About AKU

About Alkaptonuria

Alkaptonuria, also known as AKU or Black Bone Disease, is an extremely rare genetic condition that can cause significant damage to the bones, cartilage and tissues of those affected. AKU normally only affects one in every 250,000 people worldwide.

It is a recessive condition caused by a mutation in one chromosome. So if two people carry the faulty gene, their child has a 25% chance of developing AKU.

AKU stops patients’ bodies from breaking down a chemical called homogentisic acid (HGA) which the body naturally produces while digesting food. HGA builds up in the body and, over time, leads to black and brittle bones and cartilage (in a process called ochronosis), and early onset osteoarthritis. It also causes eyes and ears to go blue-black.

First symptom most AKU patients experience is black or dark urine. Large quantities of HGA are excreted in the urine. If left to stand & exposed to the air, the HGA in urine will oxidise & turn black.

Black urine does not cause any harm. However, it can be used as a diagnostic tool. Babies born with AKU may have dark or red staining in their nappy as a result of HGA in the urine. Doctors should then carry out a urine or blood test to check the level of HGA in the baby’s body in order to confirm a diagnosis of AKU.

Every AKU patient will experience joint pain at some point in the lives. Typically, pain starts in the back when patients reach their thirties. Pain usually spreads into the other major joints, including the hips, knees, shoulders, elbows and feet. Patients can take pain relief medications to manage the pain, and most will eventually require surgery to replace joints once they become seriously damaged. Many AKU patients have more than one joint replacement, with some having between five and 10 joint replacements in their lifetime.

AKU can also cause serious heart problems. The HGA sticks to the vessels and valves of the heart, causing them to harden. They become blackened, brittle and narrow, causing increased pressure within the heart left ventricle and sometimes leading to heart failure.

Some AKU patients need a heart valve replacement. Care needs to be taken during aortic valve surgery to ensure that debris from the damaged tissue is not carried by the bloodstream and increase a patient’s risk of stroke.

Why an mRNA Therapy is Needed For AKU?

The largest number of known cases of AKU (>200) have been reported in Slovakia, the majority clustering in a small region in the north-west of the country. AKU arises from mutations in the HGD gene. The HGD Mutation Database, created by Dr Andrea Zatkova, reported 211 HGD gene variants from approximately 530 AKU patients reported so far.

As yet, no relationship between specific mutations and clinical manifestations has been established, although several AKU mutations have been shown to have residual catalytic activities. Until recently, the mRNA of the HGD gene was thought to be present in multiple organs.

However, a recent AKU animal model showed that the gene is expressed only in theliver and kidney. This means we can develop an mRNA therapy that can target these organs, especially the liver, to treat AKU.

It's worth nothing that there is already a licensed treatment for AKU: it’s a drug called nitisinone, which blocks the production of homogentisic acid by 99.8%. However, nitisinone also has side effects due to a significant increase in the amino acid tyrosine. This can lead to problems with the eyes and the skin, but also cognitive defects in children. That’s why an mRNA treatment is needed as a more perfect treatment.