Pigs which express tdTomato upon Cre or CRISPR editing of a genetic cassette inserted into their genome. (Pig analogue of Ai9 mice). This model system will aid translational preclinical studies for gene editing therapies.

A “turn-on” swine reporter model is developed to characterize local and systemic delivery of gene editors in vivo using viral or non-viral vectors. This adds the functionality of a reporter to preclinical gene delivery research in a large animal model that is more broadly accessible than nonhuman primates.

Gene editing has emerged as a powerful approach for targeting the genetic causes of disease, but getting the editing machinery into the right cells efficiently, safely, and at the scale needed for therapies remains one of the biggest set of challenges in the field.

Among the leading delivery vehicles are engineered virus-like particles, which resemble viruses—and share their knack for entering human cells—but carry no viral genes. Scientists load them with gene editing tools and use them to make precise changes in targeted cells.

Most efforts to improve these particles have focused on redesigning the particles themselves. A new study led by Valhalla Fellow at Whitehead Institute, Aditya Raguram and lab technician Diana Ly, focuses instead on the human cells that produce them.

As a proof of concept, the team used CRISPR gene-editing tools to insert the genetic blueprint for producing rare, protective antibodies directly into hematopoietic stem and progenitor cells of mice. Once transplanted back into mice, the edited stem cells gave rise to B cells programmed to produce the engineered antibody. A conventional vaccination would then serve as the trigger.

It worked. Even when only a few dozen stem cells were edited, vaccination triggered rare cells to expand, mature into plasma cells, and produce large amounts of antibodies that persisted long-term and could be boosted if necessary. The engineered B cells behaved just like normal immune cells, and even provided protection from disease. Mice engineered to produce a broadly neutralizing influenza antibody were spared from an otherwise lethal influenza infection.

The team went on to demonstrate their novel platform’s versatility. Engineered B cells were able to secrete non-antibody proteins, pointing to potential applications in treating genetic diseases caused by missing enzymes or other essential proteins.

The researchers also showed that stem cells carrying different antibody instructions could be combined, enabling a single immune system to produce multiple antibodies at once—an approach that could limit viral escape and ultimately lead to functional cures for rapidly mutating pathogens such as HIV.

And the team showed that human stem cells edited using the same approach gave rise to functional immune cells, providing a key proof of feasibility that the platform could one day work in humans, as well. Science Mission sciencenewshighlights.

An innovative gene-editing strategy could establish a new way for the body to manufacture therapeutic proteins—including certain kinds of highly potent antibodies the are naturally difficult to produce—by reprogramming the immune system itself.