Researchers Might Have Just Made a Breakthrough Discovery for Treating Rare Proteinopathies

It’s common knowledge among researchers who study diseases called toxic proteinopathies that this group of disorders are the result of misfolded proteins that reside in cells. Certain proteins fail to fold normally and then become toxic. A total of fifty known diseases, including Alzheimer’s, Parkinson’s, and Huntington’s disease are associated with these abnormalities.

As reported this month in Harvard Medical School, the cause of these abnormalities eluded researchers until recently.

Three highly regarded institutions writing for the July 25, 2019 publication of the journal Cell announced a discovery. They determined that the toxicities may be caused by a blockage in the secretory pathway. This pathway sends proteins to either the cell’s surface or to a cell’s protein-disposal system.

A Simple Analogy

To understand this process better, picture a distribution and shipping center. If the distribution center doesn’t dispose of rejected or defective products, the damaged merchandise would accumulate and disrupt the flow of goods. That is true whether we are speaking of a warehouse or speaking of the packing centers a living cell. The buildup of toxic proteins has been demonstrated to contribute to dozens of diseases.

About MKD and BRD4780

The researchers tracked down the genetic root of a rare disorder called MUC1 kidney disease (MKD). They knew it was caused by the accumulation of the misfolded protein MUC1, which leads to kidney failure.

The team searched a database of over 3,700 compounds at various stages of drug development. They located BRD4780, a drug that had been ineffective as a blood pressure medication. While studying MKD, the researchers discovered that the compound BRD4780 cleared up the harmful “debris” that had accumulated. The compound showed efficacy in connection with human kidney cells as well as in an MKD animal model. By testing BRD4780 in laboratory experiments (in vitro), the team found that BRD4780 was able to lower the misfolded protein levels while increasing survival in specific cells.

One Small Step for Man in the Secretory Pathway

The team then examined kidney organoids (organs grown in a lab, meant to resemble normal organs), animal models of MDK, and human kidney cells. They zeroed in on the secretory pathway. That is where they found kidney cells jammed with MUC1-fs. The failure to eliminate the misfolded protein was traced back to a step in the secretory pathway.

The MUC1-fs were packed into sacs (vesicles) that contained a receptor called TMED9. The researchers then reasoned that TMED9 could loosen its grip on MUC1-fs after binding with BRD4780. Notably, when scientists used CRISPR, similar results were achieved.

Researchers estimate that drugs with similarities to BRD4780 could reverse about twenty diseases involving misfolded proteins. Although there are currently no treatments available, BRD4780 may be just the beginning of a new wave of medicines for toxic proteinopathies.

Rose Duesterwald

Rose Duesterwald

Rose became acquainted with Patient Worthy after her husband was diagnosed with Acute Myeloid Leukemia (AML) six years ago. During this period of partial remission, Rose researched investigational drugs to be prepared in the event of a relapse. Her husband died February 12, 2021 with a rare and unexplained occurrence of liver cancer possibly unrelated to AML.

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