April 11, 2026 —
A research team led by Professor Leszek Lisowski at the Children’s Medical Research Institute (Australia), in collaboration with the Military Institute of Medicine – National Research Institute (Poland), has developed four gene therapy candidates targeting PUS3 syndrome, an ultra-rare genetic disorder. One candidate is expected to advance toward clinical use.
PUS3 syndrome is caused by mutations in the PUS3 gene, which encodes pseudouridine synthase 3—an enzyme essential for proper protein synthesis. The condition has been identified in only a small number of patients globally, with approximately 12 known cases currently tracked by the PUS3 Foundation. Due to overlapping symptoms, additional cases may remain undiagnosed.
Clinically, the disorder is characterized by severe neurological and developmental impairments, including intellectual disability, delayed development, aphasia, microcephaly, and in some cases, drug-resistant epilepsy. First described in 2020, the disease is progressive and neurodegenerative.
The therapeutic approach utilizes an adeno-associated virus serotype 9 (AAV9) vector to deliver a functional copy of the PUS3 gene into patient cells. Once inside the cell, the vector enables production of the missing enzyme, potentially restoring normal cellular function.
According to Lisowski, two of the four candidates have demonstrated particularly strong performance in preclinical studies. The research team is currently evaluating these candidates using patient-derived induced pluripotent stem cells (iPSCs), which are differentiated into neurons and brain organoids to model disease pathology.
Early in vitro findings suggest that gene delivery can restore normal cellular metabolism, supporting the potential for improved neurological function. However, further studies are required to determine which candidate will advance to clinical application.
If sufficient funding is secured, the therapy could be ready for clinical administration within approximately two years. Despite promising progress, funding remains a major challenge due to the extremely limited patient population.
The project is being conducted in collaboration with international partners, including the Gene2Cure Foundation and the PUS3 Foundation, with the goal of ensuring future access for all diagnosed patients.
