Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Study shows rapamycin reverses myocardial defects in mouse model of LEOPARD syndrome

22.02.2011
Findings demonstrate importance of targeted therapy

Congenital heart diseases affect approximately one in 100 patients, making them the most common type of birth defect and the number-one cause of pediatric deaths.

Now a new study showing that the mTOR inhibitor drug rapamycin can reverse cardiac muscle damage in a mouse model of the congenital disease LEOPARD syndrome not only identifies the first possible medical treatment for this rare condition, but also demonstrates the importance of targeted therapies in managing congenital diseases.

The research, led by investigators at Beth Israel Deaconess Medical Center (BIDMC), is published in the March issue of the Journal of Clinical Investigation (JCI), which appears on-line today.

"The genetic mutations that alter the signaling pathways involved in cardiac development have been implicated in approximately 30 percent of the defects associated with congenital heart diseases," explains the study's senior author Maria Kontaridis, PhD, a scientist in the Division of Cardiovascular Medicine at BIDMC and Assistant Professor of Medicine at Harvard Medical School. "But the molecular underpinnings of these mutations have not been clear. This new work helps illuminate their complex biochemistry."

Kontaridis's lab investigates LEOPARD syndrome and Noonan syndrome, two of a cluster of congenital diseases known as "RASopathies," which are the result of defects caused by mutations in genes in the RAS signaling pathway.

LEOPARD syndrome affects approximately 200 individuals worldwide and is clinically distinguished by multiple lentigines (freckle-like spots on the skin), as well as craniofacial defects, deafness, and blood abnormalities which can give rise to pediatric leukemias. Hypertrophic cardiomyopathy – a thickening of the heart muscle that typically leads to heart failure – is also associated with LS. With the exception of lentigines, Noonan syndrome patients exhibit nearly identical features and pathologies.

Mutations in the PTPN11 (non-receptor protein tyrosine phosphatase type 11) gene are responsible for virtually all cases of LEOPARD syndrome and about half of the Noonan syndrome cases, notes Kontaridis. Consequently, LEOPARD syndrome [LS] and Noonan syndrome have traditionally been thought to be allelic variants with the same disease etiology.

But, this new study showed that this was not the case. By creating an LS mouse model that reproduced features of the human disorder, the Kontaridis group found that the mutations in PTPN11 that cause LEOPARD syndrome are distinct, and lead to a loss of phosphatase activity and hyperactivation of the AKT/mTOR pathway -- which leads to the development of hypertrophic cardiomyopathy.

"When these mice were treated with rapamycin [an mTOR inhibitor agent best known for its role as an immunosuppressant] the hypertrophic cardiomyopathy was reversed," she explains. "Our next step will be to test rapamycin in a clinical trial to evaluate the effect of this treatment in humans with LEOPARD syndrome. Patients would be enrolled on the basis of biochemical analysis [i.e. mTOR activity] rather than clinical diagnosis."

A related study in today's on-line issue of the JCI, by a team of scientists at the University Health Network, Toronto, found that in a mouse model of Noonan syndrome, excessive activity of an enzyme called ERK (a downstream target of the RAS pathway) led to the development of hypertrophic cardiomyopathy, and that treatment with an ERK inhibitor currently being tested as an anti-cancer agent, reversed the cardiomyopathy. This study was led by UHN scientists Toshiyuki Araki and Benjamin Neel, who was also a co-corresponding author on the Kontaridis paper.

"Together, these two studies demonstrate for the first time that individualized therapy should be considered for patients with RASopathy disorders," says Kontaridis. "Our findings in LEOPARD syndrome may additionally provide the first glimpse of a much broader implication -- a potential mechanism for the treatment of other, more common congenital hypertrophy disorders."

This study was funded by grants from the National Institutes of Health, the Sao Paulo Research Foundation and the Frederick Banting and Charles Best Canada Graduate Scholarship. The work was also supported, in part, by the Milton Fund and the BIDMC Division of Cardiology, and by the Ontario Ministry of Health and Long Term Care.

In addition to Kontaridis and Neel, coauthors include BIDMC investigators Talita Marin and Kimberly Keith (co-first authors), Benjamin Davies, Jessica Lauriol, Prajna Guha, and Bo Wang; David Conner and Roderick Bronson of Harvard Medical School; Demetrios Kalaitzids of Childrens Hospital Boston; Xue Wu of the University of Toronto; Michael Bauer of Brigham and Women's Hospital; and Kleber Franchini of the State University of Campinas, Brazil.

Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and consistently ranks in the top four in National Institutes of Health funding among independent hospitals nationwide. BIDMC is a clinical partner of the Joslin Diabetes Center and a research partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox.

Bonnie Prescott | EurekAlert!
Further information:
http://www.bidmc.org

More articles from Studies and Analyses:

nachricht Drone vs. truck deliveries: Which create less carbon pollution?
31.05.2017 | University of Washington

nachricht New study: How does Europe become a leading player for software and IT services?
03.04.2017 | Fraunhofer-Institut für System- und Innovationsforschung (ISI)

All articles from Studies and Analyses >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Can we see monkeys from space? Emerging technologies to map biodiversity

An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.

Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

Im Focus: Scientists develop molecular thermometer for contactless measurement using infrared light

Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine

Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

Quantum thermometer or optical refrigerator?

23.06.2017 | Physics and Astronomy

A 100-year-old physics problem has been solved at EPFL

23.06.2017 | Physics and Astronomy

Equipping form with function

23.06.2017 | Information Technology

VideoLinks
B2B-VideoLinks
More VideoLinks >>>