Experimental protein booster offers a new way to treat rare genetic diseases microbiologystudy

Johns Hopkins Medicine laboratory scientists say they have developed a potential new way to treat a variety of rare genetic diseases marked by too low levels of specific cellular proteins. To boost those proteins, they’ve created experimental versions of a genetic “tail” that attaches to so-called mRNA molecules that churn out the proteins.

A report on the researchers’ proof-of-concept work on laboratory-cultured cells and mice is published in the Molecular Therapy Nucleic Acids journal and could pave the way for therapies for diseases in which one copy of a person’s genes is missing or altered so that only half the amount of protein is made.

Such disorders, although rare, include some forms of cancer, and immune system and neurodegenerative disorders, including SYNGAP deficiency, which results in learning disabilities and autism features in children.

There are more than 300 such conditions (haploinsufficiency diseases) and some also lead to developmental delays.

“Our research began as a way to help families find new treatment options for these diseases, in addition to gene-editing therapies that are being studied now,” says Jeff Coller, Ph.D., Bloomberg Distinguished Professor of RNA Biology and Therapeutics at The Johns Hopkins University and professor of molecular biology and genetics at the Johns Hopkins University School of Medicine.

Protein booster exploits a natural protein-making system

The research team built its therapy from systems found in nature, in which each parent contributes half their DNA to a child. DNA contains genes that are turned on and off to produce cellular proteins that make our body function properly. If one parent’s gene copy is missing, or if it contains a mistake, the other parent’s gene copy is the only source of that protein, so about half of the protein level in the cell goes missing.

Specifically, the way cells make proteins is by turning on a gene, which, in turn, makes mRNA, a genetic messenger released to start making protein. That protein-making process continues until mRNAs self-destruct. The speed and duration of this process is controlled by a short poly(A) tail of chemical molecules tacked on to mRNA. Coller likens the chemical tail to a fuse that slowly burns as protein is being made and eventually burns down to nothing so that the mRNA is degraded.

“We’ve taken advantage of this natural system by adding an artificial poly(A) tail to mRNA,” says Coller. “We can trick the cell into extending the lifespan of mRNA and boosting its protein output.”

The goal and the hope, he says, is that “even subtle increases in protein production” will help people with protein-deficient disorders.

Study findings show protein increase

Coller and postdoctoral fellow Bahareh Torkzaban, Ph.D., designed five types of mRNA boosters to attach to five human mRNAs. One mRNA makes routine proteins in cells, and the other four make proteins critical to brain function.

After the scientists administered the mRNA booster to laboratory mice, each group of mice had 1.5 to 2 times more of the protein specific to the mRNA booster than control mice that did not receive the booster.

mRNA booster design and next steps

To deliver the mRNA boosters, the scientists encased them in nanoparticles covered in lipids (fatty compounds). The nanoparticles are naturally absorbed by cells through their fatty outer membranes. “The mRNA booster is designed to work only in cells that have the mRNA that we want to target for protein production,” says Coller. “If the mRNA is not expressed in a cell, the mRNA booster won’t do anything.”

In future experiments, Coller will focus on making the best of an mRNA booster’s design to target a particular disease, and determine whether it can reverse symptoms in animal models of a disease.