Who should be eligible for gene therapy clinical trials in red blood cell pyruvate kinase deficiency (PKD)?: Toward an expanded definition of severe PKD.
Ontology highlight
ABSTRACT:
SUBMITTER: Schwartz JD
PROVIDER: S-EPMC9305868 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Pyruvate kinase (PK) deficiency is a rare genetic disease that causes chronic hemolytic anemia. There are currently no targeted therapies for PK deficiency. Here, we describe the identification and characterization of AG-348, an allosteric activator of PK that is currently in clinical trials for the treatment of PK deficiency. We demonstrate that AG-348 can increase the activity of wild-type and mutant PK enzymes in biochemical assays and in patient red blood cells treated ex vivo. These data illustrate the potential for AG-348 to restore the glycolytic pathway activity in patients with PK deficiency and ultimately lead to clinical benefit.
| S-EPMC5609468 | biostudies-literature
Project description:The HALT Polycystic Kidney Disease Trials Network consisted of two randomized, double blind, placebo-controlled trials among patients with autosomal dominant polycystic kidney disease. The trials involved 5-8years of participant follow-up with interventions in blood pressure and antihypertensive therapy. We provide a framework for designing and implementing closeout near the end of a trial while ensuring patient safety and maintaining scientific rigor and study morale.We discuss issues and resolutions for determining the last visit, tapering medications, and unblinding of participants to study allocation and results. We also discuss closure of clinical sites and Data Coordinating Center responsibilities to ensure timely release of study results and meeting the requirements of regulatory and funding authorities.Just over 90% of full participants had a 6-month study visit prior to their last visit preparing them for trial closeout. Nearly all patients wanted notification of study results (99%) and treatment allocation (99%). All participants were safely tapered off study and open label blood pressure medications. Within 6months, the trials were closed, primary papers published, and 805 letters distributed to participants with results and allocation. DCC obligations for data repository and clinicaltrials.gov reporting were completed within 12months of the last study visit.Closeout of our trials involved years of planning and significant human and financial resources. We provide questions for investigators to consider when planning closeout of their trials with focus on (1) patient safety, (2) dissemination of study results and (3) compliance with regulatory and funding responsibilities.
| S-EPMC4732941 | biostudies-literature
Project description:Pyruvate kinase deficiency (PKD) is the most common enzyme defect of glycolysis and an important cause of hereditary, nonspherocytic hemolytic anemia. The disease has a worldwide geographical distribution but there are no verified data regarding its frequency. Difficulties in the diagnostic workflow and interpretation of PK enzyme assay likely play a role. By the creation of a global PKD International Working Group in 2016, involving 24 experts from 20 Centers of Expertise we studied the current gaps in the diagnosis of PKD in order to establish diagnostic guidelines. By means of a detailed survey and subsequent discussions, multiple aspects of the diagnosis of PKD were evaluated and discussed by members of Expert Centers from Europe, USA, and Asia directly involved in diagnosis. Broad consensus was reached among the Centers on many clinical and technical aspects of the diagnosis of PKD. The results of this study are here presented as recommendations for the diagnosis of PKD and used to prepare a diagnostic algorithm. This information might be helpful for other Centers to deliver timely and appropriate diagnosis and to increase awareness in PKD.
| S-EPMC7344868 | biostudies-literature
Project description:Red cell pyruvate kinase (PK) deficiency is the most common glycolytic defect associated with congenital non-spherocytic hemolytic anemia. The disease, transmitted as an autosomal recessive trait, is caused by mutations in the PKLR gene and is characterized by molecular and clinical heterogeneity; anemia ranges from mild or fully compensated hemolysis to life-threatening forms necessitating neonatal exchange transfusions and/or subsequent regular transfusion support; complications include gallstones, pulmonary hypertension, extramedullary hematopoiesis and iron overload. Since identification of the first pathogenic variants responsible for PK deficiency in 1991, more than 300 different variants have been reported, and the study of molecular mechanisms and the existence of genotype-phenotype correlations have been investigated in-depth. In recent years, during which progress in genetic analysis, next-generation sequencing technologies and personalized medicine have opened up important landscapes for diagnosis and study of molecular mechanisms of congenital hemolytic anemias, genotyping has become a prerequisite for accessing new treatments and for evaluating disease state and progression. This review examines the extensive molecular heterogeneity of PK deficiency, focusing on the diagnostic impact of genotypes and new acquisitions on pathogenic non-canonical variants. The recent progress and the weakness in understanding the genotype-phenotype correlation, and its practical usefulness in light of new therapeutic opportunities for PK deficiency are also discussed.
| S-EPMC7556514 | biostudies-literature
Project description:The food environment is a critical place in the food system to implement interventions to support sustainable diets and address the global syndemic of obesity, undernutrition, and climate change, because it contains the total scope of options within which consumers make decisions about which foods to acquire and consume. In this paper, we build on existing definitions of the food environment, and provide an expanded definition that includes the parameter of sustainability properties of foods and beverages, in order to integrate linkages between food environments and sustainable diets. We further provide a graphical representation of the food environment using a socio-ecological framework. Next, we provide a typology with descriptions of the different types of food environments that consumers have access to in low-, middle-, and high-income countries including wild, cultivated, and built food environments. We characterize the availability, affordability, convenience, promotion and quality (previously termed desirability), and sustainability properties of food and beverages for each food environment type. Lastly, we identify a methodological approach with potential objective and subjective tools and metrics for measuring the different properties of various types of food environments. The definition, framework, typology, and methodological toolbox presented here are intended to facilitate scholars and practitioners to identify entry points in the food environment for implementing and evaluating interventions that support sustainable diets for enhancing human and planetary health.
| S-EPMC7230632 | biostudies-literature
Project description:Pyruvate dehydrogenase complex (PDC) deficiencies are mostly due to mutations in the X-linked PDHA1 gene. Males with hemizygous PDHA1 mutations are clinically more severely affected, while those with mosaic PDHA1 mutations may manifest milder phenotypes. We report a patient harboring a novel, mosaic missense PDHA1 mutation, c.523G > A (p.A175T), with a severe clinical presentation of congenital microcephaly, significant brain abnormalities, persistent seizures, profound developmental delay, and failure to thrive. We review published cases of PDHA1 mosaicism.
| S-EPMC5121365 | biostudies-other
Project description:Citrullinemia is an inborn error of metabolism due to deficiency of the urea cycle enzyme, argininosuccinate synthetase [L-citrulline:L-aspartate ligase (AMP-forming), EC 6.3.4.5]. The disease was first described in humans but was recently reported in dairy cattle in Australia. Here we report the nucleotide sequence of the normal bovine cDNA for argininosuccinate synthetase and the mutation present in animals with citrullinemia. Analysis of DNA from affected animals by Southern blotting did not readily identify the mutation in the bovine gene. RNA (Northern) blotting revealed a major reduction in the steady-state amount of mRNA in the liver of affected animals to less than 5% of controls. The bovine cDNA was cloned and sequenced and revealed 96% identity with the deduced human sequence at the amino acid level. Starting with mutant bovine liver, the mRNA was reverse-transcribed; the cDNA product was amplified with the polymerase chain reaction, cloned, and sequenced. The sequence revealed a C----T transition converting arginine-86 (CGA) to a nonsense codon (TGA). A second C----T transition represented a polymorphism in proline-175 (CCC----CCT). The mutation and the polymorphism were confirmed by amplification of genomic DNA and demonstration with restriction endonuclease enzymes of both the loss of an Ava II site in DNA from mutant animals at codon 86 and the presence or absence of a Dde I site at codon 175. The loss of the Ava II site can be used for rapid, economical, nonradioactive detection of heterozygotes for bovine citrullinemia.
| S-EPMC298189 | biostudies-other
Project description:Objective A clinical trial (REQUIRE) was started to investigate the use of an ultrasound renal denervation system in the treatment of resistant hypertension (RHT). We analyzed the prevalence of patients who were eligible for inclusion in this cross-sectional study at the time of screening. Methods Nine-hundred ninety-nine consecutive hypertension (HT) patients who were treated in our hospital as outpatients were classified into the following categories: patients treated with at least 3 types of antihypertensive drugs including diuretic agents who were eligible for enrolment in SYMPLICITY HTN-Japan (SH-J) with an office systolic blood pressure (SBP) of ?160 mmHg, who were ?80 years of age, and an estimated glomerular filtration rate (eGFR) of ?45 mL/min/1.73 m2 (RHT-S); and patients who were treated similar medications and who were eligible for enrolment in REQUIRE, with an SBP of ?150 mmHg, ?75 years of age, and an eGFR of ?40 mL/min/1.73 m2 (RHT-R). We investigated the proportion of patients in each category. We also investigated HT patients (1,423 cases) who were enrolled in the Chikushi Anti-Hypertension Trial (CHAT), a research network that includes general practitioners. Results Eleven patients (1.1%) with RHT-S and 18 patients (1.8%) with RHT-R were identified. After the exclusion of patients with secondary HT and a diastolic blood pressure (DBP) of <90 mmHg (applied in REQUIRE), 5 patients (0.5%) with RHT-S and 4 patients (0.4%) with RHT-R remained. In the analysis of the CHAT study, only 2 (0.1%) patients with RHT-R remained. Conclusion The number of eligible patients in the REQUIRE trial was decreased, largely due to the strict age restriction and the new DBP limitation. The prevalence of eligible patients in REQUIRE was estimated to be approximately 0.5 to 0.8 times that in SH-J. Since patient enrollment will be difficult, drastic measures may be required to recruit eligible patients.
| S-EPMC5799049 | biostudies-literature
Project description:Over the last several decades, our understanding of the genetic variation, pathophysiology, and complications of the hemolytic anemia associated with red cell pyruvate kinase deficiency (PKD) has expanded. Nonetheless, there remain significant gaps in our knowledge with regard to clinical care and monitoring. Treatment remains supportive with phototherapy and/or exchange transfusion in the newborn period, regular or intermittent red cell transfusions in children and adults, and splenectomy to decrease transfusion requirements and/or anemia related symptoms. In this article, we review the clinical diversity of PKD, the current standard of treatment and for supportive care, the complications observed, and future treatment directions.
| S-EPMC5053227 | biostudies-literature
Project description:Background: Pyruvate kinase deficiency (PKD) is the most frequent congenital enzymatic defect of glycolysis, and one of the most common causes of hereditary non spherocytic hemolytic anemia. Therapeutic interventions are limited, in part because of the incomplete understanding of the molecular mechanisms that compensate for the metabolic defect. Methods: Mass spectrometry-based metabolomics analyses were performed on red blood cells (RBCs) from healthy controls (n=10) and PKD patients (n=5). Results: In PKD patients, decreases in late glycolysis were accompanied by accumulation of pentose phosphate pathway (PPP) metabolites, as a function of oxidant stress to purines (increased breakdown and deamination). Markers of oxidant stress included increased levels of sulfur-containing compounds (methionine and taurine), polyamines (spermidine and spermine). Markers of hypoxia such as succinate, sphingosine 1-phosphate (S1P), and hypoxanthine were all elevated in PKD subjects. Membrane lipid oxidation and remodeling was observed in RBCs from PKD patients, as determined by increases in the levels of free (poly-/highly-unsaturated) fatty acids and acyl-carnitines. Conclusion: In conclusion, in the present study, we provide the first overview of RBC metabolism in patients with PKD. Though limited in scope, the study addresses the need for basic science to investigate pathologies targeting underrepresented minorities (Amish population in this study), with the ultimate goal to target treatments to health disparities.
| S-EPMC8567077 | biostudies-literature