The results of this mouse model study led to a full-scale clinical trial, funded by the European Commission, with use of nitisinone as a treatment for AKU expected to be approved across Europe once the trial comes to an end. Levels of plasma HGA dropped by 88% – a figure that was maintained over the mouse lifetime, with joint tissue from nitisinone-treated AKU mice showing no pigmented tissue. Perhaps most importantly though, a significant difference was found between HGA concentrations before and after treatment with nitisinone. The researchers were also able to determine that pigmentation of connective tissue increased linearly with increasing age. The concentration of plasma HGA was found to be 0.149 ± 0.019 mM, whilst HGA levels in WT mice were below the level of UV detection. With this in mind, funding obtained from Britain’s Big Lottery Fund went to a research team at the University of Liverpool to develop a mouse model of AKU.Ī colony of Hgd-/- (the genetic equivalent of human AKU) mice were bred by the research team in Liverpool and the mice were established as a model of the plasma biochemistry of AKU and its associated arthropathy. In order for a clinical trial to succeed, a more reliable endpoint would have to be suggested, and this required more knowledge of how the disease developed. There was a small-scale clinical trial run in the US between 20, but too few patients were recruited and the clinical endpoint (the success of the treatment) was defined very narrowly. However, physicians had long suspected that nitisinone, a chemical that was first developed for use as a weed-killer, could be used to treat AKU – nitisinone was being used effectively to treat tyrosinemia (a condition that results from disruption to the same metabolic pathway as AKU). Whilst AKU is a serious condition, for many years it was not seen as prevalent enough among the population to be lucrative for drug developers. High levels of homogentisic acid within the human body eventually leads to ochronosis – a progressive pigmentation of connective tissues and eventually severe joint disease, which can become fatal later in life. The lack of a functional copy of this enzyme results in a vast increase in circulating concentration of homogentisic acid (HGA), leading to a darkening of the urine upon exposure to air. The inhibition of alkaptonuria by the chemical nitisinone in a mouse model led to a full-scale clinical trial funded by the European Commission – the results of which are expected to produce medicine for a condition for which there was previously no treatment available.Īlkaptonuria (AKU) is caused by a deficiency of homogentisate 1,2 dioxygenase, an enzyme that is required for breaking down the two amino acids tyrosine and phenylalanine.
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