2017 Clinical trials update in new treatments of β‐thalassemia

Abstract

The underlying basis of b-thalassemia pathology is the diminished b-globin synthesis leading to a-globin accumulation and premature apoptotic destruction of erythroblasts, causing oxidative stress-induced ineffective erythropoiesis, bone marrow hyperplasia, splenomegaly, and increased intestinal iron absorption with progressive iron overload. Better understanding of the molecular mechanisms underlying this disease led to the recognition of new targets with potential therapeutic utility. Agents such as JAK2 inhibitors and TGF-b ligand traps that reduce the ineffective erythropoiesis process are already being tested in clinical trials with promising results. Other agents that aim to reduce oxidative stress (activators of Foxo3, HRIeIF2aP, Prx2, Hsp70, and PK anti-oxidant systems and inhibitors of HO-1) and to decrease iron overload (hepcidin agonists, erythroferrone inhibitors and exogenous transferrin) are also under experimental investigation. Significant progress has also been made in the area of allogeneic hematopoietic stem cell transplantation with several ongoing clinical trials examining new condition regimens as well as different donor selection and stem cell source options. Gene therapy has reached a critical point and phase 1 clinical trials have recently been launched to examine the effectiveness and especially long term safety. Epigenetic manipulation and genomic editing of the g-or b-globin gene are novel and promising experimental gene therapy approaches for b-thalassemia giving hope for cure for this chronic disease. This review outlines the key points of the molecular mechanisms underlying b-thalassemia in relation to the development of new therapies and an update is given both at the pre-clinical and clinical level.

Extracellular Vesicle Characteristics in β-thalassemia as Potential Biomarkers for Spleen Functional Status and Ineffective Erythropoiesis

“…No correlation was found with iron-overload parameters. EV HSP70 can potentially be used as a novel biomarker for monitoring ineffective erythropoiesis in β-TM, and perhaps in the future, might be considered a therapeutic target (Arlet et al, 2014; Sankaran and Weiss, 2015; Makis et al, 2016). …”

“…In β-thalassemia erythroblasts, the free α-globin chains interact with HSP70, sequestering it in the cytoplasm and leaving GATA1 unprotected. Its consequent degradation results in end-stage maturation arrest and apoptosis, which further aggravates the ineffective erythropoiesis observed in β-TM (Arlet et al, 2014; Sankaran and Weiss, 2015; Makis et al, 2016). In addition, HSP70 can be released by stressed cells as free soluble protein or via EVs; extracellular membrane-bound HSP70 is involved in immune system stress response (De Maio and Vazquez, 2013), and tumor-related EV HSP70 also induces muscle catabolism and wasting in a mouse model (Zhang et al, 2017).…”

Preclinical and Clinical Advances of GalNAc-Decorated Nucleic Acid Therapeutics

“…THA-GalNAc can be efficiently assembled using readily available starting materials and conjugated to ASOs using a solution-phase conjugation strategy, providing a clinically applicable GalNAc-ASO modality. Ionis has added the THA-C6 triantenerrary GalNAc to eight liver-targeted ASOs, including ISIS-APO(a)-L Rx ,97, 98, 99 IONIS-ANGPTL3-L Rx , 98 IONIS-GSK4-L Rx , IONIS-HBV-L Rx (ISIS-GSK6-L Rx ),100, 101 IONIS-APOCIII-L Rx , IONIS-GHR-L Rx , 102 IONIS-AGT-L Rx , and IONIS-TMPRSS6-LRx 103 …”

Epidemiologic and clinical characteristics of nontransfusion‐dependent thalassemia in the United States

“…This study of 138 patients with NTDT across four US thalassemia centers shows that NTDT affects a diverse population in the United States and is associated with significant morbidity. These results demonstrate the current profile of NTDT in the United States, which is needed as potential new treatments for thalassemia that target the pathophysiology of the disease are assessed in clinical trials . Changes in patient demographics, the high number of patients born and transfused outside of the United States, differences in complications by genotype and age, and the importance of LIC monitoring are important findings of this study.…”