Novel Vector Development is Essential as Gene Therapy Emerges as a New Therapeutic Modality in Cardiology

Roger Hajjar, MD

Gene therapies have been evaluated for cardiac disease indications for over 20 years. Despite this robust research, gene therapy remains a novel modality in the field, and more work is needed.

With this in mind, Roger Hajjar, MD, the director of the Mass General Brigham Gene and Cell Therapy Institute, gave a talk entitled, “The Quest to Overcome the Challenges in Cardiac Gene Therapy,” at the American Heart Association’s (AHA) Scientific Sessions 2023, held November 10-13 in Philadelphia, Pennsylvania. In his talk, he emphasized the potential of gene therapy to treat a surprising variety of cardiac indications but stressed the need for the continued development of new cardiotropic vector types in order to ensure optimal safety and efficacy. Following the presentation, CGTLive™ spoke with Hajjar to learn more about the challenges and potential benefits of bringing gene therapy to cardiology.

CGTLive: Can you give some background information about the talk you gave at the conference?

Roger Hajjar, MD: [Cases of] cardiac diseases continue to increase in number in the US and European Union. Even though we've made great strides in terms of pharmacological treatment and device therapies there continues to be a big unmet need for a large number of patients, who when diagnosed with congestive heart failure have a 5-year survival of 50% or less. The need for novel therapies has always been there.

Gene therapy, which is usually used for monogenic or inherited diseases, has been applied in the cardiac field for now over 20 years. It first started with patients with ischemic heart disease, where attempts were made using plasmids or adenovirus vectors to induce new vessel growth. That was followed a few years later with novel vectors, such as adeno-associated vectors, where injection down the coronary arteries was attempted in multiple clinical trials to revive the failing heart.

After maybe 20 years of work, and failures and successes that have been associated with cardiac gene therapy, we are now at the cusp of a new era where cardiac gene therapy is utilizing novel vectors that have been discovered and developed over the last 10 years. These are much more specific to the heart and minimally invasive techniques [are used] to deliver these vectors to the heart. The applications are going to be in different areas, including common diseases like congestive heart failure; and that includes heart failure with reduced ejection fraction, heart failures with preserved ejection fraction, and ischemic heart disease. There is also a lot of promise in monogenic and inherited cardiomyopathies, where focusing on 1 specific gene that's dysregulated can improve the lives of patients who are affected with these monogenic diseases. In addition, cardiac regeneration utilizing gene therapy approaches will also come to the fore in the next few years. There's a lot of excitement in the cardiac field for gene therapy and gene-editing to produce tangible results for a large patient population.

How would you summarize the key points of your presentation?

I think beyond giving a history of cardiac gene therapy in the last 20 years, the presentation focused on novel vectors that are emerging. Adeno-associated vectors have been kind of the mainstay over the last 10 to 15 years in cardiac gene therapy, but we're seeing the evolution of novel capsules that are much more targeted to the heart and the detarget the liver, lung, and other tissues so there's less issues in these novel capsids with safety. The presentation also focused on other novel vectors such as modified RNA, which was used for the vaccines, and circular RNA, which is a novel type of RNA that has sustained expression. These vectors are really going to open up more avenues in the next few years to treating cardiac disorders.

Furthermore, the presentation also examined modes of delivery to the heart. These are either intravenous delivery (systemic delivery), which requires a higher dose of the vectors; or intracoronary delivery, which requires a minimally invasive procedure—that's a cardiac catheterization, which is quite routine in the cardiology practice—that goes straight to the coronary arteries and delivers down those coronary arteries.

We focused also on the safety of these vectors. It's very clear that the higher the dose, the more safety issues there are. We've seen in extracardiac trials, there's been a lot of adverse events based on the massive doses that have to be given with adeno-associated virus vectors. With the emergence of novel, more cardiotropic vectors, and minimally invasive techniques to deliver locally, we are now able to deliver much lower amounts of vector—100 times less. That will basically allow us to have a safer vector when we deliver these next generation capsids. That was really important to convey because at this point, with these very large amounts of vector that are being delivered, we do have a limit in terms of the safety issue. That needs to be overcome with development of these novel, more cardiac-targeted capsids.

This transcript has been edited for clarity.

REFERENCE
1. Hajjar R. The Quest to Overcome the Challenges in Cardiac Gene Therapy. Presented at: AHA Scientific Sessions 2023; November 10-13; Philadelphia, Pennsylvania. HF.EC.158