Imagine human cells genetically engineered to treat disease, to free diabetics from their daily insulin shots, to better attack cancer patients’ tumors, or to treat patients with rare conditions.
What if genetically enhanced cells could scavenge toxic substances from the blood of patients with metabolic disorders, relieving them of the challenge of daily enzyme injections and problematic immune responses?
To realize these and many more possibilities, researchers must develop finely tuned cellular machines that can thrive inside the body while evading destruction by the immune system. Such is the goal of two approaches currently under development at Flagship Pioneering companies. One of these arms red blood cells with therapeutic proteins to treat disease while calming an overactive immune system. The other implants capsules of medicine-producing cells into a patient's body.
These experimental treatments build on more than 200 years of experience with cell transplantation. In 1825, James Blundell performed the first successful cell transplants by transfusing blood to a woman dying of postpartum hemorrhage. In 1954, a kidney transplant between identical twin brothers marked the first successful solid organ transplantation. The first successful stem-cell transplant occurred two years later, also between identical twins. By 2017, a series of advances had enabled the development and approval of immune cells known as CAR-Ts. The first CAR-Ts were launched as powerful new treatments for leukemia, and efforts to evaluate them as treatments for other cancers continue apace.
Over these two centuries of progress, researchers have learned how to keep finicky cells alive during production, through delivery, and well after they are administered to patients. Transplanted cells can be incredibly powerful, if sensitive to small changes in their environment. But the most daunting hurdle for this form of therapy is the potential for a recipient’s body to view transplanted cells as dangerous outsiders that require elimination. In a worst-case scenario, the patient’s immune system may not only destroy a transplant but respond in a way that proves life threatening or even fatal.
A universal cell—one that could be transplanted into anyone, without risk of immune rejection—is the innovation that many in the field have come to see as key to unleashing the full power of cell therapy.
While cell transplants made from a patient’s own cells, or delivered between identical twins, can maintain peace with the immune system, the customized nature of these treatments limits their applicability and attractiveness as therapeutic products. A universal cell—one that could be transplanted into anyone, without risk of immune rejection—is the innovation that many in the field have come to see as key to unleashing the full power of cell therapy. Rubius Therapeutics, a Flagship Pioneering company launched in 2014, is founded on the premise that the body’s own red blood cells (RBCs) perfectly meet the same need.
RBCs are by far the most frequently transplanted tissue in medicine and, if sourced from a universal donor, can be given to any patient without the need for immunosuppression because the body does not see them as intruders. However, the unique biology of these cells presents its own challenges. RBCs lack a nucleus and the protein production equipment found in most other cells, which means biologists cannot use standard molecular tools to compel them to churn out a therapeutic protein. While some researchers have tried to get around this by loading RBCs with medicines, the process is inefficient and shortens the cell’s life span.
Rubius takes a different approach, building on work that its partners at MIT’s Lodish Lab have done to determine the sequence of molecular factors needed to coax fully equipped precursor cells into becoming red blood cells. Armed with this knowledge, researchers at Rubius are now able to add one or more therapeutic genes to the precursor cells and then wait for those cells to use the gene to make a protein. The modified cells expel their nucleus and the modified gene as they develop, but they retain their cargo of therapeutic proteins.
The result is a highly efficient and broadly applicable system with the potential to deliver therapeutic agents throughout the body for several months. Rubius’ Red Cell Therapeutics™ cells can carry their payloads internally, hiding proteins that might otherwise draw the ire of the immune system. The therapeutic action—say, the enzymatic breakdown of a toxic buildup in patients with phenylketonuria (PKU)—can take place inside the cell itself. Alternatively, the beneficial protein can be carried on the cell surface, where it can interact with other cells in the body.
Again, red blood cells can’t pump out proteins. So medicines that have to be released into the body call for cells with a different set of capabilities. This in turn speaks to another avenue of innovation—namely, the idea of creating ‘packages’ of living cells that not only are able to secrete specific proteins at therapeutic concentrations but can do so while remaining shielded from the immune system.
Flagship Pioneering company Sigilon Therapeutics has spent the past few years since its founding in 2016 refining a technology platform with this objective in mind. Sigilon’s approach involves packing protein-producing cells into a small capsule that allows the free entry of oxygen and nutrients and the outward flow of therapeutic compounds. At the same time, the capsule prevents the body’s immune system from attacking the transplanted cells. Past attempts to create systems of this kind have been stymied by the tendency of the immune system to attack the capsule itself, resulting in scar tissue that effectively neutralizes the implant and chokes the living cells inside.
Depending on the needs of a patient, living drug factories could be implanted under the skin or in the abdomen.
Sigilon, in contrast, has been able to employ recent breakthroughs in materials science that allow for the capsule to be hidden from the body’s defense systems. As a result, no scar tissue forms, and the drug-producing cells, hidden under their invisibility cloak, are able to survive for up to a year after implantation. Sigilon envisages numerous applications of the platform, including treatments for diabetes, hemophilia, and cancer. Depending on the needs of a patient, living drug factories could be implanted under the skin or in the abdomen. Some applications would use donor or engineered human cells. Yet others would use cells from nonhuman animals, which would open up many more possibilities for genetic modifications and potentially simplify production.
Both of these new platforms have the potential for incredible versatility and therapeutic value. Both could replace a missing protein or deliver a cancer-fighting peptide. In the case of Red Cell Therapeutics, different product lines can be made by simply swapping out one therapeutic gene for another. For Sigilon’s encapsulated cell therapies, the transplanted cells themselves could be re-engineered or exchanged for a new cell type. And both technologies are strongly advantaged over first-generation cell therapies—including current CAR-Ts—in that a single product can be administered to many different patients in an ‘off-the-shelf’ way, rather than requiring patient-by-patient re-engineering and complex bespoke production workflows. This should not only greatly reduce the cost of making these medications but significantly improve the speed and ease with which patients could be treated.
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