Check out “What’s New in Research” to find out about discoveries and advancements from our research community. This month, we feature new research from Brigham researchers on a robotic drug delivery system, a molecular link for Alzheimer’s disease, HIV/AIDS treatment and life expectancy, how war-zone stress may lead to changes in the brain and more.
Robotic Capsule Developed to Deliver Drugs to the Gut
Oral drug delivery is the most common and cost-effective way to deliver a treatment. But drugs must make it through the harsh, acidic environment of the stomach, resist degradation by enzymes, penetrate the barrier posed by the mucus of the small intestine and overcome many other obstacles before they can be absorbed. Because of these challenges, many drugs—including common drugs like insulin—must be delivered through other means. Investigators from Brigham and Women’s Hospital and MIT have developed RoboCap, an orally ingestible robotic drug delivery device that overcomes many of the challenges of the gastrointestinal environment to deliver its payload. The team tested the device in preclinical models using insulin and vancomycin, an antibiotic usually delivered intravenously. When ingested, RoboCap’s gelatinous coating is dissolved in the stomach. The environment of the small intestine activates RoboCap, which vibrates and rotates to clear mucus, enhance mixing and deposit the drug payload in the small intestine where the drug is likely to be absorbed. In a swine model, RoboCap increased drug permeability for both insulin and vancomycin by more than 10-fold.
“Peptides and proteins are important drugs, but the degradative environment of the gastrointestinal tract and poor absorption has limited the ability to deliver these drugs orally,” said co-corresponding author C. Giovanni Traverso, MB, BChir, PhD, of the Division of Gastroenterology, Hepatology and Endoscopy at the Brigham and the Department of Mechanical Engineering at MIT. “RoboCap’s mucus-clearing and churning movements are designed to overcome these barriers and help deliver drugs to where they are needed.”
Read more in Science Robotics.
Molecular Link Found Connecting a Neurodevelopmental Disorder to Alzheimer’s Disease
A new study led by investigators from Brigham and Women’s Hospital uses a human “brain-in-a-dish” model to show that neurons carrying a mutation associated with the neurodevelopmental disorder known as Christianson syndrome (CS), share features with Alzheimer’s disease neurons. CS is a rare neurologic disorder characterized by intellectual disability, autistic behaviors, nonverbal status, and postnatal microcephaly that can result from the disruption of an endosomal membrane protein known as NHE6. Using CRISPR engineering and human stem-cell derived neurons, the researchers created deletions of the NHE6 protein and measured subsequent levels and activity of related proteins. They found that NHE6 knockouts had elevated levels of tau proteins and defects in autophagy—the process that should remove highly phosphorylated tau from the cell. In Alzheimer’s disease, tau accumulates and aggregates within neurons in abnormal structures called “tangles . These new findings not only point to possible shared mechanisms, but also potentially mutual therapeutic targets for CS and Alzheimer’s disease.
“This study presents crucial information about the role that loss of NHE6 function plays within neurodegeneration in humans and in conditions like Christianson syndrome,” said senior author Tracy Young-Pearse, PhD from the Department of Neurology. “Additionally, we showed that we could rescue the elevated tau phenotype by enhancing autophagic-lysosomal function. This opens the door for key opportunities for therapeutic intervention and suggests that developing drugs that fix the autophagy problem may be beneficial for these disorders.”
Read more in Stem Cell Reports.
Greater Predicted Life Expectancy Confirms Importance of HIV/AIDS Treatment
Since the introduction of the first antiretroviral therapy (ART) drug for HIV/AIDS treatment 35 years ago, life expectancy in Sub-Saharan Africa has steadily increased. ART medications are specifically designed to help an individual’s immune system fight HIV and in turn suppress HIV replication. However, there is a limited understanding of the combined effects of HIV and ART on disability and healthy longevity for individuals with the disease. Investigators from the Brigham collaborated alongside international partners in South Africa to compare people with both virally suppressed and unsuppressed HIV, with people who were uninfected with HIV. The team used data they collected in an observational, longitudinal, population-based cohort study that included baseline interviews and blood collection, as well as subsequent follow-up interviews and blood collection about four years later. Their modeling analysis found that those receiving ART medication were predicted to live considerably longer and with less disability than those with unsuppressed HIV. This research illustrates the role of ART in healthy aging, as well as the continued importance for international global health organizations to provide HIV treatment to those all over the world, including in Africa.
“It was exciting for us to find that ― at the population level ― achieving high rates of viral suppression among people with HIV will not only lead to increases in life expectancy but also to healthier aging,” said senior author Jennifer Manne-Goehler, MD of the Division of Infectious Diseases. “This confirms the critical importance of maintaining support for antiretroviral programs as a way to ensure the best long-term health outcomes for people growing older with HIV.”
Read more in The Lancet HIV.
War-Zone Related Stress May Lead to Changes in the Microstructure of the Brain
Military service members who have returned from theaters of war are at increased risk of mental health problems. But few studies have examined the physical effects that war-zone related stress may have on the structure of the brain. A new study led by investigators at Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, investigates microstructural changes in the limbic and paralimbic gray matter regions of the brain—areas that control basic emotions and drives. The team analyzed diffusion-weighted MRI scans from 168 male veterans who had participated in the Translational Research Center for TBI and Stress Disorders (TRACTS) study, which took place in 2010 to 2014 at the Veterans Affair Rehabilitation Research and Development TBI National Network Research Center. The team found that war-zone related stress was associated with alterations of the limbic gray matter microstructure, independent of a diagnosis of a mental health disorder or mild traumatic injury. These structural alterations were, in turn, associated with cognitive functioning, including impaired response inhibition as well as improved verbal short-term memory and processing speed.
“These findings suggest that war zone-related stress may lead to microstructure alterations in the brain,” said corresponding author Inga K. Koerte, MD, of the Psychiatry Neuroimaging Laboratory in the Brigham’s Department of Psychiatry. “These changes may underlie the deleterious outcomes of war zone-related stress on brain health. Given these findings, military service members may benefit from early therapeutic interventions following deployment.”
Read more in JAMA Network Open.
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