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National Institutes of Health (NIH) Research Updates – May 2021

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

Drug testing approach uncovers effective combination for treating small cell lung cancer

Small cell lung cancer (SCLC) is an aggressive, highly malignant cancer that commonly originates within the tissues of the lung. The shorter doubling time, higher growth fraction and earlier development of metastases set this disease apart from its generally less aggressive non-small cell (NSCLC) counterpart.

In a recent study conducted by the National Cancer Institute, researchers investigated a drug combination that targets a vulnerability in the reproduction process of cancer cells. The rapid cell growth that occurs in many forms of cancer can cause damage to their DNA, forcing them into a constant state of repair known as replication stress. Early clinical trials, in support of the research findings, demonstrated the ability of the combined drug therapy to shrink the tumors of patients with SCLC.

Many patients with SCLC show an initial positive response following treatment with chemotherapy, however in the absence of an effective follow-up treatment, the disease usually returns in a matter of weeks. To find an alternative method of treating SCLC, a team of scientists from the National Cancer Institute (NCI) collaborated with Dr. Craig Thomas and his research team at the National Center for Advancing Translational Sciences (NCATS). Using NCATS’ matrix screening platform, the combined teams explored an oncology-focused library of nearly 3,000 investigational and approved drugs for their ability to combat SCLC cells in the laboratory.

“We wanted to identify novel drugs and combinations to leverage this vulnerability therapeutically,” said NCI’s Dr. Anish Thomas, who led the study. “We saw potential opportunities because the armamentarium of new chemicals and drugs was rapidly expanding.”

The NCAT matrix combination screening platform incorporates highly integrated robotic with customized software for data analytics to quickly screen a large number of compounds and test different drug combinations on cellular, molecular or biochemical processes for their effectiveness on treating the disease of interest. Scientists can then further examine the most promising drugs and drug combinations to determine the most effective doses of each drug and gain a better understanding of the mechanisms by which these drugs act.

As a result of this effort, the team discovered a number of chemotherapeutic drug combinations that were effective at causing DNA damage and drugs that were designed to block DNA repair. Among the most effective was the FDA approved chemotherapy drug topotecan and an investigational drug called M6620, or berzosertib, which is capable of inhibiting the ATR enzyme that plays a role in DNA repair.

“A lot of exciting advances have led to the clinical availability of ATR inhibitors, including berzosertib,” said Dr. Michele Ceribelli, translational scientist at NCATS and a co-author of the study. “Blocking the ATR enzyme means cancer cells can’t respond to DNA damaging agents properly. This makes chemotherapy even more effective.”

The NCI research team tested the berzosertib-topotecan drug combination in a clinical trial involving 25 SCLC patients who either had relapsed after initial treatment or for whom their therapy had stopped working. As a result, more than one third of the study’s participants showed improvement of their condition, and in some cases lasting up to a period of six months.

“There are a lot of unknowns within the translational process,” said Dr. Thomas. “Such large combination screening experiments can reveal pharmacologic relationships from an increasingly diverse collection of compounds and drugs. In the best-case scenario, the outcomes of these screens can help clinical teams prioritize their efforts.”

The scientists also concluded that in patients who showed a reduction in tumor size following treatment also exhibited a higher level of activity in genes that are involved in rapid cell growth and DNA repair. These findings show promise for the development of a more personalized approach in the treatment of SCLC.

Study Identifies How Suppressed HIV Keeps Immune System on Edge

Following the discovery of the virus that causes HIV in the early 1980’s, doctors have used a treatment regiment comprised up a combination of various antiretroviral drugs to reduce the viral load, slowing the progression of the disease. The prescribed course of treatment known as antiretroviral therapy (ART), is effective in forcing the virus into an inactive state. While there is currently no cure for HIV infection, suppression of the virus allows the infected person to live with a manageable chronic condition, and reduces the risk of HIV transmission to non-infected individuals.

Significant advances have been made in the treatment of HIV, and the prevention of developing AIDS, the advanced stage of HIV infection. However, even though ART therapy can fully suppress the virus in HIV infected individuals, the virus continues to have the ability to overstimulate the immune system creating a host of ongoing health related issues.

In a recent study, IRP researchers have identified several pathways in which repressed HIV are chronically stimulating the immune system, resulting in atypical age-related ailments such as cardiovascular and kidney disease, and neurological conditions. The research team theorizes that HIV infection persistently over stimulates the immune system, even in a repressed state following successful antiretroviral therapy. HIV that is left untreated can lead to serious health complications as the immune system deteriorates, paving the way for life threatening opportunistic infections and diseases. Much like any other viral infection, HIV also stimulates the body’s natural defenses in the process of destroying immune cells.

“HIV can only infect and replicate in activated immune cells, so the more it activates the immune system, the more it creates targets — that’s how it spreads,” says Dr. Leonid Margolis, NICHD/DIR senior investigator and the study’s senior author. “Even when HIV is completely suppressed by antiviral drugs, there is some residual immune activation that remains, and we don’t know what triggers it.”

In the absence of a currently viable model for testing these activation mechanisms in a controlled laboratory setting, Dr. Margolis’s research team assisted in the development a novel methodology utilizing tissue from human tonsils that were removed during surgery. Tonsil tissue contains a high amount of immune cells and when cultured in the lab, provides an excellent model for studying viruses like NIH that infect those cells. Using this method, the research team was able to determine immune cell activity by measuring their secretion of cytokines that regulate immune system activity.

Using their model, Dr. Margolis’ team determined that ART drugs alone do increase immune cell activity, as some scientists have proposed. Similarly, treating the tissue model with large amounts of cytokines to simulate the high level of immune activation triggered during the early stages of HIV infection, known as a ‘cytokine storm’, also did not cause the tissue to continue over-producing cytokines within a 12 day time period. The team then exposed the tissue to proteins produced by the HIV virus and HIV-infected cells still failed to have any measurable effect on stimulating the immune cells.

However, when testing their model using inactivated HIV viral particles, this triggered sustained increases in cytokine production. The researchers also found that the tissue released more cytokines when it was exposed to tiny capsules called extracellular vesicles released from HIV-infected cells, even when those infected cells had been treated with an antiviral drug.

“These small vesicles mediate cell-cell interactions,” Dr. Margolis explains. “They contain proteins and RNA. They’re the way that cells talk to each other. We don’t know, unfortunately, which infected tissues in the body produce vesicles containing viral proteins and RNA and which don’t. We now know that vesicles from HIV-infected tissue activate the immune system, but we don’t know their source.”

The researchers also discovered that inactivated HIV viruses trip cellular detectors called toll-like receptors (TLRs) present on immune cells, which engage the immune system to respond to invaders. When the tissue model was treated with chemicals that inhibit a particular TLR called TLR8, the inactivated HIV viruses did not activate an elevated cytokine response.

“The general idea of our work is, if you can suppress immune activation, there is a good chance that these diseases would not develop,” says Dr. Margolis. “Of course, it’s very difficult because we need our immune systems to protect us. We need very fine tuning that specifically suppresses immune activation by HIV, but the general immune response should be preserved. For this, we need to know detailed mechanisms.” Gaining a better understanding of the underlying mechanisms which cause a chronic, elevated immune response from fully suppressed NIH infection, potential therapies can be targeted to reduce the early development of age-related illnesses in people living with HIV.

Experimental antiviral for COVID-19 effective in hamster study

In a study recently conducted by the National Institute of Allergy and Infectious Disease (NIAID), researchers discovered that an antiviral drug, known as MK-4482, significantly decreased the levels of virus and damage in the lungs of hamsters that were treated for SARS-CoV-2 infection, the virus responsible for causing COVID-19 disease.

The research team found that treatment with MK-4482 was effective when provided up to a period of 12 hours prior to infection or within 12 hours following infection of the hamsters with the virus. The results of the study suggest that MK-4482 could potentially mitigate high-risk exposure to SARS-CoV-2, and may be effective in treating the infection either alone or in combination with other drug therapies.

While the antiviral drug, Remdesivir, has already been FDA approved for use in treating COVID-19, it must be administered intravenously, limiting its use to clinical settings. One of the primary advantages of MK-4482 is that is can be delivered orally, a considerable benefit in providing treatment during the COVID-19 pandemic.

In a collaborative study between NIAID and the University of Plymouth in the UK, the research team prepared three groups of hamsters: a pre-infection treatment group; a post-infection treatment group; and an untreated control group. For the two treatment groups, MK-4482 was administered orally every 12 hours for a period of three days. At the conclusion of the study, the animals in each of the treatment groups had 100 times less infectious virus in their lungs than the control group. Animals in the two treatment groups also had significantly fewer lesions in the lungs than the control group. The researchers were able to determine the treatment doses in the current study based upon prior experiments with SARS-CoV-1 and MERS-CoV  that were performed in mouse models in which MK-4482 was effective in inhibition replication of the related viruses.

With funding support from NIAID, Emory University’s Drug Innovation Ventures group in Atlanta, developed MK-4482 (also known as molnupiravir and EIDD-2801) to treat influenza. Merck and Ridgeback Biotherapeutics are now jointly developing and evaluating MK-4482 as a potential COVID-19 treatment. The drug is currently in Phase 2 and 3 human clinical studies.

RNA-Targeting Therapeutic Restores Protein Absent in Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder characterized by progressive muscle degeneration and a decline in muscle strength over time. It is caused by the lack of a spinal motor neuron protein required for muscle development and movement. A research team from the National Institute of Neurological Disorders and Stroke (NINDS), in a collaborative study with Oxford University, have identified a promising new therapeutic for the treatment of this debilitating genetic disease.

The genes distributed throughout our DNA are used as templates to create messenger RNA (mRNA), which cells then use to manufacture a variety of proteins needed for their survival. In many genetic diseases, a change in a gene can lead to the creation of a defective protein or may stop the synthesis of the protein entirely. In SMA, mutations in both copies of the SMN1 gene cause a lack of the survival motor neuron (SMN) protein. Without the SMN protein, neurons involved in movement die, resulting in muscle degradation.

The progression rate and severity of SMA depend in part on how many copies of another gene, SMN2, patients have in their cells. Patients with more copies of SMN2 will tend to develop milder symptoms later in life, whereas those with fewer copies may develop more severe symptoms, including life-threatening paralysis, at an early age. The SMN2 gene is similar in structure to SMN1 and can partially function as a ‘backup’ gene. However, only approximately 10% of the SMN protein that is produced by SMN2 is fully functional and not able to sustain the survival of the motor neurons.

“Only a minority of the protein that’s produced by the SMN2 gene is the fully functional form,” says Dr. Audrey Winkelsas, the study’s first author and postdoctoral fellow in the lab of NINDS senior investigator Dr. Kenneth Fischbeck. “That’s why it’s a good therapeutic target: if we can change how much functional protein is made from SMN2, then that, in theory, could affect disease severity.”

“That’s been shown in animal studies to be very effective at blocking disease onset and mitigating the disease’s manifestations,” adds Dr. Fischbeck, the study’s senior author.

Two of the existing treatments for SMA, nusinersen and risdiplam, alter the way SMN2 mRNA is created, resulting in an increased production of fully functional SMN protein. Nusinersen is a type of molecule called an antisense oligonucleotide (ASO), which are strands of RNA-like genetic material that can bind to specific sequences on RNA molecules and cause certain effects depending on their structure. The team developed several ASOs designed to affect SMN2 mRNA in a different manner from nusinersen by binding to a different part of the mRNA molecule.

When cells taken from SMA patients were treated with the experimental ASOs, they found dramatically increased levels of both the functional and non-functional forms of the SMN protein. Control cells that were treated with an ASO incapable of binding to any RNA molecules showed did not exhibit an increase. The treatment also raised levels of Gemin6 and Gemin8, proteins which aid in the function of the SMN protein. Additional experiments revealed that, unlike nusinersen and risdiplam, the experimental ASOs work by stabilizing SMN2 mRNA, which allows more of it to be used for SMN protein synthesis before breaking down.

“Our approach is complimentary or additive,” says Dr. Fischbeck. “The idea is to enhance the effect of existing treatments so as to reduce the burden of the disease in patients, particularly in older patients who don’t respond as much to available treatments.”

To test this theory, the researchers treated cells taken from SMA patients with a combination of one of their experimental ASOs and another that affects SMN2 mRNA in the same way as nusinersen. This resulted in a higher increase in SMN protein levels than the nusinersen-like ASO did on its own. Their findings support the theory that their approach may in fact be synergistic with existing treatments for SMA along with a wide range of genetic diseases.

Oxford University has applied for a U.S. patent for the new ASO-based treatment for SMA, which would allow the institution to license the technology to any pharmaceutical company for further development.

NIH scientists develop breath test for methylmalonic acidemia

A multidivisional team of researchers at the National Institute of Health (NIH) have developed a breath test for measuring how well patients with methylmalonic acidemia (MMA), a rare genomic disease, respond to receiving liver or combined liver and kidney transplantation. This unique test can also be used to assess the severity of the MMA to determine if they would benefit from surgical or experimental genomic therapies targeting the liver. The recent study, published in Genetics in Medicine, was led by a team of scientists at the National Human Genome Research Institute (NHGRI), with collaborators from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institute of Mental Health (NIMH).

Patients with MMA are unable to properly digest certain proteins and fats (lipids), causing a build up a toxic level of methylmalonic acid in the blood. This disorder may result in serious illnesses that can lead to stroke, kidney failure, pancreatitis, liver damage and, in severe cases, death. There is currently no known cure for MMA, however the symptoms of the disease can be managed through a low-protein diet and dietary supplements. In extreme cases, patients may receive liver or combined liver and kidney transplants, which aid in restoring metabolic proteins to normal levels.

“Vast fluctuations in metabolic substances in the bodies of patients make it difficult for us to tell if treatments like genome editing and transplants are likely to be successful,” said Dr. Charles Venditti, NHGRI senior investigator and senior author of the study. “Instead of looking at levels, we decided to measure metabolism itself.”

One form of MMA is caused by mutations in the methylmalonyl-CoA mutase gene (MMUT), which encodes for the MMUT protein. MMUT helps break down food into a chemical byproduct called propionate, which is followed by an integral process involved in metabolism called oxidation. Through oxidation, a healthy body converts propionate into energy and carbon dioxide, which is exhaled, but that process is faulty for people with MMA.

Because MMUT protein function is compromised in people with MMA, Dr. Venditti and his team chose to assess how well the MMUT protein helped break down propionate in both patients who did and not did not receive treatment. The researchers believed this would act as a proxy for how much oxidation was happening in a patient’s body.

“We wanted to measure exhaled carbon dioxide because we planned to use a breath test to track oxidation of propionate in a non-invasive way,” said Dr. Irini Manoli, NHGRI associate investigator and co-author of the study. “The trick was to somehow ‘mark’ the carbon dioxide so we could see which patients are unable to oxidize propionate because of a faulty MMUT protein.”

The carbon dioxide we exhale as a result of propionate breaking down in the body contains carbon 12, a lighter more common form of carbon. Since exhaled carbon dioxide  containing carbon 12 is released by several metabolic processes in the human body, simply measuring carbon dioxide exhaled by MMA patients would not show how well MMUT helped oxidize propionate. To detect if the MMUT protein was functioning properly, researchers gave patients a dose of carbon 13, a heavier, less abundant version of carbon, via a commercially available food additive.

The team recruited 57 study participants, including 19 MMA patients who had received transplants (liver, kidney or both) and 16 healthy volunteers. Researchers gave participants a dose of the food additive containing carbon 13 via a drink or through a feeding tube, and then collected their breath samples after a two-minute wait. The researchers measured how much of the exhaled carbon dioxide contained the usual carbon 12 as compared to the added carbon 13. As expected, MMA patients who did not receive any treatment had lower levels of carbon 13 than healthy volunteers while MMA patients with liver transplants had higher levels of carbon 13, similar to the healthy volunteers.

The result indicated that the MMUT protein was helping oxidize the carbon 13 molecules by bonding with inhaled oxygen molecules. Higher levels of carbon 13 oxidation also correlated with better clinical outcomes, such as improved cognition and slower decline in kidney function. “Our next goal is to see if this specialized breath test can detect increase in carbon 13 propionate oxidation after gene, mRNA or genome editing therapies,” said Dr.Venditti “This way, we can also use this test to measure how effective these treatments are in restoring MMUT function.”


Upcoming Events:

Wednesday, May 12, 2021, 8:00 am to Thursday, May 13, 2021, 5:30 pm (registration required)
NHLBI Systems Biology Symposium

National Center for Complementary and Integrative Health (NCCIH) Events:

Friday, June 18, 2021

Assessing and Measuring Target Engagement: Mechanistic and Clinical Outcome Measures for Brain Disorders of Aging

Wednesday, August 25, 2021

Relating Target Engagement to Clinical Benefit: Biomarkers for Brain Disorders of Aging