Diagnosing disease, providing genetic counseling, and delivering care have long been central to the work of geneticists. That is beginning to change. “Today we can perform a true surgery on DNA, modifying the alteration at the core of the problem,” said Ernesto Goulart, PhD, professor in the Department of Genetics and Evolutionary Biology at the Institute of Biosciences of the University of São Paulo (IB-USP) in São Paulo, Brazil.

The most recent evidence came last year, when researchers at the Children’s Hospital of Philadelphia, Philadelphia, developed, in 6 months, a genome-editing therapy tailored to the mutation of a single patient, an infant with carbamoyl phosphate synthetase 1 (CPS1) deficiency, an ultrarare urea cycle disorder with an estimated early-childhood mortality rate of 50%. The case, described in The New England Journal of Medicine in May 2025, is the first report of a personalized genome-editing intervention for a single patient with complete preclinical validation.

The advances that led to this case began with understanding how the classic clustered regularly interspaced short palindromic repeats technology (CRISPR) works and why it is insufficient. “The first version of CRISPR works like scissors that cut both strands of DNA at the desired point,” Goulart explained. “When the double strand is cut, the cell activates natural repair mechanisms to join these ends. In this process, small insertions or deletions can occur randomly. Although this serves to inactivate a disease-causing gene, the randomness raises concerns about precision and the introduction of off-target alterations.”

To overcome this limitation, next-generation tools have emerged, such as base editing and prime editing. Instead of cutting both DNA strands, these new editors act in a more precise and controlled manner. “In base editors, a modified version of the Cas enzyme loses the ability to cut DNA but retains the property of guiding the complex to the exact point in the genome,” Goulart said. “A coupled enzyme directly converts one nitrogenous base to another, correcting point mutations without causing strand breakage. It’s a direct evolution of a molecular toolbox that keeps growing.” It was precisely this ability to correct a point mutation without cutting the DNA that made intervention possible in the infant with CPS1 deficiency.

The Challenge of Reaching the Target

Developing the right genomic editor is only part of the challenge. Getting it to the right organ in the patient’s body is another. Guilherme Baldo, PhD, associate professor of physiology at the Federal University of Rio Grande do Sul, a member of the Brazilian National Technical Commission on Biosafety (CTNBio), and a specialist with the National Network of Experts in Advanced Therapies at Anvisa, Brazil’s health regulatory agency, said this challenge is even more pronounced in metabolic and neurodegenerative diseases.

“One of the main difficulties for these therapies to reach clinical practice is the efficient delivery of these molecules in vivo,” he said. “Many lysosomal storage diseases, such as mucopolysaccharidoses, involve organs that are difficult to access, such as the brain and the osteoarticular system. Delivering therapeutic amounts of genomic editors to these tissues in a targeted manner is an obstacle that must still be overcome.”

To address these barriers, researchers have been testing in situ administration — direct delivery into specific brain regions — in addition to developing advanced carriers such as lipid nanoparticles and next-generation viral vectors coated with high-affinity peptides. Lipid nanoparticles, for example, were the vehicle used in the CPS1 case to deliver the genomic editor to liver cells.

Brazil on the Genome Editing Map

Brazil has made concrete regulatory advances in gene therapy. In March 2024, Anvisa approved valoctocogene roxaparvovec (Roctavian), the first gene therapy product registered for human use in the country, indicated for severe hemophilia A. However, Baldo sees contradictions in this progress.

“We live in two opposing realities in the country,” he said. “In the agricultural sector, CTNBio is a global reference for agility in evaluating genome-editing products. The real bottleneck is in human health. Although Anvisa has evolved with robust regulations for advanced therapies, clinical trial approval remains slow when compared with that of the US Food and Drug Administration or the European Medicines Agency, a problem compounded by the logistical bottleneck in importing cutting-edge inputs.”

Goulart outlined four stages of the national supply chain and the challenges associated with each:

1. Scientific research and laboratory work: Brazil has high capacity, with centers of excellence in universities and hospitals.
2. Preclinical validation: Infrastructure is moderately developed but has critical limitations, especially for tests in nonhuman primates. One partial local solution is the use of organoids — structures created from the patient’s own stem cells that allow testing of the edit before a clinical trial.
3. Manufacturing according to Good Manufacturing Practice (GMP) standards: This remains a critical bottleneck because of the scarcity of biofactories capable of producing genetic medicines on an industrial scale.
4. Technology transfer and clinical trials: This stage remains fragile because of bureaucratic obstacles, high costs, and dependence on private funding.

At the IB-USP laboratory, Goulart’s team uses induced pluripotent stem cells, reprogrammed from the patient’s own skin or blood, to create these organoids and test the effectiveness of editing directly on the individual’s mutation before clinical trials.

“Our researchers have mastered the science, but the transition from laboratory testing to clinical trials requires biofactories with GMP standards that academia cannot afford on its own,” Baldo said. “Without a state policy for local vector production and incentives for biotech companies, we will continue importing multimillion-dollar therapies instead of building biotechnological sovereignty and lowering costs for the Unified Health System [SUS, Brazil’s public health system].”

Even the most precise technology cannot necessarily reverse damage accumulated before a diagnosis of a genetic disorder. In Brazil, Law No. 14.154/2021 provides for the phased expansion of neonatal screening in the SUS to include up to 50 rare and genetic diseases, but implementation remains uneven across the states.

“The therapeutic window is the dividing line between preventing damage and merely managing the consequences,” Baldo said. “In degenerative diseases, tissues lose functional capacity rapidly; applying gene editing after the onset of established symptoms is usually too late. Expanding newborn screening and improving access to genetic sequencing changes the game by identifying the mutation in the presymptomatic phase. Early diagnosis is not just screening — it is the ethical and scientific prerequisite for these technologies to succeed.”

With these developments, patients and their families are arriving at doctors’ offices with questions about “CRISPR cures.” For such cases, Goulart summarized what clinicians need to know:

• Early referral: When a rare or hereditary disease is suspected, expedite molecular investigation. Access to approved clinical trials or therapies requires rigorous genetic confirmation.
• Mapping open clinical trials: Guide families to official clinical trial registries, such as ClinicalTrials.gov and the Brazilian Registry of Clinical Trials, to identify protocols recruiting patients in Brazil or abroad.
• Managing expectations: Explain that personalized interventions still occur within rigorous experimental protocols and that the commercialization of therapies requires safety validation and prior regulatory approval.

“We are experiencing a moment of great euphoria for developers, doctors, and especially for families,” Goulart concluded. “DNA surgery is no longer fiction. Doctors in clinical practice need to become familiar with this molecular science because prescribing genetic treatments and monitoring patients who have undergone them is already a reality in modern medicine.”

This story was translated from Medscape’s Portuguese edition.