Getting to the Heart of Things in the Field of Cardiovascular Gene Therapy

T he field of gene therapy has been traditionally associated with the development of therapies for monogenic diseases; however, increasingly gene therapy strategies are being developed for polygenic and multifactorial disease. Heart disease and vascular disease together are amongst the leading causes of morbidity and mortality in Western societies. Although progress has been made in conventional therapies for the treatment of conditions such as heart failure, atherosclerosis, and restenosis; alternative cost-effective, stable, long-term (i.e., lifelong) treatments are still required. Gene therapy strategies have the potential to offer an alternative to long-term drug therapies and surgery, and as in other areas of gene transfer, cardiovascular gene transfer is beginning to be translated from the bench to the clinic.

This issue of Human Gene Therapy highlights the wide range of cardiovascular (CV) gene transfer research, illustrating that progress is being made and that, in common with other areas of gene therapy, there are still significant challenges to face and hurdles to overcome. Such issues include efficiency of gene transfer, route of administration, and tissue-restrictive expression. In addition, becoming increasingly apparent are the difficulties in the extrapolation and translation of strategies effective in rodents to larger animal models. Clearly these issues are not specific to CV gene therapy, but the diverse nature of this area of research highlights the issues that the gene therapy field as whole faces in translating research from the bench to clinical trials.

Three of the papers in this issue (by Gao et al., Bish et al., and Du et al.) report on the translation of CV gene therapies effective in rodent models to larger animal models (nonhuman primate, rabbit, and canine models) and the successes and problems encountered. Gao and colleagues report on the use of AAV vectors for cardiac gene transfer in nonhuman primates. The authors demonstrate efficient and widespread cardiac gene transfer in nonhuman primates, using an AAV6 vector (in comparison with AAV8 and AAV9). This has important implications for the development of vectors aimed at clinical trials for both heart disease and disorders such as Duchenne/Becker muscular dystrophy, in which cardiac gene transfer, in addition to skeletal muscle gene transfer, is also essential. However, it should be noted that this research is in contrast to data collated from rodent studies, in which AAV9 vectors have consistently shown the highest efficiencies in cardiac tissue.

The same group (Bish et al.) also report on the use of AAV6 to deliver short hairpin RNA (shRNA) to knock down expression of phospholamban, a negative regulator of sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) in healthy canines. Similar shRNA methods using adenoviral gene transfer have been used successfully to restore function in failing rat heart. However, although Bish and colleagues demonstrate effective knockdown of phospholamban in the canine heart, it is unexpectedly associated with severe cardiac toxicity. It appears that shRNA treatment in the canine heart is associated with unexpected alterations in microRNA profiles, relating to the cardiac toxicity. Although phospholamban–SERCA2A remains a prime target for heart failure models, it is clear that transferring technologies between small and large animal models is not clearcut, and that precise control of levels of gene expression maybe required in order to restrict deleterious side effects.

Du and colleagues demonstrate that helper-dependent adenovirus can be used to achieve persistent expression of IL-10 in the artery wall in a rabbit model of atherosclerosis. Improvements in targeting gene therapy to the vasculature can potentially prevent systemic side effects. IL-10 has been demonstrated to be highly atheroprotective in rodent models of atherosclerosis, but the authors found no impact on lesion size or other atherogenic markers in this rabbit model; highlighting issues of levels of transgene expression and/or the site of expression.

Further vascular targeting strategies are highlighted by von der Leyen and colleagues. They report on the use of nonviral plasmid–lipoplexes expressing inducible nitric oxide synthase (iNOS) in a phase 1/2a clinical trial assessing restenosis after coronary intervention in humans. The inhibition of neointimal lesion formation after iNOS expression has been demonstrated in rodent models; however, although the safety and applicability of such approaches are highlighted by von der Leyen and colleagues, the degree of transgene expression seems to be hampering this translation into humans.

There is a clear need for the development of CV gene therapy regimens to provide safe, lifelong, cost-effective treatments and, as highlighted in this issue of Human Gene Therapy, progress in diverse areas of CV research is clearly being made. These articles reinforce some of the known issues involved in CV gene therapy translational research, such as efficiency of gene transfer; however, Bish and colleagues identify emerging difficulties of microRNA dysregulation that some novel gene therapy approaches will need to address before strategies are successful in humans and become a cornerstone of CV therapeutics.