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

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. Astrix Government Staffing Services provides detailed insight each month into active NIH Research.

Recent NIH Research

NIH researchers discover new genetic eye disease

National Eye Institute (NEI) researchers discovered a new disease affecting the macula. NEI is part of the National Institutes of Health (NIH), a medical research agency that is a part of the U.S. Department of Health and Human Services.

Macular dystrophies are a group of degenerative diseases that cause progressive vision loss by damaging the macula, the small central area of the retina responsible for sharp, straight-ahead vision. These diseases are typically due to mutations in genes such as ABCA4BEST1PRPH2, and TIMP3.

Patients with Sorsby Fundus Dystrophy, a genetic eye disease characterized by TIMP3 variants, typically experience symptoms in adulthood. They frequently have rapid visual acuity fluctuations resulting from choroidal neovascularization– new, abnormal blood vessels that develop beneath the retina and leak fluid, causing vision impairment. The TIMP3 gene variants identified so far are all in the mature protein after cleaving from the RPE cells.

“We found it surprising that two patients had TIMP3 variants not in the mature protein but in the short signal sequence the gene uses to ‘cut’ the protein from the cells. We showed these variants prevent cleavage, causing the protein to be stuck in the cell, likely leading to retinal pigment epithelium toxicity,” said Bin Guan, Ph.D., lead author.

To confirm that the two new TIMP3 variants are linked to this unusual maculopathy, the research team conducted clinical investigations and genetic testing of family members.

“Discovering novel disease mechanisms, even in known genes like TIMP3, may help patients that have been looking for the correct diagnosis, and will hopefully lead to new therapies for them,” said Rob Hufnagel, M.D., Ph.D., senior author and director of the Ophthalmic Genomics Laboratory at NEI.

NEI Intramural Research Program supported this research. The National Eye Institute (NEI) is a medical research body in the United States government, part of the National Institutes of Health. The NEI is the federal government’s primary agency for studying the visual system and eye diseases. NEI funds basic and clinical science programs to create sight-saving medications and address the specific needs of individuals with vision loss. For further information, visit https://www.nei.nih.gov.

Treating Parkinson’s Disease with Pinpoint Precision

Parkinson’s disease affects an estimated seven to ten million people worldwide. In the United States, approximately one million people live with Parkinson’s disease. Dopamine-producing neurons in the brains of individuals with Parkinson’s disease deteriorate and stop communicating messages. People experience physical symptoms such as tremors, stiffness, and poor coordination as dopamine levels fall.

Five distinct dopamine receptors differ somewhat in structure and function. The most common drug, levodopa, or L-DOPA can worsen some movement problems when taken for long periods. That is because L-DOPA and similar medicines cannot differentiate between these receptors, so they interact with either the wrong ones or all of them simultaneously.

“That’s a problem if you’re trying to develop drugs to target individual receptor subtypes,” explains Dr. Sibley, IRP senior investigator. “Many drugs available today cross-react with other receptors, which can lead to side effects.”

IRP researchers are developing a drug that, when taken alongside other treatments, could more effectively slow the progression of Parkinson’s disease while reducing side effects. IRP scientists used high-throughput drug screening robots to sift through the nearly 400,000 compounds in NCATS’ library to find something that worked. They conducted the screen twice: once looking for ‘antagonists’ that shut down the D3 receptor and once to see that they activated the receptor-activated receptor.

“You go through many rounds of testing slightly different versions of a starting compound to see what changes on the molecule improve activity and selectivity and which changes decrease activity,” postdoctoral fellow and co-investigator Dr. Moritz explains.

The IRP researchers eventually narrowed it down to one highly selective for the D3 receptor, meaning it interacted strongly with that receptor but weakly or not at all with other types of dopamine receptors. To enhance the compound’s effects on the D3 receptor, the IRP team collaborated with Kevin Frankowski, Ph.D., a medicinal chemist at the University of North Carolina, to synthesize and test variants with minor chemical modifications. They found a drug candidate called ML417 that showed promise.

“In our manuscript, we showed that ML417 is actually the most selective D3 agonist currently known,” Dr. Sibley says. “We then worked with a computational chemist at NIH, Dr. Lei Shi, to learn why this compound is so selective. We found that it interacts with the D3 receptor in a way that is unique compared with other molecules that activate that receptor.

Because ML417 targets D3 receptors, it has significant potential as a drug to treat Parkinson’s disease-related mobility issues. The D3 receptor is predominantly expressed in the brain regions that control movement.

Although more research is needed, preliminary studies in animal models conducted in collaboration with IRP senior investigator Judith Walters, Ph.D., suggest that ML417 may have immunomodulatory effects.

The IRP team is also working with outside NIH colleagues to test the hypothesis that lowering D3 receptors can help prevent relapse in opioid pill users attempting to quit.

“Translational science is just so important,” notes Dr. Sibley. “It’s the way forward for developing novel therapeutics for treating many different diseases and disorders.”

Leveraging Turncoat Immune Cells to Combat Cancer

Macrophages are a type of white blood cell that normally help protect the body from infection and disease. They have a receptor protein on their surfaces known as CD206 that activates the phagocytosis process, which is more formally defined as ‘cell eating.’ When CD206 is activated, macrophages capture and bind to foreign threats before pushing them into their interior for digestion. However, cancer cells can push back by switching the CD206 receptor off which allows them to hijack the macrophages turning them into tumor-associated macrophages that supports tumor growth.

A new study by IRP senior investigators Udo Rudloff, M.D., Ph.D., and Juan Marugan, Ph.D. found a way to fight back against this cancer defense mechanism. The approach uses a small molecule drug to “reprogram” macrophages and other cells that have been hijacked by the tumor, restoring their anti-tumor activity.

“Initially, immunotherapy was all about immune cells such as T cells,” says Dr. Rudloff, “but in the last decade people have recognized that other cells, like these macrophages, can be very helpful as well.”

Dr. Rudloff and his research team searched the NIH’s National Center for Advancing Translational Sciences (NCATS) library of molecules for a molecule with a similar CD206. In computer modeling, they discovered a few that met this criterion. They picked one to test in animal models to see how well it worked and how long it stayed in the body before being broken down once they had narrowed down the candidate molecules to a small set.

“We were able to find molecules that worked very efficiently doing the same thing that the CD206 receptor did: activate the immune system and change the immune environment to suppress the growth of all kinds of tumors,” says Dr. Marugan. “This will be a new modality of immunotherapy using a small molecule.”

This potential new therapy also appears to be “tumor agnostic,” which means it may work on any tumor that displays a high quantity of tumor-associated macrophages with CD206 receptors. Current animal and cell studies are showing that the therapy is highly effective against pancreatic, colorectal, breast, skin malignancy melanoma, and bone cancer osteosarcoma. The researchers are now in the final stages of testing and seeking a pharmaceutical industry partner to help begin the first-in-class human clinical trials for cancer.

Reprogramming macrophages may also be beneficial in other conditions. Dr. Rudloff and Dr. Marugan are collaborating with Japanese researchers who are developing a potential therapy for diabetic retinopathy, a disease complication caused by hyperglycemia in which macrophages with the CD206 receptor play an essential role.

Trial of potential universal flu vaccine opens at NIH Clinical Center

A novel influenza vaccine has been developed by scientists at the National Institute of Allergy and Infectious Diseases (NIAID). It is now being tested in Phase 1 clinical trial at the NIH Clinical Center in Bethesda, Maryland. The safety of a candidate vaccine, BPL-1357, and its capacity to elicit immune responses will be evaluated in the study.

“Influenza vaccines that can provide long-lasting protection against a wide range of seasonal influenza viruses as well as those with pandemic potential would be invaluable public health tools,” said NIAID Director Anthony S. Fauci, M.D. “The scientific community is making progress on this pressing global health priority. The BPL-1357 candidate influenza vaccine being tested in this clinical trial performed very well in pre-clinical studies, and we look forward to learning how it performs in people.”

BPL-1357 is a “live attenuated” vaccine, meaning that it uses weakened influenza viruses to help the body build immunity against infection by natural influenza viruses. The weakened viruses in the vaccine are unable to cause illness.

An animal study by NIAID investigator Jeffery K. Taubenberger showed that mice intramuscularly or intranasally administered two doses of BPL-1357 vaccine survived exposure to each of the six different influenza virus strains and subtypes not included in the vaccine at lethal doses.

The single-site trial can enroll up to 100 people aged 18 to 55 years, will last approximately seven months for each participant, and is led by NIAID investigator Matthew J. Memoli. In the Phase 1 trial, participants will be assigned to one of three groups and given two doses of placebo or vaccine, each administered 28 days apart, in a 1:1:1 ratio. Group A gets BPL-1357 intramuscularly plus nasal saline placebo. Group B will be administered intranasal doses of the candidate vaccine with an intramuscular placebo at both visits to the clinic. In contrast, Group C gets the inactive substance injections only once. Neither the researchers nor participants are aware of group assignments. Volunteers must have not received any vaccination for the flu in the previous eight weeks and must commit to avoiding seasonal flu vaccines for two months after the second dose.

“With the BPL-1357 vaccine, especially when given intranasally, we are attempting to induce a comprehensive immune response that closely mimics immunity gained following a natural influenza infection,” said Dr. Memoli. “This is very different than nearly all other vaccines for influenza or other respiratory viruses, which focus on inducing immunity to a single viral antigen and often do not induce mucosal immunity.”

The National Institutes of Health (NIH) funds and directs research on the causes of infectious and immune-mediated diseases and develops new methods to prevent, diagnose, and treat these illnesses. For additional information about the trial, visit clinicaltrials.gov and search on the trial identifier NCT05027932.

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