The world’s first genetic test for Huntington’s disease using nanopore-based DNA sequencing technology is now available at Guy’s and St Thomas’ NHS Foundation Trust. The test could drastically cut the waiting time for the most complicated cases of Huntington’s disease and has huge potential for other genetic disorders in the future.

The breakthrough was achieved by a collaboration between Viapath, the NIHR Guy’s and St Thomas’ Biomedical Research Centre and its academic partner King’s College London, and the London South Genomic Laboratory Hub.

The team used MinION DNA sequencing devices made by Oxford Nanopore Technologies that provide results much faster than traditional testing methods. They have shown for the first time that these sequencing devices can meet the stringent, internationally recognized standards for use in clinical laboratories, providing ‘proof-of-principle’ that this new technology can be used in the NHS.

The MinION is a small hand-held device that ‘decodes’ individual strands of DNA in real-time. It identifies any changes in the DNA sequence and then matches these to a library of known genetic sequences to detect presence of the genetic disorder. Most current technologies provide segments of DNA sequence that need to be analysed at a later date, which leads to a longer wait for results.

Huntington’s disease is an inherited neuro-degenerative disorder which stops parts of the brain working properly, with symptoms worsening over time, and is usually fatal within 20 years. Currently individuals with symptoms of Huntington’s disease have a blood test and can wait up to four weeks for the result.

Dr Deborah Ruddy, consultant clinical geneticist at Guy’s and St Thomas’, said: “This technology means that test results for people with symptoms of Huntington’s disease could be reduced to less than one week. We are now conducting research to determine where else this new technology could speed up diagnosis of other genetic disorders.

“Although there is no cure for Huntington’s disease as yet, treatment and support can help reduce some of the problems it causes. The technology can reduce the distress that patients and families experience whilst waiting for results, and also administer treatments and make support available to patients sooner than previously possible.”

This is the first time that Oxford Nanopore Technology has been used in an NHS laboratory accredited by the United Kingdom Accreditation Service (UKAS), which requires the technology to meet stringent quality control standards and produce reliable results on every sample.

Professor Jonathan Edgeworth, Viapath’s Medical Director, said: “This advance was made possible through a research partnership involving front-line clinicians, academics and healthcare scientists. Everyone came together with a single vision to speed up the pathway moving scientific discovery and technological advance to the bed-side. This approach will be of immense benefit to patients. We are evaluating whether this technology can speed up diagnosis of a range of diseases including infections and cancers, to more rapidly identify best treatments based on individual DNA profiles.”

www.guysandstthomasbrc.nihr.ac.uk/

www.nihr.ac.uk/patientdata

A new study from BUSM and BUSPH identifies a pattern of inflammation associated with cardio-metabolic risks among participants in the Black Women’s Health Study, as well as two independent groups of vulnerable women. These findings could help underserved patients benefit from precision medicine and personalized profiles of disease risk.
According to the researchers, body mass index alone is an imperfect measure of obesity-associated disease risks, such as for Type 2 diabetes, because there are some individuals with chronic obesity who are apparently protected from cardio-metabolic complications and lean individuals with high cardiovascular and diabetes risks. Abnormal, unresolved inflammation in blood and adipose (fat) tissue, rather than obesity per se, is thought to be important for development of disease. Certain biomarkers show promise in predicting obesity-associated diabetes risk; however, the clinical utility of single biomarkers is limited for complex disease phenotypes such as these.
The research team took a data-driven, systems biology approach to discover six cytokine signatures associated with Type 2 diabetes risk in a vulnerable population: African American women with obesity and varying degrees of metabolic health. These six distinct signatures are patterns of sixteen cytokines/chemokines that promote or reduce inflammation.
Analyses of plasma samples from participants in the Black Women’s Health Study, formed the basis for the discovery dataset, which was then validated in two separate groups, African American women volunteers with obesity who had donated plasma to the Komen Tissue Bank, and African American women with obesity who were breast reduction surgical patients at a safety net hospital in Greater Boston. The patterns or signatures in the validation cohorts closely resembled the distributions in the discovery cohort.
“These findings are highly relevant to an understudied and underserved population that experiences elevated risks for co-morbidities of obesity. The overall impact of this report is high because of the potential utility of the new signatures just discovered and validated, which could assist clinical decision making with more personalized information,” explained corresponding author Gerald V. Denis, PhD, Associate Professor of Pharmacology and Medicine at BUSM.

Boston University School of Medicine
www.bumc.bu.edu/busm/2018/05/08/new-study-provides-insight-into-blood-signatures-of-inflammation/

Mathilde came into the world with chubby cheeks and a full head of auburn hair. But she was a very sick baby, and was immediately transferred on January 19, 2013 to the Neonatal Intensive Care Unit at the Montreal Children’s Hospital of the McGill University Health Centre (MCH-MUHC). By the time she arrived, she was sicker than initially expected; Mathilde’s small head was of particular concern to doctors. She underwent neurological tests, and sadly, they came back abnormal: her brain hadn’t developed properly and her brain white matter (or myelin) was found to be atypical. Doctors confirmed she was suffering from an unidentified kind of genetic leukoencephalopathy, a family of diseases affecting both the nerve cells and the white matter. Mathilde passed away when she was two-and-a-half months old, surrounded by the people who loved her most.
Thanks to an international effort led by physician-scientists at Rady Children’s Institute for Genomic Medicine (RCIGM)-San Diego in California, Dr. Geneviève Bernard’s team at the Research Institute of the McGill University Health Centre (RI-MUHC) was able to confirm the diagnosis for Mathilde: she died from VARS-related disorder, an extremely rare neurodevelopmental condition. Their findings are paving the way for the first step in developing potential therapies for this rare neurodegenerative condition.
Investigators performed advanced genetic tests on blood samples from seven children with neuro-developmental disabilities who were evaluated by doctors in San Diego, Montreal and Cairo. This led to the discovery of mutations in the VARS gene, which had not previously been linked to human disease.
“These children showed epileptic seizures and abnormalities evident on brain MRI scans,” said lead study’s author Joseph Gleeson, MD, director of neurodevelopmental genetics at RCIGM and professor of neuroscience and pediatrics at UC San Diego School of Medicine. “Although no treatment currently exists for this condition, the results are important as the first step in guiding research directed at targeted therapies.”
The genetic mutations identified in the study led to a defect in the enzyme responsible for generating proteins containing the amino acid valine, which is necessary for cellular health. Genetic variations that damage these types of enzymes are associated with a variety of human diseases including microcephaly and neuropathy.
In this study, the team found that enzymatic activity was significantly reduced in cells from their young patients. The findings suggest that children with this disorder may benefit from treatments to support the synthesis of new valine-containing proteins in the brain.

McGill University Health Centrehttps://tinyurl.com/yxjg3dp5

Researchers have discovered a way to better predict progression of Alzheimer’s disease. By imaging microglial activation levels with positron emission tomography (PET), researchers were able to better predict progression of the disease than with beta-amyloid PET imaging, according to a study published.
According to the Alzheimer’s Association, an estimated 5.3 million Americans are currently living with Alzheimer’s disease. By 2025, that number is expected to increase to more than seven million. The hallmark brain changes for those with Alzheimer’s disease include the accumulation of beta-amyloid plaques. When microglial cells from the central nervous system recognize the presence of beta-amyloid plaques, they produce an inflammatory reaction in the brain.
“The 18-kD translocator protein (TSPO) is highly expressed in activated microglia, which makes it a valuable biomarker to assess inflammation in the brain,” said Matthias Brendel, MD, MHBA, at Ludwig-Maximilians-University of Munich in Germany. “In our study, we utilized TSPO-PET imaging to determine whether microglial activation had any influence on cognitive outcomes in an amyloid mouse model.”
In the study, researchers compiled a series of PET images for 10 transgenic mice with beta-amyloid proteins and seven wild-type mice. TSPO PET imaging of activated microglia was conducted at eight, 9.5, 11.5 and 13 months, and beta-amyloid PET imaging was performed at eight and 13 months. Upon completion of the imaging, researchers then subjected the mice to a water maze in which the mice were to distinguish between a floating platform that would hold their weight and one that would sink. The tasks were performed several times a day during a 1.5-week period. Memory performance in the water maze was assessed by measuring the average travel time from the start point to a platform each day of training and by calculating the travelled distance at the last day of training. After completing the water maze task, immunohistochemistry analyses were performed for microglia, amyloid and synaptic density.
Transgenic mice with the highest TSPO PET signal in the forebrain or other areas associated with spatial learning tended to have better cognitive performance in the water maze, while beta-amyloid signals in the same areas of the brain showed no correlation to cognitive outcomes in the maze. Researchers found that an earlier microglial response to amyloid pathology in transgenic mice also protected synaptic density at follow-up. Specifically, transgenic mice with higher TSPO expression at eight months had much better cognitive outcomes in the water maze and higher synaptic density as confirmed by immunochemistry analyses.
“This study provides the first evidence that the level of microglial activation could be a far better predictor of current and future cognitive performance than beta-amyloid levels,” noted Brendel. “Keeping the limitations of mouse models in mind, it could be crucial to modify an individual’s microglial activation state to ameliorate future cognitive decline. We believe that a balanced microglia activation is crucial for prevention of cognitive impairment.”
Society of Nuclear Medicine and Molecular Imaging https://tinyurl.com/y6jyl4mw

QIAGEN announced on August 1st that its careHPV™ Test, one of the only molecular diagnostics for high-risk human papillomavirus (HPV) designed to screen women in low-resource settings, has been added to the World Health Organization (WHO) list of prequalified in vitro diagnostics (IVDs). HPV is the primary cause of cervical cancer, so screening women for the presence of the virus is a critical aspect for prevention and early treatment of the deadly cancer. The careHPV Test was launched globally in 2010 and through numerous pilot studies has demonstrated to be a more sensitive alternative to cytology and visual inspection based methods for the detection of pre-cancerous cell abnormalities. The WHO’s evidence-based listing is expected to expand the availability of this critical diagnostic tool in countries that rely on the global organization’s list in making purchasing decisions. The WHO Prequalification status will significantly broaden access to HPV DNA testing to areas of the world with a high burden of cervical cancer.
 
“The WHO prequalified IVD listing is a ‘stamp of approval’ for our innovative careHPV Test, and this will encourage authorities to adopt efficient, highly accurate HPV screening for prevention of cervical cancer in settings with limited healthcare infrastructure,” said Thierry Bernard, Senior Vice President, Molecular Diagnostics Business Area, for QIAGEN. “China routinely uses careHPV in rural or low-resource areas, and QIAGEN partners with non-governmental organizations and health ministries in developing countries. We expect the WHO listing to drive further dissemination of this important tool for women’s health.”
 
QIAGEN’s fast, portable and easy-to-use careHPV Test combines the power of advanced molecular technologies with innovative design features for areas lacking consistent electricity, water or a controlled laboratory environment. For example, the system has color-coded, easy-to-understand menus and self-contained reagents. The test tolerates temperature variations that occur in rural clinics lacking refrigeration due to limited electricity or water, and can provide results much faster than traditional laboratory based methodologies. The careHPV Test was developed with support from PATH, an international nonprofit organization, and is manufactured by QIAGEN in Shenzhen, China.
 
“High-quality molecular HPV tests that are easy to run are critical for expansion of cervical cancer prevention strategies in low-resource settings. WHO prequalification of careHPV is excellent news that will help countries to choose the best and most suitable technology for their programs. To achieve higher coverage of at-risk women and make an impact in cervical cancer prevention, we need to move to affordable and cost-effective strategies with HPV testing leveraging self-sampling potentially,” said Dr. Silvia de Sanjosé, Director of Scale-Up project at PATH, a global organization that works to accelerate health equity by bringing together public institutions, businesses, social enterprises, and investors to solve the world’s most pressing health challenges.
 
The careHPV Test for low-resource settings is highly complementary with QIAGEN’s digene HC2 HPV Test, the world’s most validated and sensitive diagnostic test for detection of high-risk HPV. The digene HC2 HPV Test is recognized as the “gold standard” in HPV screening and is widely used in developed countries and in large cities in emerging markets.
 
Cervical cancer is the fourth most common cancer among women worldwide, with an estimated 528,000 new cases and 266,000 deaths in 2012, the most recent year for which WHO publishes statistics. An estimated 80% of new cases and deaths occur in developing countries, where awareness of the disease and access to preventive tests and medical treatment is low. In many low-resource areas, cervical cancer has eclipsed breast cancer as the primary cancer killer of women.