Alkaptonuria (AKU; MIM 203500), is a rare disorder of tyrosine metabolism.

AKU is an iconic disease; it was the first human disorder that was recognized to conform to Mendelian autosomal recessive inheritance by Archibald Garrod over a century ago and represents the prototype “inborn error of metabolism”.

The disease arises from autosomal recessive genetic deficiency of the enzyme homogentisate 1,2 dioxygenase (HGD) and is characterised by accumulation of homogentisic acid (HGA) and pathological HGA polymerization known as ochronosis. A potential disease-modifying drug, nitisinone (brand name: Orfadin®), is currently undergoing clinical trial. It is however not considered a cure for AKU because it causes a large and potentially harmful increase in circulating tyrosine.

In May 2011, PTL entered into a partnership agreement with the AKU society (www.alkaptonuria.info) to investigate (HGD) – the deficient enzyme in AKU. PTL was awarded funding from The Wellcome Trust to investigate developing a cure for AKU (http://www.wellcome.ac.uk/Funding/Innovations/Funded-projects/therapeutics/index.htm).

Here, we will develop two most promising post-state-of-the-art therapeutic approaches for repair and replacement of disease-causing HGD mutations:

  • Drug repurposing
  • HGD enzyme replacement therapy