Tbx18 transduction

Last updated
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

Bradycardia Heart rate that is below the normal range

Bradycardia is a condition typically defined wherein an individual has a resting heart rate of under 60 beats per minute (BPM) in adults, although some studies use a heart rate of less than 50 BPM. Bradycardia typically does not cause symptoms until the rate drops below 50 BPM. When symptomatic, it may cause fatigue, weakness, dizziness, sweating, and at very low rates, fainting.

Cardiac pacemaker Network of cells that facilitate rhythmic heart contraction

The contraction of cardiac muscle in all animals is initiated by electrical impulses known as action potentials. The rate at which these impulses fire, controls the rate of cardiac contraction, that is, the heart rate. The cells that create these rhythmic impulses, setting the pace for blood pumping, are called pacemaker cells, and they directly control the heart rate. They make up the cardiac pacemaker, that is, the natural pacemaker of the heart. In most humans, the concentration of pacemaker cells in the sinoatrial (SA) node is the natural pacemaker, and the resultant rhythm is a sinus rhythm.

Systole

The systole is the part of the cardiac cycle during which some chambers of the heart muscle contract after refilling with blood. The term originates, via New Latin, from Ancient Greek συστολή (sustolē), from συστέλλειν, and is similar to the use of the English term "to squeeze".

Sinus node dysfunction

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.

Sinoatrial node Group of cells located in the wall of the right atrium of the heart

The sinoatrial node is a group of cells located in the wall of the right atrium of the heart. These cells have the ability to spontaneously produce an electrical impulse, that travels through the heart via the electrical conduction system causing it to contract. In a healthy heart, the SA node continuously produces action potential, setting the rhythm of the heart and so is known as the heart's natural pacemaker. The rate of action potential production is influenced by nerves that supply it.

Third-degree atrioventricular block

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

Electrical conduction system of the heart Transmits signals generated usually by the sinoatrial node to cause contraction of the heart muscle

The electrical conduction system of the heart transmits signals generated usually by the sinoatrial node to cause contraction of the heart muscle. The pacemaking signal generated in the sinoatrial node travels through the right atrium to the atrioventricular node, along the Bundle of His and through bundle branches to cause contraction of the heart muscle. This signal stimulates contraction first of the right and left atrium, and then the right and left ventricles. This process allows blood to be pumped throughout the body.

Heart block

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.

Supraventricular tachycardia Abnormally fast heart rhythm arising from improper electrical activity in the upper part of the heart

Supraventricular tachycardia (SVT) is an abnormally fast heart rhythm arising from improper electrical activity in the upper part of the heart. There are four main types: atrial fibrillation, paroxysmal supraventricular tachycardia (PSVT), atrial flutter, and Wolff–Parkinson–White syndrome. Symptoms may include palpitations, feeling faint, sweating, shortness of breath, or chest pain.

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.

Sinoatrial block

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.

An ectopic pacemaker 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.

Homeobox protein Nkx-2.5

Homeobox protein Nkx-2.5 is a protein that in humans is encoded by the NKX2.5 gene.

<i>TBX5</i> (gene)

T-box transcription factor TBX5 is a protein that in humans is encoded by the TBX5 gene.

TBX2

T-box transcription factor 2 Tbx2 is a transcription factor that is encoded by the Tbx2 gene on chromosome 17q21-22 in humans. This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. Tbx2 and Tbx3 are the only T-box transcription factors that act as transcriptional repressors rather than transcriptional activators, and are closely related in terms of development and tumorigenesis. This gene plays a significant role in embryonic and fetal development through control of gene expression, and also has implications in various cancers. Tbx2 is associated with numerous signaling pathways, BMP, TGFβ, Wnt, and FGF, which allow for patterning and proliferation during organogenesis in fetal development.

HCN4 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.

Ankyrin-B, also known as Ankyrin-2, is a protein which in humans is encoded by the ANK2 gene. Ankyrin-B is ubiquitously expressed, but shows high expression in cardiac muscle. Ankyrin-B 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 ankyrin-B cause a dominantly-inherited, cardiac arrhythmia syndrome known as ankyrin-B syndrome as well as sick sinus syndrome; mutations have also been associated to a lesser degree with hypertrophic cardiomyopathy. Alterations in ankyrin-B expression levels are observed in human heart failure.

Arrhythmia Group of conditions in which the heartbeat is irregular, too fast, or too slow

Arrhythmia, also known as cardiac arrhythmia or heart arrhythmia, is a group of conditions in which the heartbeat is irregular, too fast, or too slow. The heart rate that is too fast – above 100 beats per minute in adults – is called tachycardia, and a 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 or chest pain. While most types 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.

BRL-32872

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.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.