Byers, SharonGronthos, StanJackson, Matilda2017-02-242017-02-242015http://hdl.handle.net/2440/103497Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disorder that is characterised by a deficiency in the α-L-iduronidase (IDUA) enzyme, resulting in the accumulation of undegraded heparan sulphate and dermatan sulphate glycosaminoglycans (gags) within the lysosome of nearly every cell. MPS I is a multi-tissue and organ disease, presenting with profound mental retardation and skeletal abnormalities. Haematopoietic stem cell (HSC) transplant and enzyme replacement therapy, two clinically available forms of treatment, are able to correct the soft tissue aspects of MPS disease, but have had a limited effect on the more complex skeletal and neurological symptoms. Stem cell therapy utilizing mesenchymal stem cells (MSC) has the potential to overcome these limitations due to their ability to differentiate into cells that are the major sites of MPS pathology. MSCs naturally produce and secrete significantly higher levels of multiple MPS enzymes than HSCs in vitro and can be engineered to over-express multiple MPS enzymes using a lentiviral system. MSCs were found to secrete up to 5,559 fold greater IDUA enzyme after lentiviral transduction in vitro, suggesting a greater potential to cross-correct MPS pathology than HSCs. Lentiviral transduction was stable and persistent in vitro, and over-expression of MPS enzyme did not affect MSC in vitro differentiation down osteogenic, adipogenic, chondrogenic or neurogenic lineages. Systemically administered human derived MSCs distribute widely, to multiple MPS I affected organs, including the brain, and persist in vivo for at least two months post administration. Significantly elevated brain and serum IDUA activity was observed two and six months post administration, respectively, and was associated with sustained functional improvements in neuromuscular strength, motor control, coordination and spatial learning. MSCs were found to limit astroglial activation and modulate brain inflammatory gene expression of Cd68, Gfap and Tnf in vivo. Vertebral body width also returned towards normal. However, no improvement in gag storage or elevations of IDUA were observed in other tissues. For the first time, this thesis has investigated the biochemical and behavioural changes due to i.v. administered hMSCs in MPS I mice. This thesis demonstrates that MSCs can exert added neurological improvements in MPS I pathology through exhibiting a combined effect between their superior enzyme secretion and anti-inflammatory effects. While minimal changes were noted in MPS I associated somatic pathology, MSCs could be administered in combination with already implemented ERT and/or BMT, which have both shown resolution in patients stored gag, therefore providing additional clinical benefits to MPS I children.Mucopolysaccharidosis type Imesenchymal stem cellsgene therapyTheses10.4225/55/58af96776eb72