorder of purine metabolism leading to severe combined immunodeficiency (ADA-SCID). Without treatment, the condition is fatal and requires early intervention. Haematopoietic stem cell transplantation is the major treatment for ADA-SCID, although survival following different donor sources varies considerably. Unlike other SCID forms, 2 other options are available for ADA-SCID: enzyme replacement therapy (ERT) with pegylated bovine ADA, and autologous haematopoietic stem cell gene therapy (GT). Due to the rarity of the condition, the lack of large scale outcome studies, and availability of different treatments, guidance on treatment strategies is limited. We have reviewed the currently available evidence and together with our experience of managing this condition propose a consensus management strategy. IntroductionAdenosine deaminase (ADA) deficiency is a rare inherited disorder of purine metabolism characterized by the accumulation of metabolic substrates that lead to abnormalities of immune system development and function and a variety of systemic defects. The initial and most devastating presentation of the disease is the result of the immune defects; affected infants characteristically present with severe opportunistic infection and failure to thrive and an immunologic profile consistent with severe combined immunodeficiency (ADA-SCID). Without treatment, the condition is fatal in the first year of life and therefore necessitates early intervention. Allogeneic hematopoietic stem cell transplantation (HSCT) has long been considered the mainstay of treatment of ADA-SCID. However, unlike other SCID forms, 2 other treatment options are available for ADA-SCID, namely, enzyme replacement therapy (ERT) with pegylated bovine ADA (Pegadamase, Adagen, or PEG-ADA) and autologous HSC gene therapy (GT).The availability of different treatment modalities presents an opportunity for improved patient care but also presents difficulties in deciding on the specific choice of treatment for individual patients. Making the correct choice is further complicated by the fact that ADA deficiency is not purely an immune defect, unlike other SCID forms, and the systemic manifestations, which can be of major clinical consequence, must also be managed. The rarity of the condition (estimated at anything from 1:200 000 to 1:1 million births) means that any one center has access to only small numbers of patients precluding large-scale prospective studies from which formal and robust outcome data can be accrued. For these reasons, we have gathered experts with experience in management of patients using the different treatment modalities to collect and review the available retrospective data and to construct a consensus management strategy that may be of use to physicians managing this difficult patient population. ADA-SCIDSCID arises from a variety of molecular defects that have profound effects on lymphocyte development and function, including defects in the lymphocyte-specific signaling molecules (comm...

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“…9 In humans, infants receiving unconditioned stem cell grafts can develop mixed T-cell chimaerism, where because donor cells mediate systemic detoxification the host can support the development of endogenous ADAdeficient T-cell populations. These observations support the decision to withdraw ADA enzyme replacement therapy ahead of gene therapy (or indeed allogeneic transplantation) as an important measure to ensure a selective advantage for only the gene-corrected infused cells.…”

Section: Poor Immune Reconstitution In Older Patientsmentioning

confidence: 99%