Scientists at UCLA have identified a new compound that could treat certain types of genetic disorders in muscles. It is a big first step in what they hope will lead to human clinical trials for Duchenne muscular dystrophy.
Duchenne muscular dystrophy, or DMD, is a degenerative muscle disease that affects boys almost exclusively. It involves the progressive degeneration of voluntary and cardiac muscles, severely limiting the life span of sufferers.
In a new study, senior author Carmen Bertoni, an assistant professor in the UCLA Department of Neurology, first author Refik Kayali, a postgraduate fellow in Bertoni's lab, and their colleagues demonstrate the efficacy of a new compound known as RTC13, which suppresses so-called "nonsense" mutations in a mouse model of DMD.
The findings appear in the current online edition of the journal Human Molecular Genetics.
"We are excited about these new findings because they represent a major step toward the development of a drug that could potentially treat this devastating disease in humans," Bertoni said. "We knew that the compounds were effective in cells isolated from the mouse model for DMD, but we did not know how they would behave when administered in a living organism."
Nonsense mutations are generally caused by a single change in DNA that disrupts the normal cascade of events that changes a gene into messenger RNA, then into a protein. The result is a non-functioning protein. Approximately 13 percent of genetic defects known to cause diseases are due to such mutations. In the case of DMD, the "missing" protein is called dystrophin.
For the study, Bertoni and Kayali collaborated with the laboratory of Dr. Richard Gatti, a professor of pathology and laboratory medicine and of human genetics at UCLA. Working with the UCLA Molecular Shared Screening Resource facility at the campus's California NanoSystems Institute, the Gatti lab screened some 35,000 small molecules in the search for new compounds that could ignore nonsense mutations. Two were identified as promising candidates: RTC13 and RTC14.
The Bertoni lab tested RTC13 and RTC14 in a mouse model of DMD carrying a nonsense mutation in the dystrophin gene. While RTC14 was not found to be effective, RTC13 was able to restore significant amounts of dystrophin protein, making the compound a promising drug candidate for DMD. When RTC13 was administered to mice for five weeks, the investigators found that the compound partially restored full-length dystrophin, which resulted in a significant improvement in muscle strength. The loss of muscle strength is a hallmark of DMD.
The researchers also compared the level of dystrophin achieved to the levels seen with another experimental compound, PTC124, which has proved disappointing in clinical trials; RTC13 was found to be more effective in promoting dystrophin expression. Just as important, Bertoni noted, the study found that RTC13 was well tolerated in animals, which suggests it may also be safe to use in humans.
The next step in the research is to test whether an oral formulation of the compound would be effective in achieving therapeutically relevant amounts of dystrophin protein. If so, planning can then begin for clinical testing in patients and for expanding these studies to other diseases that may benefit from this new drug.
Other study authors included Jin-Mo Ku, Gregory Khitrov, Michael E. Jung and Olga Prikhodko, all from UCLA. The researchers report no conflicts of interest. The work has been supported in large part by the Muscular Dystrophy Association (MDA) and, more recently, by the National Institutes of Health.
The UCLA Department of Neurology, with over 100 faculty members, encompasses more than 20 disease-related research programs, along with large clinical and teaching programs. These programs cover brain-mapping and neuroimaging, movement disorders, Alzheimer's disease, multiple sclerosis, neurogenetics, nerve and muscle disorders, epilepsy, neuro-oncology, neurotology, neuropsychology, headaches and migraines, neurorehabilitation, and neurovascular disorders. The department ranks in the top two among its peers nationwide in National Institutes of Health funding.
For more news, visit the UCLA Newsroom and follow us on Twitter.
Mark Wheeler | EurekAlert!
Underwater Snail-o-Bot gets kick from light
27.02.2020 | Max-Planck-Institut für Intelligente Systeme
Existing drugs may offer a first-line treatment for coronavirus outbreak
27.02.2020 | Norwegian University of Science and Technology
Researchers at the University of Bayreuth have discovered an unusual material: When cooled down to two degrees Celsius, its crystal structure and electronic properties change abruptly and significantly. In this new state, the distances between iron atoms can be tailored with the help of light beams. This opens up intriguing possibilities for application in the field of information technology. The scientists have presented their discovery in the journal "Angewandte Chemie - International Edition". The new findings are the result of close cooperation with partnering facilities in Augsburg, Dresden, Hamburg, and Moscow.
The material is an unusual form of iron oxide with the formula Fe₅O₆. The researchers produced it at a pressure of 15 gigapascals in a high-pressure laboratory...
Study by Mainz physicists indicates that the next generation of neutrino experiments may well find the answer to one of the most pressing issues in neutrino physics
Among the most exciting challenges in modern physics is the identification of the neutrino mass ordering. Physicists from the Cluster of Excellence PRISMA+ at...
Fraunhofer researchers are investigating the potential of microimplants to stimulate nerve cells and treat chronic conditions like asthma, diabetes, or Parkinson’s disease. Find out what makes this form of treatment so appealing and which challenges the researchers still have to master.
A study by the Robert Koch Institute has found that one in four women will suffer from weak bladders at some point in their lives. Treatments of this condition...
The operational speed of semiconductors in various electronic and optoelectronic devices is limited to several gigahertz (a billion oscillations per second). This constrains the upper limit of the operational speed of computing. Now researchers from the Max Planck Institute for the Structure and Dynamics of Matter in Hamburg, Germany, and the Indian Institute of Technology in Bombay have explained how these processes can be sped up through the use of light waves and defected solid materials.
Light waves perform several hundred trillion oscillations per second. Hence, it is natural to envision employing light oscillations to drive the electronic...
Most natural and artificial surfaces are rough: metals and even glasses that appear smooth to the naked eye can look like jagged mountain ranges under the microscope. There is currently no uniform theory about the origin of this roughness despite it being observed on all scales, from the atomic to the tectonic. Scientists suspect that the rough surface is formed by irreversible plastic deformation that occurs in many processes of mechanical machining of components such as milling.
Prof. Dr. Lars Pastewka from the Simulation group at the Department of Microsystems Engineering at the University of Freiburg and his team have simulated such...
12.02.2020 | Event News
16.01.2020 | Event News
15.01.2020 | Event News
27.02.2020 | Life Sciences
27.02.2020 | Health and Medicine
27.02.2020 | Physics and Astronomy