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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

Engineered Factor VIII: A Comprehensive Review of Molecular Biology, Design Strategies, and AAV-Mediated Gene Therapy

  • Albina Khairetdinova1
  • Valentin Artemyev1,2
  • Ekaterina A. Astakhova1,2
  • Syune Ambaryan1
  • Matvey Pilagov1
  • Anna Maznina2
  • Victoria S. Lobanova3
  • Sofya G. Feoktistova1
  • Olga N. Mityaeva1,2
  • Pavel Yu. Volchkov1,2,4
4 affiliations
  1. 1Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies, Moscow 125315, Russia
  2. 2Moscow Center for Advanced Studies, Kulakova str. 20, Moscow 123592, Russia
  3. 3Morozov’s Moscow City Children Clinical Hospital, Beregovoy Proezd 5A/1, Moscow 121087, Russia
  4. 4Moscow Clinical Scientific Center N.A. A.S. Loginov, Moscow 111123, Russia
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Abstract

Coagulation factor VIII (FVIII) is a key therapeutic protein for hemophilia A, an inherited bleeding disorder caused by FVIII deficiency or dysfunction. The development and production of FVIII-based therapeutics remains challenging due to the intrinsic complexity of FVIII biosynthesis, folding, secretion, and functional stability. Advances in the understanding of the FVIII life cycle, as well as studies of its natural homologs, have created opportunities to develop improved FVIII variants. In parallel, therapeutic strategies to restore FVIII activity have evolved from replacement therapy with exogenous FVIII to gene-based delivery of a functional F8 copy. Among these approaches, AAV-mediated gene therapy has emerged as a clinically viable platform with a generally favorable safety profile, prompting the development of multiple therapeutic candidates for hemophilia A. This review summarizes established and current knowledge of FVIII structure, biosynthesis, and immunology in the context of developing effective and clinically applicable AAV-mediated therapies for hemophilia A. Particular attention is given to engineered FVIII variants and the latest clinical findings in AAV gene therapy, as well as to long-term efficacy and safety.

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Cite

BibTeXRIS
BibTeX
@article{khairetdinova2026engineered,
  title = {{Engineered Factor VIII: A Comprehensive Review of Molecular Biology, Design Strategies, and AAV-Mediated Gene Therapy}},
  author = {Albina Khairetdinova and Valentin Artemyev and Ekaterina A. Astakhova and Syune Ambaryan and Matvey Pilagov and Anna Maznina and Victoria S. Lobanova and Sofya G. Feoktistova and Olga N. Mityaeva and Pavel Yu. Volchkov},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = nov,
  doi = {10.3390/ijms27219928},
  url = {https://www.mdpi.com/1422-0067/27/21/9928},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Engineered Factor VIII: A Comprehensive Review of Molecular Biology, Design Strategies, and AAV-Mediated Gene Therapy
AU  - Albina Khairetdinova
AU  - Valentin Artemyev
AU  - Ekaterina A. Astakhova
AU  - Syune Ambaryan
AU  - Matvey Pilagov
AU  - Anna Maznina
AU  - Victoria S. Lobanova
AU  - Sofya G. Feoktistova
AU  - Olga N. Mityaeva
AU  - Pavel Yu. Volchkov
PY  - 2026
DA  - 2026/11/05
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27219928
UR  - https://www.mdpi.com/1422-0067/27/21/9928
AB  - Coagulation factor VIII (FVIII) is a key therapeutic protein for hemophilia A, an inherited bleeding disorder caused by FVIII deficiency or dysfunction. The development and production of FVIII-based therapeutics remains challenging due to the intrinsic complexity of FVIII biosynthesis, folding, secretion, and functional stability. Advances in the understanding of the FVIII life cycle, as well as studies of its natural homologs, have created opportunities to develop improved FVIII variants. In parallel, therapeutic strategies to restore FVIII activity have evolved from replacement therapy with exogenous FVIII to gene-based delivery of a functional F8 copy. Among these approaches, AAV-mediated gene therapy has emerged as a clinically viable platform with a generally favorable safety profile, prompting the development of multiple therapeutic candidates for hemophilia A. This review summarizes established and current knowledge of FVIII structure, biosynthesis, and immunology in the context of developing effective and clinically applicable AAV-mediated therapies for hemophilia A. Particular attention is given to engineered FVIII variants and the latest clinical findings in AAV gene therapy, as well as to long-term efficacy and safety.
SN  - 1422-0067
ER  -