Part the First: Gene Editing as a Cure for Genetic Disease. The recent politics of American science has been depressing in the extreme, and last week I promised to cover recent good things in basic and clinical science. I can’t think of anything better than a baby has been treated successfully for a rare, lethal mutation. This success can lead to an age of genetic medicine in which most inborn errors of metabolism, a fancy phrase for mutation, can be treated.
The first inborn errors of metabolism were described in the first decade of the twentieth century by Sir Archibald Garrod, long before the physical nature of the gene was understood. Now we know genes, for the most part, and also how to replace or edit mutant genes It is still early, but the potential represented by the gene editing described here surpasses traditional gene therapy and in the words of the authors of the paper described here “can potentially address more than 90% of pathogenic variants in genetic diseases that, although rare individually, collectively affect hundreds of millions of people worldwide.”
This case was published on 15 May 2025 in The New England Journal of Medicine: Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease [paywall, but accessible with registration; the news release from Children’s Hospital of Philadelphia (CHOP) is here]. This is the remarkable story of Baby KJ, who was born with the very rare deficiency of the enzyme carbamoyl-phosphate synthetase 1. That mouthful means that a person with the deficiency cannot get rid of ammonia, which is a byproduct of protein metabolism. Early-onset CPS-1 deficiency has a mortality rate of ~50% in infancy. Those who do not die early are at severe risk of irreversible brain and liver injury due to high levels of ammonia. The urea cycle is outlined here, for those who want a short biochemistry lesson.
The ultimate cure for Baby KJ will probably be a liver transplant, but brain damage usually occurs before a patient with Baby KJ’s condition grows large enough for the transplant. Baby KJ’s doctors as part of a team with 45 members developed his treatment plan in less than seven months, and during the middle of his eighth month he received the second dose of his treatment. The nature of this treatment could allow for repeated doses of the therapy, thereby obviating the need for an eventual liver transplant. After treatment Baby KJ began to eat an increased amount of dietary protein and his nitrogen-scavenging medication was reduced to half of the starting dose. So far, no adverse events have occurred. Baby KJ will be monitored during a long follow-up period, but as of now he is a healthy baby with happy parents and three happy siblings.
Baby KJ’s treatment is a form of “programmable gene-editing technology based on clustered regularly interspaced short palindromic repeats (CRISPR).” Where did CRISPR originate? Bacteria. These single-cell prokaryotes use several strategies to protect themselves from pathogens such bacterial viruses that kill bacterial cells just like they kill plant and animal cells. One of these is CRISPR, for which Emmanuelle Charpentier and Jennifer Doudna were awarded the Nobel Prize in Chemistry in 2020. Another is bacterial restriction enzymes, which are the “magic scissors” that cut foreign DNA in specific places and render the DNA nonfunctional in the host cell. Hamilton Smith, Daniel Nathans, and Werner Arber were awarded the Nobel Prize in Physiology or Medicine in 1978 for the discovery of restriction enzymes and demonstrating their utility for viral genome mapping and genetic engineering. Without restriction enzymes and the other enzymes essential for manipulation of DNA in the test tube, gene cloning is inconceivable. Genetic engineering would not have developed as it did, and possibly never.
The authors conclude with the following:
Therapies similar to (Baby KJ’s) could be developed for hundreds of hepatic (liver) inborn errors of metabolism…corrective gene editing lends itself to rapid customization for individual patients owing to the platform nature of the technology. Shared components among gene-editing therapies could include the same lipid nanoparticle formulation and mRNA, with the gRNA (guide RNA) customized to each patient’s variant.
We assessed (the therapy) for editing efficiency in mice and for safety in nonhuman primates. Such studies might not be necessary for future patient-specific treatments; perhaps cell-based studies would be sufficient. Although (the therapy) was developed under emergency conditions for a devastating neonatal-onset metabolic disorder, we anticipate that rapid deployment of patient-specific gene-editing therapies will become routine for many genetic diseases.
I anticipate this, too. The technical details of Baby KJ’s treatment are straightforward but complicated. The link from CHOP covers them in some detail. But what is much more important about the case of Baby KJ than the specific details of his treatment is how he was saved from an early death by a very long chain of basic research into the biochemistry of the urea cycle, bacterial metabolism and genetics, eukaryotic molecular genetics and recombinant DNA (cloning), and the molecular biology of DNA metabolism and gene expression. Without one link in this chain, Baby KJ would have died within a few months. As we have discussed many times here, the greatest discoveries are often serendipitous. No one knew in these beginnings that the mechanism by which bacteria fight off viral infections and adapt to environmental stress would lay the foundation for correcting mutations in humans. But here we are.
And where did support for this foundational research come from? The National Institutes of Health and the National Science Foundation and their counterparts in other countries and a smattering of smaller awards from other funding agencies. This string of discoveries began after World War II and has continued uninterrupted through 2024.
We can concentrate here on the specifics of the team that did this research and consider the support for the paper in NEJM describing Baby KJ’s rescue. The paper has 45 authors:
Kiran Musunuru, M.D., Ph.D. https://orcid.org/0000-0003-3298-0368, Sarah A. Grandinette, B.S., Xiao Wang, Ph.D., Taylor R. Hudson, M.S., Kevin Briseno, B.S., Anne Marie Berry, M.S., Julia L. Hacker, M.S., Alvin Hsu, B.S., Rachel A. Silverstein, B.S., Logan T. Hille, Ph.D., Aysel N. Ogul, Nancy A. Robinson-Garvin, Ph.D., Juliana C. Small, Ph.D., Sarah McCague, M.S., Samantha M. Burke, B.S.N., Christina M. Wright, M.D., Ph.D., Sarah Bick, M.D., Venkata Indurthi, Ph.D., Shweta Sharma, M.S., Michael Jepperson, M.S., Christopher A. Vakulskas, Ph.D. https://orcid.org/0000-0001-8510-4332, Michael Collingwood, B.S., Katie Keogh, Ph.D., Ashley Jacobi, B.S., Morgan Sturgeon, Ph.D., Christian Brommel, M.S., Ellen Schmaljohn, Ph.D., Gavin Kurgan, Ph.D., Thomas Osborne, B.S., He Zhang, Ph.D., Kyle Kinney, Ph.D. https://orcid.org/0000-0002-1029-3279, Garrett Rettig, Ph.D., Christopher J. Barbosa, Ph.D., Sean C. Semple, Ph.D., Ying K. Tam, Ph.D., Cathleen Lutz, Ph.D., Lindsey A. George, M.D., Benjamin P. Kleinstiver, Ph.D., David R. Liu, Ph.D., Kim Ng, M.D., Sadik H. Kassim, Ph.D., Petros Giannikopoulos, M.D., Mohamad-Gabriel Alameh, Ph.D., Fyodor D. Urnov, Ph.D. https://orcid.org/0000-0001-7542-4084, and Rebecca C. Ahrens-Nicklas, M.D., Ph.D.
This is obviously an international team with the following affiliations:
Children’s Hospital of Philadelphia, Philadelphia
Perelman School of Medicine at the University of Pennsylvania, Philadelphia
Innovative Genomics Institute, University of California, Berkeley, Berkeley
Broad Institute of MIT and Harvard, Harvard University, Howard Hughes Medical Institute, Cambridge, MA
Massachusetts General Hospital–Harvard Medical School, Boston
Aldevron, Fargo, ND
Integrated DNA Technologies, Coralville, IA
Acuitas Therapeutics, Vancouver, BC, Canada
Jackson Laboratory, Bar Harbor, ME
Danaher Corporation, Washington, DC
University of California, San Francisco, San Francisco
Since NEJM identifies authors by terminal degree, we can see that thirteen (13) of these authors have a BS or MS degree. Those in academic institutions are probably undergraduate or graduate students or research technicians. Those working in Biotech are development scientists. One has a BSN and was possibly the nurse-manager for Baby KJ’s treatment. The students and technicians would have been supported by their academic institutions and NIH. The other authors had a PhD, MD, or MD-PhD. Virtually all would have been supported by NIH during their education, just as support for this work comes from NIH. One wonders today how many have had their promising careers severely interrupted or ended for no good reason over the past few months during which this paper was in the works at NEJM.
The research was supported by grants from the National Institutes of Health (U01TR005355 and U19NS132301, to Drs. Musunuru and Ahrens-Nicklas; R35HL145203, to Dr. Musunuru; U19NS132303, to Dr. Urnov; and DP2CA281401 and P01HL142494, to Dr. Kleinstiver). In-kind contributions were made by Acuitas Therapeutics, Integrated DNA Technologies, Aldevron, and Danaher. Additional funding was provided by the Children’s Hospital of Philadelphia Research Institute’s Gene Therapy for Inherited Metabolic Disorders Frontier Program. What is the “return on investment” for this work? It can’t be calculated. But listening to Trump apparatchiks talk about supporting “gold standard” science after their devastation of it is hard to take. The “Gold Standard” refers to a fetish and nothing more, and when applied to scientific research it has no meaning.
The successful treatment of Baby KJ’s inborn error of metabolism represents a major productive investment in human health and wellbeing, one that is generalizable to many inborn errors of metabolism, i.e., genetic errors simply in need of relatively simple editing, provided the edits can be delivered to the proper place. It is frankly ridiculous that the current powers-that-be fail to recognize this. Or that this research could be extended to many other similar disorders for the “retail cost” of a few F-35s.
But here we are, again. One other point: When the teams that are doing this research at CHOP and other similar institutions are disbanded by fiat, they will not be brought back together just because someone had second thoughts at some time in the future. Social entropy (disorder induced by scattering) is stronger than physical entropy, because the only thing required to reduce physical entropy is more energy.
Finally, for those who can manage access, a companion piece covers “the science behind the study” in Personalized Gene Editing to Treat an Inborn Error of Metabolism. Peter Marks, who resigned as Director of the Center for Biologics Evaluation and Research at the FDA (letter of resignation, well worth the read) in March 2025, also has an accompanying editorial on Progress in the Development of N-of-1 Therapy. He notes “there could be hundreds to thousands of diseases that could be treated through an approach similar” to the one described here.
Sir Archibald Garrod would be as impressed, as we should be.
PS: Baby KJ was always intended to be the major part of this Coffee Break, but life intervened over the past several days. Rather than slap a few links in here without vetting them, I hope the community will accept my apology. More good news next week, leavened with reality. And over the next few days let us remember, without the politics that clouds its history, that Memorial Day was intended to be something more important than the three-day weekend when summer begins. Next week, on May 30th we can take time to remember, and renew our efforts stop adding to the already much too large toll honored on this day.
