19 research outputs found
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
The possible use of combined electrical impedance and ultrasound velocity measurements for the non-invasive measurement of temperature during mild hyperthermia
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
Validation of BCL11A As Therapeutic Target in Sickle Cell Disease: Results from the Adult Cohort of a Pilot/Feasibility Gene Therapy Trial Inducing Sustained Expression of Fetal Hemoglobin Using Post-Transcriptional Gene Silencing
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)
The effects of intravitreal bevacizumab on patients with macular edema secondary to branch retinal vein occlusion
Defining global strategies to improve outcomes in sickle cell disease: a Lancet Haematology commission
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 prevenÂ
table severe chronic complications, which considerably
affect their quality of life, career progression, and finanÂ
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 subÂSaharan 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, healthÂcare 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 longÂawaited momentum following
the development of innovative pointÂofÂcare 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