Marc Buchet
4 Jul 2025
First-in-Human In Vivo Gene Editing Shows Promise for Treating Rare Genetic and Metabolic Diseases
The recent breakthroughs described in the joint works of Shamima Rahman and Julien Baruteau represent a major milestone in the clinical application of in vivo gene editing, targeting rare and life-threatening inherited metabolic diseases. These papers detail two pioneering case studies where CRISPR-based gene editing technologies were applied directly in living human patients, offering a personalized and potentially curative approach to diseases once considered incurable.
Background: A Paradigm Shift in Treatment Approach
Rare inherited metabolic disorders typically stem from single-gene mutations, resulting in the body’s inability to produce or process essential proteins or enzymes. Traditional therapies—such as enzyme replacement or dietary restrictions—often provide partial relief at best and do not address the underlying genetic cause.
The studies in focus break from convention by introducing in vivo gene editing, where a patient’s DNA is precisely edited inside their body, aiming for a one-time treatment that reprograms the liver to produce the missing or malfunctioning protein.
Case 1: Patient-Specific Gene Editing for OTC Deficiency
The first paper describes a compassionate use case of ornithine transcarbamylase (OTC) deficiency, a devastating X-linked urea cycle disorder causing dangerous ammonia buildup. A male infant with severe neonatal onset—previously considered untreatable without liver transplantation—received a novel CRISPR-Cas9-based in vivo gene editing therapy delivered via lipid nanoparticles (LNPs).
Key steps included:
Isolation and analysis of the patient’s specific mutation.
Design of a personalized guide RNA and donor template.
Intravenous administration of the CRISPR-Cas9 components targeting hepatocytes (liver cells).
Outcome:
Successful editing of the faulty OTC gene in a subset of liver cells.
A notable reduction in plasma ammonia levels.
No serious adverse events linked to the gene editing procedure during early monitoring.
The patient showed signs of metabolic stabilization without a liver transplant.
This case demonstrates the potential for tailored, one-time genetic correction, opening a door for diseases where systemic enzyme therapy is ineffective.
Case 2: First-in-Human Gene Editing for Phenylketonuria (PKU)
The second study discusses the first clinical trial applying gene editing to treat Phenylketonuria (PKU), a rare condition resulting from a deficiency in phenylalanine hydroxylase (PAH). PKU patients must follow strict dietary regimes to avoid neurological damage.
Researchers used a CRISPR-Cas9 system delivered using AAV (adeno-associated virus) vectors targeted to liver cells. The therapy aimed to:
Restore endogenous PAH activity in hepatocytes.
Reduce toxic phenylalanine levels in the bloodstream.
Highlights:
Enrollment of adult patients with confirmed PAH mutations.
AAV vectors specifically delivered editing machinery to the liver.
Longitudinal follow-up showed editing efficiency of up to 30% in targeted cells.
Phenylalanine levels dropped significantly, enabling dietary liberalization.
Liver function remained normal; no vector-related toxicity was observed.
This first-in-human application provides proof of concept that in vivo gene editing can work at clinically meaningful levels, transforming long-term disease management.
Implications for the Pharmaceutical Industry
These pioneering interventions mark a shift toward precision, patient-specific therapeutics, with several implications for the pharma sector:
Custom-Tailored Therapies: The ability to design and deliver individualized gene editing constructs could become a new model of drug development, especially for ultra-rare diseases.
Regulatory Innovation: The success of these cases may push regulators to redefine pathways for compassionate use and gene-editing approvals, particularly when conventional therapies are non-viable.
Manufacturing and Delivery: Lipid nanoparticles and AAVs represent different delivery paradigms, each with implications for scalability, cost, and targeting accuracy.
Ethical Considerations: While somatic editing avoids germline controversies, long-term surveillance for off-target effects will be essential for public trust and scientific validation.
Challenges Ahead
Despite the promise, hurdles remain:
Editing efficiency and durability across patient populations must be validated.
There is a need for robust post-treatment monitoring, especially regarding immune responses and potential genotoxicity.
Cost-effectiveness and accessibility will be key to ensuring global impact.
https://onlinelibrary.wiley.com/doi/10.1002/jimd.70056