Johns Hopkins Medicine researchers say they have successfully used a cell’s natural process for making proteins to “slide” genetic instructions into a cell and produce critical proteins missing from those cells. If further studies verify their proof-of-concept results, the scientists may have a new method for targeting specific cell types for a variety of disorders that could be treated with gene therapies. Such disorders include neurodegenerative diseases that affect the brain, including Alzheimer’s disease, forms of blindness and some cancers.
For those looking to develop treatments for diseases where cells lack a specific protein, it’s critical to precisely target the cell causing the disease in each structure, such as the brain, to safely kickstart the protein-making process of certain genes, says Seth Blackshaw, Ph.D., professor of neuroscience in the Sol Snyder Department of Neuroscience and member of the Institute for Cell Engineering at the Johns Hopkins University School of Medicine. Therapies that don’t precisely target diseased cells can have unintended effects in other healthy cells, he adds.
Two methods currently used to deliver protein-making packages into cells vary widely in their effectiveness in both animal models and people. “We wanted to develop a gene expression delivery tool that’s broadly useful in both preclinical and clinical models,” says Blackshaw.
One current method of sending biochemical packages involves so-called “mini promoters” that direct the expression, or protein-making process of certain stretches of DNA. Blackshaw says this method often fails to express genes in the right cell type.
Another method, called serotype-mediated gene expression, involves delivering tools that latch on to proteins that stud the surface of certain types of cells. However, Blackshaw says such methods are hit-or-miss in their ability to specifically target only one type of cell, and they often fail to work in people even after successful testing in animal models.
The current proof-of-principle study, described Oct. 1 in Nature Communications, has roots in previous research by Johns Hopkins Assistant Professor of Pathology Jonathan Ling, Ph.D., who published “maps” depicting how various cell types use alternative splicing of messenger RNA, a cousin of DNA, to construct genetic templates that produce an ever-changing set of proteins in the cell. The changes depend on a cell’s type and location. Cells normally use alternative splicing to vary the types of proteins a cell can make.
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