Bacterial voltage gated ion channels for cardiac reprogramming

Unmet Need

Untreated cardiovascular disease (CVD) can lead to irreversible heart damage. This occurs when ischemia — inadequate blood flow — leads to the death of heart muscle fibers that conduct electrical impulses. Consequently, scar tissue, or fibrosis, forms which lacks electrical activity and impairs the heart’s ability to function properly. In 2020 CVD was listed as an underlying cause of death for some 920,000 individuals in the US with estimated costs exceeding $400B. This not only encompasses the direct expenses associated with patient care, but also indirect costs related to lost work, diminished productivity, and mortality, among others. Existing methods to treat CVD focus on preventing ischemia and largely rely on pharmacological intervention and surgical procedures. Pharmacological approaches include the use of small molecule drugs such as statins to lower blood cholesterol levels, anticoagulants to decrease blood-clotting, and angiotensin-converting enzyme (ACE) inhibitors and beta-blockers to reduce the workload of the heart. However, these therapies do not address deficits in the heart’s electrical activity. Sodium channels are important for cardiac function. Ion movement across a membrane generates action potentials which triggers heart muscle contraction. Dysfunction in these channels can disrupt cardiac electrical activity leading to arrythmias and impaired heart function. The use of mammalian sodium channels as a therapeutic option faces significant challenges, notably their large size, which exceeds the capacity of standard gene delivery vectors. There is a need for new therapies that can target damaged heart muscle and restore its electrical impulses.

Technology

Duke inventors have developed a gene therapy that can restore electrical activity in damaged heart tissue. This is intended to be used by physicians in patients with cardiac conduction disorders, such as cardiac impairment following a heart attack, or myocardial infarction (MI). Specifically, engineered prokaryotic sodium channels (BacNa_vs) enhance electrical excitability and action potential conduction in tissues they are delivered to. Here, the inventors identified and engineered prokaryotic sodium channels which are advantageous due to their small size and compatibility with gene delivery vectors. This has been demonstrated in cell culture studies and animal models of MI. In cell culture, various human cell lines including dermal fibroblasts, ventricular fibroblasts, astrocytes, and HEK293 cells were successfully transformed into electrically excitable cells. Specifically, in a cell culture model of interstitial fibrosis, the introduction of BacNa_vs significantly enhanced electrical conduction. Further, in vivo studies in a non-human primate model of MI revealed that delivering BacNa_vs through adeno associated virus (AAV) markedly improved left ventricular function. This potential treatment method serves to rewire the heart following ischemia and cell death improving outcomes for patients.

Other Applications

This technology could also be used as a therapy for inherited arrythmias or for developing model cardiomyocyte systems for drug testing.

Advantages

• Restores electrical excitability of non-electrically conductive cells such as in scar tissue
• Proof-of-concept in non-human primates
• Genes are small enough to fit into common gene delivery vectors (e.g., AAV)