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Title: A gene therapy approach for Argininosuccinic aciduria
Author: Baruteau, J. C.
ISNI:       0000 0004 7226 0522
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2017
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Argininosuccinate lyase (ASL) is central to two metabolic pathways: i) the liver-based urea cycle, which detoxifies ammonia, ii) the citrulline-nitric oxide cycle, which synthesises nitric oxide from L-arginine. Patients deficient in argininosuccinate lyase present with argininosuccinic aciduria characterised by hyperammonaemia and a multi-organ disease with a severe neurological phenotype. Compared to other urea cycle disorders, argininosuccinic aciduria presents a low frequency of hyperammonaemic crises but a high frequency of cognitive impairment. This paradox questions the causative role of hyperammonaemia in the neuropathology. An observational UK-wide study was designed to study the natural history. Data about clinical status, neuroimaging and hASL genotyping were collected from 56 patients. Six had molecular analysis performed in this work. A homogeneous neurological phenotype was observed in most patients. hASL sequencing was available in 19 patients and 20 mutations (1) were found. A genotype-phenotype correlation showed that the prognosis was more likely related to genotype rather than severity of hyperammonaemia. The hypomorph mouse model AslNeo/Neo mimicking the human disease was used to study the neuropathology in argininosuccinic aciduria and showed a neuronal disease with oxidative/nitrosative stress. To define the role of hyperammonaemia in this finding, a gene therapy approach using an adeno-associated viral vector (AAV) encoding the murine Asl gene was delivered in AslNeo/Neo mice. The long-term correction of both pathways was observed: i) the urea cycle after a single systemic injection in adult mice; ii) the citrulline-nitric oxide cycle in the brain after a single systemic injection at birth. The neuronal disease persisted if ammonaemia only was normalised but was dramatically reduced after correction of both ammonaemia and neuronal ASL activity. This demonstrated the key-role of a neuronal disease independent from hyperammonaemia in argininosuccinic aciduria. This work provides new insight in the neuropathology of argininosuccinic aciduria and a proof of concept of successful AAV-mediated gene therapy.
Supervisor: Waddington, S. N. ; Gissen, P. ; Mills, P. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available