What is Carbamoyl phosphate synthetase 1 (CPS1) deficiency:
Carbamoyl phosphate synthetase 1 (CPS1) deficiency is an ultra-rare urea cycle disorder, affecting approximately 1 in 1,300,000 people. CPS1 is among the most severe of the urea cycle disorders and is associated with a mortality rate of 50% in early infancy. Currently, the treatment for CPS1 is a liver transplant. However, newborns who are too small for this surgery must wait until they become strong enough for the procedure. During the waiting period, the condition is managed through dietary restriction and medication. Unfortunately, the longer the wait for surgery, the greater the risk of permanent damage or even death.
Recently, however, scientists have trialled a new approach, personalised gene editing, as a potential treatment for CPS1 deficiency.
Treating CPS1 with personalised gene editing:
When an baby was diagnosed with CPS1 deficiency shortly after birth at the Children’s Hospital of Philadelphia (CHOP), the team of researchers and clinicians saw the opportunity to use the personalised gene editing pathway platform that they had been building and optimising for the last two years. They immediately began designing a customised gene therapy specific to the unique changes identified in the baby’s genetic code, with the hope that this would reverse these changes and result in the production of a functional CPS1 enzyme.
In this first-in-the-world case, the process from diagnosis of IMD to delivery of the personalised medicine took less than 6 months. This included complete customisation of the gene editing platform to target changes in the baby’s genetic code, multiple rounds of safety testing and approval from government regulators.
Three doses of the personalised gene editing medicine were delivered safely to the baby. After each treatment, the baby’s condition improved, allowing for an increase in dietary protein and a reduction in the amount of medicine required. The baby is now growing more rapidly and hopes to return home with their parents in the future.
Can personalised gene editing help more people living with an IMD:
Given that CPS1 deficiency is an ultra-rare disorder, and it is unlikely that many other people with CPS1 deficiency will have the exact same genetic variation that was targeted and fixed with this personalised gene editing medicine, it is not likely that this specific treatment would be directly applicable to other people. However, this groundbreaking case provides proof of principle that personalised gene editing is feasible in humans and was relatively safe and effective in this case.
Looking forward, there is optimism that the personalised gene editing platform showcased in this case can be easily modified not only to individuals with different genetic variants of CPS1 deficiency but also to individuals with other IMDs. This adaptability has the potential to significantly expand the number of people who could benefit from personalised treatment. Furthermore, this flexible nature also significantly reduces the scale of new research that needs to be completed for each individual and increases the cost-effectiveness of the treatments.
Dr Paul Gissen, Clinical Professor of Paediatric Metabolic Medicine at UCL Great Ormond Street Institute of Child Health, closely followed the developments; “The research conducted at CHOP is a leap forward in what is possible for people with inherited metabolic disorders. It showed that when we put the right minds, technology and funding together, rapid detection and treatment of IMDs are possible. If we can create similar circumstances in the UK, it is absolutely possible that this can also be done here”
The UK is hoping to be at the forefront of personalised medicine, investing in this type of research as part of the Rare Disease Action Plan. Furthermore, efforts are underway to put infrastructure in place so that these types of medicines can be delivered in UK hospitals in the future. It is hoped that personalised gene editing will become a transformative approach to curing many IMDs in the not-too-distant future.
Want to read more?
Click this link to read a paper published in the New England Journal of Medicine: New England Journal of Medicine: Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease
Want to learn more about gene therapies?
Complete our gene therapy e-module for an overview and understanding of gene therapy, including what it is and the different types you may hear about. Interested? Check it out, here: Gene Therapies
What is a urea cycle disorder?
The proteins we consume in our food are broken down into their building blocks and reassembled into new products that serve various essential functions in the body, for example, to grow and build muscle.
Once the new protein products have fulfilled their purpose, they need to be broken down and eliminated from the body. During this breakdown process, toxic waste products like ammonia are generated. In the liver, the urea cycle converts ammonia into a harmless substance called urea, which is then excreted through urine.
Enzymes are specialised proteins that carry out a specific function in cells. Enzymes help critical chemical reactions occur in our bodies. In the urea cycle, enzymes play a vital role in converting ammonia to urea.
In individuals with urea cycle disorders, one or more of these enzymes in this pathway do not function correctly, and this prevents the breakdown of ammonia to urea. As a result, ammonia can accumulate to toxic levels in the body and eventually reach the brain, which can lead to permanent damage or even death.
CPS1 is one such enzyme involved in this pathway. In CPS1 deficiency, the CPS1 enzyme in this pathway does not function properly, impairing the breakdown of ammonia, leading to its dangerous build-up.
What is gene editing?
Our body is made up of billions of cells, these are small entities that carry out many functions needed to keep us alive. Each cell contains a library of instructions which tell the cells what to do, the language that these instructions use is a special code that is made from a molecule called DNA, this is also known as the genetic code. These instructions provides the blueprint to build cells and the instructions to produce all of the proteins and enzymes in the cell. The proteins and enzymes carry out many of the essential functions of that cell.
Genes are like single books within the library that contain the instructions for one specific protein or enzyme, each of which can carry out one or a small number of essential functions in the cell. For more information on genes!
A small change to the instructions, called a mutation, within a single gene can result in incorrect directions for producing a protein or enzyme, leading to a version that does not function properly. Mutations are thought to be partly responsible for many different IMDs. Since the genetic code is identical in every cell, this means no cell can produce the functional version of that specific protein. This fundamental mechanism forms the foundation of many IMDs.
Gene editing makes a precise change the mutated part of a single gene within the cell. The mutation is removed and replaced with the correct instructions. This technology finds the exact location of the mutation in the genetic code and creates precise, highly targeted changes in the genetic code, ensuring only the mutated section is altered. This will allow for a functional protein enzyme to be produced.
The goal is to change the genetic code in as many cells as possible to ensure the functional protein is produced in all the cells where it is needed. For more information on gene editing!
This one-time change in the genetic code may lead to the cell producing functional variants of the protein or enzyme for the rest of the person’s life and potentially results in a long-lasting treatment.
What is personalised gene editing?
Traditionally, pharmaceutical companies have focused on developing gene editing therapies that target common changes to the genetic code. This approach allows more patients to be treated using the same therapy and makes the high costs of development and manufacturing more effective.
However, many mutations are unique to the individual, and even people who share an IMD may have different changes to their genetic code. This is because multiple different changes to the same gene can lead to the same outcome, the protein or enzyme not functioning properly. This is where personalised gene editing becomes crucial. Personalised gene editing is designed for a single person, where the specific, unique change in their genetic code is found and precisely targeted for change in a tailored therapeutic approach.
This is exactly what researchers and clinicians at the Children’s Hospital of Philadelphia and the University of Pennsylvania have been working on, building a platform for customised gene editing to help treat rare IMDs.
