Impact of Vutrisiran on Quality of Life and Physical Function in Patients with Hereditary Transthyretin-Mediated Amyloidosis with Polyneuropathy

INTRODUCTION: Hereditary transthyretin (ATTRv; v for variant) amyloidosis, also known as hATTR amyloidosis, is a progressive and fatal disease associated with rapid deterioration of physical function and patients' quality of life (QOL). Vutrisiran, a subcutaneously administered RNA interference (RNAi) therapeutic that reduces hepatic production of transthyretin, was assessed in patients with ATTRv amyloidosis with polyneuropathy in the pivotal HELIOS-A study. METHODS: The phase 3 open-label HELIOS-A study investigated the efficacy and safety of vutrisiran in patients with ATTRv amyloidosis with polyneuropathy, compared with an external placebo group from the APOLLO study of the RNAi therapeutic patisiran. Measures of QOL and physical function were assessed. RESULTS: At month 18, vutrisiran improved Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score (least squares mean difference [LSMD] in change from baseline [CFB]: –21.0; p = 1.84 × 10–10) and Norfolk QOL-DN domain scores, compared with external placebo. This benefit relative to external placebo was evident across all baseline polyneuropathy disability (PND) scores and most pronounced in patients with baseline PND scores I–II. Compared with external placebo, vutrisiran also demonstrated benefit in EuroQoL-Visual Analog Scale (EQ-VAS) score (LSMD in CFB: 13.7; nominal p = 2.21 × 10–7), 10-m walk test (LSMD in CFB: 0.239 m/s; p = 1.21 × 10–7), Rasch-built Overall Disability Score (LSMD in CFB: 8.4; p = 3.54 × 10–15), and modified body mass index (mBMI) (LSMD in CFB: 140.7; p = 4.16 × 10–15) at month 18. Overall, Norfolk QOL-DN, EQ-VAS, and mBMI improved from pretreatment baseline with vutrisiran, whereas all measures worsened from baseline in the external placebo group. At month 18, Karnofsky Performance Status was stable/improved from baseline in 58.2/13.1% with vutrisiran versus 34.7/8.1% with external placebo. CONCLUSION: Vutrisiran treatment provided significant clinical benefits in multiple measures of QOL and physical function in patients with ATTRv amyloidosis with polyneuropathy. Benefits were most pronounced in patients with earlier-stage disease, highlighting the importance of early diagnosis and treatment

In vitro generation of platelets: Where do we stand?

Millions of platelets, specialized cells that participate in haemostatic and inflammatory functions, are transfused each year worldwide, but their supply is limited. Platelets are produced by megakaryocytes by extending proplatelets, directly into the bloodstream. Bone marrow structure and extracellular matrix composition together with soluble factors (e.g. Thrombopoietin) are key regulators of megakaryopoiesis by supporting cell differentiation and platelet release. Despite this knowledge, the scarcity of clinical cures for life threatening platelet diseases is in a large part due to limited insight into the mechanisms that control the developmental process of megakaryocytes and the mechanisms that govern the production of platelets within the bone marrow. To overcome these limitations, functional human tissue models have been developed and studied to extrapolate ex vivo outcomes for new insight on bone marrow functions in vivo. There are many challenges that these models must overcome, from faithfully mimicking the physiological composition and functions of bone marrow, to the collection of the platelets generated and validation of their viability and function for human use. The overall goal is to identify innovative instruments to study mechanisms of platelet release, diseases related to platelet production and new therapeutic targets starting from human progenitor cells

Bone marrow microenvironment of MPN cells

In this chapter, we will discuss the current knowledge concerning the alterations of the cellular components in the bone marrow niche in Myeloproliferative Neoplasms (MPNs), highlighting the central role of the megakaryocytes in MPN progression, and the extracellular matrix components characterizing the fibrotic bone marrow

Latest culture techniques: Cracking the secrets of bone marrow to mass-produce erythrocytes and platelets ex vivo

Since the dawn of medicine, scientists have carefully observed, modeled and interpreted the human body to improve healthcare. At the beginning there were drawings and paintings, now there is three-dimensional modeling. Moving from two-dimensional cultures and towards complex and relevant biomaterials, tissue-engineering approaches have been developed in order to create three-dimensional functional mimics of native organs. The bone marrow represents a challenging organ to reproduce because of its structure and composition that confer it unique biochemical and mechanical features to control hematopoiesis. Reproducing the human bone marrow niche is instrumental to answer the growing demand for human erythrocytes and platelets for fundamental studies and clinical applications in transfusion medicine. In this review, we discuss the latest culture techniques and technological approaches to obtain functional platelets and erythrocytes ex vivo. This is a rapidly evolving field that will define the future of targeted therapies for thrombocytopenia and anemia, but also a long-term promise for new approaches to the understanding and cure of hematologic diseases

Pathogenetic and clinical study of a patient with thrombocytopenia due to the p.E527K gain-of-function variant of SRC

The SRC gene was the first proto-oncogene to be discovered. Its product SRC is a nonreceptor protein tyrosine kinase that is the prototype, and a ubiquitously expressed member, of the SRC family kinases. SRC has been investigated for decades in mouse and in vitro models: these studies have indicated that SRC signalling has a central role in many cellular functions and in oncogenesis. 1 In platelets, SRC mediates signal activation pathways downstream different integrins and G protein-coupled receptors.2 However, much remains to be understood about SRC functions in human megakaryocytes and platelets. Recently, the first germline mutation in SRC causing human disease was reported in two families. Here we report the investigation of a new unrelated individual carrying the p.E527K variant that provides additional information on the clinical and pathogenetic features of the disorder and the role of SRC in human megakaryocytes