Key points
- Carbamoyl-phosphate synthetase 1 deficiency affects urea cycle
- It affects approximately 1 in 1.3m individuals
- Around half of infants do not survive disease beyond early infancy
- CRISPR enables scientists to cut, correct faulty genes with precision
ISLAMABAD: Just six months after a new-born at the Children’s Hospital of Philadelphia was diagnosed with a rare and life-threatening metabolic disorder, doctors successfully developed a personalised treatment using a pioneering gene-editing approach that could dramatically alter the child’s future — and potentially benefit others with rare conditions.
The disorder, known as carbamoyl-phosphate synthetase 1 deficiency, affects the urea cycle, leading to dangerously high levels of ammonia in the bloodstream. This build-up can result in severe, permanent brain damage. The condition is extremely rare, affecting approximately 1 in 1.3 million individuals. Among infants diagnosed, around half do not survive beyond early infancy, according to The Wall Street Journal.
“This baby had the most severe form of the most serious metabolic condition affecting the urea cycle,” explained Dr Ahrens-Nicklas, the study’s lead author and a metabolic paediatrician at the hospital’s division of human genetics. “This meant we had to accelerate the personalised therapy pathway we were already developing.”
Liver transplants
Although liver transplants can improve survival, many infants suffer irreversible neurological damage due to elevated ammonia levels before they are large enough to undergo the procedure. Such complications can include developmental delays, intellectual disabilities, and significant brain swelling.
The new treatment, detailed in a study published in The New England Journal of Medicine and presented at the American Society of Gene and Cell Therapy conference, utilises CRISPR — a revolutionary gene-editing tool.
CRISPR acts like molecular scissors, enabling scientists to cut and correct faulty genes with precision. In this case, the team devised a treatment tailored specifically to the baby’s genetic mutation.
They achieved this by streamlining a base-editing method that altered a single component of the child’s genome to address the exact variant of the condition.
Corrected genetic material
The corrected genetic material was delivered directly to liver cells via lipid nanoparticles — tiny fat-based carriers designed to transport the therapy to its target in the body. This patient-specific strategy marks a significant milestone in the field of personalised medicine.
According to Dr Ahrens-Nicklas, the ultimate aim is to reuse core elements of the therapy, such as the lipid nanoparticle and mrna, and simply swap in new, individualised genetic instructions for each patient’s unique mutation.
Dr Kiran Musunuru, director of the Penn Cardiovascular Institute’s Genetic and Epigenetic Origins of Disease Programme, likened it to a GPS: “You can change where the GPS is pointing based on the specific gene sequence you’re targeting.”
Innovative gene-editing approach
This innovative gene-editing approach could pave the way for more rapid development of personalised treatments for rare diseases. One key benefit is that the therapy can be administered again later in life if needed, unlike many existing delivery methods.
Remarkably, the therapy was developed within six months of the infant’s birth. The child received two infusions at seven and eight months of age. Seven weeks later, doctors were able to increase the baby’s dietary protein and halve the medication dose, all without adverse side effects.
This breakthrough offers renewed hope to doctors and families of children with rare genetic disorders who previously had few or no treatment options, Dr Musunuru noted.
“The next step is to establish genomic centres of excellence, where bespoke treatments can be developed for patients in real time,” he added.
