KJ, an American baby who will turn one this summer, was diagnosed with an ultra-rare disease within days of being born. Tests revealed that he suffered from a severe metabolic disorder that causes a range of severe symptoms and premature death in approximately half of those affected.
His future seemed tied to constant treatments and, at best, a liver transplant to try to alleviate the ravages of the disease he had, known as carbamoyl phosphate synthetase 1 (CPS1) deficiency. However, a personalized therapy based on gene editing has changed his outlook. This is the first time this therapy has been customized for use on a single baby.
The disorder is due to a genetic alteration that causes patients to be unable to eliminate ammonia from their bodies, a substance that results from the metabolism of proteins and is usually excreted as urea in the urine. Those affected by CPS1 deficiency do not produce urea and therefore accumulate ammonia in their blood, leading to multiple complications and potentially severe brain damage. The disease affects one in 800,000 to 1,300,000 live births.
"Children born without CPS1 die within 72 hours in a deep coma if not treated," explains Vicente Rubio, a research professor affiliated with the CSIC at the Institute of Biomedicine in Valencia and one of the Spanish scientists with extensive experience in CPS1 and rare diseases related to the urea cycle.
To carry out the treatment, "ammonia must be rapidly removed from the blood through dialysis, which is challenging in newborns; halt the body's ammonia production by restricting proteins in the diet and providing glucose; and trap and eliminate amino acids containing ammonia through the administration of non-toxic chemical compounds (benzoate, phenylbutyrate) that react with these amino acids."
Liver transplantation is curative, the specialist continues, "but it is challenging in newborns, generally not being possible before 6 months of age."
"If the treatment we use is insufficient and there are persistently high levels of ammonia in the blood, the child may not die, but will develop permanent mental disability, often before being able to undergo a liver transplant," Rubio clarifies.
An international team led by Rebecca Ahrens-Nicklas and Kiran Musunuru, researchers at the Children's Hospital of Philadelphia (USA), has developed a therapy based on base editing, the second generation of CRISPR tools, specific to KJ's case. The treatment was developed in record time, during the baby's first six months of life, including all necessary research stages.
The treatment, administered in two doses when the baby was between seven and eight months old, has shown promising results, as detailed in a publication this week in the prestigious journal The New England Journal of Medicine. Seven weeks after the first therapy infusion, the first results were observed. To date, the baby is doing well and continues to grow; tolerates a diet with a higher protein content and receives half the dose of the medication to eliminate ammonia that he had been taking since diagnosis. The researchers have not detected any serious adverse effects.
The developed treatment, designed ad hoc for KJ's case, is based on the use of base editors, a strategy that allows for a much more precise modification than the original CRISPR 'scissors' of the mutated nucleotide, the genetic alteration causing the disease in this patient's case. In KJ's case, one of the 'copies', inherited from his father, which the baby had mutated, was edited.
The strategy was first tested in liver cells in culture and then in animal models of mice and non-human primates, after which the researchers obtained permission for its use in KJ.
To deliver the therapy to his liver cells, scientists used lipid nanoparticles similar to those used in the administration of messenger RNA-based vaccines.
The first of many who can benefit from a methodology that can be scaled to fit the individual needs of patients," stated Ahrens-Nicklas in a statement distributed by the Children's Hospital of Philadelphia (USA).
Some limitations, such as the fact that the follow-up has been very limited (the first therapy infusion was done in February of this year) and that a liver biopsy to check the corrective effect of gene editing has not been possible at this stage of development due to the serious risk it would pose to the baby.
This study "represents a milestone because it corrects the mutation of one of the two CPS1 genes (the gene from the father). If the correction of that gene were complete, the child would no longer manifest the disease because having one of the two active genes is sufficient for normality," explains the specialist.
The finding brings a cure for the disorder "or at least allows for consideration of a partial cure that makes the wait until liver transplantation possible for the child without causing brain damage, something that would have been very difficult to completely avoid for a complete deficit like that of the child in the study," Rubio adds.
Lluís Montoliu, a researcher at the National Center for Biotechnology, recalls that Musunuru is a well-known scientist in the field of genetic research who has previously demonstrated the utility of base editors, for example in inactivating the PCSK9 gene involved in cases of familial hypercholesterolemia.
Exceptionality of the approach but also pointing out that there is much data still unknown about the therapy. For example, regarding the treatment's safety, "they still do not know if other genes may have been affected or, which is unlikely, if editing in the gonads could have occurred." Long-term studies are needed to "draw robust conclusions," the researcher states.
This new contribution from Musunuro continues, "it is a paradigmatic case of developing a 'ad hoc' therapy for a single patient," the researcher points out, highlighting the exceptionality of the approach but also noting that there is still much unknown about the therapy. For example, regarding the safety of the treatment, "they still do not know if other genes may have been affected or, which is unlikely, if editing has occurred in the gonads." Long-term studies are needed to "draw robust conclusions," the researcher points out.
On the other hand, Montoliu is also critical of the fact that the therapy has been developed for a single person, making the approach "hardly scalable." Additionally, the "lack of controls means that only the success of the treatment can be explained. If there is a failure, this explanation cannot be given because it may be caused by different factors that were not controlled in the experimental design."Finally, the researcher also raises an important issue that needs to be addressed, which is the accessibility and affordability of these treatments, as pointed out by Montoliu. "What will be the cost and who will be able to receive them," he questions.