Epilepsy Drug Discovered in Fish Model Shows Promise in Pediatric Clinical Trial
“Bench-to-bedside” describes research that has progressed from basic science in animal models that has led to therapies used in patients. Now, a study in the journal Brain describes what could be considered a direct “aquarium-to-bedside” approach, taking a drug discovered in a genetic zebrafish model of epilepsy and testing it, with promising results, in a small number of children with the disease. The study was supported by NINDS.
“This is the first time that scientists have taken a potential therapy discovered in a fish model directly into people in a clinical trial,” said Dr. Vicky Whittemore, NINDS program director. “These findings suggest that it may be possible to treat neurological disorders caused by genetic mutations through an efficient and precision medicine-style approach.”
Dr. Scott C. Baraban, the William K. Bowes Jr. endowed chair in neuroscience research and professor of neurological surgery at the University of California, San Francisco, postdoctoral fellow Dr. Aliesha Griffin and colleagues used a zebrafish model of Dravet syndrome to test the drug lorcaserin and found that it suppressed seizure activity in the fish. Dravet syndrome is a severe form of pediatric epilepsy characterized by frequent daily drug-resistant seizures and developmental delays. It is caused by a genetic mutation, which Baraban’s group was able to introduce into the zebrafish to cause epilepsy.
Designer Compound May Untangle Damage Leading to Some Dementias
In a study of mice and monkeys, NIH-funded researchers showed that they could prevent and reverse some of the brain injury caused by the toxic form of a protein called tau. The results, published in Science Translational Medicine, suggest that the study of compounds, called tau antisense oligonucleotides, that are genetically engineered to block a cell’s assembly line production of tau, might be pursued as an effective treatment for a variety of disorders.
Cells throughout the body normally manufacture tau proteins. In several disorders, toxic forms of tau clump together inside dying brain cells and form neurofibrillary tangles, including Alzheimer’s disease, tau-associated frontotemporal dementia, chronic traumatic encephalopathy and progressive supranuclear palsy. Currently there are no effective treatments for combating toxic tau.
“This compound may literally help untangle the brain damage caused by tau,” said the study’s senior author, Dr. Timothy Miller of Washington University, St. Louis.
Grants from NINDS and NIA supported the research.
Antisense oligonucleotides are short sequences of DNA or RNA programmed to turn genes on or off. Led by Sarah L. DeVos, a graduate student in Miller’s lab, the researchers tested sequences designed to turn tau genes off in mice that are genetically engineered to produce abnormally high levels of a mutant form of the human protein. Tau clusters begin to appear in the brains of 6-month-old mice and accumulate with age. The mice develop neurologic problems and die earlier than control mice.
Injections of the compound into the fluid filled spaces of the mice brains prevented tau clustering in 6- to 9-month-old mice and appeared to reverse clustering in older mice. The compound also caused older mice to live longer and have healthier brains than mice that received a placebo. In addition, the compound prevented the older mice from losing their ability to build nests.
“These results open a promising new door,” said NINDS program director Dr. Margaret Sutherland. “They suggest that antisense oligonucleotides may be effective tools for tackling tau-associated disorders.”
Aspirin May Help Increase Pregnancy Chances in Women With High Inflammation
A daily low dose of aspirin may help a subgroup of women, those who have previously lost a pregnancy, to successfully conceive and carry a pregnancy to term, according to an analysis by NIH researchers. The women who benefited from the aspirin treatment had high levels of C-reactive protein (CRP), a substance in the blood indicating system-wide inflammation, which aspirin is thought to counteract. The study appears in the Journal of Clinical Endocrinology and Metabolism.
Researchers at NICHD analyzed data originally obtained from the Effects of Aspirin in Gestation and Reproduction trial. The trial sought to determine if daily low-dose aspirin could prevent subsequent pregnancy loss among women who had one or two prior losses.
For the current study, researchers classified the women into 3 groups: low CRP (below .70 mg per liter of blood), mid CRP (from .70 to 1.95) and high CRP (at or above 1.95). Women within each group received either daily low-dose aspirin or a placebo. In their analysis, researchers found no significant differences in birth rates between those receiving aspirin and those receiving placebo in both the low-CRP and mid-CRP groups. For the high-CRP group, those taking the placebo had the lowest rate of live birth at 44 percent, while those taking daily aspirin had a live-birth rate of 59 percent. Aspirin also appeared to reduce CRP levels in the high-CRP group.
Stem Cell Secretions May Protect Against Glaucoma
A new study in rats shows that stem cell secretions, called exosomes, appear to protect cells in the retina, the light-sensitive tissue in the back of the eye. The findings, published in Stem Cells Translational Medicine, point to potential therapies for glaucoma, a leading cause of blindness in the U.S. The study was conducted by NEI researchers.
Exosomes are tiny membrane-enclosed packages that form inside of cells before getting expelled. Long thought of as part of a cellular disposal system, exosomes are packed, scientists have recently discovered, with proteins, lipids and gene-regulating RNA. Studies have shown that exosomes from one cell can be taken up by another by fusing with the target cell’s membrane, spurring it to make new proteins. Exosomes also facilitate cell-to-cell interactions and play a signaling role, prompting research into their potential therapeutic effect.
In his study, NEI postdoctoral fellow Dr. Ben Mead investigated the role of stem cell exosomes on retinal ganglion cells, a type of retinal cell that forms the optic nerve that carries visual information from the eye to the brain. The death of retinal ganglion cells leads to vision loss in glaucoma and other optic neuropathies.
Stem cells have been the focus of therapeutic attempts to replace or repair tissues because of their ability to morph into any type of cell in the body. However, from a practical standpoint, using exosomes isolated from stem cells presents key advantages over transplanting whole stem cells.
“Exosomes can be purified, stored and precisely dosed in ways that stem cells cannot,” Mead said.
Another important advantage of exosomes is they lack the risks associated with transplanting live stem cells into the eye, which can potentially lead to complications such as immune rejection and unwanted cell growth.