Nanobody Penetrates Brain Cells to Halt the Progression of Parkinson’s

Calendar August 10, 2022 | Posted by admin

Researchers from the Johns Hopkins University School of Medicine have helped develop a nanobody capable of getting through the tough exterior of brain cells and untangling misshapen proteins that lead to Parkinson’s disease, Lewy body dementia, and other neurocognitive disorders. The research, published last month in Nature Communications, was led by Xiaobo Mao, an associate professor of neurology at the School of Medicine, and included scientists at the University of Michigan, Ann Arbor. Their aim was to find a new type of treatment that could specifically target the misshapen proteins, called alpha-synuclein, which tend to clump together and gum up the inner workings of brain cells. Emerging evidence has shown that the alpha-synuclein clumps can spread from the gut or nose to the brain, driving the disease progression.

Nanobodies—miniature versions of antibodies, which are proteins in the blood that help the immune system find and attack foreign pathogens—are natural compounds in the blood of animals such as llamas and sharks and are being studied to treat autoimmune diseases and cancer in humans. In theory, antibodies have the potential to zero in on clumping alpha-synuclein proteins, but have a hard time getting through the outer covering of brain cells. To squeeze through these tough brain cell coatings, the researchers decided to use nanobodies instead. The researchers had to shore up the nanobodies to help them keep stable within a brain cell. To do this, they genetically engineered them to rid them of chemical bonds that typically degrade inside a cell. Tests showed that without the bonds, the nanobody remained stable and was still able to bind to misshapen alpha-synuclein.

The team made seven similar types of nanobodies, known as PFFNBs, that could bind to alpha-synuclein clumps. Of the nanobodies they created, one—PFFNB2—did the best job of glomming onto alpha-synuclein clumps and not single molecules, or monomer of alpha-synuclein, which are not harmful and may have important functions in brain cells. Additional tests in mice showed that the PFFNB2 nanobody cannot prevent alpha-synuclein from collecting into clumps, but it can disrupt and destabilize the structure of existing clumps.

The structure of alpha-synuclein clumps (left) was disrupted by the nanobody PFFNB2. The debris from the disrupted clump is shown on the right.

“Strikingly, we induced PFFNB2 expression in the cortex, and it prevented alpha-synuclein clumps from spreading to the mouse brain’s cortex, the region responsible for cognition, movement, personality, and other high-order processes,” says Ramhari Kumbhar, the co-first author and a postdoctoral fellow at the School of Medicine.

“The success of PFFNB2 in binding harmful alpha-synuclein clumps in increasingly complex environments indicates that the nanobody could be key to helping scientists study these diseases and eventually develop new treatments,” Mao says.

Source: https://hub.jhu.edu/

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Sugary Protein Could Play Key Role In Alzheimer’s Disease

Calendar June 28, 2022 | Posted by admin

In a bit of “reverse engineering” research using brain tissues from five people who died with Alzheimer’s disease, Johns Hopkins Medicine researchers say they discovered that a special sugar molecule could play a key role in the development of Alzheimer’s disease. If further research confirms the finding, the molecule, known as a glycan, could serve as a new target for early diagnostic tests, treatments and perhaps prevention of Alzheimer’s disease, say the researchers.

Alzheimer’s disease is the most common form of dementia in the United States. Affecting an estimated 5.8 million Americans, the progressive disorder occurs when nerve cells in the brain die due to the buildup of harmful forms of proteins called amyloid and tau.

Cleaning up the disease-causing forms of amyloid and tau is the job of the brain’s immune cells, called microglia. Earlier studies found that when cleanup is impaired, Alzheimer’s disease is more likely to occur. In some people, this is caused by an overabundance of a receptor on the microglia cells, called CD33.

A sugar molecule, known as a glycan, could serve as a new target for early diagnostic tests, treatments, and perhaps prevention of Alzheimer’s disease

“Receptors are not active on their own. Something needs to connect with them to block microglia from cleaning up these toxic proteins in the brain,” says Ronald Schnaar, Ph.D., the John Jacob Abel Professor of Pharmacology at the Johns Hopkins University School of Medicine and director of the laboratory that led the study.

Past studies by the researchers showed that for CD33, these “connector” molecules are special sugars. Known to scientists as glycans, these molecules are ferried around the cell by specialized proteins that help them find their appropriate receptors. The protein-glycan combination is called a glycoprotein.

The study was published online April 20 in the Journal of Biological Chemistry.

Source: https://www.hopkinsmedicine.org/

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How To Uncloak Cancer Cells And Reveal Them To The Immune System

Calendar February 27, 2020 | Posted by admin

Scientists at Johns Hopkins report they have designed and successfully tested an experimental, super small package able to deliver molecular signals that tag implanted human cancer cells in mice and make them visible for destruction by the animals’ immune systems. The new method was developed, say the researchers, to deliver an immune system “uncloaking” device directly to cancer cells.

Conventional immune therapies generally focus on manipulating patients’ immune system cells to boost their cancer-killing properties or injecting drugs that do the same but often have toxic side effects. A hallmark of cancer biology is a tumor cell’s ability to essentially hide from the immune system cells whose job is to identify and destroy cancer cells. Current cellular immunotherapies, notably CAR-T, require scientists to chemically alter and enhance a patient’s own harvested immune system T-cells — an expensive and time-consuming process, say the researchers. Other weapons in the arsenal of immunotherapies are drugs, including so-called checkpoint inhibitors, which have broad effects and often lead to unwanted immune-system-associated side effects, including damage to normal tissue.

By contrast, the Johns Hopkins team sought an immune system therapy that can work like a drug but that also individually engineers a tumor and its surrounding environment to draw the immune system cells to it, says Jordan Green, Ph.D, professor of biomedical engineering at the Johns Hopkins University School of Medicine.

A microscopic image of the nanoparticles used in the study. The black scale bar is 100 nm in size
 “And our process happens entirely within the body,” Green says, “requiring no external manipulation of a patient’s cells.“

To develop the new system, Green and his team, including Stephany Tzeng, Ph.D., a research associate in the Department of Biomedical Engineering at Johns Hopkins, took advantage of a cancer cell’s tendency to internalize molecules from its surroundings. “Cancer cells may be easier to directly genetically manipulate because their DNA has gone haywire, they divide rapidly, and they don’t have the typical checks and balances of normal cells,” says Green.

The team created a polymer-based nanoparticle — a tiny case that slips inside cells. They guided the nanoparticles to cancer cells by injecting them directly into the animals’ tumors. “The nanoparticle method we developed is widely applicable to many solid tumors despite their variability on an individual and tumor type level,” says Green, also a member of the Johns Hopkins Kimmel Cancer Center. Once inside the cell, the water-soluble nanoparticle slowly degrades over a day. It contains a ring of DNA, called a plasmid, that does not integrate into the genome and is eventually degraded as the cancer cell divides, but it stays active long enough to alter protein production in the cell.

The additional genomic material from the plasmid makes the tumor cells produce surface proteins called 4-1BBL, which work like red flags to say, “I’m a cancer cell, activate defenses.” The plasmid also forces the cancer cells to secrete chemicals called interleukins into the space around the cells. The 4-1BBL tags and interleukins are like magnets to immune system cells, and they seek to kill the foreign-looking cancer cells.

Results of the proof-of-concept experiments were published online in the Proceedings of the National Academy of Sciences.

Source: https://www.hopkinsmedicine.org/

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Nano Packets Of Genetic Code Seed Cells Against Brain Cancer

Calendar July 17, 2018 | Posted by admin

In a “proof of concept” study, scientists at Johns Hopkins Medicine say they have successfully delivered nano-size packets of genetic code called microRNAs to treat human brain tumors implanted in mice. The contents of the super-small containers were designed to target cancer stem cells, a kind of cellular “seed” that produces countless progeny and is a relentless barrier to ridding the brain of malignant cells.

Nanoparticles releasing microRNAs (light blue) inside a human brain cancer cell

“Brain cancer is one of the most widely understood cancers in terms of its genetic makeup, but we have yet to develop a good treatment for it,” says John Laterra, MD, PhD, professor of neurology, oncology and neuroscience at the Johns Hopkins University School of Medicine and a research scientist at the Kennedy Krieger Institute. “The resilience of cancer stem cells and the blood-brain barrier are major hurdles.”

Blood that enters the brain is filtered through a series of vessels that act as a protective barrier. But this blood-brain barrier blocks molecular medicines that have the potential to revolutionize brain cancer therapy by targeting cancer stem cells, says Laterra.

“To modernize brain tumor treatments, we need tools and methods that bypass the blood-brain barrier,” says Jordan Green, PhD, professor of biomedical engineering, ophthalmology, oncology, neurosurgery, materials science and engineering and chemical and biomolecular engineering at the Johns Hopkins University School of Medicine. “We need technology to safely and effectively deliver sensitive genetic medicines directly to tumors without damaging normal tissue.”

A case in point, Green says, is glioblastoma, the form of brain cancer that Arizona Sen. John McCain is battling, which often requires repeated surgeries. Doctors remove the brain tumor tissue that they can see, but the malignancy often returns quickly, says Laterra. Most patients with glioblastoma live less than two years after diagnosis.

Results of the experiments were published online in Nano Letters.

Source: https://engineering.jhu.edu/

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