Research

JTB Foundation-based Research

The JTB Foundation is proud to support Dr. Andrew Landstrom, a pediatric cardiology and genetic scientist at Duke University School of Medicine.   Dr. Landstrom specializes in caring for children and young adults with genetic diseases of the heart, including cardiac channelopathies and cardiomyopathies.  He leads a basic science laboratory exploring the causes of sudden cardiac arrest-predisposing diseases with a goal of identifying children who are at-risk and developing new therapies to treat the underlying disease.

With funding from the JTB Foundation, Dr. Landstrom is working with colleagues to determine a cause of arrhythmic cardiomyopathy (AC) resulting from mutations in the gene DSP.  DSP mutations cause development of fat in the normal heart muscle, something that is common among patients with AC, which results in arrhythmias and heart failure.  In addition, DPS mutations tend to cause inflammation and can often lead to myocarditis.  Myocarditis, also known as inflammatory cardiomyopathy, is an inflammation of the heart muscle that is not often seen other forms of AC. Myocarditis is typically caused by a viral infection and has been seen at higher rates in hospitalized patients with COVID 19. 

The near-term aim of Dr. Landstrom’s study is to determine whether mutations in DSP lead to AC development that is worsened by inflammation, suggesting that inflammation fuels AC progression.  To test this, he will use induced pluripotent stem cell-derived cardiac myocytes following genome editing to create a DSP mutation that is associated with inflammatory AC in a family.  He will then test whether inflammatory triggers worsen the development of AC features in these cells.  Dr. Landstrom’s work is designed to provide valuable insight into how inflammation impacts AC development in patients with DSP mutations. This research will increase understanding not only of a particular genetic cardiac disease, but it will also shed important light on why some patients with inflammation of the heart develop heart failure. 

2022 Research Update!

JTB Foundation Project Update
Aug 3, 2022

With generous support from the John Taylor Babbitt Foundation, we have made significant progress toward exploring the role of inflammation in arrhythmic cardiomyopathy (AC). Mutations in the gene DSP can cause development of fat and scar in the normal heart muscle, which is a common feature of patients with AC, that can result in heart failure and life-threatening arrhythmias. In addition, some patients with DSP mutations will also have inflammation of the heart muscle called myocarditis. It is unclear whether this myocarditis triggers worsening AC and potentially whether treating it may slow progression of AC. To figure this out, we have identified a DSP mutation that has led to both AC and numerous episodes of myocarditis. We have created this mutation in an otherwise “healthy” line of induced pluripotent stem cells (iPSCs). These iPSCs are being grown and expanded to confirm that the mutation is present and that there are no “off target” mutations. Once validated, we can then guide these iPSC to differentiate into cardiac myocytes (iPSC-CMs). In effect, this will create the beating heart cells hosting this DSP variant in a dish in the lab so that we can test whether inflammatory triggers make development of AC worse, or whether preventing inflammation might reduce signs of AC in the iPSC-CMs. In addition, funding from the John Taylor Babbitt Foundation has brought together other experts in the field to work with us on this study, including Dr. Anwar Chahal, Director of the Cardiovascular Genetics Program at U Penn, and Dr. Devyani Chowdhury Director of Cardiology Care for Children in Lancaster, PA). Together, we believe these iPSC-CMs can serve as a valuable model to understand how DSP variants cause AC and what role inflammation may have in worsening the disease.

We would like to highlight a relevant article, lead by Dr. Chahal and co-authored by Dr. Landstrom, which appeared in Circulation “Inflammation and Immune Response in Arrhythmogenic Cardiomyopathy: State-of-the-Art Review”.

Full Citation:
Asatryan B, Asimaki A, Landstrom AP, Khanji MY, Odening KE, Cooper LT, Marchlinski FE, Gelzer AR, Semsarian C, Reichlin T, Owens AT, Chahal CAA. Inflammation and Immune Response in Arrhythmogenic Cardiomyopathy: State-of-the-Art Review. Circulation. 2021. Nov 16;144(20):1646-1655. PMID: 34780255

In addition, Dr. Landstrom had the privilege of giving a series of talks to families through the Sudden Arrhythmia Death Syndrome (SADS) Foundation over the summer about this topic, related topics such as gene therapy, and other advances in arrhythmic cardiomyopathy and other SADS diseases.

2022 “Research advances in SADS conditions: A sneak peek into tomorrow”. Keynote Speaker. 2022 SADS Virtual Family Conference. Virtual. (July 16)
2022 “Advances in gene therapy for arrhythmic cardiomyopathy”. Webinar. Living with SADS. Sudden Arrhythmia Death Syndrome Foundation. Virtual (Apr 27)
2022 “Gene therapy for cardiac arrhythmia syndromes: What parents and families should know”. Webinar. Living with SADS. Sudden Arrhythmia Death Syndrome Foundation. Virtual (Mar 22)

All of these talks are available to the public after a registration process (for free I believe):

https://www.sads.org/what-now/living-with-sads-webinars/

2022 Sees Progress and Promise in Treating and Curing HCM

2022 saw not only a major advance in treatment for hypertrophic cardiomyopathy (HCM), but also the launch of a new effort aimed at curing this disease and related cardiomyopathies. On the treatment side, the U.S. Food and Drug Administration (FDA) approved a first-of-its-kind medication for treatment of a class of HCM patients in May. The drug, sold by Bristol Myer Squibb (BMS) as CAMZYOS (mavacamten), treats adults with symptomatic obstructive HCM, and has been shown to increase capacity for activity and reduce shortness of breath. CAMZYOS targets the source of symptomatic, obstructive HCM and is the first and only FDA-approved treatment of its kind.

The path to mavacamten was laid in 2021 by four physicians and researchers – Christine Seidman, James Spudich, Jonathan Seidman, and Leslie Leinwand — who co-founded a company called MyoKardia. MyoKardia focused on discovering, developing, and commercializing targeted therapies to treat those heritable cardiomyopathies and genetically-driven forms of heart failure that result from biomechanical defects in heart muscle contraction. MyoKardia developed mavacamten and, in 2020, BMS acquired MyoKardia, subsequently bringing the drug to market as CAMZYOS.

Dr. Christine Seidman is also a co-leader on an award-winning project called CureHeart. Led by Professor Hugh Watkins of the University of Oxford, CureHeart aims to develop the first cures for inherited heart muscle diseases by applying genetic therapies to repair faulty genes. In July 2022, CureHeart was selected as the winner of the British Heart Foundation’s Big Beat Challenge, a competitive, £30 million innovation project targeting unmet needs in heart disease.

CureHeart will utilize gene-editing technology to cure inherited heart muscle diseases in two ways. First, in cases where the faulty gene produces an abnormal protein in the heart, the goal is to correct or silence the faulty gene by re-writing single spelling mistakes or by switching off the entire copy of the faulty gene. Second, in cases where the faulty gene fails to produce enough protein for the heart muscle to function properly, the goal is to increase production of the protein by correcting the function of the faulty copy of the gene or by stimulating the normal copy of the gene to produce more.

CureHeart leverages a multinational research partnership including leading experts from the UK, USA, and Singapore in complementary areas of science and medicine. With the Big Beat Challenge win, CureHeart is poised to make ground-breaking progress in ameliorating and curing heritable cardiomyopathies. 2022 has brought new firsts to the treatment of HCM and we look forward to more exciting developments in 2023.

Past Updates

2022 Research Update
2021 Research Update
2020 Research Update
2019 Research Update
2018 Research Update
2017 Research Update
2016 Research Update
2014 Research Update
2013 Research Update
2012 Research Update
2011 Research Update

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