Interplay between α-thalassemia and ß-hemoglobinopathies: Translating genotype-phenotype relationships into therapies.

α-Thalassemia represents one of the most important genetic modulators of ß-hemoglobinopathies. During this last decade, the ongoing interest in characterizing genotype-phenotype relationships has yielded incredible insights into α-globin gene regulation and its impact on ß-hemoglobinopathies. In this review, we provide a holistic update on α-globin gene expression stemming from DNA to RNA to protein, as well as epigenetic mechanisms that can impact gene expression and potentially influence phenotypic outcomes. Here, we highlight defined α-globin targeted strategies and rationalize the use of distinct molecular targets based on the restoration of balanced α/ß-like globin chain synthesis. Considering the therapies that either increase ß-globin synthesis or reactivate γ-globin gene expression, the modulation of α-globin chains as a disease modifier for ß-hemoglobinopathies still remains largely uncharted in clinical studies.

The Australian Aplastic Anaemia and other Bone Marrow Failure Syndromes Registry.

The bone marrow failure syndromes (BMFS) are a diverse group of acquired and inherited diseases which may manifest in cytopenias, haematological malignancy and/or syndromic multisystem disease. Patients with BMFS frequently experience poor outcomes, and improved treatment strategies are needed. Collation of clinical characteristics and patient outcomes in a national disease-specific registry represents a powerful tool to identify areas of need and support clinical and research collaboration. Novel treatment strategies such as gene therapy, particularly in rare diseases, will depend on the ability to identify eligible patients alongside the molecular genetic features of their disease that may be amenable to novel therapy. The Australian Aplastic Anaemia and other Bone Marrow Failure Syndromes Registry (AAR) aims to improve outcomes for all paediatric and adult patients with BMFS in Australia by describing the demographics, treatments (including supportive care) and outcomes, and serving as a resource for research and practice improvement.

Low mortality in vaccinated immunocompromised haematology patients infected with SARS-CoV-2.

Coronavirus disease 2019 (COVID-19) infection in patients with haematological neoplasms has been associated with increased mortality; however, many studies in this patient group were reported early in the pandemic. The authors evaluated outcomes of COVID-19 infection in patients with haematological conditions following widespread vaccination, newer viral variants and increasingly effective antiviral therapies. A 4% mortality rate was found and contemporary risk factors for hospitalisation including older age, nonvaccination or partial COVID-19 vaccination status and infection with non-Omicron strain were identified.

SLN124, a GalNac-siRNA targeting transmembrane serine protease 6, in combination with deferiprone therapy reduces ineffective erythropoiesis and hepatic iron-overload in a mouse model of ß-thalassaemia.

Beta-thalassaemia is an inherited blood disorder characterised by ineffective erythropoiesis and anaemia. Consequently, hepcidin expression is reduced resulting in increased iron absorption and primary iron overload. Hepcidin is under the negative control of transmembrane serine protease 6 (TMPRSS6) via cleavage of haemojuvelin (HJV), a co-receptor for the bone morphogenetic protein (BMP)-mothers against decapentaplegic homologue (SMAD) signalling pathway. Considering the central role of the TMPRSS6/HJV/hepcidin axis in iron homeostasis, the inhibition of TMPRSS6 expression represents a promising therapeutic strategy to increase hepcidin production and ameliorate anaemia and iron overload in ß-thalassaemia. In the present study, we investigated a small interfering RNA (siRNA) conjugate optimised for hepatic targeting of Tmprss6 (SLN124) in ß-thalassaemia mice (Hbbth3/+ ). Two subcutaneous injections of SLN124 (3 mg/kg) were sufficient to normalise hepcidin expression and reduce anaemia. We also observed a significant improvement in erythroid maturation, which was associated with a significant reduction in splenomegaly. Treatment with the iron chelator, deferiprone (DFP), did not impact any of the erythroid parameters. However, the combination of SLN124 with DFP was more effective in reducing hepatic iron overload than either treatment alone. Collectively, we show that the combination therapy can ameliorate several disease symptoms associated with chronic anaemia and iron overload, and therefore represents a promising pharmacological modality for the treatment of ß-thalassaemia and related disorders.