Reducing Inflammation in the Brain

One limitation in drug development is that many drugs only travel through the bloodstream, meaning it is difficult to get them to the brain, due to the blood-brain barrier. This can make treating neurological conditions, including Alzheimer’s disease, difficult.

While beta-amyloid remains the primary target for many researchers, there are other potential drug targets that researchers are considering. Previous research has shown that inflammation is a hallmark of neurodegenerative disorders, including Alzheimer’s disease.

Many studies have linked the neuroinflammation seen in Alzheimer’s disease to a transcription factor — a protein that turns genes on and off — called PU.1.

Now, a team of researchers has developed a drug using siRNA that interrupts PU.1, in an attempt to reduce inflammation in microglial cells.

In this study, researchers from MIT who have previously shown that inflammation can be decreased by inhibiting the PU.1 protein, showed that siRNA delivered to the microglia could reduce PU.1 expression.

They developed seven lipid nanoparticle (LNP) formulations to carry the siRNA they had developed into the cells. LNP formulations have already been used in Pfizer’s mRNA COVID-19 vaccine, and have been shown to be safe and effective.

To determine which of the LNP formulations they had developed was the most effective at getting the siRNA into the nucleus of the cell they tested them on in vitro cultures of human stem cell-derived microglia-like cells (iMGLs).

To test the best way to get past the blood-brain barrier, researchers then carried out experiments on mice. They injected the mice normally into the bloodstream or into the cerebrospinal fluid which runs between the spine and space between the skull and the brain. They found injection into cerebrospinal fluid was the most effective at being absorbed by the microglia.

Sources:

William T. Ralvenius, Jason L. Andresen, Margaret M. Huston, Jay Penney, Julia Maeve Bonner, Owen S. Fenton, Robert Langer, Li-Huei Tsai. Nanoparticle-Mediated Delivery of Anti-PU.1 siRNA via Localized Intracisternal Administration Reduces Neuroinflammation. First published: 28 November 2023 https://doi.org/10.1002/adma.202309225 

Advanced Materials. (2023). Innovative therapy delivery system may help fight brain inflammation. MedicalNewsToday. Retrieved December 19, 2023 from https://www.medicalnewstoday.com/articles/innovative-therapy-delivery-system-may-help-fight-brain-inflammation 

Photo by MART  PRODUCTION from Pexels: https://www.pexels.com/photo/technology-computer-head-health-7089331/