Breaking News
October 22, 2018 - Compression Collar May Protect Brain of Female Soccer Players
October 22, 2018 - Technique visualizes neuron communication
October 22, 2018 - Advancement in medical imaging methods for health care
October 22, 2018 - Takeda presents vedolizumab phase 3 VISIBLE 1 trial results for treatment of moderately to severely active ulcerative colitis
October 22, 2018 - Immunotherapy increases survival in some patients with metastatic triple negative breast cancer
October 22, 2018 - Exelixis presents CABOSUN and METEOR trial results in patients with advanced renal cell carcinoma
October 22, 2018 - LYNPARZA Phase III SOLO-1 results show improved outcome for patients with advanced BRCA-mutated ovarian cancer
October 22, 2018 - Brainlab unveils ExacTrac Dynamic at ASTRO meeting in San Antonio, Texas
October 22, 2018 - Not exercising is worse than smoking, diabetes or heart disease finds study
October 22, 2018 - Shorter course of trastuzumab could be an option for women with HER2+ early breast cancer
October 22, 2018 - Map of Mouse Hippocampus Could Be Weapon Against Alzheimer’s
October 22, 2018 - Psychotropic polypharmacy is common in Alzheimer’s disease
October 22, 2018 - Texas A&M and UTA establish Texas Genomics Core Alliance
October 22, 2018 - Analyzing mouse’s potential as animal model of decision-making
October 22, 2018 - Radiotherapy can prolong survival in prostate cancer
October 22, 2018 - A genetic mutation involved in relapse
October 21, 2018 - Report reveals growing impact of cannabis on young people
October 21, 2018 - NSF awards $5 million grant to help scientists magnify societal impact of research
October 21, 2018 - Fertility Rates Down for Each Urbanization Level 2007 to 2017
October 21, 2018 - Genetically engineered 3-D human muscle transplant in a murine model
October 21, 2018 - Moms’ tight work schedules may affect their children’s sleep
October 21, 2018 - AHA: No Direct Link Between Preeclampsia and Cognitive Impairment, Study Finds
October 21, 2018 - Weight loss success linked with active self-control regions of the brain
October 21, 2018 - Scripps researchers successfully test potential new smoking-cessation treatment in rodents
October 21, 2018 - More accurate and less stressful way to measure a baby’s heartbeat
October 21, 2018 - Researchers show better cardiorespiratory fitness leads to longer life
October 21, 2018 - Healthy candies for diabetic patients
October 21, 2018 - Environment impact of microplastics remains unclear
October 21, 2018 - Antibiotics for appendicitis? Surgery often not needed
October 21, 2018 - AHA and AMA recognize more than 800 medical practices, health systems for blood pressure control
October 21, 2018 - Scientists obtain clearest ever image of Ebola virus protein
October 21, 2018 - Study reveals connection between two proteins known to be hyperactive in cancer
October 21, 2018 - Gabapentin Beats Pregabalin for Chronic Sciatica
October 21, 2018 - Cosmetic surgeons offering incomplete information for breast augmentation customers
October 21, 2018 - Chronic sleep disruption in early adult life accelerates AD-related tau pathology
October 21, 2018 - Take 10 for Mindfulness – Drugs.com MedNews
October 21, 2018 - Length of breathing disruption in OSA may be better predictor of mortality risk
October 21, 2018 - ApoE4 gene linked with chronic inflammation increases risk for Alzheimer’s disease
October 21, 2018 - Mother-daughter conflict associated with suicide risk in abused adolescent girls
October 21, 2018 - Scientists molding bacteria into unnatural shapes
October 21, 2018 - High diet quality associated with lower risk of death in colorectal cancer patients
October 21, 2018 - Discharged mental health patients ‘at greater risk of dying’
October 21, 2018 - Research provides insight into neurobiology of aggression and bullying
October 21, 2018 - As billions in tax dollars flow to private Medicaid plans, Who’s minding the store?
October 21, 2018 - Neuroscientists identify brain region that appears to be related to food preference decisions
October 21, 2018 - Deaths related to air pollution in the U.S. decreased by 47% between 1990 and 2010
October 21, 2018 - Study shows correlation between spatial memory and the sense of smell
October 21, 2018 - Increased cardiorespiratory fitness associated with reduced long-term mortality
October 21, 2018 - IU researchers receive $1.55 million from NIH to improve chronic-disease management
October 21, 2018 - Income and wealth affect the mental health of Australians, study shows
October 21, 2018 - Patients with hypertension and psoriasis more often require cardiovascular interventions
October 20, 2018 - Leading hip-hop videos depict use of tobacco and marijuana products, study finds
October 20, 2018 - Dose Range of IV Ketamine for Adjunct Tx of Depression Tested
October 20, 2018 - Infants can distinguish between leaders and bullies, study finds
October 20, 2018 - Mad Cow disease found on Aberdeenshire farm
October 20, 2018 - Study identifies factors associated with prescription opioid misuse among students
October 20, 2018 - Scientists uncover key regulator of mTORC1 in cancer growth
October 20, 2018 - Pounds Regained After Weight-Loss Op Can Tell Your Doc a Lot
October 20, 2018 - Sending parents letters to fight childhood obesity doesn’t work
October 20, 2018 - Supervised aerobic exercise can support major depression treatment
October 20, 2018 - Mindfulness-based program effective for reducing stress in infertile women
October 20, 2018 - Molecule capable of halting and reverting neurodegeneration caused by Parkinson’s disease identified
October 20, 2018 - Midazolam-mediated alterations of PER2 expression may have functional consequences during myocardial ischemia
October 20, 2018 - Sweat bees are ideal for studying the genes underlying social behavior
October 20, 2018 - Weight loss success associated with brain areas involved in self-control
October 20, 2018 - KHN’s ‘What the Health?’ Republicans’ preexisting political problem
October 20, 2018 - Research provides a more complete picture of suffering caused by terrorist attacks
October 20, 2018 - Eradicating Helicobacter pylori infections may be a key treatment for Parkinson’s disease
October 20, 2018 - Breast Cancer as a Dynamic Disease
October 20, 2018 - University of Pittsburgh wins NSF grant for big data research to prevent complications from anesthesia
October 20, 2018 - Skin-to-skin contact may promote attachment between parents and preterm infants
October 20, 2018 - Recommendations Developed to Verify NGT Placement in Children
October 20, 2018 - Weight loss can be boosted fivefold thanks to novel mental imagery technique
October 20, 2018 - Children with autism are more likely to be overweight, obese
October 20, 2018 - Nurses making conscientious objections to ethically-relevant policies lack support
October 20, 2018 - Prion strain diversity may be greater than previously thought
October 20, 2018 - Antidepressant treatment may lead to improvements in sleep quality of patients with depression
October 20, 2018 - Study reports increased risk of death in children with inflammatory bowel disease
October 20, 2018 - Number of Autism Genes Now Tops 100
October 20, 2018 - Total diet replacement programmes are effective for treating obesity
Extracellular RNA in urine may provide useful biomarkers for muscular dystrophy

Extracellular RNA in urine may provide useful biomarkers for muscular dystrophy

image_pdfDownload PDFimage_print

Massachusetts General Hospital (MGH) researchers have found that extracellular RNA (exRNA) in urine may be a source of biomarkers for the two most common forms of muscular dystrophy, noninvasively providing information about whether therapeutic drugs are having the desired effects on a molecular level. The report published in online journal Nature Communications, is the first to show that urine exRNA can be used to monitor systemic diseases that do not directly affect the urinary tract.

“Our findings could facilitate drug development by offering a convenient, painless and relatively low-cost assay that may reduce and perhaps eventually eliminate the need for multiple invasive muscle biopsies to track disease activity and therapeutic response,” says Thurman Wheeler, MD, MGH Department of Neurology, senior author of the report. “Urine exRNA monitoring could determine whether a drug is reaching its target long before clinical effects on muscle function could be detected and may enable early identification of whether dosage adjustments may be required, something that would be impossible with invasive muscle biopsies.”

There are several types of muscular dystrophy, all of which lead to progressive muscle weakness and loss of muscle mass. Duchenne muscular dystrophy (DMD) is the most common form, with symptoms that usually begin in children under the age of 5. Myotonic muscular dystrophy (DM) is the most common adult-onset form and has two subtypes—DM1 and DM2. Each form is caused by a different gene mutation. In DMD, the mutation affects the gene for dystrophin, a protein essential to the strength of muscle fibers. DM-associated mutations—in the DMPK gene for DM1 and in the CNBP gene for DM2—involve excessive repeats of nucleotides, leading to abnormal processing of RNA molecules.

The mutation associated with DM1 affects RNA splicing, the process that removes non-coding segments from an RNA molecule. A single gene can normally give rise to several different proteins, with the differences being determined by alternative RNA splicing patterns. The DM1 mutation interferes with appropriate splicing of RNAs encoding several other proteins, and analysis of RNA splice variants in muscle biopsies has been used to determine disease severity in patients. In animal models, splice variants in muscle tissue have been used to indicate whether potential therapies are reaching their molecular target. A less invasive way of assessing disease severity and therapeutic response could expand the number of patients who could receive therapeutic drugs or participate in clinical trials. For example, a recent clinical trial for a DM1 drug was restricted to adult patients partially because of the need for repeat muscle biopsies.

Carried through bodily fluids like blood and urine in membrane bubbles called vesicles, exRNA encompasses messenger, non-coding, and microRNA molecules and can reflect mutations, deletions and other molecular variants. A few muscular-dystrophy-associated RNA or protein biomarkers have been identified in the blood of patients. Even though it seemed unlikely that exRNA from the skeletal and cardiac muscle tissues affected by DM1 could pass through the kidney’s filtration system into the urine, urine is such an easily accessible fluid that Wheeler’s team analyzed vesicles from both blood and urine for exRNAs that could reflect results of the DM1 mutation.

Their experiments comparing urine exRNAs from DM1 patients, patients with two other forms of muscular dystrophy and unaffected control volunteers identified 10 transcripts that are alternatively spliced in a pattern unique to DM1 patients, most of which had been previously found in patient muscle biopsies. A composite biomarker incorporating these 10 transcripts was 100 percent accurate in distinguishing DM1 patients from unaffected controls in a different group of participants. Samples taken from untreated DM1 patients over several months indicated consistency of splicing patterns within an individual, suggesting that repeat sampling could accurately reflect disease state and treatment response.

Along with developing a more precise assay for rapid measurement of alternative RNA splicing in urine and other bodily fluids, the team showed that splicing patterns in total RNA from the cells in the urine were different from and less useful as biomarkers than those from exRNAs and found that exRNAs in blood could not distinguish between DM1 patients and controls. They also found that the splicing patterns of some urine exRNA transcripts reflected the severity of DM1 symptoms, and that a small group of asymptomatic patients with the DM1 mutation had urine exRNA splicing patterns midway between those of symptomatic patients and unaffected controls.

A group of drugs being evaluated for the treatment of DMD manipulate splicing of the dystrophin gene in order to remove a specific exon—a protein-coding segment of RNA—producing a shortened but partially functional version of the dystrophin protein. The MGH team showed that urine exRNAs from six untreated DMD patients accurately reflected the specific gene mutation in each patient. In two DMD patients being treated with eteplirsen—an FDA-approved DMD drug that induces skipping of the target exon—analysis of urine exRNA was able to confirm the drug was reaching its molecular target, the first such confirmation not provided by muscle biopsy.

“Our demonstration of disease-specific splice variants in urine exRNA suggests the value of biofluids as a means of identifying novel splice variants that may help correlate gene variants with symptoms for several diseases for which noninvasive biomarkers are unavailable,” says Wheeler, an assistant professor of Neurology at Harvard Medical School. “These findings support studies of exRNA from urine, blood or cerebrospinal fluid as biomarker replacements for tissue biopsies in other conditions with altered RNA splicing—including other types of muscular dystrophy, spinal muscular atrophy and amyotrophic lateral sclerosis.”


Explore further:
New research increases understanding of Duchenne muscular dystrophy

More information:
Layal Antoury et al, Analysis of extracellular mRNA in human urine reveals splice variant biomarkers of muscular dystrophies, Nature Communications (2018). DOI: 10.1038/s41467-018-06206-0

Journal reference:
Nature Communications

Provided by:
Massachusetts General Hospital

Tagged with:

About author

Related Articles