Tbx18 transduction

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Tbx18 transduction

Tbx18 transduction is a method of turning on genes in heart muscle cells as a treatment for certain cardiac arrhythmias. Currently this therapy is in the very early stages of experimentation, having only been applied to rodents. [1] Before this treatment can be used in humans, successful tests on larger animals need to be completed followed by human clinical trials. This treatment is one of the many forms of gene therapy that are currently being researched for use in different diseases.[ citation needed ]

Tbx18 gene therapy is aimed at treating a group of arrhythmias known as sick sinus syndrome. In a healthy heart, sinoatrial (SA) nodal cells act as the heart’s pacemaker and cause the heart to beat in a regular rhythm. Approximately 10 thousand of the 10 billion cells in the heart are SA nodal cells. [2] Although they make up a relatively small portion of the heart SA node cells play a crucial role in the heart’s function. The problem in sick sinus syndrome is that the SA node is not functioning properly and is causing an irregular heartbeat. Currently the treatment for sick sinus syndrome is to remove the SA nodal cells that are not functioning properly (?) and to implant an electronic pacemaker to maintain a regular rhythm. [3]

The Tbx18 gene is required for development of pacemaker cells in the heart during fetal development but is normally not functional after birth. [4] Expression of Tbx18 after birth requires adenovirus vectors to deliver the gene into the atrial myocytes. Tbx18 transduction converts atrial muscle cells into SA node cells that initiate the heartbeat. An engineered virus carrying the Tbx18 gene is injected into animals and infects atrial muscle cells. Inside atrial muscle cells the Tbx18 gene is expressed. Tbx18 turns on genes that drive SA node cell development, simultaneously turning off genes that create atrial muscle cells. Tbx18 gene therapy has been successful in rodent hearts, converting atrial muscle cells into SA node cells by expression of the Tbx18 transcription factor. Tbx18 expression in atrial myocytes was shown to convert them into functional SA nodal cells in an experiment done in rodents. [5] These converted SA node cells are able to respond to the nervous system, allowing the heart to be regulated as normal.[ citation needed ]

Adenoviral TBX18 gene transfer could create biological pacemaker activity in vivo in a large-animal model of complete heart block. Biological pacemaker activity, originating from the intramyocardial injection site, was evident in TBX18-transduced animals starting at day 2 and persisted for the duration of the study (14 days) with minimal backup electronic pacemaker use. Relative to controls transduced with a reporter gene, TBX18-transduced animals exhibited enhanced autonomic responses and physiologically superior chronotropic support of physical activity. Induced sinoatrial node cells could be identified by their distinctive morphology at the site of injection in TBX18-transduced animals, but not in controls. No local or systemic safety concerns arose. Thus, minimally invasive TBX18 gene transfer creates physiologically relevant pacemaker activity in complete heart block, providing evidence for therapeutic somatic reprogramming in a clinically relevant disease model. [6]

The currently used electronic pacemakers have drawbacks such as equipment malfunction, limited battery life, lack of nervous system regulation, and risks associated with implantation of the device in one’s chest. Creation of a biological pacemaker could prove to be a feasible alternative that eliminates some of the problems associated with electronic pacemakers. Various gene and cell-based approaches of creating a biological pacemaker have been looked at over the last few years. [7] The method of turning on Tbx18 genes in heart muscle cells is a new method being researched that, so far, has shown promise for being effective.[ citation needed ]

Related Research Articles

<span class="mw-page-title-main">Bradycardia</span> Heart rate below the normal range

Bradycardia, also called bradyarrhythmia, is a resting heart rate under 60 beats per minute (BPM). While bradycardia can result from various pathologic processes, it is commonly a physiologic response to cardiovascular conditioning or due to asymptomatic type 1 atrioventricular block.

<span class="mw-page-title-main">Cardiac pacemaker</span> Network of cells that facilitate rhythmic heart contraction

The cardiac pacemaker is the heart's natural rhythm generator. It employs pacemaker cells that produce electrical impulses, known as cardiac action potentials, which control the rate of contraction of the cardiac muscle, that is, the heart rate. In most humans, these cells are concentrated in the sinoatrial (SA) node, the primary pacemaker, which regulates the heart’s sinus rhythm.

<span class="mw-page-title-main">Sinus node dysfunction</span> Medical condition

Sinus node dysfunction (SND), also known as sick sinus syndrome (SSS), is a group of abnormal heart rhythms (arrhythmias) usually caused by a malfunction of the sinus node, the heart's primary pacemaker. Tachycardia-bradycardia syndrome is a variant of sick sinus syndrome in which the arrhythmia alternates between fast and slow heart rates.

<span class="mw-page-title-main">Sinoatrial node</span> Group of cells located in the wall of the right atrium of the heart

The sinoatrial node is an oval shaped region of special cardiac muscle in the upper back wall of the right atrium made up of cells known as pacemaker cells. The sinus node is approximately 15 mm long, 3 mm wide, and 1 mm thick, located directly below and to the side of the superior vena cava.

<span class="mw-page-title-main">Pacemaker potential</span>

In the pacemaking cells of the heart (e.g., the sinoatrial node), the pacemaker potential (also called the pacemaker current) is the slow, positive increase in voltage across the cell's membrane (the membrane potential) that occurs between the end of one action potential and the beginning of the next action potential. This increase in membrane potential is what causes the cell membrane, which typically maintains a resting membrane potential around -65 mV, to reach the threshold potential and consequently fire the next action potential; thus, the pacemaker potential is what drives the self-generated rhythmic firing (automaticity) of pacemaker cells, and the rate of change (i.e., the slope) of the pacemaker potential is what determines the timing of the next action potential and thus the intrinsic firing rate of the cell. In a healthy sinoatrial node (SAN, a complex tissue within the right atrium containing pacemaker cells that normally determine the intrinsic firing rate for the entire heart), the pacemaker potential is the main determinant of the heart rate. Because the pacemaker potential represents the non-contracting time between heart beats (diastole), it is also called the diastolic depolarization. The amount of net inward current required to move the cell membrane potential during the pacemaker phase is extremely small, in the order of few pAs, but this net flux arises from time to time changing contribution of several currents that flow with different voltage and time dependence. Evidence in support of the active presence of K+, Ca2+, Na+ channels and Na+/K+ exchanger during the pacemaker phase have been variously reported in the literature, but several indications point to the “funny”(If) current as one of the most important.(see funny current). There is now substantial evidence that also sarcoplasmic reticulum (SR) Ca2+-transients participate to the generation of the diastolic depolarization via a process involving the Na–Ca exchanger.

<span class="mw-page-title-main">Third-degree atrioventricular block</span> Medical condition

Third-degree atrioventricular block is a medical condition in which the electrical impulse generated in the sinoatrial node in the atrium of the heart can not propagate to the ventricles.

<span class="mw-page-title-main">Cardiac conduction system</span> Aspect of heart function

The cardiac conduction system transmits the signals generated by the sinoatrial node – the heart's pacemaker, to cause the heart muscle to contract, and pump blood through the body's circulatory system. The pacemaking signal travels through the right atrium to the atrioventricular node, along the bundle of His, and through the bundle branches to Purkinje fibers in the walls of the ventricles. The Purkinje fibers transmit the signals more rapidly to stimulate contraction of the ventricles.

Heart block (HB) is a disorder in the heart's rhythm due to a fault in the natural pacemaker. This is caused by an obstruction – a block – in the electrical conduction system of the heart. Sometimes a disorder can be inherited. Despite the severe-sounding name, heart block may cause no symptoms at all in some cases, or occasional missed heartbeats in other cases, or may require the implantation of an artificial pacemaker, depending upon exactly where in the heart conduction is being impaired and how significantly it is affected.

<span class="mw-page-title-main">Supraventricular tachycardia</span> Abnormally fast heart rhythm

Supraventricular tachycardia (SVT) is an umbrella term for fast heart rhythms arising from the upper part of the heart. This is in contrast to the other group of fast heart rhythms – ventricular tachycardia, which start within the lower chambers of the heart. There are four main types of SVT: atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia (PSVT), and Wolff–Parkinson–White syndrome. The symptoms of SVT include palpitations, feeling of faintness, sweating, shortness of breath, and/or chest pain.

<span class="mw-page-title-main">Multifocal atrial tachycardia</span> Fast heart rhythm associated with exacerbations of COPD

Multifocal atrial tachycardia (MAT) is an abnormal heart rhythm, specifically a type of supraventricular tachycardia, that is particularly common in older people and is associated with exacerbations of chronic obstructive pulmonary disease (COPD). Normally, the heart rate is controlled by a cluster of cells called the sinoatrial node. When a number of different clusters of cells outside the SA node take over control of the heart rate, and the rate exceeds 100 beats per minute, this is called multifocal atrial tachycardia.

<span class="mw-page-title-main">Wandering atrial pacemaker</span> Medical condition

Wandering atrial pacemaker (WAP) is an atrial rhythm where the pacemaking activity of the heart originates from different locations within the atria. This is different from normal pacemaking activity, where the sinoatrial node is responsible for each heartbeat and keeps a steady rate and rhythm. Causes of wandering atrial pacemaker are unclear, but there may be factors leading to its development. It is often seen in the young, the old, and in athletes, and rarely causes symptoms or requires treatment. Diagnosis of wandering atrial pacemaker is made by an ECG.

<span class="mw-page-title-main">Junctional rhythm</span> Medical condition

Junctional rhythm also called nodal rhythm describes an abnormal heart rhythm resulting from impulses coming from a locus of tissue in the area of the atrioventricular node, the "junction" between atria and ventricles.

A biological pacemaker is one or more types of cellular components that, when "implanted or injected into certain regions of the heart," produce specific electrical stimuli that mimic that of the body's natural pacemaker cells. Biological pacemakers are indicated for issues such as heart block, slow heart rate, and asynchronous heart ventricle contractions.

<span class="mw-page-title-main">Sinoatrial block</span> Medical condition

A sinoatrial block is a disorder in the normal rhythm of the heart, known as a heart block, that is initiated in the sinoatrial node. The initial action impulse in a heart is usually formed in the sinoatrial node and carried through the atria, down the internodal atrial pathways to the atrioventricular node (AV) node. In normal conduction, the impulse would travel across the bundle of His, down the bundle branches, and into the Purkinje fibers. This would depolarize the ventricles and cause them to contract.

<span class="mw-page-title-main">Ectopic pacemaker</span> Cardiac condition

An ectopic pacemaker, also known as ectopic focus or ectopic foci, is an excitable group of cells that causes a premature heart beat outside the normally functioning SA node of the heart. It is thus a cardiac pacemaker that is ectopic, producing an ectopic beat. Acute occurrence is usually non-life-threatening, but chronic occurrence can progress into tachycardia, bradycardia or ventricular fibrillation. In a normal heart beat rhythm, the SA node usually suppresses the ectopic pacemaker activity due to the higher impulse rate of the SA node. However, in the instance of either a malfunctioning SA node or an ectopic focus bearing an intrinsic rate superior to SA node rate, ectopic pacemaker activity may take over the natural heart rhythm. This phenomenon is called an escape rhythm, the lower rhythm having escaped from the dominance of the upper rhythm. As a rule, premature ectopic beats indicate increased myocyte or conducting tissue excitability, whereas late ectopic beats indicate proximal pacemaker or conduction failure with an escape 'ectopic' beat.

<span class="mw-page-title-main">HCN4</span> Protein-coding gene in the species Homo sapiens

Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 is a protein that in humans is encoded by the HCN4 gene.

<span class="mw-page-title-main">Ankyrin-2</span> Protein-coding gene in the species Homo sapiens

Ankyrin-2, also known as Ankyrin-B, and Brain ankyrin, is a protein which in humans is encoded by the ANK2 gene. Ankyrin-2 is ubiquitously expressed, but shows high expression in cardiac muscle. Ankyrin-2 plays an essential role in the localization and membrane stabilization of ion transporters and ion channels in cardiomyocytes, as well as in costamere structures. Mutations in ANK2 cause a dominantly-inherited, cardiac arrhythmia syndrome known as long QT syndrome 4 as well as sick sinus syndrome; mutations have also been associated to a lesser degree with hypertrophic cardiomyopathy. Alterations in ankyrin-2 expression levels are observed in human heart failure.

<span class="mw-page-title-main">Arrhythmia</span> Group of medical conditions characterized by irregular heartbeat

Arrhythmias, also known as cardiac arrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults – is called tachycardia, and a resting heart rate that is too slow – below 60 beats per minute – is called bradycardia. Some types of arrhythmias have no symptoms. Symptoms, when present, may include palpitations or feeling a pause between heartbeats. In more serious cases, there may be lightheadedness, passing out, shortness of breath, chest pain, or decreased level of consciousness. While most cases of arrhythmia are not serious, some predispose a person to complications such as stroke or heart failure. Others may result in sudden death.

Cardiac physiology or heart function is the study of healthy, unimpaired function of the heart: involving blood flow; myocardium structure; the electrical conduction system of the heart; the cardiac cycle and cardiac output and how these interact and depend on one another.

<span class="mw-page-title-main">BRL-32872</span> Chemical compound

BRL-32872 is an experimental drug candidate that provides a novel approach to the treatment of cardiac arrhythmia. Being a derivative of verapamil, it possesses the ability to inhibit Ca+2 membrane channels. Specific modifications in hydrogen bonding activity, nitrogen lone pair availability, and molecular flexibility allow BRL-32872 to inhibit K+ channels as well. As such, BRL-32872 is classified as both a class III (K+ blocking) and class IV (Ca+2 blocking) antiarrhythmic agent.

References

  1. ↑ Kapoor, N., Liang, W., Marbán, E., and Cheol Cho, H. (2013). Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of Tbx18. Nature Biotechnology. 31: 54-62.
  2. ↑ Kapoor, N., Liang, W., Marbán, E., and Cheol Cho, H. (2013). Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of Tbx18. Nature Biotechnology. 31: 54-62.
  3. ↑ Tung, R., Shen, W., Hayes, D., Hammill, S., Bailey, K., and Gersh, B. (1994). Long-Term Survival After Permanent Pacemaker Implantation for Sick Sinus Syndrome. The American Journal of Cardiology. 74: 1016–1020.
  4. ↑ Wiese, C., Grieskamp, T., Airik, R., Mommersteeg, M., Gardiwal, A., deVries, C., Gossler, K., Moorman, A., Kispert, A., and Christoffels, V. (2009). Formation of the Sinus Node Head and Differentiation of Sinus Node Myocardium Are Independently Regulated by Tbx18 and Tbx3. Circulation Research. 104: 388-397.
  5. ↑ Kapoor, N., Liang, W., Marbán, E., and Cheol Cho, H. (2013). Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of Tbx18. Nature Biotechnology. 31: 54-62.
  6. ↑ Y-F. Hu, J. F. Dawkins, H. C. Cho, E. Marbán, E. Cingolani,(2014).Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block. Sci. Transl. Med. 6, 245ra94
  7. ↑ Li, R.A. (2012). Gene-and cell-based bio-artificial pacemaker: what basic and translational lessons have we learned? Gene Therapy. 19: 588-595.
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