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 an alternative method of immunotherapy delivery, a new protein that may contribute to Alzheimer’s disease, limitations after traumatic injury among women and Black or Hispanic patients, predicting surgical complications after prostate surgery, 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.
Safety and efficacy of intraventicular immunovirotherapy with oncolytic HSV-1 for CNS cancers
Metastatic or leptomeningeal disease (LMD), the spreading of a brain cancer to the meninges, is a devastating cancer complication that does not respond well to conventional therapies. While researchers can directly inoculate some brain tumors with an engineered virus that selectively targets cancer cells, this invasive technique is not feasible for widespread or surgically inaccessible malignancies, such as in LMD. Researchers from the Brigham and collaborators demonstrated that an alternative method of immunotherapy delivery, intraventricular (IVT) treatment, can be used to administer multiple therapeutic doses in mouse models of human metastatic medulloblastoma, prolonging survival while surmounting concerns about toxicity associated with the IVT method.
Researchers including Joshua Bernstock, MD, PhD, of the Brigham’s Department of Neurosurgery and University of Alabama at Birmingham’s Department of Pediatrics, previously treated pediatric cerebellar brain cancer with the immunotherapy tested in this study, oncolytic HSV (oHSV) G207, by directly inoculating tumors. In this study, Bernstock and colleagues showed that administering protective pre-treatments and targeting the brain’s ventricle system (cavities filled with cerebrospinal fluid) with low-dose oHSV G207 significantly extended survival in mice with a highly aggressive cancer, with tumor bioluminescence disappearing in G207-treated mice while it continued to increase in controls.
“We determined the cause of toxicity from intraventricular oHSV and established methods for mitigating toxicity to treat disseminated brain tumors in mice,” Bernstock said. “Our data demonstrating the preclinical safety and efficacy of intraventricular G207 are highly translatable and support future clinical trials of this therapeutic approach.”
Read more in Clinical Cancer Research.
Researchers Identify a New Protein that May Contribute to Alzheimer’s Disease
Alzheimer’s disease (AD) currently has no cure and is predicted to affect over 100 million people worldwide by 2050. Ongoing research is focused on two key neurotoxic proteins: amyloid beta (Aβ) and tau. While these proteins have been shown to be associated with AD, for some people with the disease, the levels of Aβ and tau do not consistently explain or correlate with the severity of cognitive decline. To identify other proteins that may be directly involved with fundamental aspects of AD, like synaptic loss and neurodegeneration, investigators at the Brigham exposed laboratory neurons to human brain extracts from about 40 people who either had AD, were protected from AD despite having high Aβ and tau levels, or were protected from AD with little or no Aβ and tau in their brains. The researchers identified and validated ganglioside GM2 activator (GM2A) as a protein able to reduce neuronal firing and induce a loss of neurite integrity. These protein characteristics may contribute to the cause of AD, progression, or both.
“Our data helps identify a new and potentially important protein that may be associated with the pathogenesis of Alzheimer’s disease,” said senior author Tracy Young-Pearse, PhD, from the Department of Neurology. “Interestingly, GM2A has been previously implicated as a causative agent in a lysosomal storage disorder very similar to Tay-Sachs disease, another condition like AD that destroys neurons.”
Read more in Molecular Neurodegeneration.
Black and Hispanic Female Survivors of Trauma Experience Greatest Functional Limitations Post-Injury
Survivors of traumatic injury often face many long-term health consequences including physical disabilities, mental illness and issues with social integration. A research team from the Brigham investigated the intersection of race, ethnicity, and sex and the post-injury functional limitations of those affected by trauma. More than 4,000 patients with moderate to severe injuries were assessed six to 12 months post-injury. For the purpose of the study, the term “new functional limitations” was coined and defined as limitations in one’s ability to perform one or more of six daily activities, including walking upstairs, walking on flat surfaces, showering, eating, going to the bathroom or cooking, as a result of the injury. The researchers found that Black and Hispanic women are most likely to experience functional limitations. The researchers found that women and Black or Hispanic patients are most likely to have new functional limitations after six to 12 months.
“More than half of the racial and sex-related disparities in post-injury functional limitations among Black or Hispanic females are related to the unique experience of being both a minority and female, and the relationships that are established with their environment, social networks, and the healthcare system,” said Juan Herrera-Escobar, MD, MPH, of the Brigham’s Center for Surgery and Public Health. “Future research should focus on identifying modifiable intermediate factors contributing to this intersectional disparity so that programs can be developed to improve post-injury outcomes for Black and Hispanic women.”
Read more in JACS.
Frailty Index Accurately Predicts Postoperative Complications After Prostate Surgery
The Five-item Frailty Index (5i-FI) is a tool used by physicians to predict surgical risk and postoperative complications after a procedure. Researchers from the Brigham looked at whether the 5i-FI could be used to predict surgical complications in endoscopic surgery for benign prostatic obstruction (BPO). Patients who received either transurethral resection of the prostate (TURP) between 2009 and 2019, photoselective vaporization of the prostate (PVP), or laser enucleation of the prostate (LEP) were assessed for frailty using the 5i-FI. The frailty scores were then compared against any complications experienced, major complications, length of stay in the hospital, and 30-day postoperative readmission. The team found that a 5i-FI score greater than two is predictive of these instances.
“The 5-item Frailty Index is an easy tool that predicts postoperative complications after endoscopic surgery for benign prostatic hyperplasia,” said first author Muhieddine Labban, MD, of the Division of Urology and the Center for Surgery and Public Health.
“After weighting for patients’ frailty scores and demographics, LEP and PVP were associated with lower odds of complications and shorter hospital stays. Nevertheless, both LEP and PVP are less likely to be used among men with higher frailty scores,” said senior author Quoc‐Dien Trinh, MD, of the Brigham’s Division of Urology and Center for Surgery and Public Health. “Preoperative frailty assessment using the 5i-FI could improve risk stratification.”
Read more in World Journal of Urology.
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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