Allogeneic hematopoietic stem cell transplantation for inherited metabolic disorders

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) has been used to treat patients with inherited metabolic disorders (IMDs) for more than 40 years. In the first two decades, various IMDs were treated by HSCT with a wide variety of donor sources and conditioning regimens selected at the institutional level. However, HSCT was not always successful due to posttransplant complications such as graft failure. In the third decade, myeloablative conditioning with targeted busulfan-based pharmacokinetic monitoring was established as an optimal conditioning regimen, and unrelated cord blood was recognized as an excellent donor source. During the fourth decade, further improvements were made to transplant procedures, including modification of the conditioning regimen, and the survival rate after HSCT markedly improved. Simultaneously, several long-term observational studies for patients after HSCT clarified its therapeutic effects on growth and development of cognitive function, fine motor skills, and activities of daily living when compared with enzyme replacement therapy. Although immune-mediated cytopenia was newly highlighted as a problematic morbidity after HSCT for IMDs, especially in younger patients who received unrelated cord blood, a recent study with rituximab added to the conditioning raised expectations that this issue can be overcome.

CNS Repopulation by Hematopoietic-Derived Microglia-Like Cells Corrects Progranulin deficiency

“…Hematopoietic stem cell transplantation (HSCT) is the recommended treatment for several genetic disorders with severe and rapid neurodegeneration, including several lysosomal storage disorders (LSDs) and peroxisomal disorders (PSDs) 1 , 2 . HSCT is also a promising investigational therapy for other neurological diseases, including Friedreich’s ataxia 3 , Pelizaeus–Merzbacher disease 4 , and several neuronopathic LSDs 5 .…”

“…HSCT is also a promising investigational therapy for other neurological diseases, including Friedreich’s ataxia 3 , Pelizaeus–Merzbacher disease 4 , and several neuronopathic LSDs 5 . Despite its proven benefit, HSCT’s use for neurological indications has been limited to a few fatal diseases because its risk-benefit assessment is usually unfavorable 1 , 6 . One of the caveats of HSCT is the common use of allogeneic cells (allo-HSCT) which exposes the recipient to immunological complications while often providing insufficient therapeutic correction 1 .…”

“…Despite its proven benefit, HSCT’s use for neurological indications has been limited to a few fatal diseases because its risk-benefit assessment is usually unfavorable 1 , 6 . One of the caveats of HSCT is the common use of allogeneic cells (allo-HSCT) which exposes the recipient to immunological complications while often providing insufficient therapeutic correction 1 . To overcome this risk, autologous transplants of gene-modified HSPCs are being developed 7 – 9 .…”