Posts tagged triheptanoin
Articles and news from the latest research reports.
Mouse Version of an Autism Spectrum Disorder Improves When Diet Includes a Synthetic Oil
When young mice with the rodent equivalent of a rare autism spectrum disorder (ASD), called Rett syndrome, were fed a diet supplemented with the synthetic oil triheptanoin, they lived longer than mice on regular diets. Importantly, their physical and behavioral symptoms were also less severe after being on the diet, according to results of new research from The Johns Hopkins University.
(Image caption: Mitochondria (arrows) in muscle cells from mice with Rett syndrome improved in appearance after the mice were given triheptanoin oil. Top: Muscle from mice given regular food. Bottom: Muscle from mice given food supplemented with triheptanoin. Left: Healthy mice. Right: Mice with a genetic mutation that mimics Rett syndrome.)
Researchers involved in the study think that triheptanoin improved the functioning of mitochondria, energy factories common to all cells. Since mitochondrial defects are seen in other ASDs, the researchers say, the experimental results offer hope that the oil could help not just people with Rett syndrome, but also patients with other, more common ASDs.
A description of the research was published on Oct. 9 in the journal PLOS ONE.
ASDs affect an estimated one in 68 children under 8 years of age in the United States. Rett syndrome is a rare ASD caused by mutations in the MECP2 gene, which codes for methyl-CpG-binding-protein 2 (MeCP2). Rett syndrome includes autismlike signs, such as difficulty communicating, socializing and relating to others. Other hallmarks are seizures, decreased muscle tone, repetitive involuntary movements, and gastrointestinal and breathing problems. These other signs are also seen in some patients with other ASDs, suggesting underlying similarities in their causes. While the causes of most ASDs are unknown and thought to be complex, Rett syndrome is unique — and could be a source of insight for the others — because it is caused by an error in a single gene.
The research team used mice lacking the MeCP2 protein, which left them with severe Rett syndrome. In examining those mice, what stood out, according to Gabriele Ronnett, M.D., Ph.D., who led the research project at the Johns Hopkins University School of Medicine, was that they weighed the same as healthy mice but had large fat deposits accompanied by lower amounts of nonfat tissue, such as muscle. This suggested that calories were not being used to support normal tissue function but instead were being stored as fat.
This possibility led Ronnett and her research team to consider the role of mitochondria, which transform the building blocks of nutrients into a high-energy molecule, ATP. This molecule drives processes such as the building of muscle and the growth of nerve cells. Mitochondria use a series of biochemical reactions, collectively called the TCA cycle, to make this transformation possible. According to Susan Aja, Ph.D., a research associate and lead member of the research team, “If the components of the TCA cycle are low, nutrient building blocks are not processed well to create ATP. They are instead stored as fat.”
Ronnett suspected, she says, that some of Rett syndrome’s neurological symptoms could stem from metabolic deficiencies caused by faulty mitochondria and reduced energy for brain cells. “Rett syndrome becomes apparent in humans 6 to 18 months old, when the energy needs of the brain are particularly high, because a lot of new neural connections are being made,” says Ronnett. “If the mitochondria are already defective, stressed or damaged, the increased demand would be too much for them.”
Previous small clinical trials in people with a different metabolic disorder suggested that dietary intervention with triheptanoin could help. Triheptanoin is odorless, tasteless and a little thinner than olive oil. It is easily processed to produce one of the components of the TCA cycle.
When Rett syndrome mice were weaned at 4 weeks of age, they were fed a diet in which 30 percent of their calories came from triheptanoin, mixed in with their normal pelleted food. Though far from a cure, the results of the triheptanoin treatment were impressive, the researchers say. Treated mice had healthier mitochondria, improved motor function, increased social interest in other mice and lived four weeks — or 30 percent — longer than mice who did not receive the oil. The team also found that the diet normalized their body fat, glucose and fat metabolism.
“You can think of the mitochondria of the Rett syndrome model mice as damaged buckets with holes in them that allow TCA cycle components to leak out,” says Aja. “We haven’t figured out how to plug the holes, but we can keep the buckets full by providing triheptanoin to replenish the TCA cycle.”
“It is still too early to assume that this oil will work in humans with ASDs, but these results give us hope,” says Ronnett. “It’s exciting to think that we might be able to improve many ASDs without having to identify each and every contributing gene.”
According to Aja, additional mouse studies are needed to learn if female mice respond to the treatment, to perform a wider range of physiology and behavior tests, and, importantly, to assess the effects of triheptanoin treatment on the brain, which is considered the main driver of many Rett symptoms. The team would also like to provide triheptanoin at earlier ages, perhaps via the mothers’ milk, to mimic developmental ages at which most children are diagnosed with Rett syndrome.
Triheptanoin is currently made for research purposes only and is not available as a medicine or dietary supplement for humans.
(Source: hopkinsmedicine.org)
Medicinal oil reduces debilitating epileptic seizures associated with Glut 1 deficiency, trial shows
Two years ago, the parents of Chloe Olivarez watched painfully as their daughter experienced epileptic seizures hundreds of times a day. The seizures, caused by a rare metabolic disease that depleted her brain of needed glucose, left Chloe nearly unresponsive, and slow to develop.
Within hours, treatment with an edible oil dramatically reduced the number of seizures for then-4-year-old Chloe, one of 14 participants in a small UT Southwestern Medical Center clinical trial.
“Immediately we noticed fewer seizures. From the Chloe we knew two years ago to today, this is a completely different child. She has done amazingly well,” said Brandi Olivarez, Chloe’s mother.
For Chloe and the other trial participants who suffer from the disease called Glut1 deficiency (G1D), seizure frequency declined significantly. Most showed a rapid increase in brain metabolism and improved neuropsychological performance, findings that suggested the oil derived from castor beans called triheptanoin, ameliorated the brain glucose-depletion associated with this genetic disorder, which is often undiagnosed.
“This study paves the way for a medical food designation for triheptanoin, thus significantly expanding therapeutic options for many patients,” said Dr. Juan Pascual, Associate Professor of Neurology and Neurotherapeutics, Physiology, and Pediatrics at UT Southwestern and lead author of a study on the findings, published in JAMA Neurology.
For the estimated 38,000 Americans suffering from this disease, the only proven treatment has been a high-fat ketogenic diet, which only works for about two-thirds of patients. In addition, this diet carries long-term risks, such as development of kidney stones and metabolic abnormalities.
Based on the results of this trial, triheptanoin appears to work as efficiently as the ketogenic diet; however, more research needs to be done before the oil is made available as a medical food therapy, researchers said.
“Triheptanoin byproducts produced in the liver and also in the brain refill brain chemicals that we found are preferentially diminished in the disorder, and this effect is precisely what defines a medical food rather than a drug,” said Dr. Pascual, who heads UT Southwestern’s Rare Brain Disorders Program, maintains an appointment in the Eugene McDermott Center for Human Growth and Development, and holds The Once Upon a Time Foundation Professorship in Pediatric Neurologic Diseases.
The oil, approved for use in research only, is an ingredient in some cosmetic products and is added to butter in some European countries. It is not commercially available in the U.S. for clinical use.
Triheptanoin’s success as an experimental treatment for other metabolic diseases, along with preclinical success in G1D mice, led Dr. Pascual and his trial collaborator, Dr. Charles Roe, Clinical Professor of Neurology and Neurotherapeutics, to first conceive the idea and then launch this trial for G1D patients. The 14 pediatric and adult patients in the study consumed varying amounts of the oil, based on their body weight, four times a day. Given the trial’s success, Dr. Pascual plans further research to refine the optimal dosage toward the goal of facilitating medical food designation of triheptanoin as a new G1D treatment.
While some trial participants reported mild stomach upset as a side effect, for Chloe the oil has been a miracle medicine without negative effects. Her parents, Brandi and Josh Olivarez of Waco, Texas, continue to be amazed by her progress.
“Before, she was having so many seizures a day that she couldn’t even talk. Now she sings all the time, she can eat whatever she wants, and her speech is greatly improved. She still has some learning delays, but has come a long way,” said Mrs. Olivarez.
Many Glut1 patients suffer from movement disorders that limit their physical capabilities, but that does not appear to be the case with Chloe. As for the seizures, she still has minor ones occasionally, but they are not debilitating.
“She is now able to run a solid mile without stopping. This would not have been possible without the oil,” Mrs. Olivarez said. “Before, she had almost no muscle tone, was lethargic and had a very wide gait due to trying to balance herself while walking, which was very tiring for her.”
To better understand this disease, UT Southwestern established a patient-completed registry to track G1D incidence and what treatments work or do not work for those registered.