Highlights:

• A small genetic “fingerprint,” known as a microRNA, was linked with stroke and the long- term effects of stroke on your body.
• MicroRNA levels can be measured from a simple blood test, creating the opportunity for a more affordable and more practical option than examining actual brain tissue or using other conventional tests.
• MicroRNAs naturally point to promising drug targets, so the findings of this study are more likely to lead to new medications that can reduce the extent of brain injury after stroke and help patients recover faster and more fully.

 

By Dr. Joel Salinas with staff insertions

Researchers at UT Health San Antonio and Massachusetts General Hospital identified a connection between a small genetic “fingerprint,” called a microRNA, and people who have experienced a stroke. MicroRNAs, which are products of gene functioning, were previously believed to be as insignificant as snippets of film left on a film editor’s cutting-room floor. However, over many years scientists have come to appreciate how these small pieces of genetic material found all over the body are more than leftovers—they play a critical role in turning genes on or off. This has major consequences on bodily functions and central processes in health, disease and recovery from injury.

“We wanted to see if there was an easier, non-invasive method to know what was going on at the molecular level in the brains and bodies of people at risk for stroke or who have experienced a stroke,” said Joel Salinas, M.D., M.S., M.B.A., a neurologist at the Massachusetts General Hospital McCance Center for Brain Health and one of the researchers leading the investigation at the Framingham Heart Study along with colleagues at the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases at UT Health San Antonio. “Studying microRNAs in blood samples from hundreds of people who have had a stroke or who went on to have stroke seemed promising to us, because discovering patterns in microRNA levels might give hints about genetic chain reactions leading to stroke or that occur as a consequence of stroke. The added benefit of any links is that they almost immediately point to potential applications in drug development, because microRNAs by default are targets for pharmacologic intervention.”

Framingham Heart Study

Building off a prior study, researchers measured microRNA (miR) levels in available blood samples routinely collected in one of the largest and longest-running community-based research cohorts in the U.S., the Framingham Heart Study. They identified a significant reduction in miR-574-3p levels in the blood of people who had a stroke months and even years prior. To be as confident as possible in this finding, the researchers accounted for many other factors that could falsely influence their results, yet the findings remained the same.

“When we felt confident enough that spotting this link was unlikely to be just a fluke, we dug deeper to see what this finding with miR-574-3p meant for the biology of your brain and your entire body if you’ve had a stroke,” Dr. Salinas said. “We found this specific miRNA seemed to serve as an indicator of your brain’s response, and of systemic cellular response, to stroke in the short, medium and long term.”

Implications

The findings of this study will help inform future investigations into how these small—yet powerful—genetic mechanisms influence many related diseases and how targeting microRNAs with new potential drugs might confer a protective effect on a person’s resilience and recovery after stroke.

“We know many of the risk factors for stroke, such as hypertension, and have developed new drugs and interventions for the treatment of an acute stroke,” said Sudha Seshadri, M.D., professor of neurology at UT Health San Antonio, director of the university’s Glenn Biggs Institute and senior investigator with the Framingham Heart Study. “But we do not yet understand all the molecular and biological changes that occur in people who are at risk for stroke and those who have had a stroke. If we did, we could better predict and prevent downstream complications like dementia.”

MicroRNAs are messengers in the communication pathways within the cell and are emerging as an efficient way to understand and intervene in many brain diseases, Dr. Seshadri said. “We are excited to further expand our studies to more persons, and to persons of different race and ethnic backgrounds,” she added.

The study appeared in August in the journal PLOS ONE.

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The University of Texas Health Science Center at San Antonio, now called UT Health San Antonio®, is one of the country’s leading health sciences universities. With missions of teaching, research, healing and community engagement, its schools of medicine, nursing, dentistry, health professions and graduate biomedical sciences have produced 36,500 alumni who are leading change, advancing their fields and renewing hope for patients and their families throughout South Texas and the world. To learn about the many ways “We make lives better®,” visit www.uthscsa.edu.

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Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $925 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, genomic medicine, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2018 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of “America’s Best Hospitals.” To learn more about the MGH Henry and Allison McCance Center for brain health, visit www.massgeneral.org/brain-health.

 

SAN ANTONIO (Sept. 9, 2019)  ̶  September is Blood Cancer Awareness Month, and this year patients with myelofibrosis, a rare blood cancer, have reason to celebrate. In mid-August, the U.S. Food and Drug Administration approved the first new medication in nearly a decade for patients with myelofibrosis.

Ruben Mesa, M.D., FACP, was part of the international research team that led development of the new drug. Dr. Mesa is director of the Mays Cancer Center, home to UT Health San Antonio MD Anderson Cancer Center.

And due to the drug’s effectiveness in treating myelofibrosis, fedratinib (brand name Inrebic), is being studied to see if it may also be beneficial for patients with other blood cancers, inflammatory diseases and possibly, one day, for diseases related to aging or that involve blood clots, such as heart attacks or stroke.

Swelling of the spleen a major symptom

On Aug. 16, the FDA approved fedratinib for adults with intermediate-2 or high-risk primary or secondary myelofibrosis. Myelofibrosis is a blood cancer that begins in the bone marrow, where red blood cells, white blood cells and platelets are made. It is one of a related group of blood cancers and chronic leukemias called myeloproliferative neoplasms, or MPNs, that can lead to acute leukemia. Patients with myelofibrosis may experience severe anemia, night sweats, weight loss and significant and painful enlargement of the spleen, an organ involved with filtering the blood.

“Think about a healthy spleen as being about the size of your fist. With myelofibrosis, the spleen can swell to the size of a football or even a full-term pregnancy,” explained Dr. Mesa. He was an investigator on the fedratinib studies while he was a researcher, chair of the Division of Hematology and Medical Oncology, and deputy director of the Mayo Clinic Cancer Center in Scottsdale, Ariz. Dr. Mesa continued his research and advocacy for the approval of fedratinib after being recruited to UT Health San Antonio’s cancer center in August 2017

He has assembled a team of myelofibrosis experts at the Mays Cancer Center who provide care to patients from around the world. And now that the new drug has been approved, the team can now prescribe fedratinib to eligible patients.

“The pressure of the enlarged spleen can be very painful, pressing on nearby organs. Patients also may experience fatigue, night sweats or shortness of breath associated with anemia. Bone pain and weight loss are also common,” Dr. Mesa said. There is no cure for most myelofibrosis patients.

According to the MPN Research Foundation, about 18,000 individuals in the United States have myelofibrosis and approximately 300,000 live with one of the three MPN blood marrow disorders, which also include essential thrombocythemia and polycythemia vera.

Study examines regulation of the JAK 2 gene

FDA approval of fedratinib was based on the Phase 3 JAKARTA clinical trial. The drug inhibits the JAK 2 gene, which makes a protein that promotes the growth and division of blood cells in the bone marrow. The investigators proved that fedratinib regulates part of the chemical process to limit the overproduction of damaged blood cells, controlling the uncomfortable swelling of the spleen and other disabling symptoms.

Before the trial, 289 patients received MRIs or CT scans to measure the size of their spleen. The primary objectives of the trial were reducing the patients’ spleen size by 35% and decreasing overall symptoms by 50%.

Participants were randomly assigned to three groups, with neither the doctors nor patients knowing which treatment was being administered. One group received 500 mg of fedratinib, a second group received 400 mg and the third group received a placebo. The oral medication was taken once a day for 24 weeks.

In the 400 mg group, 37% of patients had spleen reduction of more than 35%, compared to 1% in the placebo group. And while 40 percent of patients in the 500 mg group achieved greater than 35 percent reduction in spleen size, 21 percent had serious side effects, including a small group diagnosed with Wernike’s encephalopathy, a neurological disease caused by a low level of thiamine. For this reason, the FDA recommends the 400 mg dosage and cautions doctors to test patients’ blood levels for low thiamine levels before starting them on fedratinib.

“For these patients, doctors are advised to prescribe thiamine and get this reading up to the recommended level before prescribing fedratinib, and then to closely monitor thiamine levels while the patient is on this medication,” Dr. Mesa said.

Only second drug approved for myelofibrosis

Until fedratinib was approved, ruxolitinib was the only drug available to treat patients with myelofibrosis. “Now with fedratinib, physicians and patients have another treatment option, especially for patients who do not respond well to ruxolitinib,” said Dr. Mesa, who also was involved in the ruxolitinib research.

Dr. Mesa also led development of the National Comprehensive Cancer Network’s Guidelines for Myeloproliferative Neoplasms, published in 2017. In 2018 he was appointed to the national board of directors of the Leukemia & Lymphoma Society.

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UT Health San Antonio MD Anderson Cancer Center is one of only four National Cancer Institute-designated Cancer Centers in Texas. The partnership between UT Health San Antonio and MD Anderson Cancer Center, coming together in the UT Health San Antonio MD Anderson Cancer Center, provides leading-edge cancer care, propels innovative cancer research and educates the next generation of leaders to end cancer in South Texas. To learn more, visit www.UTHealthsaMDAnderson.org.