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New drugs to give babies with rare diseases a better start in life

rare diseases baby start life
rare diseases baby start life

Professor Georg Hoffmann explains how an orphan drug could offer a new treatment pathway for babies born with potentially fatal rare diseases.

Urea cycle defect disorder can lead to severe damage

There are eight different urea cycle defect disorders. Altogether they affect about one in every 40,000 births, although some are as rare as one in a few hundred thousand.

They are defined as disorders in which you cannot make urea. Urea is a waste product made from the normal cycle of the breakdown of proteins in the liver. Babies with urea cycle defects are lacking one of the enzymes that form the urea cycle. If anything in the cycle is impaired, ammonia builds up in the cells. Ammonia is toxic and if it accumulates it can cause brain damage, coma and even death.

No ‘red flag’ symptoms

Unfortunately, there are no red flag symptoms of urea cycle defects. Babies mostly present in the first few days of life, with drowsiness and seizures and may fall into a coma. The only way to be sure a baby has a urea cycle defect is to do a blood test to check for ammonia levels. In the last 10 to 15 years, neonatologists have had guidelines that indicate when doctors should test for ammonia. But it may still not be put into practice early enough. Some children may go undetected until death or, when diagnosis does happen, it‘s too late and there has already been a lot of brain damage. There are many tragic histories of families when it wasn’t detected in time.

To treat it we use dialysis to filter out the ammonia. But this is a very difficult treatment for a baby that may only be a few hours or days old. We use a very strict, protein-controlled baby formula with just enough protein for the baby to grow but no more than the body can process. We also use medications that can bind to ammonia and allow it to be excreted.

The search for viable long-term treatments

These babies need treatment for the rest of their lives, unless they have some types of gene therapy. However, the outcome of gene therapy in urea cycle defects is unsure. In our experience about 50 per cent of babies we treat do not survive to 10 years old. Those that survive may have severe brain damage. So this is not really a viable long-term treatment.

An option is a full liver transplant. Children with urea cycle defects are very high on the priority list for donor livers across Europe but, even so, it’s difficult to find enough donor organs. It’s also very difficult to transplant a liver. For neonates mortality in 10 years after a liver transplant is about 30 per cent. At one year old this falls to below 10 per cent.

Future orphan drugs clinical studies show that you can infuse liver cells into the liver to treat urea cycle defects. We are participating in such a study and have shown that using this treatment doesn`t cause harm compared to a control group. Initial data shows that using this treatment is effective in babies and young children with urea cycle defects.

The overall aim is to use the liver cells as a bridging treatment to allow children time to grow so they have a better chance of a successful liver transplant. The hope is that it will be available as an orphan drug at the end of the year. It’s exciting to have treatments with the potential to make a big difference to outcomes.

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