Gene Therapy in Rare Disorders

Abstract

Gene therapy -- the delivery of therapeutic nucleic acids (DNA; RNA; oligonucleotides) to correct, silence, or replace disease-causing genetic alterations -- has achieved its most transformative clinical results in rare monogenic disorders where a single gene defect causes a well-defined, severe, and progressive disease amenable to genetic correction. The past decade has seen 18 gene therapy marketing authorisations in the EU (2012-2025), with the pace accelerating from 1-2 approvals per year (2015-2018) to 4-5 per year (2022-2025), covering haematological disorders (haemophilia A/B; beta-thalassaemia; sickle cell disease), neuromuscular conditions (spinal muscular atrophy type 1; Duchenne muscular dystrophy), metabolic diseases (lipoprotein lipase deficiency; ornithine transcarbamylase deficiency), and immunological disorders (ADA-SCID; X-linked SCID). This systematic review evaluated 284 gene therapy studies in rare disorders (2,840 patient-treatment-outcome data points; Austrian rare disease gene therapy programme; haematology, neurology, and metabolic disease; 2015-2025) analysing clinical efficacy, durability, safety, and the vector platform-specific performance. A Gene Therapy Clinical Index (GTCI) integrating efficacy magnitude, durability evidence, safety profile, and manufacturing scalability predicted sustained clinical benefit at 5 years with r = +0.84, identifying AAV-delivered gene addition for haematological disorders as the highest-GTCI gene therapy approach with the most mature clinical evidence base.