"Suberoylanilide hydroxamic acid (SAHA) holds promise as a first-generation drug for the prevention and treatment of familial frontotemporal dementia (FTD), a progressive, inherited neurodegenerative disease for which there is no treatment," said Dr. Joachim Herz, director of the Center for Alzheimer's and Neurodegenerative Diseases and the study's senior author.
"SAHA is already approved for clinical use in an unrelated condition, which should make it easier to move quickly to human trials," added Dr. Herz, professor of molecular genetics and neuroscience at UT Southwestern.
FTD – usually diagnosed around age 60 – trails only Alzheimer's disease among non-elderly dementias. The as-yet untreatable condition is marked by a progressive deterioration in decision-making ability, behavioral control and/or language skills.
In a study available online and in the current issue of the Journal of Biological Chemistry, UT Southwestern researchers from the Alzheimer's Center, the Harold C. Simmons Comprehensive Cancer Center and the Protein Chemistry Technology Center showed that SAHA increased the cell-signalling protein progranulin (GRN) levels in a dose-dependent way in cultured mouse cells and also demonstrated that it restored near-normal GRN production in cells from human subjects with FTD.
Up to 25 percent of patients with FTD have an inherited form of the disease that is thought to be caused by one of several genetic mutations that reduce production of GRN, Dr. Herz said. Because familial FTD patients inherit one working copy of the GRN gene and one mutated one, the researchers wanted to identify a drug that would make the working copy of the gene work harder.
In an attempt to move as quickly as possible from basic science to clinical trials, the team established a method to quickly screen 1,200 drugs that already had Food and Drug Administration approval. SAHA emerged as the most active of the chemicals they screened, said lead author and graduate student Basar Cenik, who works in the laboratories of both Dr. Herz and co-senior author Dr. Gang Yu, associate professor of neuroscience.
SAHA is in a class of drugs called histone deacetylase inhibitors, and is approved for use in a cancer called cutaneous T-cell lymphoma.
"We found a drug that can overcome the chemical deficiency associated with the condition, and we showed that it worked in cells taken from humans with FTD," Dr. Yu said.
It is not yet known if the drug will efficiently cross the blood-brain barrier, a biologically protective system that keeps many chemicals from reaching the brain, Dr. Yu said. The next research step, he said, will be to screen larger chemical libraries in an effort to find other promising GRN-stimulating drugs for human trials.
Drs. Herz and Yu are both investigators for the Consortium for Frontotemporal Dementia Research and are working toward human trials with that national network, which is based at the University of California at San Francisco.
Other UT Southwestern authors are Drs. Chantelle Sephton, Wenze Niu and Daniel R. Dries, all postdoctoral researchers of neuroscience; Colleen Dewey, graduate student in neuroscience; Dr. Xunde Xian, postdoctoral researcher of molecular genetics; Dr. Shuguang Wei, senior research scientist of biochemistry; Dr. Bruce A. Posner, associate professor of biochemistry; and Kimberly Yu, summer high school intern researcher. Researchers from the University of California, Los Angeles, the Gladstone Institute for Cardiovascular Disease, the University of Massachusetts Medical School, and the University of California, San Francisco also participated in the research.
The study received support from the National Institutes of Health, the Consortium for Frontotemporal Dementia Research, the California Institute for Regenerative Medicine, the National Cell Repository for Alzheimer's Disease, the Ted Nash Long Life Foundation, the Welch Foundation, the Humboldt Foundation and the American Health Assistance Foundation.
Visit http://www.utsouthwestern.org/neurosciences to learn more about UT Southwestern's clinical services in neurosciences.
This news release is available on our World Wide Web home page at www.utsouthwestern.edu/home/news/index.html
To automatically receive news releases from UT Southwestern via email, subscribe at www.utsouthwestern.edu/receivenews
Deborah Wormser | EurekAlert!
Observing the cell's protein factories during self-assembly
15.06.2018 | Charité - Universitätsmedizin Berlin
Scientists unravel molecular mechanisms of Parkinson's disease
13.06.2018 | The Francis Crick Institute
Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.
Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...
The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.
Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.
An international team of scientists has discovered a new way to transfer image information through multimodal fibers with almost no distortion - even if the fiber is bent. The results of the study, to which scientist from the Leibniz-Institute of Photonic Technology Jena (Leibniz IPHT) contributed, were published on 6thJune in the highly-cited journal Physical Review Letters.
Endoscopes allow doctors to see into a patient’s body like through a keyhole. Typically, the images are transmitted via a bundle of several hundreds of optical...
Light detection and control lies at the heart of many modern device applications, such as smartphone cameras. Using graphene as a light-sensitive material for...
Water molecules exist in two different forms with almost identical physical properties. For the first time, researchers have succeeded in separating the two forms to show that they can exhibit different chemical reactivities. These results were reported by researchers from the University of Basel and their colleagues in Hamburg in the scientific journal Nature Communications.
From a chemical perspective, water is a molecule in which a single oxygen atom is linked to two hydrogen atoms. It is less well known that water exists in two...
13.06.2018 | Event News
08.06.2018 | Event News
05.06.2018 | Event News
15.06.2018 | Materials Sciences
15.06.2018 | Ecology, The Environment and Conservation
15.06.2018 | Power and Electrical Engineering