Cardiovascular Gene Therapy – New Virus: New Hope

Cardiovascular disease (CVD) remains the biggest killer in the developed world, accounting for ~40,000 premature deaths annually in the UK alone. The leading cause of CVD related mortality results from the build-up of fatty deposits in the arteries feeding blood back to the heart (atherosclerosis), resulting in a gradual narrowing of the vessels.  If untreated, this develops into coronary artery disease, where the vessel occlusion can become so significant that the depletion of oxygen and nutrient rich blood from the heart manifests itself as chest pain (angina), eventually inducing heart failure.

To alleviate this, the patient will undergo one of two possible clinical procedures: angioplasty, where a stent is guided, inserted and expanded across the occlusion to re-widen the vessel and restore blood flow, or, where the blockage is too significant to warrant the insertion of a stent or there is a significant risk that the insertion of a stent could induce a heart attack, the patient may undergo coronary artery bypass graft (CABG) operation.

In CABG, a section of vein is removed from the patient’s leg (saphenous vein) and is grafted across the blocked vessel.  Because the pressure in the arterial circulation is significantly higher than the venous circulation, the layer of smooth muscle cells surrounding the vessel must thicken (remodel) in order to withstand the increased arterial pressure.  However, an estimated 50% of graft procedures fail within 10 years due to excessive remodeling resulting in vessel blockage.  To prevent this, scientists and clinicians are developing gene therapy procedures to genetically alter the smooth muscle cells in the grafted vessel outside the body (ex vivo gene therapy), whilst the patient is undergoing CABG by using a virus called adenovirus serotype 5 (Ad5) to overexpress a therapeutic gene called TIMP-3 which prevents excessive remodeling of smooth muscle cells (George et al., 2011).

However, previous research has demonstrated that the Ad5 receptor, hCAR, is not actually expressed on the target smooth muscle cells (Parker et al., 2013), and so an extremely high and potentially toxic amount of virus would need to be applied to the vessel in order to achieve enough expression of the therapeutic gene to show a beneficial effect. In this month’s Human Gene Therapy, Dakin et al., (2015) have explored the possibility that another type of adenovirus, called Ad49, might be suited for gene therapy in CABG.

Comparing the ability of Ad49 to infect primary smooth muscle cells, either cultured from residual patient material or in whole vessels, they found that Ad49 was significantly better at delivering its DNA payload to smooth muscle cells.  Furthermore, since the vessel is only available outside of the patient for ex vivo gene therapy for 20-30 minutes during the clinical procedure, the authors studied the ability of the vector to deliver its DNA payload within a restricted cell contact time. They discovered that Ad49 was able deliver its DNA payload very rapidly (within 10-20 minutes) to target smooth muscle cells, whilst Ad5 was unable to mediate such high levels of DNA delivery within the same timescales.  Additionally, since pre-existing immunity against the viral delivery vector can significantly hamper the effectiveness of gene therapies, the authors evaluated the prevalence of immunity against both Ad49 and Ad5 and discovered that whilst levels of Ad5 immunity in the population were around 40%, no patients presented any antibodies against Ad49.

Whilst several questions remain unanswered about Ad49 in relation to the virus receptor, whether the virus can be manipulated to express a therapeutic gene and how toxic the virus might be to humans, it certainly seems that new gene therapies, based on Ad49, may hold great promise for translational cardiovascular gene therapy applications.

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Dakin, R.S., Parker, A.L. et al., (2015). Efficient Transduction of Primary Vascular Cells by the Rare Adenovirus Serotype 49 Vector. Human Gene Therapy124, S135-S142.

George, S., Wan, S. et al., (2011). Sustained Reduction of Vein Graft Neointima Formation by Ex Vivo TIMP-3 Gene Therapy. Circulation124, S135-S142.

Parker, A.L., White, K.M. et al., (2013). Pseudotyping the adenovirus serotype 5 capsid with both the fibre and penton of serotype 35 enhances vascular smooth muscle cell transduction. Gene Therapy20, 1158–1164.

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