The year 2025 witnessed consolidation of CRISPR-Cas9 and AAV-mediated gene therapy as curative options for inherited blood disorders, with expanding clinical evidence for sickle cell disease, beta-thalassemia, and hemophilia following landmark regulatory approvals in 2023-2024 [1][2][3][4][5].
Bibliometric analysis revealed accelerating gene therapy research from experimental approaches to clinical translation, with strong interdisciplinary collaboration and rising clinical trials marking a transformative era for previously incurable inherited blood disorders [1]. CRISPR-Cas9 therapy (Casgevy/exagamglogene autotemcel) received approval from MHRA, FDA, and EMA for transfusion-dependent beta-thalassemia and sickle cell disease in patients aged ≥12 years, representing the first regulatory approvals for CRISPR therapeutic gene editing [2].
Safety and efficacy studies demonstrated disease-specific responses in CRISPR-treated sickle cell HSPCs, with higher overall editing efficiency but increased DNA damage responses and chromosomal rearrangements compared to healthy donor cells, highlighting the need for safety studies in clinically relevant patient-derived samples [3]. Hemophilia gene therapy using AAV vectors showed efficacy data extending to 8 years for factor IX and 5 years for factor VIII deficiency, with safety data being reassuring despite variable efficacy among vector types and individuals [4]. Novel approaches including CRISPR-loaded nanocarriers for in vivo CAR-T generation and lipid nanoparticle delivery demonstrated scalable, economical alternatives to ex vivo manufacturing [5].
Why it matters:
For clinicians: Gene therapy represents a paradigm shift from lifelong disease management to potential cure with single interventions. CRISPR-Cas9 therapies achieve transfusion independence in beta-thalassemia and elimination of vaso-occlusive crises in sickle cell disease through BCL11A enhancer editing and fetal hemoglobin reactivation. AAV gene therapy for hemophilia reduces or eliminates bleeding complications and factor infusions. However, implementation challenges include high costs, myeloablation requirements, specialized center expertise, long-term safety monitoring, and limited global access. Patient selection requires careful assessment of disease severity, treatment alternatives, and individual risk-benefit profiles.
For researchers: Outstanding questions include optimizing editing efficiency while minimizing off-target effects, addressing variable durability of therapeutic benefit, developing strategies for patients with pre-existing AAV immunity, creating more accessible delivery platforms (in vivo vs. ex vivo), and expanding applications to other monogenic disorders. The success validates therapeutic genome editing while underscoring the need for continued safety surveillance, particularly regarding potential genotoxicity and long-term consequences of permanent genetic modifications.
References
- Sweileh WM. Knowledge mapping and bibliometric insights into gene therapy for rare inherited hematologic pathologies: focus on sickle cell disease, hemophilia, and thalassemia. Orphanet J Rare Dis. 2025;20(1):556. doi: 10.1186/s13023-025-03957-0
PubMed: https://pubmed.ncbi.nlm.nih.gov/41188895/ - Kattamis A, Thompson AA. Editorial: First Regulatory Approvals for CRISPR-Cas9 Therapeutic Gene Editing for Sickle Cell Disease and Transfusion-Dependent β-Thalassemia. Acta Haematol. 2024;147(2):117-120. doi: 10.1159/000536943
PubMed: https://pubmed.ncbi.nlm.nih.gov/38425279/ - Ferrari S, Vavassori V, Canarutto D, et al. Safety and efficacy studies of CRISPR-Cas9 treatment of sickle cell disease highlights disease-specific responses. Mol Ther. 2024. [Epub ahead of print]
PubMed: https://pubmed.ncbi.nlm.nih.gov/39044427/ - Pipe SW, Sabatino DE. Gene Therapy: A New Hope in Hemophilia A Treatment. Blood. 2022. [Epub ahead of print]
PubMed: https://pubmed.ncbi.nlm.nih.gov/36226233/ - Saha R, Al-Kadasi AM, Alshahrani MY, et al. Recent Advances in Gene Therapy for Hemophilia: Projecting the Perspectives. Biomedicines. 2024;12(7):XXX. doi: 10.3390/biomedicines12071XXX
PubMed: https://pubmed.ncbi.nlm.nih.gov/39062568/