Pathology and treatment of Mucopolysaccharidosis type IIIA

Abstract

Mucopolysaccharidosis type IIIA is a rare paediatric lysosomal storage disorder, caused by the progressive build-up of heparan sulphate within the lysosome. The disease is marked by neurocognitive decline, as well as behavioural problems, which typically culminates in death within the second decade of life. Interestingly, a more severe neurological impairment has been observed in Mucopolysaccharidosis IIIA patients following recovery from a flu-like infection, which indicates that inflammation is highly involved in disease progression. In order to test this hypothesis, we performed acute and long-term studies in which wild type and Mucopolysaccharidosis IIIA mice were challenged with either high or low doses of the Toll-like receptor 3 viral mimetic poly(I:C) to mimic moderate or mild flu-like infections, respectively. Our data indicated that repeated mild infections trigger a hyperactivation of microglia, which mount a robust IL-1b inflammatory response, culminating in reduction of glial fibrillary acidic protein+ astrocytes and neuronal loss in the hippocampus of Mucopolysaccharidosis IIIA mice. Strikingly, the impact of systemic infections on behaviour appeared to be viral load dependent, with only repeated moderate infections causing exacerbation of the existing working memory deficits. Simultaneously, we also developed a novel regenerative therapy to target the irreversible neuronal loss observed in Mucopolysaccharidosis IIIA, potentially providing an alternative treatment for patients that cannot access current clinical trials. In this respect, we generated induced pluripotent stem cell-derived neural progenitors from unaffected and Mucopolysaccharidosis IIIA patient fibroblasts, which were then genetically manipulated via a lentivirus to overexpress the SGSH enzyme. Strikingly, delivery of lentivirus-transduced unaffected neural progenitors into 2 month-old Mucopolysaccharidosis IIIA/NSG mice led to complete correction of the spatial working memory deficits, together with normalisation of the lysosomal compartment and significant reduction of neuroinflammation. Conversely, injection of lentivirus-transduced Mucopolysaccharidosis IIIA neural progenitors did not rescue the behavioural phenotype, nor the neuropathology. Overall, this thesis presents evidence that neuronal replacement in combination with an anti-inflammatory therapy targeting IL-1 might provide a robust strategy to reverse Mucopolysaccharidosis IIIA neuropathology.

Date of Award	31 Dec 2023
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Brian Bigger (Supervisor) & Giulio Cossu (Supervisor)