Using mRNA to treat cardiovascular disease
mRNA is easier to sequence, scale and manufacture, and it carries fewer risks of insertional mutagenesis.
Researchers are now refining modified mRNA therapies to deliver targeted treatments more precisely, potentially opening new avenues for cardiac repair and regeneration. Sunday’s session, “RNA Therapeutics for Cardiovascular Disease and Beyond,” will explore how these novel technologies and targeted therapies could deliver safe, precise treatments. It will also include a presentation from Lior Zangi, PhD, on mRNA therapeutic approaches.
Nucleotide-modified mRNA (modRNA) usage has been a hot topic across medical specialties. During the COVID-19 pandemic, modified mRNA demonstrated its utility as a safe and effective vaccine platform.
In cardiology, modified mRNA offers potential advantages for repairing damaged heart tissue, said Zangi, who holds the Chan Soon-Shiong Professorship in Cardiovascular Research and is a professor of cardiology and genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai in New York.
In his lecture, “Selective Modified mRNA Therapeutics for Cardiovascular Disease,” Zangi will share highlights from preclinical research and clinical trials, including recent advancements, emerging strategies and key takeaways.
“I will discuss the lessons learned from previous clinical efforts, including the factors that may have limited [modRNA’s] therapeutic efficacy, and highlight how advances in mRNA design, delivery, tissue specificity and translational control have created new opportunities to improve outcomes,” Zangi said.
Modified mRNA offers a transient method of gene delivery. Compared with traditional gene- and protein-based approaches, Zangi said, it is easier to sequence, scale and manufacture and carries minimal risk of insertional mutagenesis because it does not permanently alter the genome.
Modified mRNA is highly adaptable, allowing researchers to customize the amount, duration and cellular specificity of protein expression, he said. This adaptability could support applications ranging from vaccination and protein replacement to regenerative medicine and cancer therapy.
However, Zangi said the therapy has limitations and is not suited to prolonged gene delivery because its effects are transient.
“Unmodified or improperly formulated mRNA can activate innate immune responses, while the inherent instability of mRNA can limit its half-life and translational efficiency,” he said. “Effective in vivo delivery also remains a major obstacle, particularly for achieving tissue- and cell-specific targeting while minimizing accumulation in nontargeted organs.”
To help address concerns like prolonged activity, dose-dependent toxicity and biodistribution variability, Zangi and others have developed Selective modRNA Translation systems (SMRTs) that promote cell-type-specific protein expression in cardiomyocytes or noncardiomyocyte populations.
“Continued advances in mRNA chemistry, sequence engineering, translational control and targeted delivery are critical for improving the safety, specificity and therapeutic efficacy of mRNA-based medicines,” he said.
Potential applications for SMRTs range from repairing heart tissue after myocardial infarction and promoting recovery from cardiovascular injury to treating chronic conditions such as ischemic heart disease.
