This year, Rensselaer Polytechnic Institute researchers will begin work on a radically new approach to treating and preventing genetic diseases such as Alzheimer’s.

It’s thanks to a grant from the National Institutes of Health’s TARGETED Challenge, which funds scientific research on ways to deliver gene editing tools directly to cells in the human body. 

A delivery mechanism that works within the body itself could be a game changer, said William Lawler, a doctoral student at RPI, who is working on the project.

“Currently, gene editing tools, such as CRISPR, can only treat cells that have been removed from the body and processed in the lab. That limits the kinds of cells and conditions that can be treated,” Lawler said. “Our goal is to develop a technology that, once in the body, will correct the genetic mutations in brain cells linked to Alzheimer’s disease.”

The biggest obstacle to this kind of gene editing technology? The human body’s own immune system.

“The immune system is likely to treat a gene editing therapy as a threat and destroy it before it can do what it’s supposed to do,” Lawler explained.

To make things even more challenging, the body’s defenses are especially robust at the blood-brain barrier, where specialized blood vessels rigorously control what enters the brain and the central nervous system. 

To both dodge the body’s immune system and enter brain cells, the researchers will take inspiration from viruses that are experts in those areas.

“Some viruses are extremely good at evading the immune system. Others seek out specific kinds of cells — the rabies virus, for example, has a component that steers it to the central nervous system. We want to combine some of these attributes into a system that’s more ideal for therapeutic purposes,” Lawler said.

This approach does not use the parts of viruses that cause diseases. Rather, the researchers will adapt the benign proteins that encase viruses to package and deliver a gene editing tool in the body. 

To construct these packages, the researchers will also incorporate exosomes, the human body’s own intercellular mail delivery system. Exosomes are essentially miniature cells that transport molecules among cells. Over the last several years, scientists have been studying how exosomes could be repurposed to deliver therapies. 

In the first step of the research, the RPI researchers will test a way to biomanufacture exosomes “tagged” with the component of the rabies virus that directs it toward brain cells. Within the exosomes, the researchers will incorporate proteins from viruses that allow it to go undetected by the immune system. 

“Think of the exosome as a box used to ship a gene editing tool to the correct destination. The rabies protein is the shipping address, and the viral proteins act as the padding inside the box that protects the item inside. Once the package is opened within a brain cell, that item can get to work editing the cell’s genetic code,” Lawler explained. 

“Genome editing tools, such as CRISPR, are powerful tools with applications that range from disease treatment to engineering cells to producing chemicals of interest. The technology we are developing with NIH’s TARGETED Challenge funding will address some of the limitations of current technologies, such as precision of genome editing” said Mattheos Koffas, Ph.D., Lawler’s doctorate adviser and Dorothy and Fred Chau ʼ71 Career Development Constellation Professor in Biocatalysis and Metabolic Engineering. Koffas is a member of the Center for Biotechnology and Interdisciplinary Studies. 

“While our focus in the immediate future is on disease treatment, we will also apply this technology in metabolic engineering of cells for improving the production of pharmaceuticals, nutraceuticals, and commodity chemicals,” Koffas said.

Lawler and Koffas are simultaneously working on a new kind of gene editing tool that their delivery technology would transport and have established a company that will commercialize their discoveries. 

“One of the really exciting things about gene editing therapies that work inside the body is that they could be used to treat many diseases that have a genetic cause, not just Alzheimer’s,” Lawler said. “I’ve always been interested in the entrepreneurial side of science and am very excited to see where this RPI spin-off company will go.” 

“In the end, NIH’s TARGETED award will allow us to give back to the community that funds our research better methods that improve people’s lives” Koffas concluded.