Hot topics in cardiovascular gene therapy
Panel discussion focuses on genetic medicines including siRNAs, adeno-associated viruses and gene editing.
Targeting the genetic roots of cardiovascular disease is moving from scientific promise to clinical reality.
But as gene-based therapies advance, questions about safety, delivery, effectiveness and cost are becoming increasingly important. Currently, the U.S. Food and Drug Administration has approved some therapies for a subset of conditions, while others are in clinical trials.
Elizabeth McNally, MD, PhD, will outline the promises and challenges of gene therapy Friday during the panel discussion “Optimization of Therapies, Clinical Implementation Strategies and Communication Between Stakeholders,” as part of the Genomic and Precision Medicine Symposium: Cardiovascular Gene Therapy — Session 3.
“We can expect discussions of different approaches to delivering genetic medicines and gene therapy ranging from siRNAs (small interfering RNAs) to adeno-associated viruses (AAVs) to gene editing,” said McNally, who is Elizabeth J. Ward Professor of Medicine and director of the Center for Genetic Medicine at Northwestern University’s Feinberg School of Medicine in Chicago. “This will include aspects of how we can best deliver these treatments to the heart while minimizing the (side)effects.”
SiRNA can regulate gene expression, allowing selective reduction in the production of a specific protein through RNA interference. McNally said treatments such as patisiran and vutrisiran use RNA interference to target the TTR gene to treat transthyretin amyloid cardiomyopathy (ATTR-CM) and neuropathy. Antisense oligonucleotides (ASOs), such as inotersen and eplontersen, can also target TTR.
“Clinically, there is a good experience with siRNA and ASO treatments, which are generally well tolerated,” McNally said.
Another potential discussion topic is AAVs, which can be used as delivery mechanisms for gene replacement therapy, making them well suited to treat certain genetic disorders where a gene product is lacking. Researchers have developed newer AAVs with better ability to reach the heart. However, McNally said this line of therapy is not without its drawbacks.
McNally said adeno-associated viral delivery can activate complement — part of the innate immune system that enhances the ability of antibodies to clear microbes and injured cells from an organism — and elicit toxicity in the liver and other organs.
“This, along with immune responses to the virus and the gene product, can limit efficacy and also create side effects,” she said.
McNally said gene editing is another promising potential therapy because it can correct underlying genetic defects, including those linked to genetic cardiovascular disease. Clinical trials are investigating the possibility of treating familial hypercholesterolemia and transthyretin amyloidosis. Although early results from those trials are promising, McNally said there is a need to proceed cautiously.
“Gene editing requires careful attention to delivery mechanisms, both for efficacy and to minimize off-target effects,” she said.
Whatever approach is taken, McNally said cardiologists should be aware of several important considerations.
“Each approach needs to address overall molecular and clinical efficacy and address whether one dose is sufficient and what the barriers may be to repeat dosing,” she said. “Many of these therapeutic agents or drugs are very costly to produce and deliver, and so this needs to be carefully weighed. For many diseases, the timing of when to treat is also a central question.”
Genomic and Precision Medicine Symposium: Cardiovascular Gene Therapy — Session 3
4:45-5:45 p.m. | Friday, Nov. 6 | S401D
