Infantile-onset or later-onset form of lysosomal acid lipase deficiency results in premature mortality in humans. Current treatment is denied approval in certain European countries due to its exorbitant cost. Our results indicate that anti-FGF19/FGFR4 treatment as combinational therapy might reduce the cost of disease management in affected patients.
Eingereicht von: Vinay Sachdev, PhD
Firma/Universität: Medical University of Graz
Lysosomal acid lipase deficiency (LAL-D) (OMIM #278000) is a rare autosomal recessive lysosomal storage disease characterized by progressive accumulation of cholesteryl esters and triglycerides in the liver, spleen and other organs. Complete loss of LAL in infants, known as Wolmann disease (WD), result in vomiting, diarrhoea, poor weight gain, malabsorption, lipodystrophy, cachexia, failure to thrive, and consequential early mortality within the first year of life. The later onset form, cholesteryl ester storage disease (CESD), is caused by a partial loss of LAL activity and is phenotypically characterized by gastrointestinal symptoms with hyperlipidemia, elevated transaminases, hepatomegaly and microvesicular steatosis ultimately resulting in premature demise. Although the enterohepatic phenotype carries perhaps the most relevant burden regarding the disease lethality in LAL-D patients, knowledge behind their bile acid (BA) metabolism is scarce and the mechanistic aspects of the disease are elusive. The murine model of LAL deficiency (LAL-/- mice) resembles a phenotypic model of human CESD and a biochemical and histopathologic model of human WD.
Results of a study from medical university of Graz identifies an important endocrinal factor fibroblast growth factor (FGF)15 (human orthologue known as FGF19) as BA modulator in LAL-/- mice. They determined that increased intestinal FGF15 signalling in Lal-/- mice impair hepatic BA synthesis resulting in reduced plasma BA concentrations, fecal BA excretion and elevated fecal neutral sterol and fat loss. This cascade ultimately results in a range of metabolic adaptations including hyperlipidemia and hepatomegaly as demonstrated by the severe pathological phenotype of LAL-D patients. They are currently in talks with prospective clinicians in Austria and abroad to measure FGF19 concentrations in LALD patients. Based on correlation results the medical university will design clinical intervention to include anti-FGF19/FGFR4 therapy as a combinational therapy with enzyme replacement therapy. The results will pave the way to reduce the cost of therapy and disease management in LAL-D patients.