"We were surprised by the extent to which T cells picked up the nanoparticles and expressed a functional chimeric antigen receptor (CAR) after intravenous injection," Dr. Jonathon Epstein of the Perelman School of Medicine at the University of Pennsylvania told Reuters Health by email. "We really didn't know if it would work. We were also surprised in our earlier studies by how quickly the extracellular matrix was resorbed after CAR T removal of the activated fibroblasts."
"The widespread use of mRNA COVID vaccines is reassuring with regard to safety, but the lipid nanoparticles (LNPs) used for this approach are slightly different and will have to be tested for safety and toxicity themselves," he added.
As reported in Science, building on previous work (https://go.nature.com/3KicSgg), the team generated transient antifibrotic CAR T cells in mice by delivering modified mRNA in LNPs to T cells targeting active fibroblasts. The effect had to be temporary, they explain, because long-term suppression of fibroblasts would also impair wound healing over the long-term.
They tested the efficacy of the approach by injecting the targeted LNPs into a mouse model of heart failure. Delivery of the modified mRNA encoding the CAR to T cells produced transient CAR T cells in the mice, effectively reprogramming the mouse T cells to attack activated fibroblasts for a few days, after which the T cells reverted to normal. One week after treatment, no evidence of anti-fibroblast T cell activity was seen.
Despite the brief duration of activity, the mRNA injections reduced heart fibrosis in the mice and restored cardiac function after injury, consistent with the team's previous studies.
Dr. Epstein said, "We'd like to see if the approach will work in large animal models of fibrosis and heart disease, which will enhance our chances of successfully translating the findings to humans." The team will also test the approach in other animal models of fibrosis - i.e., liver, lung, and kidney - as well as arthritis, where fibrosis in the joints causes pain and restricted movement.
Dr. Jeffery Molkentin, Division Director, Molecular Cardiovascular Biology and Executive Co-Director, The Heart Institute at Cincinnati Children's Hospital Medical Center in Ohio, commented on the study in an email to Reuters Health.
"The ground-breaking aspect of the current paper is that they used LPN delivery of a stabilized mRNA coding for the fibroblast-targeting chimeric T-cell receptor, and this delivery was enhanced by coating the LNPs in antibodies that target T-cells specifically," he said. "What this means therapeutically is that we can now generate CAR T cells for cancer approaches, or the current concept of deleting fibroblasts in the heart, by simply injecting LNPs containing the appropriate modified mRNA, just like the current SARS-CoV2 vaccine."
The work "paves the way for more broad scale application of CAR T cell technology without the need for elaborate cellular production laboratories," he said. "Now, this entire process of generating CAR T cells can be done within the patient by targeting of LNPs to circulating T-cells."
However, he noted, "the long-term question is if the CAR T cell approach for culling cardiac fibroblasts will work in longstanding fibrotic heart disease in humans, which can extend for decades. Also, will this approach be safe in humans, especially if applied over many years. For example, fibroblasts might play important biologic roles in other tissues, and perhaps over time there could be on-target toxicity."
SOURCE: https://bit.ly/3qBpLdw Science, online January 6, 2022.
By Marilynn Larkin
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