Check out “What’s New in Research” to find out about discoveries and advancements from Brigham researchers. This month, we feature new research from Brigham researchers on an ingestible device to make the stomach feel full, small molecule compounds with the potential to become miRNA-based  therapeutics, a new framework for identifying genetic risk of disease, the effects of transplanting older organs, cell-type specific genetic risk for Alzheimer’s disease and more.  

Novel Ingestible Devices Developed to Create the Illusion of Satiety

Gio Traverso

Obesity interventions, such as gastric bypass surgery, can alter the signaling of the vagal nerve, which plays a crucial role in regulating digestion. In addition to traditional obesity interventions, new weight-management medications, such as Wegovy, are becoming increasingly popular options for patients with obesity since they are non-invasive and require minimal lifestyle modifications. Developing a variety of non-invasive, convenient weight-management options for patients with obesity is essential to help reduce comorbidities such as diabetes, hypertension, cancer and heart disease.

Investigators from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, and MIT have created a pill-size device, called the vibrating ingestible bioelectronic stimulator (VIBE),that safely travels through the gastrointestinal tract and takes up space in the stomach by vibrating upon contact with gastric fluid, stimulating vagal nerve receptors and creating the sensation of fullness. The team placed the device in the stomach of swine and saw an average of 31% reduction in food intake. Additionally, the research team found that the device remained in the digestive system, on average, for 30 minutes, suggesting that it should be swallowed before meals. While additional preclinical studies are needed, the findings  suggest that the ingestible device could be an effective and sustainable method to prevent weight gain and reduce the number of calories consumed during meals.

“Our study demonstrates the effectiveness of a low-cost, non-invasive intervention to reduce food intake and calorie consumption. The device functions effectively in the stomach and induces satiety,” said corresponding author Giovanni Traverso, MB, PhD, MBBCH, a gastroenterologist in the Division of Gastroenterology, Hepatology and Endoscopy at the Brigham. “The device has the potential to revolutionize therapeutic options for patients with obesity. However, future studies will need to explore the physiological effects of the device before it’s available for patients.”

Read more in Science Advances.

Study Identifies Small Molecule Drugs With Potential for miRNA-based Therapeutics

Anna Krichevsky

MicroRNAs (miRNAs) do not code for proteins. Instead, they regulate gene expression. Since specific miRNAs are dysregulated across multiple diseases, they make attractive targets for therapeutics. However, current approaches using synthetic miRNA mimics and inhibitors are limited by their ineffective delivery into cells and occasional toxic side-effects.

In comparison, small molecules are more effective at penetrating the blood-brain barrier and many are already approved for human treatments. Surprisingly, very few miRNA-modulating small molecules have been discovered to date.

Researchers at Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, performed a high-throughput screen to identify small molecule compounds that can modulate miRNAs in human induced pluripotent stem cell (iPSC)-derived neurons. The investigators tested nearly 1,900 compounds, many of which are already clinically approved or currently in trials, and created a dataset of 1,370 drug-like compounds that could regulate more than 300 miRNAs.

The team further demonstrated that cardiac glycosides, a family of drugs used to treat heart rate-related disorders, could upregulate miR-132 — a neuroprotective miRNA downregulated in Alzheimer’s disease and other tauopathies. Human and rat neurons treated with these compounds showed reduced Tau accumulation and resilience against Tau-mediated toxicity.

“Our findings highlight cardiac glycosides as promising treatments for neurodegenerative diseases,” said corresponding author Anna M. Krichevsky, PhD, of the Department of Neurology. “This study provides a valuable resource for further miRNA-based drug discovery and therapeutics.”

Read more in Nature Communications.

New Framework to Identify Genetic Risk of Disease Could Lead to Targeted Therapeutics

Calum MacRae

Genome-wide association studies (GWAS) on patient blood samples are useful for identifying the genetic basis of blood cell traits and their links to common diseases. While previous experiments have focused on characterizing clinical parameters such as cell count, few have evaluated the dynamic effects of factors—such as inflammation, microbiome or medications—on blood cell contributions to disease development and progression. This lack of insight into underlying biological mechanisms behind such chronic progressive conditions has hindered the advancement of targeted therapeutics.

Researchers at Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, developed a framework to identify potentially hidden genetic contributors to disease by applying different stress tests to human blood cells. Using a range of physical, chemical and pharmacological stimuli, the investigators recorded evoked cellular responses and genetic variants associated with them in nearly 2,600 individuals.

The team found links between a range of blood-response characteristics and subsets of common diseases and were able to define the genetics underlying these distinct subsets of disease. In one example, they utilized the framework to identify and demonstrate a population of activated neutrophils (white blood cells) that can contribute to inflammation in cardiometabolic diseases. These findings expand the clinical measures currently available to genetically map subtypes of complex diseases.

“We were able to build on existing technology to identify new disease-associated traits,” said author Calum A. MacRae, MD, PhD, of the Division of Cardiovascular Medicine. “These tools, when combined with AI, can help improve the classification of common diseases and bring drug discovery into the clinic.”

Read more in Nature Genetics.

Older Organs Accelerate Aging in Transplant Recipients

Stefan Tullius

Most organ transplantations involve supply from older donors to younger recipients. Aging cells can become senescent, a condition in which they stop multiplying and secrete chemicals that negatively affect neighboring cells. Senescent cells accumulate in older donor organs, and have the potential to compromise transplant outcomes.

A study led by researchers from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, found that in preclinical models, transplanting older organs can trigger senescence in younger recipients. They observed that young and middle-aged mice that received heart transplants from older mice had impaired physical capacity, with reduced running times and grip strengths. Middle-aged mice who received older hearts also showed increased anxiety-related behavior, impaired memory and poorer learning performances.

The authors found that these accelerated aging-related effects in younger recipients were driven by the release of senescence-associated factors and mitochondrial DNA from older transplants. Treating older donor mice with senolytics, or senescence-inhibiting drugs, before organ extraction reduced symptoms of senescence in the recipient mice.

“Currently, due to insufficient supply in clinical organ transplantation, donor and recipient ages differ substantially,” said principal investigator Stefan G. Tullius, MD, PhD, of the Division of Transplant Surgery. “Our results suggest that senolytic treatments can be a potential therapeutic approach for improving the outcomes of older organs.”

Read more in American Journal of Transplantation.

Cell-Type-Specific Genetic Risk Contributes to Distinct Stages of Alzheimer’s Disease Progression

Hyun-Sik Yang

Developing treatments for Alzheimer’s disease (AD) is difficult because complex underlying mechanisms drive different types of cells that may contribute to the disorder. Microglia and astrocytes, resident immune and support cells in the central nervous system, are known to exclusively express several genes linked to risk of AD — particularly AD dementia. However, it was previously unclear exactly how and when these genetic risk factors contributed to other, distinct stages of AD progression, such as the accumulation of amyloid-β plaques and tau tangles.

Researchers led by a team at Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, identified the impact of AD genetic risk specific to each major brain cell type on key disease processes. They implemented single nucleus RNA sequencing to calculate cell-type-specific AD polygenic risk scores from two large clinical research study datasets.

Using autopsy data spanning all stages of disease severity, along with independent neuroimaging data from asymptomatic, preclinical stages of AD, the investigators were able to characterize the contributions of cell-specific risk genes. Astrocyte-specific genetic risk contributed to earlier stages of disease progress, like amyloid-β accumulation, while microglia-specific risk played a part in later phases of plaque and tau tangle accumulation, and cognitive decline.

“Our results provide human evidence for how genetic risk in specific brain cells affects AD processes, some even before the onset of clinical symptoms.,” said Hyun-Sik Yang, MD, of the Department of Neurology. “Future studies could extend our technique to other aspects of AD or even other diseases, in order to help develop targeted treatments.”

Read more in Nature Communications.

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