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A study published in The New England Journal of Medicine looks at a new CRISPR gene therapy for children with a rare genetic disease.
Dr Alena Pance, Senior Lecturer in Genetics, University of Hertfordshire, said:
“The authors searched thoroughly for off-target effects because this would seriously jeopardise the use of the approach in therapy. However, as far as the document I could see goes, there is no attempt to assess the cell type targeting efficacy, meaning whether the genetic tools (CRISPR and guide RNA) are reaching hepatocytes and what percentage or proportion of these cells are being corrected. This is very important because this will determine the level of physiological improvement of the disease hence also the value of the intervention.
“CRISPR-based therapy has been used to correct genetic diseases before as the authors mention in their introduction. The best example is the recently approved therapy for sickle cell disease. The approach used in that case, as well as the one in development for Duchenne muscular dystrophy, is different though in the sense that sickle cell anaemia is overcome by using CRISPR tools to de-silence a foetal globin gene that leads to functional haemoglobin. This is done outside the body using Haematopoietic stem cells which give rise to all cell types in the blood, these cells are obtained from the patient, modified and then put back to re-populate the bone marrow, so in this way full correction can be achieved. The DMD approach consists in using CRISPR to cause skipping of the portion of the dystrophin gene that has the most frequent mutations in it. These mutations lead to deficiency in dystrophin expression by generating a stop signal so the protein isn’t made, so by making the machinery ‘hope over’ this region, a smaller but functional dystrophin is made thereby restoring muscle mass and function. In this case, the therapy is administered intravenously and though not all the muscle cells are corrected, and the proportion varies, it is sufficient for a significant restoration to make a physiological difference. Many different cell types will be targeted but as only muscle cells produce dystrophin, it doesn’t really matter.
“In the case of CPS1, the therapy consists in substituting a nucleotide for the correct one, so this is a highly precise corrective change. As opposed to the two examples described which can be applied to a variety of mutations causing the same disease, the approach in the paper is applicable to the one specific nucleotide change or in other words this specific form of the disease. The paper explains that the patient has in fact two different mutations affecting each of the genes from their father and their mother, only one, the paternal mutation, is targeted. The approach is applicable to any disease caused by a single nucleotide change, however more often than not, diseases are caused by a variety of variants so perhaps more general strategies could be more effective than very precise ones. It will depend on how accurate the general vs specific options can be in terms of targeting the right cell types and DNA sequences.”
Comments provided by our friends at the Spanish SMC:
Dr Miguel Ángel Moreno-Mateos, Tenured scientist CSIC & PI, Andalusian Center for Developmental Biology, CSIC-Pablo de Olavide University, said:
“Since the emergence of CRISPR-Cas technology, progress has been made to develop a variety of tools that have the potential to contribute to the cure of many genetic diseases. This work demonstrates how, by detecting a specific congenital disease in the first days after birth, a robust protocol can be implemented with the ultimate goal of curing, at least partially, a patient with a particular genetic alteration that causes a rare disease. This protocol contains several steps, including i) characterization of the mutation or mutations that cause the disease, ii) design and comparison of the efficiency of various CRISPR-Cas approaches, which in this case are based on base editing and include various Cas proteins with different DNA recognition capabilities, iii) genetic and physiological safety testing of CRISPR-Cas reagents and lipid nanoparticle-based complexes both in vivo and in vitro, and iv) finally, targeted treatment in the patient’s liver in two doses seven months after birth, following approval by the relevant agencies.
“Although this has been a very specific approach, partly motivated by the devastating nature of the disease, it represents a milestone that demonstrates that these therapies are now a reality. In any case, as the article reports, the patient will be monitored for a long time to ensure his well-being and determine whether additional doses are needed to further improve the symptoms of the disease.
“On the other hand, given the risk involved and as the article itself acknowledges, the percentage of gene editing in the patient himself and any possible unwanted edits have not been evaluated, although they were determined in in vivo and in vitro studies. However, based on the physiological results, everything indicates that, at least so far, the therapy has been successful and has significantly improved the patient’s quality of life.
“In summary, this work is proof of principle for a rapid and effective protocol for CRISPR-Cas therapies for the cure of human diseases in general and so-called rare diseases in particular, opening the door to other similar treatments in the near future.”
Prof Marc Güell, coordinator of the Translational Synthetic Biology research group and full professor at Pompeu Fabra University (UPF), said:
Is the study of good quality?
“It seems to me to be a study of the highest quality and totally extraordinary. In fact, I was deeply moved to read it. It reflects the great potential of gene editing for therapeutic purposes. The researchers and clinical team have done a very thoughtful design with all the precautionary steps that the situation allows: characterisation of mutations, design of editors to correct, measurement of efficiency and off-target [unwanted effects], as well as testing the reagents in cell and animal models. Extraordinary work in record time.”
How does this work fit with the existing evidence?
“Great proof of concept that it is not impossible to treat very rare diseases at the individual level.”
Are there any major limitations to be taken into account?
“We will have to characterise the precision gene editing process in the future (patient safety permitting). For now, it has been possible to measure the positive clinical effects, but for patient safety reasons it has not been possible to obtain liver tissue to characterise the efficiency of gene editing.
“It’s a great demonstration, but it’s also worth noting that this correction has been done in the liver; other tissues are much more difficult to gene edit, for now.”
What are the implications for the real world?
“Individualised, tailor-made therapies for a single patient are no longer a dream. Obviously, the process followed is of very high complexity and will require a lot of work to see how to scale it up and expand it to other cases. In any case, this work sheds a lot of light on the future.”
Prof Gemma Marfany, Professor of Genetics at the University of Barcelona (UB) and CIBERER member, said:
“This is the first case of a fully customised therapy, for a single baby (what is called ‘n of 1 therapy’), treated in vivo with a base-editing therapy for a very severe ultrarare disease. The disease causes the accumulation of ammonium, which is highly toxic to neurons and can lead to death in the first months of life. With the help of several leading biotech companies, a novel and very precise strategy has been designed to uniquely modify the mutated nucleotide in the gene to reverse the effect, and instead of a truncated protein, produce the complete protein. In addition, instead of using therapeutic viruses, lipid particles have been used to deliver the gene-editing system to the liver, in three doses within weeks of each other, avoiding an unwanted immune response and achieving remission of the most dangerous symptoms, reducing palliative medication and allowing incorporation of a normal diet.
“It is truly a unique case, a successful proof of concept, designed and applied in record time, in which researchers and clinicians have not skipped a single preclinical step, as they have generated human cellular models and also a humanised mouse model with the patient’s mutation to test the safety of the dose and the efficiency of the therapeutic strategy. In addition, they have had all the approvals from the relevant bioethics committees. It seems to me to be a scientific ‘miracle’ that has made it possible to cure a very rare severe disease, and provides knowledge to treat many other diseases.”
‘Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease’ by K. Musunuru et al. was published in The New England Journal of Medicineat 18:00 UK time on Thursday 15 May 2025.
DOI: 10.1056/NEJMoa2504747
Declared interests
Dr Miguel Ángel Moreno-Mateos: “I have collaborated with one of the authors of the paper, Benjamin P. Kleinstiver, with whom I published a research paper three years ago.”
Prof Gemma Marfany: no conflicts of interest
Dr Alena Pance: No conflicts.
For all other experts, no reply to our request for DOIs was received.