In order to discuss the state of art and the main challenges related to gene therapy and genomic medicine in cardiology, the ESC Council on Cardiovascular Genomics contributed to workshop organised by the ESC Cardiovascular Round Table in Munich in March 2023, building a shared vison between industry and experts. This meeting was a very nice opportunity to exchange ideas between experts, researchers, and partners from industry.
While gene therapy may sound like a sci-fi dream, this approach is actually approved in Europe for non-cardiac conditions like spinal muscular atrophy and Leber’s congenital amaurosis. Also, in cardiology, many therapeutic approaches are nowadays part of the clinical arena, allowing to modulate gene expression and variant expressivity, with very convincing results in the field of cardiac amyloidosis and cardiomyopathies, by example.
But let’s take a step back to basics. Following the European Medical Agency definition, a gene therapy medical product is an active substance which contains or consists of a recombinant nucleic acid used in or administered to human beings with a view to regulating, repairing, replacing, adding or deleting a genetic sequence. Its therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence.
Gene therapy approaches may be classified as gene replacement therapy, in which a functional transgene is provided through an adequate vector to target cells in order to be translated, and as gene editing, that through the CRISPR/Cas9 technique directly modifies the DNA sequence to impede the gene expression.
Gene therapy is not new to the cardiovascular scenario, although the first trials failed to improve clinical outcomes in ischemic heart disease and heart failure, respectively increasing the expression of vascular endothelial growth factor and Sarco-Endoplasmic Reticulum Calcium ATPase (SERCA).
After these first attempts, the interest towards this approach has been recently renewed and several clinical trials on cardiovascular gene therapy are ongoing or in the planning phase.
But what are the challenges related to the technique? Firstly, the target disease: this should be ideally monogenic, precisely defined in disease classification systems and technically targetable. This raises the question of developing appropriate disease classification systems, with a need for a rapid evolution of the disease ontology systems towards more granularity. Secondly, the delivery system: adeno-associated viruses (AAV) and in particular the cardiotropic AAV9 are the most frequently used. However, age-dependent, pre-existing neutralizing antibodies may affect the transfection efficacy, and the limited capacity (4.7 kb) may limit its use in larger genes. The delivery system, the transgene and the protein may trigger immunogenic reactions leading to adverse events including hepatotoxicity and thrombotic microangiopathy, hence the need of an adequate immunosuppressive treatment. Still unknown is the durability of the transgene expression, and at the moment, the option of a re-administration is unfeasible due to the possible immune reaction. Overall, the heart remains a difficult organ to target. In the field of targeted cardiac therapies, we have to acknowledge that the most recent and efficient approaches are given for diseases for which the physio-pathological mechanisms involve more accessible organs, such as the liver (eg ATTR amyloidosis, familial hypercholesterolemia).
Several challenges in clinical trials design are also present. Due to ethical issues the trials are necessarily single arm and with a low patient number. Concerns are raised around the achievable endpoints in such trials, often dealing with rare disease, or extremely rare disease. Consequently, the endpoints cannot be strong as survival and major cardiovascular events, but should rather be surrogate endpoints including biomarkers, functional improvement, imaging parameters. By this, those trials will never be as strong as the one defining mortality or heart failure hospitalizations. Also, long term efficacy and safety are still unknown, and therefore long-term follow-up should be planned. Those aspects raise concerns regarding the evolution of our healthcare systems, that will have to appropriately allocate budgets and re-define the role of every healthcare provider regarding the rapid evolution of medicine towards personalize therapy.
Furthermore, patients’ selection is also challenging. Theoretically gene therapy may be administered in the pre-clinical phase of the disease, avoiding the development of the phenotype, however, it would be ethically unacceptable to perform this kind of treatment in a healthy individual. On the other hand, treating patients with very advanced disease could bring no advantage due to the severity of the condition and not because of the inefficacy of the treatment. And we should not underestimate the challenge of acceptance of such therapies, in particular in some groups including the religious dimension.
Overall, several challenges are still to be overcome, but engineered capsid to enhance heart delivery, effective immunosuppressive regimens, population and doctor’s education, definition of adequate surrogate endpoints, appropriate patients’ selection (taking also into consideration the unmet needs) will be key to succeed in the development of this approach.