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A novel technology to improve Enzyme Replacement Therapy for Mucopolysaccharidosis I and Fabry disease

Projectomschrijving

In dit project is de toepassing van liposomaal enzym voor behandeling van de ziekte van Fabry en MPS type 1 onderzocht.

Deze erfelijke ziekten worden veroorzaakt door een deficiëntie van een lysosomaal enzym, leidend tot een stapeling van macromoleculen en aantasting van organen. Voor beide ziekten is enzymtherapie beschikbaar. Het effect hiervan is echter wisselend. Therapie-gerelateerde factoren zijn een ongunstige verdeling van het enzym over de weefsels in het lichaam, het niet passeren van de bloed-hersen-barrière en antistofvorming.

BBB-therapeutics ontwikkelde speciale GSH-PEG liposomen die leiden tot verbeterde opname van geneesmiddelen in de hersenen. Het enzym, verpakt in GSH-PEG liposomen, leidde echter niet tot een verbeterde opname in de hersenen van MPS1 muizen. Antistofvorming was toegenomen, mogelijk door de langere circulatietijd.
Voor de ziekte van Fabry werden PEG-liposomen gebruikt. Alleen bij jonge Fabry muizen werd een gering effect op antistofvorming gezien. Er was geen verbetering in weefseldistributie of afname van stapeling in organen.

Uitkomst

Liposomale enzymtherapie is niet veelbelovend om de behandeling met enzymtherapie te optimaliseren.

Verslagen


Samenvatting van de aanvraag

Lysosomal storage disorders (LSDs) comprise a group of rare progressive multisystem disorders caused by an inherited deficiency of a lysosomal enzyme. Enzyme replacement therapy (ERT) by repeated infusions with the recombinantly produced enzyme is approved for mucopolysaccharidoses (MPSs) types I, II, and VI, and for Gaucher-, Fabry- and Pompe disease. ERT relies on the receptor-mediated uptake of the enzyme and its subsequent delivery to the lysosomes. While this treatment modality was proven to be highly effective and safe in Gaucher disease, in which the macrophages need to be targeted, in the MPSs and in Fabry disease the efficacy of ERT is less impressive as there is significant residual disease impacting on the quality of life of patients. In addition, disease progression has been regularly observed despite ERT. Several factors explain this relatively limited effectiveness. First, antibodies generated to the infused enzyme can interfere with its activity or uptake. Antibodies may neutralize activity, inhibit uptake by the targeted cells and tissues and/or enhance mistargeting to phagocytic cells. This has been shown to occur both in Fabry disease and in the MPSs. Second, infused enzymes are in general unable to cross the blood-brain barrier and can thus not prevent neurocognitive decline in diseases in which the central nervous system is affected, e.g. the severe and intermediate phenotypes of MPS I. Also, in Fabry disease, the infused enzyme is not adequately delivered to organs most affected by the disease, such as the kidneys. It is likely that improved targeting of infused enzymes, combined with protection from the effects of circulating antibodies, may improve the effectiveness of therapy. Our proposed strategy uses a glutathione coated pegylated (GSH-PEG) liposomal delivery system to improve delivery of the enzymes to the affected organs, including targeting to CNS. In addition, we expect that these liposomes can also prevent an immune response and/or prevent interference of antibodies with activity and uptake as the encapsulation shields the enzyme and its epitopes from the immunoreactive cells and from antibodies. The proposed project will focus on studies in cell cultures and in relevant mouse models, to provide a proof-of-principle that GSH-PEG liposomes containing lysosomal enzymes leads to better clearance of accumulated substrates in the clinically relevant tissues as compared to unshielded enzyme. The AMC, with its clinical and laboratory expertise on LSDs, combined with to-BBB’s experience in generating GSH-PEG liposomes containing drugs and their knowledge on targeting the brain, will create the optimal platform for this study. Our collaboration with the Stem Cell & Neurotherapies Lab in Manchester provides essential expertise for this project on MPSI brain pathology in the mouse model and on antibody studies in MPSs. We expect that the results from these fundamental studies may pave the way for the initiation of a phase I/II study in MPS I and FD patients. When proven successful, the novel technology may be applied to other (neuronopathic) LSD’s.

Onderwerpen

Kenmerken

Projectnummer:
113303004
Looptijd: 100%
Looptijd: 100 %
2013
2016
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Prof. dr. C.E.M. Hollak
Verantwoordelijke organisatie:
Amsterdam UMC - locatie AMC