DocWire News Editors

DocwireNews

A research team from the Boston Children’s Hospital recently created the first tissue model of an inherited <a href="https://www.docwirenews.com/condition-center/electrophysiology-condition-center/high-influenza-activity-increased-ventricular-arrhythmia/">heart arrhythmia</a> and treated it with gene therapy in an animal model. This work not only provides more information regarding the condition but supports gene therapy as a one dose treatment for patients with the disease. These findings were published in two separate papers in the journal Circulation.
&#8220;Our hope is to give gene therapy in a single dose that would work indefinitely,&#8221; explained Vassilios Bezzerides, MD, PhD, a cardiologist in the Inherited Cardiac Arrhythmias Program at Boston Children&#8217;s Hospital who took part in both studies. &#8220;Our work provides proof-of-concept for a translatable gene therapy strategy to treat an inherited cardiac arrhythmia.&#8221;
Both studies were centered on catecholaminergic polymorphic ventricular tachycardia (CPVT), an arrhythmia that commonly causes sudden death in young adults and children. This inherited disease is often brought about through stress or exercise, with symptoms first manifesting around age 12. Currently, treatment options for CPVT patients are beta-blockers and other drugs, surgical disruption of the heart’s nerves, implanting a defibrillator, and having patients avoid exercise.
&#8220;Treatments for CPVT are currently pretty inadequate: 25 to 30 percent of patients will have recurrent life-threatening arrhythmias despite treatment,&#8221; said Bezzerides.
<h2>Using Stem Cells to Recreate CPVT</h2>
To better understand CPVT at a molecular level, researchers recreated the condition in a tissue model. This work was led by William T. Pu, MD of the Boston Children’s Hospital and Kevin Kit Parker, PhD, of Harvard’s School of Engineering, Arts, and Sciences (SEAS) and Boston Children’s. This portion of the CPVT research was published on <a href="https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.119.039711">July 17 in Circulation</a>.
These researchers first obtained blood samples from two patients with CPVT that was caused by mutations in RYR2, the gene most closely linked to CPVT. This gene codes for a calcium channel protein that enables cells to release the ion and cause heart contraction.
Next, the team reprogrammed these blood cells to become <a href="https://www.docwirenews.com/docwire-pick/future-of-medicine-picks/top-potential-uses-of-stem-cells-in-medicine/">induced pluripotent stem cells (iPSCs)</a> which can be used to form all cell types. In this case, these iPSCs were used to create heart muscle cells that carry the RYR2 mutations. In doing so, the researchers created a model of the arrhythmia in artificial heart muscle tissue.
&#8220;The cells were seeded on an engineered surface so that they lined up in a specific direction similar to how heart muscle is organized,&#8221; said Pu, director of Basic and Translational Cardiovascular Research at Boston Children&#8217;s. &#8220;The cells have very abnormal beating individually, but after assembly into tissue, they beat together, better modeling the actual disease. That&#8217;s why tissue-level models are important.&#8221;
The team then applied blue light to the tissue to initiate contraction, creating an impulse that propagated through the tissue and activated the cells. This system was used to simulate an exercise test in the tissue, with the researchers adding isoproterenol (an adrenaline-like hormone) to it and applying infrared light to induce faster heartbeats.
Being that CPVT manifests during exercise, this test helped show the diseases molecular mechanisms. The researchers found that calcium moved through the cardiac tissue at variable speeds, whereas in healthy tissue, it moves in even waves. This abnormal calcium release resulted in the arrhythmic contractions seen in CPVT.
&#8220;When we paced the cells faster, the CPVT tissue sustained re-entrant arrhythmias, whereas normal tissue could handle it fine,&#8221; said Pu.
The team then identified molecules activated by adrenaline and used <a href="https://www.docwirenews.com/abstracts/crispr-cas9-mediated-gene-knockout-in-intestinal-tumor-organoids-provides-functional-validation-for-colorectal-cancer-driver-genes/">CRISPR-Cas9</a> and drugs to selectively modify them. In this manner, they identified the CaM kinase (CaMKII) that modifies RYR2 and makes healthy cells release more calcium. In the CPVT cells, however, this modification builds on the effect of the preexisting RYR2 mutation and leads to excessive calcium levels. Blocking CaMKII in the tissue model eliminated arrhythmias.
&#8220;Nature designed CaMKII as part of the fight-or-flight response,&#8221; said Pu. &#8220;When you get excited, you release more calcium so the heart can beat faster. But when RYR2 is mutated, the channel is leaky, so the cell releases way too much calcium, which causes arrhythmia.&#8221;
<h2>A Gene Therapy Approach to Treating Arrhythmia</h2>
Though inhibiting CaMKII in the heart is beneficial in treating CPVT, the enzyme is also required by the brain for necessary cognitive function. To inhibit CaMKII in the heart only, the researchers tested a gene therapy technique in a mouse model of the disease. This work was led by Bezzerides and Pu, and was published in <a href="https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.038514">Circulation on June 3</a>.
They modified a virus to travel to the heart and deliver AIP, a peptide that selectively inhibits CaMKII. After this genetically altered virus was injected into the mice, Bezzerides, Pu and colleagues noted that roughly half of the heart cells expressed AIP. This quantity is high enough to treat the arrhythmia but not expressed significantly in other tissues like the brain.
Going forward, the team has plans to improve their gene therapy and apply it in larger animal models, then eventually move into clinical trials. The researchers also feel that this general approach of inhibiting CaMKII could be used to treat more common causes of heart disease as well.
<blockquote class="twitter-tweet">
Tissue models and gene therapy for a deadly heart arrhythmia<a href="https://t.co/LJznJSU9HV">https://t.co/LJznJSU9HV</a>
— Melero-Martin Lab (@MeleroMartinLab) <a href="https://twitter.com/MeleroMartinLab/status/1151479028160892930?ref_src=twsrc%5Etfw">July 17, 2019</a>
</blockquote>
<script async src="https://platform.twitter.com/widgets.js" charset="utf-8"></script>

Emily Menendez

Complete Response to Immunotherapy in HCC: Insights From IMbrave150

Hepatocellular Carcinoma

Anne Marie Morse, DO

Rob Dillard

Dr. Morse Talks About the Significance of World Sleep Day 2025

Sleep Disorders

Dr. John Fruehauf, Evolent

Advancing Therapies Have Improved the Prognosis of Metastatic Melanoma

Melanoma

Latest News

Researchers Create Gene Therapy for Arrhythmia Using a Stem Cell Model

Cardiology

A research team from the Boston Children’s Hospital recently created the first tissue model of an inherited heart arrhythmia and treated it with gene therapy in an animal ...

About Us

Editorial Policy

Advertising

Contact Us

eNewsletters

Contribute

Career Center

MashupMD

Blood Cancers Today

Cancer Nursing Today

GU Oncology Now

Urban Health Today

Bile Duct Cancer

Colorectal Cancer

Gastroesophageal Cancer

Gastric Cancer

GEP-NETs

GIST

Liver Cancer

Pancreatic Cancer

GI Oncology Now

Anemia

Deep Vein Thrombosis

Essential Thrombocythemia

Hemophilia

Immune Thrombocytopenic Purpura

Myelodysplastic Syndromes

Myelofibrosis

Myeloproliferative Neoplasms

Polycythemia Vera

Pulmonary Embolism

Sickle Cell Disease

Thrombocytopenia

Thrombophilia

Thrombosis

Thrombotic Thrombocytopenic Purpura

Venous Thromboembolism

von Willebrand Disease

Heme Today

Acute Kidney Injury

ADPKD

Anemia and Kidney Disease

Chronic Kidney Disease

COVID-19 and Kidney Disease

Diabetes and Hypertension

End-Stage Renal Disease

Gout

Hyperkalemia

IgAN

Kidney Transplantation

Metabolic Acidosis

Nephrology Times

Mesothelioma

Non-Small Cell Lung Cancer

Small Cell Lung Cancer

Lung Cancers Today

Atherosclerotic Disease

Atrial Fibrillation

Heart Failure

Hypertension

Interventional Cardiology

Lipid Management

Practice Tips With Dr. Lichaa

Preventive Cardiology

Stroke

Breast Cancer

Gynecologic Cancer

Head and Neck Cancer

Skin Cancer

Oncology

Sleep

Urology

Diabetes

Ophthalmology

— Demodex Blepharitis

Neurology

Rheumatology

Gastroenterology

Pulmonology

Infectious Diseases

— HIV

Health and Wellness

Lupus

Future of Medicine

Orthopedics

Pharmacology

Career News

More

Conferences

CardioNerds

The Sleep Source With Dr. Morse

Rheumatology Rounds With Dr. Maheswaranathan

Partners

Expert Interviews

Subscribe