HAE patient self-sampling for biomarker establishment

Abstract Background Hereditary Angioedema (HAE) is a genetic disorder that leads to frequent angioedema attacks in various parts of the body. In most cases it is caused by pathogenic variants in the SERPING1 gene, coding for C1-Inhibitor (C1-INH). The pathogenic variants in the gene result in reduced C1-INH levels and/or activity, which causes aberrant bradykinin production and enhanced vascular permeability. The standard-of-care diagnostic test is performed biochemically via measuring C1-INH level and activity as well as the C4 level. This, however, does not allow for the diagnosis of HAE types with normal C1-INH. There is an urgent need to identify and characterize HAE biomarkers for facilitating diagnostics and personalizing the treatment. The Hereditary Angioedema Kininogen Assay (HAEKA) study aims to measure the dynamics of cleaved High Molecular Weight Kininogen (HKa) and other metabolite levels during the angioedema and non-angioedema state of the disease. The metabolites will be analyzed and verified by liquid chromatography ion mobility high resolution mass spectrometry (LC/IM-QToF MS) of dried blood spot (DBS) cards upon the study completion. The study design is truly innovative: 100 enrolled participants provide blood samples via DBS: (1) every 3 months within 2 years during regular study site visits and (2) by at-home self-sampling during HAE attacks via finger pricking. We are presenting a project design that permits clinical study activities during pandemic contact restrictions and opens the door for other clinical studies during COVID-19. Results As of October 2020, there are 41 patients from 5 sites in Germany enrolled. 90 blood samples were collected during the regular visits, and 19 of the participants also performed self-sampling during the HAE attacks from which a total of 286 attack blood samples were collected. Participating patients rate the study procedures as easy to implement in their daily lives. The concept of home self-sampling is effective, reproducible, and convenient especially in times of contact restrictions due to the COVID-19 pandemic. Conclusions It is the hope that the HAEKA study will complete in 2023, reveal biomarker(s) for monitoring HAE disease activity, and may help to avoid HAE attacks via applying medication prior to the symptom onset.

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Hereditary angioedema: Differential diagnosis, diagnostic tests, and family screening

Allergy and Asthma Proceedings ◽

10.2500/aap.2020.41.200062 ◽

2020 ◽

Vol 41 (6) ◽

pp. S22-S25 ◽

Cited By ~ 4

Author(s):

Michael E. Manning

Keyword(s):

Differential Diagnosis ◽

Hereditary Angioedema ◽

Diagnostic Tests ◽

Autosomal Dominant ◽

Genetic Disorder ◽

Genetic Mutation ◽

The Body ◽

Laboratory Evaluation ◽

Family Screening ◽

Common Causes

Hereditary angioedema is a rare, autosomal dominant genetic disorder that leads to sporadic episodes of swelling, which can affect any part of the body. With a prevalence of 1 in 10,000 to 1 in 50,000, there are other, more common causes of angioedema. Differentiating between bradykinin-mediated and histamine-mediated causes of swelling remains a major challenge. It is critical to develop an appropriate differential diagnosis, work through the various conditions, and obtain the pertinent laboratory evaluation to rule in or out the proposed diagnosis. As an autosomal dominant genetic disorder, there is a 50% chance with each pregnancy of passing on the genetic mutation in the SERPING1 gene. This review addressed the differential diagnosis to consider, the appropriate laboratory evaluation, and the importance of family screening.

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Berotralstat (BCX7353) is a novel oral prophylactic treatment for hereditary angioedema: Review of phase II and III studies

Allergy and Asthma Proceedings ◽

10.2500/aap.2021.42.210034 ◽

2021 ◽

Author(s):

Michael E. Manning ◽

Jay M. Kashkin

Keyword(s):

Adverse Events ◽

Phase Ii ◽

Hereditary Angioedema ◽

Prophylactic Treatment ◽

Genetic Disorder ◽

The Body ◽

Treatment Burden ◽

On Demand ◽

Phase Ii And Iii

Background: Hereditary angioedema (HAE) is a rare genetic disorder characterized by unpredictable and potentially life-threatening episodes of swelling in various parts of the body. These attacks can be painful and debilitating, and affect apatient’s quality of life. Every patient who experiences an attack should be treated with on-demand medication to mitigateattack severity and duration. Many patients with HAE also receive long-term prophylaxis to reduce the frequency and severity of edema episodes. Although long-term prophylaxis reduces the disease burden for patients with HAE, available intravenous and subcutaneous treatments are accompanied by a significant treatment burden because of the logistical, emotional, and physical challenges posed by their long-term parenteral nature. Androgens are an effective oral prophylactic treatment; however, they are associated with significant adverse events and are not suitable for all patients. Thus, the HAE community has expressed interest in the development of alternative oral prophylactic therapies for preventing HAE attacks.Objective: Here, we review the phase II and III clinical data of berotralstat (BCX7353), which was approved by the U.S. Food and Drug Administration in December 2020.Results: Berotralstat is an oral, second-generation, synthetic, small-molecule plasma kallikrein inhibitor taken once dailyfor the prevention of HAE attacks in patients ages greater than or equal to 12 years. Results from the APeX studies (APeX-1 NCT02870972, APeX-2 NCT03485911, APeX-S NCT03472040, APex-J NCT03873116) demonstrated the efficacy of berotralstat as longterm prophylaxis for patients with HAE, which showed a reduction in the attack rate and on-demand medication usage.Berotralstat was well tolerated, and gastrointestinal treatment-emergent adverse events were generally mild and selflimited.Conclusion: Oral berotralstat is an effective and safe long-term prophylactic treatment for patients with HAE that will provide patients unable to tolerate parenteral therapies with the option of disease control. Berotralstat may be associated with reduced treatment burden compared with injectable therapies, highlighting the importance of patient preference with regard tothe administration route of their HAE prophylactic treatment.

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Patient perspectives on the treatment burden of injectable medication for hereditary angioedema

Allergy and Asthma Proceedings ◽

10.2500/aap.2021.42.210025 ◽

2021 ◽

Vol 42 (3) ◽

pp. S4-S10 ◽

Cited By ~ 2

Author(s):

Cristine Radojicic ◽

Marc A. Riedl ◽

Timothy J. Craig ◽

Jessica M. Best ◽

Jinky Rosselli ◽

...

Keyword(s):

Hereditary Angioedema ◽

Online Survey ◽

Treatment Options ◽

The Body ◽

Significant Treatment ◽

Daily Lives ◽

The Usa ◽

Current Therapies ◽

Survey Results ◽

Patients Experience

Hereditary angioedema (HAE) is a rare, chronic disease characterized by debilitating swelling episodes in various parts of the body. Patients experience significant burdens related to the symptoms and management of HAE, which can affect their daily lives and reduce their overall quality of life. Prophylactic treatment options have expanded in the past decade to the benefit of patients; however, these therapies require scheduled injections, which can be painful, burdensome, and time consuming. We conducted an online survey of patients with HAE in the USA to better understand their experiences with available prophylactic medications and the associated treatment burdens. Our survey results suggest that most patients are satisfied with their current therapies but desire novel medications with a simpler route of administration and that, although most patients experience significant treatment-related burdens, they learn to cope with these challenges over time.

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Physician and patient perspectives on the management of hereditary angioedema: a survey on treatment burden and needs

Allergy and Asthma Proceedings ◽

10.2500/aap.2021.42.210017 ◽

2021 ◽

Vol 42 (3) ◽

pp. S17-S25 ◽

Cited By ~ 1

Author(s):

Marc A. Riedl ◽

Timothy J. Craig ◽

Aleena Banerji ◽

Kavita Aggarwal ◽

Jessica M. Best ◽

...

Keyword(s):

United States ◽

Hereditary Angioedema ◽

Standard Of Care ◽

The United States ◽

The Body ◽

Current Standard ◽

Prescribing Trends ◽

Individualized Approach ◽

The Impact

Hereditary angioedema (HAE) is a rare disorder caused by genetic mutations that lead to recurrent episodes of swelling in various parts of the body. Prophylactic treatment is common for patients with HAE, and the therapeutic options have expanded in recent years. The current standard of care for prophylactic HAE therapies is subcutaneous treatment, which can be self-administered at home, greatly improving patient quality of life. As new therapies emerge, it is important for patients and physicians to discuss the risks and benefits associated with each treatment to develop an individualized approach to HAE management. We conducted surveys of patients with HAE and physicians who treat patients with HAE to identify prescribing trends for prophylactic HAE treatments and the impact that such treatments has on patients. Our results confirmed that newer, subcutaneous therapies are prescribed for HAE prophylaxis more frequently than other therapies in the United States and that treatment burdens still exist for patients with HAE. We found that physicians and patients were not always aligned on how treatment choices affect patients’ lives, which may mean that there are opportunities for enhanced patient‐physician dialog and shared decision-making in HAE management in the United States.

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Measuring Exposome Associated with Health

Global Clinical and Translational Research ◽

10.36316/gcatr.02.0030 ◽

2020 ◽

pp. 46-50

Keyword(s):

Mass Spectrometry ◽

Remote Sensing ◽

High Resolution ◽

Biological Effect ◽

High Resolution Mass Spectrometry ◽

The Body ◽

Ecological Environment ◽

Special Issue ◽

The Life Course ◽

Resolution Mass

The concept of exposome has received increasing discussion, including the recent Special Issue of Science –"Chemistry for Tomorrow's Earth,” about the feasibility of using high-resolution mass spectrometry to measure exposome in the body, and tracking the chemicals in the environment and assess their biological effect. We discuss the challenges of measuring and interpreting the exposome and suggest the survey on the life course history, built and ecological environment to characterize the sample of study, and in combination with remote sensing. They should be part of exposomics and provide insights into the study of exposome and health.

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Holistic Metabolomic Laboratory-Developed Test (LDT): Development and Use for the Diagnosis of Early-Stage Parkinson’s Disease

Metabolites ◽

10.3390/metabo11010014 ◽

2020 ◽

Vol 11 (1) ◽

pp. 14

Author(s):

Petr G. Lokhov ◽

Dmitry L. Maslov ◽

Steven Lichtenberg ◽

Oxana P. Trifonova ◽

Elena E. Balashova

Keyword(s):

Parkinson’S Disease ◽

Molecular Weight ◽

Parkinson's Disease ◽

High Resolution Mass Spectrometry ◽

Early Stage ◽

Disease Diagnosis ◽

The Body ◽

Low Molecular Weight ◽

Low Molecular Weight Compounds

A laboratory-developed test (LDT) is a type of in vitro diagnostic test that is developed and used within a single laboratory. The holistic metabolomic LDT integrating the currently available data on human metabolic pathways, changes in the concentrations of low-molecular-weight compounds in the human blood during diseases and other conditions, and their prevalent location in the body was developed. That is, the LDT uses all of the accumulated metabolic data relevant for disease diagnosis and high-resolution mass spectrometry with data processing by in-house software. In this study, the LDT was applied to diagnose early-stage Parkinson’s disease (PD), which currently lacks available laboratory tests. The use of the LDT for blood plasma samples confirmed its ability for such diagnostics with 73% accuracy. The diagnosis was based on relevant data, such as the detection of overrepresented metabolite sets associated with PD and other neurodegenerative diseases. Additionally, the ability of the LDT to detect normal composition of low-molecular-weight compounds in blood was demonstrated, thus providing a definition of healthy at the molecular level. This LDT approach as a screening tool can be used for the further widespread testing for other diseases, since ‘omics’ tests, to which the metabolomic LDT belongs, cover a variety of them.

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The effects of nano-curcumin as a nutritional strategy on clinical and inflammatory factors in children with cystic fibrosis: the study protocol for a randomized controlled trial

Trials ◽

10.1186/s13063-021-05224-6 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Saeedeh Talebi ◽

Mahammad Safarian ◽

Mahmood Reza Jaafari ◽

Seyed Javad Sayedi ◽

Zahra Abbasi ◽

...

Keyword(s):

Cystic Fibrosis ◽

Controlled Trial ◽

Genetic Disorder ◽

The Body ◽

Inflammatory Factors ◽

Secondary Outcome ◽

Nasopharyngeal Swab ◽

Nutritional Strategy ◽

Cftr Protein ◽

The Impact

Abstract Background Cystic fibrosis (CF) is a genetic disorder, which is caused by the CFTR protein defects. Along with CFTR dysfunction, inflammation plays a key role in the disease outcomes. Inflammation may develop due to the internal dysfunction of the CFTR protein or external factors. Curcumin affects the CFTR protein function primarily as a corrector and potentiator and secondary as an anti-inflammatory and antimicrobial agent. The present study aims to assess the impact of nano-curcumin on clinical and inflammatory markers in children with CF. Methods This prospective, double blind control trial will be conducted at the Akbar Children’s Hospital in Mashhad, Iran. Children with CF will be enrolled based on the eligibility criteria. Placebo and curcumin with the maximum dose of 80 mg considering the body surface of the patients will be administrated for 3 months. The primary outcome is to evaluate inflammation based on serum interleukin-6, interleukin-10, and hs-CRP, stool calprotectin, and neutrophil count of nasopharyngeal swab. The secondary outcome involved clinical assessment via spirometry, anthropometrics, and quality of life. They will be assessed before and after 3 months. Discussion Due to the multifarious effects of curcumin on CF disease, it could be proposed as a nutritional strategy in the treatment of cystic fibrosis. Trial registration Iranian Registry of Clinical Trials IRCT20200705048018N1. Registered on July 10, 2020.

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Hyaluronate/black phosphorus complexes as a copper chelating agent for Wilson disease treatment

Biomaterials Research ◽

10.1186/s40824-021-00221-x ◽

2021 ◽

Vol 25 (1) ◽

Author(s):

Seong-Jong Kim ◽

Hye Hyeon Han ◽

Sei Kwang Hahn

Keyword(s):

Targeted Delivery ◽

Wilson Disease ◽

Copper Ions ◽

Binding Capacity ◽

Genetic Disorder ◽

Chelating Agent ◽

Black Phosphorus ◽

The Body ◽

Copper Binding

Abstract Background Wilson disease (WD) is a genetic disorder of copper storage, resulting in pathological accumulation of copper in the body. Because symptoms are generally related to the liver, chelating agents capable of capturing excess copper ions after targeted delivery to the liver are highly required for the treatment of WD. Methods We developed hyaluronate-diaminohexane/black phosphorus (HA-DAH/BP) complexes for capturing copper ions accumulated in the liver for the treatment of WD. Results HA-DAH/BP complexes showed high hepatocyte-specific targeting efficiency, selective copper capturing capacity, excellent biocompatibility, and biodegradability. HA enhanced the stability of BP nanosheets and increased copper binding capacity. In vitro cellular uptake and competitive binding tests verified targeted delivery of HA-DAH/BP complexes to liver cells via HA receptor mediated endocytosis. The cell viability test confirmed the high biocompatibility of HA-DAH/BP complexes. Conclusion HA-DAH/BP complexes would be an efficient copper chelating agent to remove accumulated copper in the liver for the WD treatment.

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Diagnostic amyloid proteomics: experience of the UK National Amyloidosis Centre

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2019-1007 ◽

2020 ◽

Vol 58 (6) ◽

pp. 948-957 ◽

Cited By ~ 3

Author(s):

Diana Canetti ◽

Nigel B. Rendell ◽

Janet A. Gilbertson ◽

Nicola Botcher ◽

Paola Nocerino ◽

...

Keyword(s):

Simple Algorithm ◽

Enzymatic Digestion ◽

The Body ◽

Clinical Samples ◽

Correct Identification ◽

Pathogenic Variants ◽

Amyloidogenic Protein ◽

Patient Database ◽

Serious Disease ◽

The Uk

AbstractSystemic amyloidosis is a serious disease which is caused when normal circulating proteins misfold and aggregate extracellularly as insoluble fibrillary deposits throughout the body. This commonly results in cardiac, renal and neurological damage. The tissue target, progression and outcome of the disease depends on the type of protein forming the fibril deposit, and its correct identification is central to determining therapy. Proteomics is now used routinely in our centre to type amyloid; over the past 7 years we have examined over 2000 clinical samples. Proteomics results are linked directly to our patient database using a simple algorithm to automatically highlight the most likely amyloidogenic protein. Whilst the approach has proved very successful, we have encountered a number of challenges, including poor sample recovery, limited enzymatic digestion, the presence of multiple amyloidogenic proteins and the identification of pathogenic variants. Our proteomics procedures and approaches to resolving difficult issues are outlined.

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Concentrations of glucose, albumin, inorganic phosphate and sodium in the blood of beef calves at 2 ½ months of age and their relationships with subsequent weight gain

The Journal of Agricultural Science ◽

10.1017/s0021859600027933 ◽

1980 ◽

Vol 94 (1) ◽

pp. 95-104 ◽

Cited By ~ 1

Author(s):

G. J. Rowlands

Keyword(s):

Growth Rate ◽

Blood Glucose ◽

Growth Rates ◽

Inorganic Phosphate ◽

The Body ◽

The Other ◽

Growth Depression ◽

Blood Samples ◽

Beef Calves ◽

Body Weights

SummaryBlood samples were taken at 9, 10 and 11 weeks of age from 230 male Hereford × Friesian calves, the progeny of 12 Hereford bulls. Concentrations of blood glucose, serum albumin, inorganic phosphate and sodium were measured and correlated with body weights and growth rates until slaughter at 19½ months of age.Correlations between growth rates and glucose concentrations (0·44) and between growth rates and albumin concentrations (0·38) were observed until 4 months of age. Similar correlations between body weights and blood glucose or albumin concentrations persisted until 6 months of age. By 10 months, however, the correlations had begun to decline, and by slaughter they had become insignificant.Correlations between growth rates and inorganic phosphate or sodium concentrations were smaller, and also decreased with age.The effect of hypoglycaemia on growth rate was compared with the effect of enzootic pneumonia. Although the 10% of calves with the lowest glucose concentrations were growing 24% more slowly than the other calves at the time of sampling, this growth depression was not related to pneumonia, and they subsequently made up for most of the early loss of growth.Three blood samples were also taken from 22 Hereford bulls. No significant correlations were observed between the blood composition of the bulls and the body weights or weight gains of their progeny.

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