TY - JOUR

T1 - Surrogate Biomarkers in Gene Therapy for Orphan Diseases: Validation, Application, and Regulatory Aspects

AU - Ayupova, Aisylu

AU - Solovyeva, Valeriya

AU - Исса, Шаза

AU - Фаюд, Хайдар

AU - Rizvanov, Albert

PY - 2025/10/17

Y1 - 2025/10/17

N2 - 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.

AB - 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.

KW - Biomarkers/analysis

KW - Genetic Therapy/methods

KW - Humans

KW - Rare Diseases/therapy

KW - Reproducibility of Results

KW - hereditary diseases

KW - biomarkers

KW - surrogate endpoints

UR - https://www.mendeley.com/catalogue/d71d0bc1-6e05-3c67-81c3-05ee39d041a3/

U2 - 10.3390/ijms262010107

DO - 10.3390/ijms262010107

M3 - Review article

C2 - 41155400

VL - 26

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1422-0067

IS - 20

M1 - 10107

ER -