Base editors are a type of gene editing tool designed to make precise changes to DNA at the single-nucleotide level. They are used to correct genetic variants that cause disease.1
This article highlights the role of base editing in developing personalized treatments, with a focus on carbamoyl-phosphate synthetase 1 (CPS1) deficiency—a severe metabolic disorder with few treatment options and high mortality in infants.
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What Are Base Editors?
Base editors are a modified form of the CRISPR–Cas system. Unlike traditional CRISPR–Cas9, which cuts both strands of DNA, base editors change a single DNA letter without creating double-strand breaks.2
They work by combining a CRISPR–Cas9 nickase with a deaminase enzyme. The guide RNA directs the complex to a specific DNA sequence, where the deaminase chemically alters a single nucleotide. This method lowers the risk of unintended DNA damage and off-target effects.
The first cytosine base editors (CBEs), developed in 2016, convert cytosine (C) to thymine (T). In 2017, adenine base editors (ABEs) were introduced to convert adenine (A) to guanine (G).3
Following these two groundbreaking developments, scientists have continued to design new base editors with enhanced capacity for more complex gene editing, improved accuracy, a broader targeting scope, as well as increased safety and the potential for in vivo delivery.
These advances have enhanced their applicability in the biomedical field.
Key Components and Therapeutic Potential of Base Editors
Base editors are developed by combining two functional proteins: Cas9 nickase (nCas9) and a nucleoside deaminase. Each has a distinct role in enabling targeted DNA modification.
nCas9 is a modified version of Cas9. It contains mutations in one of the two primary amino acid residues responsible for the DNA cleavage activity of Cas9. Therefore, nCas9 binds to a guide RNA (gRNA), locates the target DNA sequence that matches the gRNA spacer, and cleaves only one strand of the DNA.2
Nucleoside deaminase is an enzyme that removes an amino group from a specific nucleoside type. In CRISPR base editors, the deaminase is combined with a particular nickase, such as an adenosine deaminase (e.g., engineered TadA) or a cytosine deaminase (e.g., APOBEC), which dictates the type of base alteration. Typically, ABEs contain adenine deaminases, while CBEs contain cytosine deaminases.
Base editors are currently under investigation in several preclinical and clinical studies. For instance, Verve Therapeutics initiated a clinical trial to assess the safety and efficacy of base editors delivered intravenously via lipid nanoparticle to silence the PCSK9 gene in the liver of patients with familial hypercholesterolemia.4 This strategy is also being explored for alleviating spinal muscular atrophy and HIV infection.5
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What Is CPS1 Deficiency?
CPS1 deficiency is a rare and life-threatening genetic condition. It impairs the body's ability to break down by-products of protein metabolism in the liver.6
This leads to a buildup of ammonia in the body (hyperammonemia), reaching toxic levels that can damage the liver and brain. Elevated ammonia can cause brain swelling, coma, or permanent neurological injury.
CPS1 deficiency is an inherited autosomal recessive disorder characterized by symptoms such as excessive sleepiness, poor feeding, abnormal movements, irregular breathing or temperature regulation, and seizures. These symptoms can recur if the patient’s diet is not carefully managed.
Standard treatment includes a low-protein diet to reduce ammonia production. This is typically followed by a liver transplant when the child is older. During this waiting period, the patient remains at a high risk of rapid organ failure due to multiple factors, including trauma and infection.
The First Personalized Gene Therapy for CPS1 Deficiency
Researchers at the Children’s Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania (Penn) developed a personalized gene therapy for CPS1 deficiency using CRISPR base-editing technology.7 This approach enables precise correction of a disease-causing mutation in liver cells without introducing double-strand DNA breaks.
After confirming the diagnosis, the patient received an initial low dose of the base editor at six months of age. The dose was increased in subsequent treatments. Clinical improvement was observed shortly after the first administration.
After three treatments, the patient demonstrated a significant improvement in his capacity to consume more dietary protein. Physicians were also able to reduce the dosage of medications that lower ammonia levels.
Another crucial outcome of the treatment was the patient's improved ability to cope with gastrointestinal illnesses and colds. Typically, infants with CPS1 deficiency exhibit poor prognosis upon contracting even minor infections or ailments.
A Breakthrough in Medicine: Personalized Gene Editing to Save KJ
So, What Does This Mean for the Future of Genetic Medicine?
The application of in vivo base editing in CPS1 deficiency represents an early example of personalized gene therapy for a rare metabolic disorder. It shows that, in some cases, a genetic diagnosis can lead to a targeted therapeutic strategy developed and delivered within months.
This approach may reduce the need for high-risk treatments such as liver transplantation in certain patients. It also demonstrates the potential of base editing as a platform for addressing other single-gene disorders.
However, several limitations remain. The cost of personalized therapy is high, and current manufacturing processes are not yet optimized for large-scale use. Regulatory frameworks for individualized genetic treatments are still evolving, and long-term safety data are limited.
Despite these challenges, the use of base editing in CPS1 deficiency suggests a broader shift toward precision approaches in genetic medicine. As tools and delivery methods improve, base editing may become a practical option for treating a wider range of rare and previously untreatable conditions.
To learn more about the safety, precision, and evolution of gene editing technologies, explore:
References and Further Reading
- Tang, J, et al. (2019). Single-nucleotide editing: From principle, optimization to application. Hum Mutat. doi: 10.1002/humu.23819.
- Rees, HA., Liu, DR. (2018). Base editing: precision chemistry on the genome and transcriptome of living cells. Nat Rev Genet. doi: 10.1038/s41576-018-0068-0.
- Porto, EM, et al. (2020). Base editing: advances and therapeutic opportunities. Nat Rev Drug Discov. doi: 10.1038/s41573-020-0084-6.
- Lee, RG, et al. (2022). Efficacy and Safety of an Investigational Single-Course CRISPR Base-Editing Therapy Targeting PCSK9 in Nonhuman Primate and Mouse Models. Circulation. doi: 10.1161/CIRCULATIONAHA.122.062132.
- Xu, W, et al. (2024). From bench to bedside: cutting-edge applications of base editing and prime editing in precision medicine. J Transl Med. doi.org/10.1186/s12967-024-05957-3
- Noori, M., et al. (2024). Carbamoly-phosphate synthetase 1 (CPS1) deficiency: A tertiary center retrospective cohort study and literature review. Mol Genet Metab Rep. doi: 10.1016/j.ymgmr.2024.101156.
- Musunuru, K, et al. Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease. N Engl J Med. 2025. doi: 10.1056/NEJMoa2504747.