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Haematopoietic stem cell gene therapy for mucopolysaccharidosis type I-Hurler
Supervisors: Professor Bobby Gaspar and Dr Claudia Montiel Equihua
Mucopolysaccharidosis I (MPS-I) arises from a defect in the lysosomal enzyme α-L iduronidase (IDUA) leading to the accumulation of toxic storage material (glycosaminoglycans, or GAGs) both peripherally and in the brain(1). Clinically this results in severe disability and/or death in early childhood. Current therapeutic strategies are limited to enzyme replacement therapy (which cannot cross the blood brain barrier) or allogeneic HSCT, which carries considerable toxicity. Gene therapy of autologous haematopoietic stem cells has shown recent promise but current vector designs are limited by their inability to correct both CNS and peripheral abnormalities(2),(3).
We have developed a vector design that can effectively express IDUA in all hematopoietic cell lineages but also specifically upregulates transgene expression in erythroid cells(4). Preliminary experiments using these vectors in cultured cells and murine bone marrow transplants have demonstrated that cells transduced with our lentiviral vector are able to produce up to 50-fold more IDUA than cells that carry a wild-type copy of the gene, reducing the level of GAGs to normal.
Hypothesis: We propose that transplanting IDUA-deficient recipients with hematopoietic stem cells transduced with our new lentiviral vector will correct different aspects of the MPS I phenotype that include cardiac function, hearing and cognitive behaviour.
Methods: We will determine the efficacy of the bLCR-EFS-IDUA vector at correcting the metabolic and functional abnormalities in MPS I mice; hematopoietic stem cells will be isolated from the bone marrow of IDUA-deficient donors, transduced with the vector and injected into conditioned IDUA-deficient recipients. IDUA activity and GAG levels will be determined in the blood and organs and correlated to the vector copy number. Cardiac function, auditory capacity and cognitive behaviour will be evaluated in transplanted recipients by echocardiography, auditory brainstem responses and a battery of behavioural tests respectively, and compared to age-matched wild-type and IDUA-deficient controls.
1) Hopwood JJ, Morris CP. The mucopolysaccharidoses. Diagnosis, molecular genetics and treatment. Mol Biol Med 1990 Oct;7(5):381-404.
2) Visigalli I, Delai S, Politi LS, Di DC, Cerri F, Mrak E, et al. Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model. Blood 2010 Dec 9;116(24):5130-9.
3) Wang D, Zhang W, Kalfa TA, Grabowski G, Davies S, Malik P, et al. Reprogramming erythroid cells for lysosomal enzyme production leads to visceral and CNS cross-correction in mice with Hurler syndrome. Proc Natl Acad Sci U S A 2009 Nov 24;106(47):19958-63.
4) Montiel-Equihua CA, Zhang L, Knight S, Saadeh H, Scholz S, Carmo M, et al. The beta-globin locus control region in combination with the EF1alpha short promoter allows enhanced lentiviral vector-mediated erythroid gene expression with conserved multilineage activity. Mol Ther 2012 Jul;20(7):1400-9.