bims-conane 2025-01-19 papers

Trends Mol Med. 2025 Jan 10. pii: S1471-4914(24)00334-4. [Epub ahead of print]

Gene therapy for β-thalassemia: current and future options.

Giulia Hardouin, Annarita Miccio, Megane Brusson.

Beta-thalassemia is a severe, hereditary blood disorder characterized by anemia, transfusion dependence, reduced life expectancy, and poor quality of life. Allogeneic transplantation of hematopoietic stem cells (HSCs) is the only curative treatment for transfusion-dependent β-thalassemia, but a lack of compatible donors prevents the use of this approach for most patients. Over the past 20 years, the rise of gene therapy and the development of lentiviral vectors and genome-editing tools has extended curative options to a broader range of patients. Here, we review breakthroughs in gene addition- and genome-editing-based therapies for β-thalassemia, the clinical outcomes enabling approval by regulatory agencies, and perspectives for further development.

Keywords: base editing; gene therapy; genome editing; lentiviral vectors; β-thalassemia

DOI: https://doi.org/10.1016/j.molmed.2024.12.001

Blood Adv. 2025 Jan 15. pii: bloodadvances.2024014792. [Epub ahead of print]

Thalassemia carriers exhibit reduced expression of CD234 on erythrocytes and levels of malaria-associated chemokines.

Renliang Huang, Xinze Li, Zhe Lu, Jing Xu, Dan Lin, Yunxue Fu, Yan Liang, Frank Petersen, Xuexia Li, Qiaomiao Zhou, Xinhua Yu.

DOI: https://doi.org/10.1182/bloodadvances.2024014792

Lancet Reg Health Southeast Asia. 2024 Nov;30 100495

Deferoxamine, deferasirox, and deferiprone triple iron chelator combination therapy for transfusion-dependent β-thalassaemia with very high iron overload: a randomised clinical trial.

Anuja Premawardhena, Sakuni Wanasinghe, Chamodi Perera, Muditha Nayana Wijethilaka, R H M G Rajakaruna, R A N K K Samarasinghe, Senani Williams, Sachith Mettananda.

Background: Many patients with β-thalassaemia die prematurely due to iron overload. In this study, we aim to evaluate the efficacy and safety of the triple combination of deferoxamine, deferasirox and deferiprone on iron chelation in patients with transfusion-dependent β-thalassaemia with very high iron overload.
Methods: This open-label, randomised, controlled clinical trial was conducted at Colombo North Teaching Hospital, Sri Lanka. Transfusion-dependent β-thalassaemia patients with ferritin >3500 ng/mL were randomised 2:1 into intervention (deferoxamine, deferasirox and deferiprone) and control (deferoxamine and deferasirox) arms. Reduction in serum ferritin after six months was the primary outcome measure. Reduction in liver iron content, improvement in cardiac T2∗, and adverse effects were secondary outcome measures.
Findings: Twenty-three patients (intervention-15, control-8) were recruited. 92% and 62% in the intervention and control arms showed a reduction in ferritin, respectively. The mean reduction of ferritin was significantly higher in intervention (-1094 ± 907 ng/mL) compared to control (+82 ± 1588 ng/mL) arm (p = 0.042). There was no statistically significant difference in the liver iron content in two arms. In the intervention arm, 67% improved cardiac T2∗ (mean change +6.72 ± 9.63 ms) compared to 20% in the control arm (mean change -3.00 ± 8.24 ms). Five patients discontinued deferiprone due to arthralgia, which resolved completely after stopping the drug.
Interpretation: Triple combination therapy with deferoxamine, deferasirox and deferiprone is more efficacious in reducing iron burden measured by serum ferritin and showed a positive trend in reducing myocardial iron content in patients with transfusion-dependent β-thalassaemia with very high iron overload. Deferiprone has the disturbing side effect of reversible but severe arthropathy.
Funding: None.

Keywords: Deferasirox; Deferiprone; Deferoxamine; Iron chelator; Iron overload; Thalassaemia; Transfusion-dependent anaemia

DOI: https://doi.org/10.1016/j.lansea.2024.100495

Blood Adv. 2025 Jan 16. pii: bloodadvances.2024015053. [Epub ahead of print]

Phase 1 Study of Quercetin, a Natural Antioxidant in Children and Young Adults with Fanconi Anemia (FA).

Fanconi anemia (FA) is a rare inherited disorder characterized by progressive bone marrow failure (BMF) and a predisposition to malignancy. Systemic reactive-oxygen species (ROS) and increased sensitivity of FA hematopoietic progenitors to ROS play a key role in the pathogenesis of BMF. Treatment with antioxidants improve hematopoietic function in Fancc-/- mice. We report the safety, tolerability, and pharmacokinetics (PK) of quercetin, a naturally occurring antioxidant in the first dose-finding Phase 1 study in patients with FA. Twelve patients (median age 7 years, range: 3-21) received oral quercetin twice daily for 4 months. Quercetin was well tolerated at all dose levels. Allometrically bodyweight-adjusted dose with a maximum adult daily dose of 4000mg/day was established as the recommended dose of quercetin. Patients in an expansion cohort (n=18) were treated using this recommended dose for 6 months. A subset of patients showed reduced ROS levels in the peripheral blood and bone marrow stem cell compartment. Patients in the analysis cohort treated with the recommended dose of quercetin achieved an a priori defined optimal response of 25% reduction in the peripheral blood (PB) ROS level compared to baseline. Platelet counts remained stable to slightly improved over the study period (p=0.06). Absolute neutrophil counts (p=0.01) and hemoglobin levels gradually declined (p=0.001). In those with evidence of BMF at baseline, 8 out of 15 patients (53%) had a hematological response at some point following quercetin treatment. Fluctuations in counts are common in patients with FA limiting accurate assessment of the impact of quercetin use in FA. NCT# 01720147.

DOI: https://doi.org/10.1182/bloodadvances.2024015053