Clinical Trials for Ornithine Transcarbamylase Deficiency 

This information was added on the 11th January 2024. We will endeavour to keep this up-to date to keep you posted on upcoming trials for OTC.

Introduction to Ornithine Transcarbamylase Deficiency

Also known as OTC, Ornithine Transcarbamylase Deficiency is a rare inherited metabolic condition named for the enzyme that people with OTC are missing and is estimated to occur between 1 in 56,500 to 1 in 77,000 people.

But what does that mean?
Many foods contain protein. You may immediately think of the more obvious foods like chicken, but protein can also be present in other foods, like sweets and vegetables. The body needs protein for growth and repair. Many people eat more protein than they need and so the body removes the excess protein.

Unused protein first gets converted into a toxic chemical called ammonia. This chemical can cause damage to the body and brain if it’s not removed and is allowed to build up. Usually, our bodies remove the ammonia through a process known as:

The Urea Cycle
The Urea Cycle takes place in the liver. It converts ammonia to a non-toxic chemical called urea. Several steps have to take place within the cycle to achieve this and each step needs an enzyme (like chemical scissors) for it to work. Urea is then removed from the body by the kidneys, before it’s excreted as urine.

In OTC deficiency, the body lacks the enzyme ornithine transcarbamylase. This means the process above cannot happen. The liver cannot convert the waste protein into urea as fast as it usually would. This can lead to high levels of ammonia.

This build up in ammonia means some babies can become ill in the first few days of life, whilst some may be diagnosed later as children. For both, the effects of high ammonia, known as hyperammonaemia, can quickly become life-threatening if untreated.

Diagnosis and Management
Currently OTC deficiency is suspected in someone with high ammonia levels, which can be picked up through a blood test. Diagnosis is then confirmed by finding a mutation in the OTC gene.

OTC deficiency is managed with a protein restricted diet, regular feeding, and medications and supplements. It’s important to get the protein balance right! Too little and there’s not enough to grow, too much and waste protein will cause high ammonia levels. Some may need a feeding tube to help with this, or might consider a liver transplant if management isn’t sufficienct.

The focus on OTC deficiency

There is a focus on OTC deficiency within the clinical trial landscape at the moment. Many researchers and companies are showing interest in this rare condition, with active and upcoming clinical trials either to study new treatments or better understand the cause and effects of OTC.

Currently, OTC is managed through diet and medication, but this doesn’t address the root cause of the issues. Liver transplant is the only cure at this time, and whilst this can be an incredible improvement for many, it can come with risks and can sometimes be seen as resolving one thing that needs managing but replacing it with another. Anyone who’s undergone organ transplant needs to take drugs to suppress their own immune system and reduce the risks of the organ being rejected by the body. Where it is an option, the decision to go ahead with a liver transplant is therefore one that needs careful consideration.

But why OTC?

There’s no clearly cited reason for the current industry focus on OTC we’re seeing. Though there could be a few of reasons for this:

  • Despite UCDs being rare, there is good understanding of the urea cycle itself.
  • OTC is also the most common of the Urea Cycle Disorders.
  • Like the other UCDs, treatment is focused solely around preventing the build-up of ammonia and the subsequent effects of this so it’s relatively easy to test and prove the how well a treatment works, with clear markers and symptoms that are easily identified and measured.
  • How and where the enzymes of the urea cycle are located is vastly important, this solely being in the liver. A liver transplant therefore can be curative. Liver transplantation although largely positive is generally considered for those with more severe illness.
  • Current treatments of diet and medication are burdensome and can be tricky to navigate and maintain.

The science behind new treatments

As we mentioned, OTC deficiency gets its name from the enzyme that is missing or faulty. Our genes (DNA) provide the instructions for making our enzymes. Clinical trials are looking at ways to deliver the full and correct instructions for making the necessary enzyme to where they’re needed. There are different ways to do this, each with its own positives and potential risks. The following information is only an introduction to some methods in development.

AAV Gene Therapies

AAV stands for adeno-associated viruses

This is a common form of gene therapy that uses a naturally occurring virus to deliver the instructions using DNA. It can sound a bit scary, but once the DNA of the virus has been swapped for the specific DNA code of the missing enzyme, it’s not really considered to be a virus anymore! This method doesn’t create permanent changes to someone’s genes. When cells divide and grow, these new cells still contain the missing or incorrect gene. This can make it challenging to use in newborns with OTC, because as the baby and their liver grows the replacement gene may be lost.

Gene Editing

A form of gene therapy

Gene editing is another form of gene therapy. Gene editing essentially does what it says, it edits someone’s genes (DNA). Editing can mean deleting, modifying, or replacing. This creates a more permanent change. For OTC the hope is to replace that faulty or missing bit of code for the enzyme, so excess protein can be safely removed from the body.

MRNA Therapy

This is not a gene theapy

Messenger RNA (mRNA) therapy doesn’t interact directly with DNA. This means it doesn’t alter the genetic code. Whilst our DNA provides the instructions for producing enzymes, mRNA works as a messenger in that production process. It relays the instructions from our genes to the “assembly line” where the enzymes are produced. mRNA is not permanent and is naturally broken down by the body. This means mRNA therapy needs to be repeated for lasting benefit, but it can also be paused or stopped if side effects occur.

Why do I need to know this?

There have been lots of updates about potential future clinical trials and new developments for OTC recently and these have been shared as and when information has become available. Metabolic Support UK is committed to empowering those living with IMDs and their families or caregivers. We provide impartial information about possible new treatments but also acknowledge that the science behind it can be complicated and easily misunderstood.

We hope that the definitions above help a little as we explore the ongoing work of some of the companies who have upcoming plans for clinical trials for OTC. Be sure to always discuss any potential risks with your consultant or the lead investigator of the clinical trial, alongside the positives.

Upcoming trials for people living with OTC deficiency

We have received the information from companies with clinical trials focusing on the treatment of OTC deficiency. More work is being done by others, such as Ultragenyx and Moderna, and we will share this as soon as it is available to us. 

Each of the tiles below are clickable and will bring you to our webpage containing further information about the specific treatment you clicked on.

A word from Metabolic Support UK

We hope this information has been helpful and provides a balanced overview of the future work in OTC. We hope this empowers you to understand the different types of investigational therapies out there and gives a brief insight into each trial. Although clinical trials must gain approvals and follow strict regulations and processes to ensure safety, all clinical trials carry some degree of risk.

If you do have an interest in participating in a clinical trial it is important you gather all information available. You can discuss this with your consultant or the lead investigator of a trial who’ll be happy to provide more information and help you make an informed decision without committing to participating.

Skip to content