Rare genetic disease-stricken newborn undergoes distinct, tailored therapeutic intervention
Story of a Young Warrior Battling a Rare Genetic Disease
Meet a brave young lad who defied the odds when he received a game-changing genome editing treatment at the tender age of 7-8 months old.This incredible feat was made possible by correcting a single letter mutation in his DNA, bringing hope to millions worldwide battling similar rare genetic disorders.
The incredible news of this innovation appeared in an article published on May 15, 2025, in The New England Journal of Medicine (NEJM). This publication marked a significant leap forward in the world of personalized therapies, especially for rare and ultra-rare congenital metabolic anomalies.
Our young hero is afflicted by the neonatal form of a disease called Carbamoyl-phosphate synthetase 1 (CPS1) deficiency, a rare condition that belongs to the family of inborn errors of metabolism. This disease leads to an enzymatic dysfunction that disrupts cellular metabolism.
This disease strikes about 1 in every 800,000 to 1.3 million births and can be lethal in approximately half of the affected infants during the first months of life. The team of Kiran Musunuru and Rebecca Ahrens-Nicklas at the Children's Hospital of Philadelphia used a cutting-edge technique called base editing to correct the mutation in this little warrior.
Base editing is a more targeted and precise technique than the classical CRISPR-Cas9 editing. Unlike CRISPR-Cas9, which acts like molecular scissors by cutting the DNA before it repairs the break, base editing modifies a single letter in the DNA of a living cell without ever cutting the DNA double helix.
The team guided the base editing tool to the exact location of the mutation using a guide RNA. They tested around thirty guide RNAs to find the one that recognized the specific DNA motifs and perfectly positioned the tool.
After identifying the best base editor adenine-RNA guide combination, the researchers conducted preclinical studies on human cells, transgenic mice, and monkeys before treating the baby. The results showed that the experimental treatment allowed for an effective correction of the targeted mutation, without significant clinical toxicity, and without causing off-target editing in the treated human hepatocytes.
To treat the baby, the therapy was administered intravenously, and protein intake could be gradually increased once the treatment was deemed successful. Two weeks later, the dose of glycerol phenylbutyrate could be halved, and the child gained weight and showed a stable neurological status.
However, the limitation of this study is its short follow-up period, which does not allow for a full evaluation of the long-term safety and efficacy. More prolonged studies are required to answer questions like the duration of the therapeutic effect, the percentage of modified liver cells, and any potential off-target effects or immune reactions.
Experts believe that the rapid deployment of personalized gene editing therapies will soon become a common practice for many genetic diseases. This breakthrough raises hope for millions of patients suffering from rare genetic diseases and could revolutionize the way we treat genetic disorders. However, the transition from proof of concept to a standard treatment will require rigorous ethical and regulatory oversight to ensure safety and efficacy.
Sources:
- Musunuru K, Grandinette SA, Wang X, et al. Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease. N Engl J Med. 2025 May 15. doi: 10.1056/NEJMoa2504747
- Gropman AL, Komor AC. Personalized Gene Editing to Treat an Inborn Error of Metabolism. N Engl J Med. 2025 May 15. doi: 10.1056/NEJMe2505721
- Marks P. Progress in the Development of N-of-1 Therapy. N Engl J Med. 2025 May 15. doi: 10.1056/NEJMe2505704
- Tsuchida CA, Wasko KM, Hamilton JR, Doudna JA. Targeted nonviral delivery of genome editors in vivo. Proc Natl Acad Sci U S A. 2024 Mar 12;121(11):e2307796121. doi: 10.1073/pnas.2307796121
- Musunuru K, Chadwick AC, Mizoguchi T, et al. In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates. Nature. 2021 May;593(7859):429-434. doi: 10.1038/s41586-021-03534-y
- Marc Gozlan
- Subscribe
- Contribute
- Reuse this content
Researchers like Kiran Musunuru and Rebecca Ahrens-Nicklas, who treated a young warrior with a rare genetic disease using base editing, have opened new avenues in science, particularly in health-and-wellness and medical-conditions. Their work, published in The New England Journal of Medicine (NEJM), indicates that personalized therapies, especially for rare and ultra-rare congenital metabolic anomalies, could significantly advance in the near future, bringing hope to millions suffering from similar medical conditions.
