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National Institutes of Health (NIH) Research Updates – January 2022

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NIH

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January 12, 2022

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The National Institutes of Health (NIH) is our nation’s medical research agency. Its mission focuses on scientific discoveries that improve health and save lives. Founded in 1870, the NIH conducts its own scientific research through its Intramural Research Program (IRP), which supports approximately 1,200 principal investigators and more than 4,000 postdoctoral fellows conducting basic, translational and clinical research. In this blog, we will highlight recent innovative NIH research.

Recent NIH Research

A high-fiber diet may lead to an improved immunotherapy response in melanoma patients

IRP Scientists have determined that a high-fiber diet may improve the immunotherapeutic response from patients being treated for melanoma. A recent study led by the Center for Cancer Research at the National Cancer Institute (NCI) in collaboration with the University of Texas MD Anderson Cancer Center focused on the ability of the gut microbiome to modulate the immune system thereby having the potential to influence the therapeutic response of cancer patients.

Immune checkpoint inhibitors have shown significant promise in the treatment of melanoma and other difficult to treat cancers, improving the longevity of people with advanced stages of the disease by restoring the immune system’s natural ability to recognize and kill tumor cells.

In this study, patients with advanced melanoma who underwent immunotherapy with immune checkpoint inhibitors who consumed at least 20 grams a day of dietary fiber survived the longest without progression of the disease than those who consumed less dietary fiber. Every 5-gram increase in daily dietary fiber intake corresponded to a 30% lower risk of progression of the disease. In contrast, the use of probiotics, which are supplements containing live microorganisms typically consumed to improve gut health, somewhat decreased the effectiveness of immune checkpoint inhibitor regimens.

“The data suggest that one can target the composition of the gut microbiota and affect the ability of the patient to respond to immunotherapy,” said Dr. Giorgio Trinchieri, chief of the Laboratory of Integrative Cancer Immunology at NCI and coleader of the study. “Consuming a diet rich in fiber, like fruits, vegetables, and legumes, could improve your ability to respond to immunotherapy. The data also suggest that it’s probably better for people with cancer receiving immunotherapy not to use commercially available probiotics.”

Suppressing a blood-clotting protein prevents gum disease in mice

A new study led by the National Institute of Dental and Craniofacial Research (NIDCR) suggests that suppressing the abnormal activity of fibrin, a blood-clotting protein, may lead to the prevention or treatment of periodontal disease. Nearly 50% of adults over the age of 30 and greater than 70% of adults over age 65 have some form of periodontal disease. Bacteria in the mouth can infect the tissue surrounding a tooth, causing inflammation in its early stages. As periodontal progresses, the underlying bone becomes damaged, leading to tooth loss. The advanced stage of this disease, called periodontitis, is driven in part of an elevated immune cell response. Until now it has been unclear what triggered this response and the mechanism by which it caused tissue and bone damage.

Fibrin normally plays a protective role at sites of injury of inflammation by helping to form blood clots and activating immune cells to fight infection. However, the buildup of excess fibrin has been linked with health problems, including a rare form of periodontitis due to a condition called plasminogen (PLG) deficiency. In affected people, mutations in the PLG gene lead to the accumulation of fibrin at various body sites, including the mouth.

To explore the connection between abnormal fibrin buildup and periodontitis, the research team, led by NIDCR investigators Dr. Niki Moutsopoulos and Dr. Thomas Bugge studied PLG deficiency in mice and performed a genetic analysis of over 1,000 people. Their findings concluded that even in the absence of PLG deficiency, variations in the PLG gene were linked to an increased risk of severe periodontitis, consistent with the idea that similar processes contribute to rare and common forms of the disease. The study further suggests that excessive buildup of fibrin in the gums—whether due to changes in genes like PLG, chronic inflammation from a bacterial infection, or some combination of the two—triggers an elevated and ultimately harmful neutrophil response that causes periodontal disease.

NIH researchers identify potential AMD drugs with stem cell-based model

Researchers at the National Eye Institute (NEI) have identified two promising drug candidates that may slow dry age-related macular degeneration (AMD), a leading cause of blindness for which no permanent cure exists. Dry AMD is when parts of the macula become thinner with age and tiny clumps of protein called drusen form causing the progressive loss of central vision.

Two of the drugs tested prevented the stem cell model from accumulating drusen, lipid-rich deposits in the retina, and the atrophy, or shrinkage, of retinal pigment epithelium (RPE) cells. RPE is a layer of tissue that nourishes the retina’s light-sensing photoreceptors. In AMD, RPE cells shrink and die leading to the death of photoreceptors and ultimately to loss of vision.

The research team led by Dr. Kapil Bharti, director of the NEI Ocular and Stem Cell Translational Research Section, and Dr. Ruchi Sharma, staff scientist in the lab and lead author of the paper, developed the experimental model using stem cell-derived mature RPE cells. Dr. Bharti’s group initially developed the cells using skin fibroblasts or blood samples donated from AMD patients. The fibroblasts or blood cells were programmed to become induced pluripotent stem cells (iPSC), and then programmed again to become RPE cells.

In the study, more than 1,200 drugs were screened via the stem cell model from a library of pharmacological agents that had been tested for a range of other conditions. Two drugs were flagged for their ability to inhibit RPE atrophy and drusen formation: A protease inhibitor called aminocaproic acid, which likely directly blocks the complement pathway outside cells and L745, which was originally tested by Merck & Co. for treating schizophrenia. L745 stops complement induced inflammation inside the cell indirectly via inactivation of the dopamine pathway.

“This stem cell-derived model of dry AMD is a game-changer. Scientists have struggled to unravel this incredibly complex disease, and this model could prove to be invaluable for understanding the causes of AMD and discovering new therapies,” said Dr. Michael Chiang, director of the NEI.

NIH study suggests women with disabilities have increased risk of birth complications

In new study conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), researchers have determined that pregnant women with disabilities have an increased risk for a broad spectrum of pregnancy and birth related complications, including mortality.

Based upon an analysis of more than 223,000 deliveries in 19 U.S. hospitals, approximately 2,199 pregnant women had a physical, sensory or intellectual disability. Compared to women without disabilities, women with disabilities had:

Greater than twice the risk for severe preeclampsia
48% higher risk for mild preeclampsia
25% higher risk for gestational diabetes
52% higher risk for placenta previa
16% higher risk for premature rupture of the membranes
27% higher risk for hemorrhage
11 times the risk for maternal death
more than six times the risk for blood clots
four times the risk for cardiovascular events, such as heart attacks
nearly three times the risk for infection
33% greater likelihood of receiving the drug oxytocin to stimulate labor, delivery with forceps or other devices to extract the fetus, or cesarean delivery

“Additional research is needed to understand the reasons for this increased risk and to develop needed interventions to reduce it,” said Dr. Jessica Gleason, NICHD research fellow and lead author of the study. The authors noted that women with disabilities are more likely to live in poverty, which may make accessing health care in a timely manner difficult. Other factors that may increase their health risks are higher rates of smoking, substance use and depression.

Experimental mRNA HIV vaccine shows promise in animals

An experimental HIV vaccine shows promise in mice and non-human primates, according to researchers at the National Institute of Allergy and Infectious Diseases (NIAID). Based upon this new study, the vaccine was determined to be safe and triggered an antibody response against an HIV-like virus. Rhesus macaques receiving a priming vaccine followed by multiple booster inoculations had a 79% lower per-exposure risk of infection by simian-human immunodeficiency virus (SHIV) compared to unvaccinated animals.

“Despite nearly four decades of effort by the global research community, an effective vaccine to prevent HIV remains an elusive goal,” said Dr. Anthony Fauci, NIAID Director, chief of the Laboratory and co-author of the paper. “This experimental mRNA vaccine combines several features that may overcome shortcomings of other experimental HIV vaccines and thus represents a promising approach.”

The research team, led by Dr. Paolo Lusso, of NIAID’s Laboratory of Immunoregulation, in collaboration with other NIAID scientists, investigators from Moderna, Inc. and colleagues at other institutions, developed an mRNA vaccine that delivers coded instructions for making two key HIV proteins, Env and Gag. Muscle cells in an inoculated animal assemble these two proteins to produce virus-like particles (VLPs) studded with numerous copies of Env on their surface. The Env proteins produced in the mice from the mRNA instructions closely resembled those in the whole virus, an improvement over previous experimental HIV vaccines.

After 13 weekly inoculations, two out of seven immunized macaques remained uninfected, while the other immunized animals had an overall delay in infection, which occurred, on average, after eight weeks. In contrast, unimmunized animals became infected on average after three weeks. Dr. Lusso noted, “The display of multiple copies of authentic HIV envelope protein on each VLP is one of the special features of our platform that closely mimics natural infection and may have played a role in eliciting the desired immune responses.”