Surrogate Biomarkers in Gene Therapy for Orphan Diseases: Validation, Application, and Regulatory Aspects

The development of gene therapies for rare hereditary disorders is hindered by small patient cohorts, incomplete characterization of natural disease history, and the impracticality of conducting long-term clinical trials. Surrogate biomarkers-quantifiable indicators predictive of clinical outcomes-represent a promising strategy to accelerate the evaluation of therapeutic efficacy. This review examines the role of surrogate endpoints in gene therapy, outlining essential validation criteria, including biological plausibility, analytical reproducibility, and clinical predictive value. Regulatory frameworks governing surrogate markers in the United States, European Union, Russia, Japan, China, and Canada are compared, with emphasis on mechanisms for expedited or conditional approval. Challenges associated with biomarker validation and extrapolation in the context of rare diseases are discussed, alongside future perspectives that integrate multi-omics technologies and artificial intelligence to enhance biomarker discovery and facilitate regulatory acceptance.