Metformin for treatment of cytopenias in children and young adults with Fanconi anemia

Fanconi anemia (FA), a genetic DNA repair disorder characterized by marrow failure and cancer susceptibility. In FA mice, metformin improves blood counts and delays tumor development. We conducted a single institution study of metformin in nondiabetic patients with FA to determine feasibility and tolerability of metformin treatment and to assess for improvement in blood counts. Fourteen of 15 patients with at least 1 cytopenia (hemoglobin < 10 g/dL; platelet count < 100 000 cells/µL; or an absolute neutrophil count < 1000 cells/µL) were eligible to receive metformin for 6 months. Median patient age was 9.4 years (range 6.0-26.5). Thirteen of 14 subjects (93%) tolerated maximal dosing for age; 1 subject had dose reduction for grade 2 gastrointestinal symptoms. No subjects developed hypoglycemia or metabolic acidosis. No subjects had dose interruptions caused by toxicity, and no grade 3 or higher adverse events attributed to metformin were observed. Hematologic response based on modified Myelodysplastic Syndrome International Working Group criteria was observed in 4 of 13 evaluable patients (30.8%; 90% confidence interval, 11.3-57.3). Median time to response was 84.5 days (range 71-128 days). Responses were noted in neutrophils (n = 3), platelets (n = 1), and red blood cells (n = 1). No subjects met criteria for disease progression or relapse during treatment. Correlative studies explored potential mechanisms of metformin activity in FA. Plasma proteomics showed reduction in inflammatory pathways with metformin. Metformin is safe and tolerable in nondiabetic patients with FA and may provide therapeutic benefit. This trial was registered at as #NCT03398824

Defining global strategies to improve outcomes in sickle cell disease ::a Lancet Haematology commission

All over the world, people with sickle cell disease (an inherited condition) have premature deaths and preventable severe chronic complications, which considerably affect their quality of life, career progression, and financial status. In addition, these people are often affected by stigmatisation or structural racism, which can contribute to stress and poor mental health. Inequalities affecting people with sickle cell disease are also reflected in the distribution of the disease—mainly in sub-Saharan Africa, India, and the Caribbean—whereas interventions, clinical trials, and funding are mostly available in North America, Europe, and the Middle East. Although some of these characteristics also affect people with other genetic diseases, the fate of people with sickle cell disease seems to be particularly unfair. Simple, effective interventions to reduce the mortality and morbidity associated with sickle cell disease are available. The main obstacle preventing better outcomes in this condition, which is a neglected disease, is associated with inequalities impacting the patient populations. The aim of this Commission is to highlight the problems associated with sickle cell disease and to identify achievable goals to improve outcomes both in the short and long term. The ambition for the management of people with sickle cell disease is that curative treatments become available to every person with the condition. Although this would have seemed unrealistic a decade ago, developments in gene therapy make this potentially achievable, albeit in the distant future. Until these curative technologies are fully developed and become widely available, health-care professionals (with the support of policy makers, funders, etc) should make sure that a minimum standard of care (including screening, prophylaxis against infection, acute medical care, safe blood transfusion, and hydroxyurea) is available to all patients. In considering what needs to be achieved to reduce the global burden of sickle cell disease and improve the quality of life of patients, this Commission focuses on five key areas: the epidemiology of sickle cell disease (Section 1); screening and prevention (Section 2); established and emerging treatments for the management of the disease (Section 3); cellular therapies with curative potential (Section 4); and training and education needs (Section 5). As clinicians, researchers, and patients, our objective to reduce the global burden of sickle cell disease aligns with wider public health aims to reduce inequalities, improve health for all, and develop personalised treatment options. We have observed in the past few years some long-awaited momentum following the development of innovative point-of-care testing devices, new approved drugs, and emerging curative options. Reducing the burden of sickle cell disease will require substantial financial and political commitment, but it will impact the lives of millions of patients and families worldwide and the lessons learned in achieving this goal would unarguably benefit society as a whole

Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease

BACKGROUND: Sickle cell disease is characterized by hemolytic anemia, pain, and progressive organ damage. A high level of erythrocyte fetal hemoglobin (HbF) comprising alpha- and gamma-globins may ameliorate these manifestations by mitigating sickle hemoglobin polymerization and erythrocyte sickling. BCL11A is a repressor of gamma-globin expression and HbF production in adult erythrocytes. Its down-regulation is a promising therapeutic strategy for induction of HbF.METHODS: We enrolled patients with sickle cell disease in a single-center, open-label pilot study. The investigational therapy involved infusion of autologous CD34+ cells transduced with the BCH-BB694 lentiviral vector, which encodes a short hairpin RNA (shRNA) targeting BCL11A mRNA embedded in a microRNA (shmiR), allowing erythroid lineage-specific knockdown. Patients were assessed for primary end points of engraftment and safety and for hematologic and clinical responses to treatment.RESULTS: As of October 2020, six patients had been followed for at least 6 months after receiving BCH-BB694 gene therapy; median follow-up was 18 months (range, 7 to 29). All patients had engraftment, and adverse events were consistent with effects of the preparative chemotherapy. All the patients who could be fully evaluated achieved robust and stable HbF induction (percentage HbF/(F+S) at most recent follow-up, 20.4 to 41.5%), with HbF broadly distributed in red cells (F-cells 58.9 to 93.6% of untransfused red cells) and HbF per F-cell of 9.0 to 18.6 pg per cell. Clinical manifestations of sickle cell disease were reduced or absent during the follow-up period.CONCLUSIONS: This study validates BCL11A inhibition as an effective target for HbF induction and provides preliminary evidence that shmiR-based gene knockdown offers a favorable risk-benefit profile in sickle cell disease. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT03282656)

Defining global strategies to improve outcomes in sickle cell disease: a Lancet Haematology Commission

All over the world, people with sickle cell disease (an inherited condition) have premature deaths and preven­ table severe chronic complications, which considerably affect their quality of life, career progression, and finan­ cial status. In addition, these people are often affected by stigmatisation or structural racism, which can contribute to stress and poor mental health. Inequalities affecting people with sickle cell disease are also reflected in the distribution of the disease—mainly in sub­Saharan Africa, India, and the Caribbean—whereas interventions, clinical trials, and funding are mostly available in North America, Europe, and the Middle East. Although some of these characteristics also affect people with other genetic diseases, the fate of people with sickle cell disease seems to be particularly unfair. Simple, effective interventions to reduce the mortality and morbidity associated with sickle cell disease are available. The main obstacle preventing better outcomes in this condition, which is a neglected disease, is associated with inequalities impacting the patient populations. The aim of this Commission is to highlight the problems associated with sickle cell disease and to identify achievable goals to improve outcomes both in the short and long term. The ambition for the management of people with sickle cell disease is that curative treatments become available to every person with the condition. Although this would have seemed unrealistic a decade ago, developments in gene therapy make this potentially achievable, albeit in the distant future. Until these curative technologies are fully developed and become widely available, health­care professionals (with the support of policy makers, funders, etc) should make sure that a minimum standard of care (including screening, prophylaxis against infection, acute medical care, safe blood transfusion, and hydroxyurea) is available to all patients. In considering what needs to be achieved to reduce the global burden of sickle cell disease and improve the quality of life of patients, this Commission focuses on five key areas: the epidemiology of sickle cell disease (Section 1); screening and prevention (Section 2); established and emerging treatments for the management of the disease (Section 3); cellular therapies with curative potential (Section 4); and training and education needs (Section 5). As clinicians, researchers, and patients, our objective to reduce the global burden of sickle cell disease aligns with wider public health aims to reduce inequalities, improve health for all, and develop personalised treatment options. We have observed in the past few years some long­awaited momentum following the development of innovative point­of­care testing devices, new approved drugs, and emerging curative options. Reducing the burden of sickle cell disease will require substantial financial and political commitment, but it will impact the lives of millions of patients and families worldwide and the lessons learned in achieving this goal would unarguably benefit society as a whol