Immune responses in patients withLysosomal Storage Disorders treated with Enzyme Replacement Therapy and Haemopoietic Stem Cell Transplantation

UoM administered thesis: Unknown

  • Authors:
  • Muhammad Saif


Lysosomal storage disorders (LSDs) are caused by defective lysosomal degradation of macromolecules resulting in accumulation of substrates in various tissues. This gradually leads to organ dysfunction and the classical clinical presentation with multisystem involvement. Historically the management of LSDs was confined to symptomatic treatment only. More recently other therapies have become available. Treatment options include cellular therapy in the form of Haemopoietic Stem Cell Transplant (HSCT), Enzyme Replacement Therapy (ERT), Substrate Reduction Therapy (SRT), Chaperone Mediated Therapy (CMT) and gene therapy. Whilst HSCT and ERT are established strategies in clinical practice for some LSDs, others are still in the development phase. The easy accessibility of ERT in the developed world (despite a high cost burden of approximately £144,000 per patient per annum in the UK), fewer risks associated with its administration and good metabolic and clinical outcome, have made ERT the treatment of choice for a number of LSDs. In recent years immune response has been identified as a significant factor in attenuating or nullifying the response to ERT. Despite recognition of this problem, there is a lack of reliable diagnostic tools to test and evaluate the antibody responses in the centres delivering ERT and far too little attention has been focused on development, optimisation and standardization of immune assays.In this project, IgG ELISA and two different functional enzyme inhibition assays (catalytic inhibition and cellular uptake inhibition) were developed and optimized. The immune response to ERT was then studied in recipients of ERT in MPSI, MPSVI and Pome disease. Our practice of delivering ERT in recipients of allogeneic HSCT prior to transplant provided us with an opportunity to study the immune response in MPSIH patients during ERT and following HSCT. We demonstrated functionally active antibodies in long term recipients of ERT in MPSI and Pompe disease. Allo-immune response in MPSVI did not inhibit the delivered enzyme therapy. A high titre inhibitory immune response was detected in the majority of MPSIH patients after exposure to ERT. This immune response was abrogated by allogeneic HSCT rendering these patients tolerant to replaced enzyme, confirming HSCT as an effective immune tolerance induction mechanism.


Original languageEnglish
Awarding Institution
Award date1 Aug 2013