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"The role of Glutamine synthetase in Liver Failure: Molecular, Functional and Therapeutic modulation"

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Gene therapy for liver failure

Hepatic encephalopathy (HE) is a complex disorder with gradual impairment in the mental performance and reactions to external stimuli. Understanding of the regulatory pathways involved in the HE would ultimately lead to a more effective therapy.

Health

Inefficient clearance of ammonia by the liver due to liver disease leads to HE. Cirrhosis is the major cause of chronic liver dysfunction and affects 1 million Europeans and 5.5 million Americans. At present, there are no interventions that have been shown to reduce ammonia in liver failure. The enzyme glutamine synthetase (GS) produces the amino acid glutamine and is the key regulator of ammonia metabolism. The EU-funded Marie Curie 'The role of glutamine synthetase in liver failure: molecular, functional and therapeutic modulation' (HE&GS) project aimed to define the role of GS in liver failure and its therapeutic potential for HE treatment. As an initial step, researchers obtained mouse knockout models in collaboration to test the importance of selective deficiency of GS in the muscle. The animals lacking muscle GS had significantly greater brain swelling and liver injury that was associated with more severe hepatic inflammation. This happens due to the greater migration of bacteria from the gut into the blood stream. Muscle depletion is frequently encountered in patients with cirrhosis and together with malnutrition is an independent prognostic factor for survival. Using mass spectrometry, researchers identified that the animals lacking muscle GS had more severe oxidative stress in the muscle proteins. These results explained why the lack of GS function in the muscle produced deficiency in energy storage and muscle loss. Project data suggested that the reconstitution of GS in the muscle is likely to be an important therapy. Researchers successfully developed a viral vector for safe delivery of a GS expressing construct to the muscle. Using this approach, it is now possible to produce a virus that can be used for the study of muscle GS replacement. The results of this project have allowed further clarification of the important role of muscle GS, the mechanisms of the reduction of GS function and their effects in liver failure. Further development of the novel gene therapy constructs will lead to a new approach for patients with liver failure and HE.

Keywords

Hepatic encephalopathy, liver failure, glutamine synthetase, mouse model, gene therapy

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