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

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, onePFFNB2—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/

Antibody-Drug Delivery System Kills Cancer Cells With Extreme Precision

It sounds like the stuff of science fiction: a man-made crystal that can be attached to antibodies and then supercharge them with potent drugs or imaging agents that can seek out diseased cells with the highest precision, resulting in fewer adverse effects for the patient.

However, that is precisely what researchers from the Australian Centre for Blood Diseases at Monash University in collaboration with the TU Graz (Austria) have developed: the world’s first metal-organic framework (MOFs) antibody-drug delivery system that has the potential to fast-track potent new therapies for cancer, cardiovascular and autoimmune diseases.

Schematic illustration of the new MOF Antibody crystals and their ability to specifically seek out cancer cells to detect them and deliver highly potent drugs with unprecedented precision

The in vitro study showed that when MOF antibody crystals bind to their target cancer cells and if exposed to the low pH in the cells, they break down, delivering the drugs directly and solely to the desired area.

The metal-organic framework, a mixture of metal (zinc) and carbonate ions, and a small organic molecule (an imidazole, a colourless solid compound that is soluble in water) not only keeps the payload attached to the antibody but can also acts as a reservoir of personalised therapeutics. This is a benefit with the potential to become a new medical tool to target specific diseases with customised drugs and optimised doses.

The findings are now published in the world-leading journal Advanced Materials.

Source: https://www.monash.edu/

COVID-19 Can Cause Antibodies that Mistakenly Target your Own Tissues

An increasing body of research is pointing toward the possibility that COVID-19 causes the development of autoantibodies linked to other autoimmune diseases — and may be tied to the long-hauler symptoms associated with coronavirus.

In the latest preprint study (which means it has not yet undergone peer review) researchers analyzed the levels of 18 different autoantibodies between four groups:

  • 29 unexposed pre-pandemic individuals from the general population
  • 20 individuals hospitalized with moderate-to-severe COVID-19
  • 9 recovering COVID-19-infected individuals with asymptomatic to mild viral symptoms during the acute phase, with samples collected between 1.8 and 7.3 months after infection
  • 6 unexposed pre-pandemic subjects with lupus (an autoimmune disease that involves different kinds of autoantibodies)
  • Autoantibodies are antibodies that mistakenly target your own tissues or organs and are associated with diseases such as rheumatoid arthritis and lupus. Unsurprisingly, the researchers found that autoantibodies were detected in five out of the six lupus subjects, compared to just 11 of 29 non-lupus, pre-pandemic controls.

However, the researchers also found that autoantibodies were detected in seven out of nine patients recovering from SARS-CoV-2 and in 12 out of the 20 hospitalized individuals with moderate to severe COVID-19. In the first group, autoantibodies were detected in all patients with reported persistent symptoms and two of the four without any long-term symptoms.

The autoantibodies that set SARS-CoV-2  infected patients apart from the pre-pandemic subjects are widely associated with myopathies (neuromuscular disorders), vasculitis (inflammation of the blood vessels), and antiphospholipid syndromes (when your body creates antibodies that make your blood much more likely to clot), all of which are conditions that share some similarities with COVID-19. The researchers note that these results underscore the importance of further investigating autoimmunity during a COVID-19 infection, and the role of autoimmunity in lingering symptoms. That said, they do urge caution in interpreting the results, which still need to undergo peer review.

It’s a signal; it is not definitive,” lead researcher Nahid Bhadelia, MD, told the New York Times. We don’t know how prevalent it is, and whether or not it can be linked to long COVID.” (Long COVID is sometimes used to describe the syndrome that causes long-hauler symptoms in those who have recovered from COVID-19.)

Still, as many as one-third of COVID-19 survivors say they still experience symptoms — and determining the role autoimmunity may play after coronavirus infection is critical.

This is a real phenomenon,” Dr. Bhadelia said. “We’re looking at a second pandemic of people with ongoing potential disability who may not be able to return to work, and that’s a huge impact on the health symptoms.”

Source: https://creakyjoints.org/
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https://www.medrxiv.org/