According to this New York Times article, the genetic repair process CRISPR may make it possible for pig hearts to replace human hearts. If this technology works, it would be good news for those awaiting transplant.
Currently, there are limited organs available with strict protocols for eligibility. A new source of suitable donor organs would be a great advance for heart transplantation.
MyoKardia’s stock prices jumped today after their recent Stage II trial of the experimental drug mavacamten (formally known as MYK-461) demonstrated a statistically significant reduction to left ventricular outflow tract gradients as well as improvement to aerobic capacity in patients with obstructive hypertrophic cardiomyopathy.
Of the 10 patients who completed the study, 8 saw their gradient reduced to normal levels after 12 weeks on the drug. The study also showed improvements in both peak oxygen consumption (peak VO2) and New York Heart Association classifications: 7 patients moved up one NYHA class while 2 patients improved by two classes.
The drug seemed to have mild to moderate side effects, though one patient was forced to drop out of the trial due to a recurrence of atrial fibrillation which necessitated discontinuation of mavacamten and a return to anti-arrythmic drugs which had been discontinued due to participation in the trial.
MyoKardia hopes to enroll between 200 and 250 patients in its next phase trial (Explorer HCM) which it plans to begin before the end of 2017.
For more information on MyoKardia and recent drugs being developed for HCM read these past blog entries:
MyoKardia HCM Drug Has Success in Cats
End of the Road for Eleclazine and Liberty HCM Study
Scientists, in a follow up to three earlier, less successful, Chinese experiments, have for the first time used a recently developed gene editing process known as “CRISPR” to remove a genetic defect from a human embryo. The specific defect that the scientists targeted was a mutation in MYBPC3, a common genetic cause of hypertrophic cardiomyopathy (HCM).
What Happened in the Study?
The study authors consisted of a multi-national team of geneticists, cardiologists, fertility experts and embryologists. Led by Dr. Shoukhrat Mitalipov of Oregon Health Sciences University, in collaboration with researchers at the Salk Institute in La Jolla, CA, China and South Korea, the researchers were able to largely remove the HCM gene MYBPC3 from very early stage human embryos.
Their research involved using eggs from 12 healthy female donors, and sperm from a male HCM patient with the MYBPC3 gene. When gene-editing components were introduced to the egg along with the sperm, prior to fertilization of the egg, approximately 3/4 of the embryos repaired themselves using the DNA blueprint provided by the normal, non-mutated copy of the gene from the unaffected female. This was somewhat surprising to researchers, who had theorized that cells would replicate using a blueprint from the repaired paternal gene – not the healthy gene of the mother.
Ultimately, genes were corrected in 42 of 58 embryos, constituting 72.4% of the total, a higher proportion than expected, and far more than any correction shown in previous experiments.
Implications for the Future
This technique is still far from general usage and will require further study and refinement. And, currently it is not legal in the United States since the Food & Drug Administration currently prohibits medical gene editing which would impact future generations.
However, it would be possible for this technique to be used alongside current technology to assist families with genetic diseases like HCM. If used in conjunction with pre-implantation genetic testing and in-vitro fertilization (PGD), the technique could repair the large proportion of embryos (roughly 50%) which must be discarded due to genetic defectiveness.
While there are critics who say that this technology will lead to “designer babies” and that it creates troubling ethical issues for society, most HCM patients believe that it provides a ray of hope, so that hopefully one day, in the not-too-distant-future, our children and grandchildren will be free of the affliction that has permeated our lives, as well as the lives of our siblings, our parents, our aunts and uncles, our cousins, our grandparents, and our great-grandparents.
Story Links:
As this story was reported by all major news sources, links to many of the articles can be found below.
Los Angeles Times – Q&A video clip with lead study author Shourkhrat Mitalipov
LA Times article regarding ethics -response to first article
NOTE THAT APPROXIMATELY A MONTH AFTER THE PUBLICATION OF THIS ARTICLE, THE RESULTS HAVE BEEN CALLED INTO QUESTION BY OTHER SCIENTISTS.
See this article in MIT Technology Review, this article in Science Magazine, this article in Nature, and this article in The Scientist, all of which cite this article in BioRxiv which poses alternative theories for the results claimed by the original paper.
A few months ago, HCMBeat featured this post about HCM Care, a new educational website and downloadable app for HCM patients and their families, featuring essential information for patients trying to understand their HCM diagnosis, explained in written and video formats. HCM Care also provides useful information about genetic testing and family screening for their family members.
Dr. Andrew Wang of Duke University’s HCM Clinic in Durham, N.C., developed HCM Care along with 8 other HCM specialists from 6 hospitals, including Mayo Clinic, Cleveland Clinic and Tufts Medical Center. Funding and support for the project were provided by MyoKardia, a San Francisco biotech company engaged in the development of a precision medicine approach to the treatment of genetic cardiomyopathies. Their HCM medication, MYK-461, is currently in clinical trials in the U.S.
Cynthia Burstein Waldman of HCM Beat had the opportunity via email to talk with Dr. Wang about his HCM practice and his involvement with the development of HCM Care. What follows is their written correspondence, edited for clarity:
Continue reading “A Conversation with Duke’s Dr. Andrew Wang – Creator of the HCM Care App”
Alcohol septal ablations (ASA) have been available to HCM patients as a treatment option for the last 20 years. While the procedure has been the subject of great controversy, some physicians have recently advocated for expanded indications of the ASA procedure.
An editorial in this week’s Journal of the American College of Cardiology from the Netherlands argues that the safety of ASA has been firmly established because mortality rates from ASA have been shown to be comparable to those from septal myectomy. The Dutch doctors maintain that past concern about ventricular arrhythmia resulting from the scar left by the ablation have not born out.
Making ASA Safer
Now, they argue, the focus should shift from justifying the procedure toward perfecting the procedure. In particular, the need for additional or repeat procedures must be reduced. Additional procedures have been necessary due to incomplete resolution of obstruction and/or the need for pacemaker implantation due to heart block, neither of which are a common consequence following myectomy. 1 in 10 patients require a pacemaker following ASA, while only 1 in 25 require one following a myectomy. 1 in 13 patients require a subsequent intervention after ASA (either another ASA or a myectomy), which is 15 times the rate of re-intervention after a myectomy.
The researchers’ suggestions for improvement include: 1) performing ASA only in hypertrophic cardiomyopathy centers of excellence that perform high volumes of the procedure; 2) improving patient selection through the use of a multi-disciplinary team which includes a cardiologist specializing in imaging, a cardiac surgeon, and an interventional cardiologist; 3) using 3D myocardial contrast echocardiography in order to select the best vessels; and 4) use of a small targeted amount of alcohol.
Impact of 3D Myocardial Contrast Echocardiography
In particular, the researchers explain that 3 dimensional myocardial contrast echocardiography (MCE) has proven to be a helpful tool in selection of the appropriate septal perforator. The use of MCE has resulted in a change in strategy in 15% to 20% of cases: either by a change in which blood vessel is selected for the alcohol or by prompting the immediate discontinuation of a procedure if the MCE shows that other parts of the heart could be affected. MCE has also improved the success rate of ASA, while allowing for a more compact scar.
Counterpoint Editorial Advocates National Registry to Quantify Results
An accompanying editorial by Dr. Paul Sorajja from Minneapolis Heart Institute argues that we do not have the data necessary to reconcile the differences in outcome between myectomy and ASA. In order to better understand the long-term potential and risks of ASA, mandatory reporting should be required. He points out that this is what is done in other multidisciplinary transcatheter-based therapies, e.g. transcatheter aortic valve replacement for the treatment of aortic stenosis and transcatheter repair of mitral regurgitation with MitraClip. These procedures require: 1) the use of multidisciplinary teams; 2) participation in a national registry (i.e., The Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry); and 3) comprehensive reporting of procedural and 1-year outcomes.
Therefore, Dr. Sorajja proposes a national registry created that includes the following information:
Updated to include a link to a BBC interview with Miles Frost’s brother Wilfred about his brother and father’s deaths from HCM.
Pippa Middleton, (sister of Dutchess Katherine of Cambridge and sister-in-law of Prince William) and her brand new husband, James Matthews, made their first public appearance as a married couple at a fundraiser for the Miles Frost Fund. The Frost Fund, founded in memory of Middleton’s late friend Miles Frost who died from undiagnosed HCM, raises money for genetic testing of family members who have lost a close relative to sudden cardiac arrest, as well as funding HCM research.
Pippa, just back from her honeymoon to French Polynesia and Australia, looked refreshed in her white jumper and carried a red heart-shaped clutch to emphasize the purpose of the occasion.
The fundraiser also attracted other royals such as Princess Eugenie and Sarah Ferguson, Duchess of York.
Here is a video of Wilfred Frost, brother of Miles Frost and son of Sir David Frost, talking about his father and brother’s deaths and the formation…
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Dr. Heidi Rehm is a human geneticist and clinical laboratory director at Harvard Medical School who has spent much of her career studying the genetics of cardiomyopathy.
Imagine her surprise when she found out that she, her mother and her daughter all have a mutation in the MYH7 gene which has been associated with dilated cardiomyopathy!
The unexpected revelation came as an indirect result of a visit to her daughter’s orthodontist. When one of her daughter’s teeth was delayed coming in, the orthodontist suggested that there might be a genetic cause for the late tooth. This provided the idea behind her high school daughter’s summer biology research project: 2 weeks in her mom’s lab sequencing her exome, looking for a genetic cause for her delayed tooth.
Though the mouth genetics turned out to be normal and the tooth eventually arrived, an totally unexpected incidental finding turned up instead: a variation in the MYH7 gene which has been associated with dilated cardiomyopathy.
Continue reading “Unwitting Geneticist Discovers Her Own Cardiomyopathy Gene: Heidi Rehm’s Story”
Pippa Middleton, (sister of Dutchess Katherine of Cambridge and sister-in-law of Prince William) and her brand new husband, James Matthews, made their first public appearance as a married couple at a fundraiser for the Miles Frost Fund. The Frost Fund, founded in memory of Middleton’s late friend Miles Frost who died from undiagnosed HCM, raises money for genetic testing of family members who have lost a close relative to sudden cardiac arrest, as well as funding HCM research.
Pippa, just back from her honeymoon to French Polynesia and Australia, looked refreshed in her white jumper and carried a red heart-shaped clutch to emphasize the purpose of the occasion.
The fundraiser also attracted other royals such as Princess Eugenie and Sarah Ferguson, Duchess of York.
Here is a video of Wilfred Frost, brother of Miles Frost and son of Sir David Frost, talking about his father and brother’s deaths and the formation of the charity.
According to researchers at the University of Michigan, family members of HCM patients who have tested negative for genes associated with HCM and without a family history of HCM will usually be found to be free of HCM during routine family screening. And, in accordance a recent Australian study, relatives of these patients may be able to benefit from less rigorous screening protocols.
In contrast, when the initial diagnosis is made in a patient who is 50 or older with no known genetic mutations, a negative family history, and sigmoidal septal pattern hypertrophy, reduced family screenings may be appropriate and less burdensome. In addition, hypertension, large family size with no other affected family members, less severe hypertrophy, and lack of life-threatening complications related to HCM may provide additional comfort to families of newly diagnosed HCM patients.
The reduced protocol would consist of a single screening of adult family members, with the caveat that if and when any additional family additional member is found to have HCM, a more traditional screening protocol be instituted.
Since the early 1960s, surgical septal reduction, also known as septal myectomy, has been used as a therapy for the treatment of obstructive hypertrophic cardiomyopathy. Pioneered at the National Institute of Health by cardiac surgeon Dr. Glenn Morrow, himself a HCM patient, septal myectomy has become a mainstay of the HCM treatment arsenal.
An alternative to septal myectomy, alcohol septal ablation (ASA), was first performed by Ulrich Sigwart in the United Kingdom at the Royal Brompton Hospital in London in 1994.
For many years, the indications for ASA procedures has been limited to older patients with obstructive HCM who were not otherwise healthy enough to undergo open heart surgery. However, some doctors are now advocating to expand the indications for ASA to include symptomatic younger patients.
(For more information about myectomy and ASA, click here and scroll to bottom of page).
Continue reading “Should Alcohol Septal Ablation Be Considered for Younger Patients?”
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