HAMBURG—David Liu used his return to the European Society of Gene & Cell Therapy (ESGCT) to review how advances in genome-editing science are converging with developments in regulation, manufacturing and economics. Liu, who previously spoke at the congress in Barcelona in 2019, said this combination could help expand therapeutic genome editing beyond the relatively small group of diseases currently being pursued in clinical development.
More than 200,000 mutations are associated with approximately 8,000 genetic diseases, affecting an estimated 400 million families. Liu said the field’s central challenge is to move beyond highly individualized treatments for rare mutations and develop approaches that can benefit broader patient populations.
Liu’s work in precision editing began with the publication of research on base editing a decade ago, followed three years later by the description of prime editing. Both technologies are built on CRISPR-Cas and can enable a wide range of genetic changes, including single-base substitutions. The technologies are also being advanced commercially by Beam Therapeutics and Prime Medicine, companies co-founded by Liu.
During his presentation, Liu described two examples of artificial intelligence being applied to prime editing. In one study, his laboratory used ProteinMPNN to redesign part of prime editors that had previously been improved through phage-assisted continuous evolution. Although those earlier PE6 editors showed greater activity, they had weaker stability and expression. The resulting PE8 variants were reported to have improved expression and editing efficiency across several cell types.
Liu also discussed OptiPrime, a free machine-learning tool designed to predict prime-editing outcomes. The system ranks potential pegRNA designs, helping researchers narrow a large number of candidates that could theoretically produce the same edit. Researchers can generate candidate sequences through the OptiPri.me website and use the results when ordering gene-synthesis components.
The researcher also reviewed the clinical and preclinical progress made in the decade since the first base-editing report. He cited nine examples in which precision genome editing had rescued disease characteristics in animal models, including models of progeria, sickle cell disease, cystic fibrosis, phenylketonuria and spinal muscular atrophy.
Several programs have advanced toward clinical testing. Beam Therapeutics reported the first clinical correction of a human pathogenic mutation in March 2025 in a patient with alpha-1 antitrypsin deficiency treated with BEAM-302. Liu also pointed to the bespoke base-editing treatment developed for Baby KJ and to developments in prime editing, including the first reported dosing of a patient in an ex vivo prime-editing program and the first patient dosing in an in vivo prime-editing trial for Wilson disease.
Liu said regulators in the United States, the United Kingdom and elsewhere were generally not blocking progress in the field. He also highlighted draft guidance issued by the U.S. Food and Drug Administration on individualized human genome-editing products, including considerations for biologics license applications and post-approval management.
The final part of Liu’s talk focused on a disease-agnostic strategy based on suppressor transfer RNAs. Approximately 30% of genetic diseases involve at least one premature stop codon, which can prevent cells from producing a complete protein. Suppressor tRNAs can potentially read through these codons and restore production of the full-length protein.
Liu’s team is developing prime editing-mediated readthrough of premature termination codons, or PERT. The approach converts an otherwise dispensable human tRNA into a suppressor tRNA that recognizes one of the three stop codons. The laboratory evaluated all 418 human tRNA genes and focused on a leucine tRNA that showed the strongest suppression activity before optimizing it further.
In a mouse model of Hurler syndrome, PERT produced approximately 7% of normal enzyme activity, a level Liu said could be sufficient to rescue the disease. He emphasized that the work remains at an early stage and that the strategy aims to avoid excessive expression of the suppressor tRNA.
Liu said broader use of gene editing will depend on continued regulatory streamlining and reductions in clinical and manufacturing risk and cost. Without those changes, he noted, many genetic diseases will remain too rare for industry to pursue. He also mentioned the Center for Therapeutic Genetics, a nonprofit collaboration involving the Broad Institute, Boston Children’s Hospital and The Jackson Laboratory, which aims to connect patients with rare diseases. The initiative has received initial commercial support from Apertura, Viralgen, Beam Therapeutics and Prime Medicine.