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August 25, 2017
Experimental Treatment for Niemann-Pick Disease Type C1 Appears Safe, Effective

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An experimental drug appears to slow the progression of Niemann-Pick disease type C1 (NPC1), a fatal neurological disease, according to results of a clinical study led by researchers at NIH. The study appears in The Lancet.

NPC1 is a rare genetic disorder that primarily affects children and adolescents, causing a progressive decline in neurological and cognitive functions. The Food and Drug Administration has not approved any treatments for the condition.

The drug, 2-hydroxypropyl-beta-cyclodextrin (VTS-270), is being tested under a cooperative research and development agreement between NIH and Sucampo Pharmaceuticals, Inc. In April 2017, Sucampo acquired Vtesse Inc., which previously had been developing VTS-270.

“The results are very encouraging and support continued development of VTS-270 for treating NPC1,” said Dr. Forbes Porter, clinical director at NICHD and the study’s senior author. “Compared to untreated patients we followed in an earlier study, participants who received VTS-270 scored better on a scale used to evaluate disease severity and progression, including elements such as speech, cognition and mobility.”

The researchers did not observe any serious adverse outcomes related to the drug. However, the participants, most of whom had already experienced hearing loss because of the disease, had additional hearing loss after treatment. Earlier studies had shown that the treatment carries the risk for hearing loss. In the current study, hearing loss was compensated with hearing aids, which enabled participants to go about their daily lives.

NCI Study Identifies Essential Genes for Cancer Immunotherapy

A new study identifies genes that are necessary in cancer cells for immunotherapy to work, addressing the problem of why some tumors don’t respond to immunotherapy or respond initially but then stop as tumor cells develop resistance to immunotherapy.

The study, from the National Cancer Institute, was led by Dr. Nicholas Restifo, a senior investigator with the Center for Cancer Research, with coauthors from NCI, Georgetown University, the Broad Institute of MIT and Harvard University, New York University and the University of Pennsylvania. It was published online in Nature on Aug. 7.

“There is a great deal of interest in cancer immunotherapy, especially for patients who have metastatic cancer,” said Restifo. “The response to immunotherapy can be fantastic, but understanding why some patients don’t respond will help us improve treatments for more patients.”

Cancer immunotherapy relies on T cells, a type of cell in the immune system, to destroy tumors. Restifo and his colleagues have previously shown that the infusion of large numbers of T cells can trigger complete regression of cancer in patients. They and others have also shown that T cells can directly recognize and kill tumor cells.

However, some tumor cells are resistant to the destruction unleashed by T cells. To investigate the basis for this resistance, the researchers sought to identify the genes in cancer cells that are necessary for them to be killed by T cells.

Midlife Cardiovascular Risk Factors May Increase Chances of Dementia

A large, long-term study suggests that middle- aged Americans who have vascular health risk factors—including diabetes, high blood pressure and smoking—have a greater chance of suffering from dementia later in life. The study, published in JAMA Neurology, was funded by NIH.

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“With an aging population, dementia is becoming a greater health concern. This study supports the importance of controlling vascular risk factors like high blood pressure early in life in an effort to prevent dementia as we age,” said Dr. Walter Koroshetz, director of the National Institute of Neurological Disorders and Stroke, which partially funded the study. “What’s good for the heart is good for the brain.”

The study was led by Dr. Rebecca Gottesman, professor of neurology at Johns Hopkins University. Her team analyzed the data of 15,744 people who participated in the Atherosclerosis Risk in Communities study, funded by the National Heart, Lung, and Blood Institute. From 1987 to 1989, the participants, who were black or white and 45-64 years of age, underwent a battery of medical tests during their initial examinations at one of four centers in four different states. Over the next 25 years they were examined four more times. Cognitive tests of memory and thinking were administered during all but the first and third exams.

Her team found that 1,516 participants were diagnosed with dementia during an average of 23 follow-up years. Initially, when they analyzed the influence of factors recorded during the first exams, the researchers found that the chances of dementia increased most strongly with age followed by the presence of APOE4, a gene associated with Alzheimer’s disease. Whites with one copy of the APOE4 gene had a greater chance of dementia than blacks. Other factors included race and education: blacks had a higher chance of dementia than whites; those who did not graduate from high school were also at higher risk.

In agreement with previous studies, an analysis of vascular risk factors showed that participants who had diabetes or high blood pressure, also called hypertension, had a higher chance of developing dementia. In fact, diabetes was almost as strong a predictor of dementia as the presence of the APOE4 gene.

“Our results contribute to a growing body of evidence linking midlife vascular health to dementia,” said Gottesman. “These are modifiable risk factors. Our hope is that by addressing these types of factors early, people can reduce the chances that they will suffer from dementia later in life.”

Breakthrough Method Yields Trove of Neuron Subtypes, Gene Regulators

With funding from the BRAIN Initiative, researchers using a new method they developed have discovered a trove of neuronal subtypes and gene regulators. It allows for the discovery of subtypes based on their unique profiles of molecular switches that regulate gene expression within the cell. This opens the door to potentially discovering changes in such profiles linked to brain disorders, say the researchers.

The new method, described Aug. 10 in Science, profiles molecular changes to the DNA (the genetic blueprint) known as epigenetic regulation. This is accomplished by sequencing the neuronal genomes in a way that detects modified DNA, producing a signature called the methylome. It turns out that each cell type has a unique methylome, even though the DNA itself is the same in every cell.

In the frontal cortex, the researchers identified 16 neuronal subtypes in mice and 21 subtypes in humans. Neurons that slow down brain activity were found to share more regulatory elements across mice and humans than neurons that speed up brain activity. Some of the latter excitatory neuron types appear to be unique to humans.

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