 Juan Carlos Lopez |
 Andy Marshall |
Last week’s ASGCT 2025 provided a stark contrast between excitement around DNA- and RNA-editing platforms and commercial interest in traditional gene replacement and cell therapy. Over the past few months, Pfizer decided to stop the commercialization of its hemophilia B gene therapy Beqvez, lentiviral gene therapy flagship Bluebird Bio agreed to acquisition by private-equity firms Carlyle and SK Capital Partners, and earlier this month, Vertex announced its was discontinuing its gene-therapy programs.The remarkable clinical progress achieved with base editing modalities over the past year was highlighted in an ASGCT keynote by Kiran Musunuru of the University of Pennsylvania on the ultra-rare condition carbamoyl-phosphate synthetase 1 (CPS1) deficiency. The fact that the UPenn group were able to design, preclinically validate and bring the treatment to a child in just 7 months is staggering:
Writing in the New England Journal of Medicine, the team led by Musunuru and Rebecca Ahrens-Nicklas describe the development of a personalized base-editing therapy with guide RNAs designed to remove the UGA stop codon in a neonate diagnosed with a Q335X variant of CPS1. Using an adenine base-editor, the team designed a bespoke, corrective therapy delivered in vivo using lipid nanoparticles (LNPs) comprising an ionizable amino lipid (ALC-0307), cholesterol, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), and a PEG lipid (ALC-0159).
After preclinical validation in cell lines, mice and non-human primates, the authors administered two intravenous doses of the base editor, dubbed ‘k-abe’ — 0.1 mg/kg at seven months of age and 0.3 mg/kg one month later. Following treatment, the patient tolerated increased dietary protein and showed a reduced need for ammonia-scavenging medication, with no serious adverse events. Long-term clinical outcomes and safety remain under evaluation.
One of the most striking features of the study is the speed of therapy development—from diagnosis to treatment in a mere seven months, during which the team had to create cell and mouse models of the disease, screen various base editors with guide RNAs covering the site of the mutation to identify the most efficient approach, carry out toxicological assays in non-human primates, and obtain FDA regulatory approval to treat the child. The workflow reported represents a blueprint for rapid development of customized gene-editing therapies for patients with ultra-rare variants and provides one of the first glimpses of a coming era in advanced therapeutics.
The FDA has taken a very progressive attitude regarding N-of-1 therapies that involve platform technologies such as base editing. An accompanying Editorial in the NEJM, authored by Peter Marks, former Director of the FDA’s Center for Biologics Evaluation and Research, elaborates on the need for a regulatory approach that takes advantage of the data from the elements that remain consistent from one therapeutic product to the next, while allowing the customization required for individual patients — in the case of base editors, a short sequence of guide RNA.
Of course, despite the openness of regulatory authorities, several hurdles remain before bespoke DNA and RNA editing therapies becomes a reality. Among them, manufacturing, scalability and distribution are particularly problematic, and represent the biggest challenges for big pharma to address before widespread adoption of such approaches. Also, existing lipid nanoparticles preferentially travel to the liver. Targeting other organs remains a huge challenge for the field so ultrarare liver disease will remain the option in reach for base editing in the near term. But despite these concerns, we think that the report by Musunuru and his colleagues is a milestone in the development of genetic medicines and underscores the potential of gene-editing approaches to deliver bespoke cures for ultra-rare diseases.
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