An inherited disease of myelin marked by slow, progressive neurological impairment is caused by mutations of a gene that controls lipid metabolism, a finding that may shed insight into mechanisms to control the course of multiple sclerosis (MS), a Yale team has found.

Mutations in a single gene, called FAM126A, causes a panoply of pathologies, such as developmental delay, intellectual disability, peripheral neuropathy, and muscle wasting, in addition to congenital cataracts. Until now the precise function of the gene was unknown.

The labs of Yale cell biologists Pietro De Camilli and Karin Reinisch found that the protein encoded by the gene, called hyccin, helps produce a lipid crucial to formation of the myelin sheaths that surround and protect the axons of neurons throughout the nervous system.

Their labs, working with other groups in the United States, Italy, and Germany, analysed cells from patients suffering from the disease known as Hypomyelination and Congenital Cataract and found that FAM126A mutations results in the destabilization of an enzyme complex crucial to production of myelin.

In MS, the course of the disease is critically dependent upon the reformation of myelin sheaths after immune system attacks then destroys them, eventually leading to the death of the neurons. The researchers hypothesize that the lipid that hyccin helps generate may play a key role in creation of myelin sheaths in normal development as well as in recovering MS patients. Yale University

An improved gene therapy treatment can cure mice with cystic fibrosis (CF). Cell cultures from CF patients, too, respond well to the treatment. Those are the encouraging results of a study presented by the KU Leuven Laboratory for Molecular Virology and Gene Therapy.

Cystic fibrosis or mucoviscidosis is a genetic disorder that makes the mucus in the body thick and sticky, which in turn causes clogging in, for instance, the airways and the gastrointestinal tract. The symptoms can be treated, but there is no cure for the disorder.

Cystic fibrosis is caused by mutations in the CFTR gene. This gene contains the production code for a protein that functions as a channel through which chloride ions and water flow out of cells. In the cells of CF patients, these chloride channels are dysfunctional or even absent, so that thick mucus starts building up.

“A few years ago, a new drug was launched that can repair dysfunctional chloride channels”, Professor Zeger Debyser explains. “Unfortunately, this medicine only works in a minority of CF patients. As for the impact of gene therapy, previous studies suggested that the treatment is safe, but largely ineffective for cystic fibrosis patients. However, as gene therapy has recently proven successful for disorders such as haemophilia and congenital blindness, we wanted to re-examine its potential for cystic fibrosis”.

That is why lead authors Dragana Vidović and Marianne Carlon examined an improved gene therapy treatment based on inserting the genetic material for chloride channels – coded by the CFTR gene – into the genome of a recombinant AAV viral vector, which is derived from the relatively innocent AAV virus. The researchers then used this vector to ‘smuggle’ a healthy copy of the CFTR gene into the affected cells.

Both in mice with cystic fibrosis and in gut cell cultures from CF patients, this approach yielded positive results. “We administered the rAAV to the mice via their airways. Most of the CF mice recovered. In the patient-derived cell cultures, chloride and fluid transport were restored”.

There is still a long way to go before gene therapy can be used to treat cystic fibrosis patients, Debyser clarifies: “We must not give CF patients false hope. Developing a treatment based on gene therapy will take years of work. For one thing, our study did not involve actual human beings, only mice and patient-derived cell cultures. Furthermore, we still have to examine how long the therapy works. Repeated doses might be necessary. But gene therapy clearly is a promising candidate for further research towards a cure for cystic fibrosis”. KU Leuven

A simple, ultrasensitive microRNA sensor developed by researchers from the School of Science at Indiana University-Purdue University Indianapolis, the IU School of Medicine and the IU Melvin and Bren Simon Cancer Center holds promise for the design of new diagnostic strategies and, potentially, for the prognosis and treatment of pancreatic and other cancers.

In a study the IUPUI researchers describe their design of the novel, low-cost, nanotechnology-enabled reusable sensor. They also report on the promising results of tests of the sensor’s ability to identify pancreatic cancer or indicate the existence of a benign condition by quantifying changes in levels of microRNA signatures linked to pancreatic cancer.

‘We used the fundamental concepts of nanotechnology to design the sensor to detect and quantify biomolecules at very low concentrations,’ said Rajesh Sardar, Ph.D., who developed the sensor. ‘We have designed an ultrasensitive technique so that we can see minute changes in microRNA concentrations in a patient’s blood and confirm the presence of pancreatic cancer.’ Sardar is an assistant professor of chemistry and chemical biology in the School of Science at IUPUI and leads an interdisciplinary research program focusing on the intersection of analytical chemistry and the nanoscience of metallic nanoparticles.

‘If we can establish that there is cancer in the pancreas because the sensor detects high levels of microRNA-10b or one of the other microRNAs associated with that specific cancer, we may be able to treat it sooner,’ said Murray Korc, M.D., the Myles Brand Professor of Cancer Research at the IU School of Medicine and a researcher at the IU Simon Cancer Center. Korc worked with Sardar to improve the sensor’s capabilities and led the testing of the sensor and its clinical uses as well as advancing the understanding of pancreatic cancer biology.

‘That’s especially significant for pancreatic cancer, because for many patients it is symptom-free for years or even a decade or more, by which time it has spread to other organs, when surgical removal is no longer possible and therapeutic options are limited,’ said Korc. ‘For example, diagnosis of pancreatic cancer at an early stage of the disease followed by surgical removal is associated with a 40 percent five-year survival. Diagnosis of metastatic pancreatic cancer, by contrast, is associated with life expectancy that is often only a year or less.

‘The beauty of the sensor designed by Dr. Sardar is its ability to accurately detect mild increases in microRNA levels, which could allow for early cancer diagnosis,’ Korc added.

Over the past decade, studies have shown that microRNAs play important roles in cancer and other diseases, such as diabetes and cardiovascular disorders. The new IUPUI nanotechnology-based sensor can detect changes in any of these microRNAs.

The sensor is a small glass chip that contains triangular-shaped gold nanoparticles called ‘nanoprisms.’ After dipping it in a sample of blood or another body fluid, the scientist measures the change in the nanoprism’s optical property to determine the levels of specific microRNAs.

‘Using gold nanoprisms may sound expensive, but it isn’t because these particles are so very tiny,’ Sardar said. “It’s a rather cheap technique because it uses nanotechnology and needs very little gold. $250 worth of gold makes 4,000 sensors. Four thousand sensors allow you to do at least 4,000 tests. The low cost makes this technique ideal for use anywhere, including in low-resource environments in this country and around the world.’ IUSM

Kidney disease is a major health concern worldwide. It’s estimated that 1 in 3 American adults are at risk of developing kidney disease, and 26 million adults already have kidney disease. Many are undiagnosed. Because kidney disease can go undetected until it’s too late, effective and consistent diagnosis is essential. Physicians on Mayo Clinic’s Rochester, Minn., campus – one of the world’s leading kidney disease centers – are at the forefront of an effort to standardize the diagnosis of kidney disease.

In a paper, Mayo Clinic researchers provide a detailed recommendation for standardizing the diagnosis of glomerulonephritis. This is a term used to describe various conditions involving inflammation of the glomeruli, which is the basic filtering unit in the kidneys. Inflammation prevents the kidneys from properly filtering toxins out of the blood and regulating fluid levels in the body, and, ultimately, can lead to permanent damage to the kidneys and potential kidney failure.

 “Earlier this year, we convened renal pathologists and nephrologists from around the world at Mayo Clinic to begin work on an effort that could transform the way kidney disease is diagnosed for patients everywhere,” says Sanjeev Sethi, M.D., Ph.D, professor, Department of Laboratory Medicine and Pathology, Mayo Clinic. “It was time to move the field toward diagnosing glomerulonephritis based on the underlying cause of the disease, which leads to a more personalized diagnosis and more targeted treatment for the patient.”

According to convention, glomerulonephritis historically has been classified by the pattern of inflammation in the glomerulus; however, this does not speak to the underlying cause of the disease. The recommendations published by Mayo Clinic provide a detailed approach to classifying and reporting glomerulonephritis that is based on pathology and etiology.

“The approach outlined in the consensus paper provides a detailed approach to diagnosing kidney disease that has many advantages for clinicians and patients,” says Fernando Fervenza, M.D., Ph.D., professor, Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic. “In addition to being focused on the individual patient’s pathology and potential cause of disease, this approach makes the data more adaptable should new diseases be identified by future research. It aligns with database reporting, and it focuses on information that is relevant to the patient and [his or her] potential treatment options.”

Drs. Sethi and Fervenza led the development of the consensus paper, which has been endorsed by the Renal Pathology Society with funding from the Fulk Foundation. The recommendations provided by the consensus report likely will form the basis of how glomerulonephritis is diagnosed and reported worldwide. Based on the recommendations, the kidney biopsy report will be disease and etiology based. This will provide the treating physician a clear pathway toward appropriate testing and evaluation of the underlying kidney disease, followed by correct and specific management of the underlying cause of the glomerulonephritis. The standardized reporting will make it easier for physicians to interpret the kidney biopsy report from various institutions. This is particularly true for Mayo physicians who see patients from different institutions. Thus, based on the etiology-driven kidney biopsy report, a patient visiting Mayo Clinic can be directed to the physician with expertise in the specific area, resulting in targeted, cost effective evaluation, and appropriate treatment of the underlying cause of kidney disease. Mayo Clinic