Estabilización sérica y localización hepática y cerebral de una porfobilinógeno deaminasa recombinante optimizada para el tratamiento precoz de las crisis de porfiria aguda intermitente

Résumé

Acute intermittent porphyria (AIP) is an autosomal dominant metabolic disease caused by hepatic deficiency of porphobilinogen deaminase (PBGD), the third enzyme of the heme synthesis pathway. The dominant clinical feature is acute neurovisceral attack associated with high production of potentially neurotoxic porphyrin precursors due to increased hepatic heme consumption. Current Standard of Care is based on a down-regulation of hepatic heme synthesis using heme replacement therapy. Recurrent hyper-activation of the hepatic heme synthesis pathway affects about 5% of patients and can be associated with neurological and metabolic manifestations and long-term complications including chronic kidney disease and increased risk of hepatocellular carcinoma. Prophylactic heme infusion is an effective strategy in some of these patients, but it induces tolerance and its frequent application may be associated with thromboembolic disease and hepatic siderosis. Orthotopic liver transplantation is the only curative treatment in patients with recurrent acute attacks. Emerging therapies including replacement enzyme therapy or gene therapies (HMBS-gene transfer and ALAS1-gene expression inhibition) are being developed to improve quality of life, reduce the significant morbidity associated with current therapies and prevent late complications such as hepatocellular cancer or kidney failure in carriers with long-standing high production of noxious heme precursors. This research is aiming at developing more efficient treatments for AIP, improving patients¿ quality of life and protecting against the long-term complications associated with high porphyrin precursor excretion. The most efficient therapy for sporadic attacks must be easy to administer and able to generate rapid action in the three compartments involved in the acute attack: i) it must restore the heme synthesis pathway in the liver to prevent further accumulations of ALA and PBG; ii) it must lead to a rapid and sustained reduction in serum PBG and ALA; iii) ideally, it must be able to cross the blood-brain barrier and protect the brain from neurotoxic precursors accumulated in the plasma during the acute attack. A second line of research was to identify metabolites secreted by the hepatocytes that reflect differential metabolic status in the liver and that may predict response to the acute attack treatment. Plasma vitamin D binding protein suffers post-translational modifications that might be considered as a promising biomarker to study and monitor the liver metabolic status in patients with AIP.