Hematopoietic Cell Transplantation in Inborn Errors of Metabolism: Hurdles to 'real' cure

Abstract

Inborn Errors of Metabolism (IEM) are a heterogeneous group of genetic diseases, including lysosomal and peroxisomal storage diseases caused by defects in genes coding for proteins involved in metabolic pathways. Most patients with a lysosomal storage disease appear healthy at birth. However, without treatment, all patients will inevitably follow a progressive deterioration and patients with a severe phenotype will ultimately face a premature death. Allogeneic hematopoietic cell transplantation (HCT), based on cross-correction of donor-derived enzyme to the recipient, is standard care for a selected group of IEM and is considered optional for others. It has largely contributed to the improved survival of IEM patients suffering from disorders amenable to HCT with current long-term survival rates of over 90% upon engraftment. However, the areas of residual disease despite HCT are unfolding as patients grow older. The objective of this thesis was to provide better insights in the residual disease of transplanted IEM patients and thereby contribute to the improvement of outcomes following HCT. The focus is mainly on Hurler syndrome patients, as this is the metabolic disorder which is transplanted most frequently. However, transplanted patients with leukodystrophies (LD) were also studied. Long-term outcomes of HCT in patients with IEM have been analyzed in-depth and show disease progression is occurring in both LD and MPS patients despite HCT and, furthermore, progresses over time. Luckily, for MPS-1 patients, psychosocial quality of life is unaffected compared to healthy children. Physical quality of life however, is significantly diminished. In order to recognize the various aspects of residual disease at an early stage and allowing timely intervention, systematic follow-up of these patients is required. Therefore, we have provided an overview of the recommended evaluations in MPS patients at baseline and during follow-up after HCT as well as their proposed frequency. Ideally, all patients are evaluated by a multidisciplinary team experienced in MPS diseases, as happens at the Sylvia Toth Center for Multidisciplinary Follow-up After Hematopoietic Cell Transplantation. The disease progression also emphasizes the need for better treatments. To design better therapies, we need to understand why and where current therapies fail. We note that the majority of progressive symptoms occur in “hard-to-reach” tissues. Two important hurdles that explain disease progression are avascularity and tissue-specific barriers, both leading to unavailability of enzyme. Multimodal treatment that overcome these hurdles could therefore be the future for successful and complete treatment of IEM. Finally, biomarkers that reflect long-term residual disease are necessary to evaluate these experimental therapies. This thesis has generated some potential markers for this purpose, such as salival or tear fluid enzyme activity and markers related to bone homeostasis in MPS patients. Patients treated with new therapies, such as autologous gene-transduced HCT, should be assessed on these markers to evaluate whether new therapies have an improved effect and thus, hopefully, improved long-term clinical outcomes and quality of life.