CRISPR Eliminates HCM Gene !

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.

Nature

The Atlantic

New York Times

Washington Post.

NPR

LA Times

Los Angeles Times – Q&A video clip with lead study author Shourkhrat Mitalipov

The Guardian

USA Today

MIT Technology Review

Gizmodo

Boston Herald

LA Times article regarding ethics -response to first article

 

A Conversation with Duke’s Dr. Andrew Wang – Creator of the HCM Care App

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.

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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:

 HCMBeat:  What got you interested in HCM?  Did you first develop an interest during your training at Johns Hopkins, or did it begin later once you arrived at Duke?

Dr. Wang:  During my internal medicine residency, HCM became fascinating to me because of the interesting physical exam findings in patients with outflow tract obstruction and the complexity of the condition causing diverse symptoms and manifestations.  In my early faculty years at Duke (soon after alcohol septal ablation was introduced for the treatment of obstructive HCM), I realized the importance of having a dedicated care approach and experience in treating HCM patients to optimize and individualize treatment, so I started our HCM Clinic at Duke in 2003.  I’ve continued to direct this clinic since then.

HCMBeat:  How many HCM patients do you see in the HCM Clinic at Duke?

Dr. Wang:  We have a dedicated, full day clinic for HCM on 3 Mondays each month.  I see approximately 6 new patient referrals for HCM and 10 returning HCM patients each clinic day.  We treat over 500 HCM patients a year at Duke.

HCMBeat:  Does Duke perform septal myectomy and/or septal alcohol ablation for obstructed HCM? How many of each type of procedure does Duke perform per year?

Dr. Wang:  Our center performs about 30 surgical myectomies which are performed by 2 dedicated cardiac surgeons and 5 alcohol septal ablations each year.

HCMBeat:  Do you have a cardiac genetics counselor at Duke? What about a pediatric HCM specialist?  How many of your diagnosed patients are genetically tested?

Dr. Wang:  Yes, we have a full-time cardiovascular genetics counselor and a pediatric HCM specialist as well.  We perform genetic testing in about 40 HCM patients a year.

HCMBeat:  How did you come up with the idea of the HCM Care website and app?

Dr. Wang:  The idea for the HCM Care website and app originated over 2 years ago and developed from my experiences with treating HCM patients.  We used to send paper copies or hand-outs of helpful educational materials to our HCM patients before or after their clinic visits.  But I realized that these materials were only general overviews, and that patients often had more specific questions about HCM and the answers were either difficult to find or not discussed at all in the handouts.  I thought that a question-based approach would allow a patient or family member to find their specific answer, and perhaps see other questions and answers relevant to their situation.  We’ve been very fortunate to work with an outstanding team of physicians, patients, software and animation designers, and videographers to develop this resource.

HCMBeat:  Are the topics addressed on the website and app the most frequent questions that you encounter from patients?

Dr. Wang:  The questions were written or selected based on several factors: 1) actual questions HCM patients have asked; 2) important topics that most HCM patients should know about the condition; and 3) information that is covered in professional guidelines for treating HCM patients but that is not written for the patient audience.

HCMBeat:  Who are some of the other HCM expert physicians who are featured, and how did you choose them? Do you plan to include other physicians in future editions?

Dr. Wang:  We invited several HCM experts from many different institutions to participate in our videos and to discuss different HCM topics.  (We thought that some patients may prefer to listen or view the information in these videos, rather than read the question and answers as text.)  We selected these physicians based on their expertise in treating HCM and knowledge of recent advancements in the field.  We hope to add more expert interviews, topics and HCM physicians as the app’s content is updated.

HCMBeat:  Currently, the website and app are informational.  Are there plans to make them more interactive?  How might it be used to assist patients with decision making?

Dr. Wang:  We are very interested in having HCM patients discuss their thoughts about specific HCM topics in future video interviews.  This patient perspective is absent in the current content, and I think patients would value hearing other HCM patients talk about their treatment and what factored into their decisions.  Although the app is not intended to provide medical advice to the individual patient, we welcome ideas for new questions or content to be added in future updates.

HCMBeat:  What has been the feedback on HCM Care from your patients? 

Dr. Wang:  Many patients have said that they previously “Googled” for information about HCM, but found it challenging to find answers to their questions.  Some have come away from their searches even more uncertain or frightened.

My patients have generally been very excited to have this educational resource.  Several have found the animation of the HCM heart very helpful by allowing them visualize obstruction.  Hopefully after having seen the app or website, they have a better, more reassured understanding of this treatable condition.  Since the launch of HCM Care in March of this year, over 1,000 users have benefited from the information provided.

HCMBeat:  On behalf of HCMBeat and the HCM Community, I would like to thank you for your efforts to help patients understand what is often an overwhelming and confusing diagnosis. I would also like to thank you for taking the time to answer these questions.

HCM Care is downloadable as an app for Android and Apple mobile devices.  The version in the Apple App store can be found here:  https://itunes.apple.com/us/app/hcm-care/id1202279004?mt=8

There is also a web-based version found here:  www.hcmcare.com

HCMCarefeature

 

Email the HCM Care team with any suggestions for new questions or with any comments at: HCMCareapp@gmail.com.

 

Unwitting Geneticist Discovers Her Own Cardiomyopathy Gene: Heidi Rehm’s Story

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”

Should Alcohol Septal Ablation Be Considered for Younger Patients?

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?”

Pre-Implantation Genetic Testing to Eradicate Genetic Disease- An Editorial

In this editorial by Lee Cooper published in today’s issue of Wired Magazine, a patient with Long QT Syndrome makes the case for the use of pre-implantation genetic diagnosis (PGD) used in tandem with in vitro fertilization (IVF) as a means to eliminate hereditary disease.

This technique has already been used in HCM; most successfully in cases caused by a single, identifiable genetic mutation. PGD combined with IVF is a potentially viable option for patients with HCM who are planning to grow their families.

Of course, there are many ethical issues raised with the use of this technology, and the use (or non-use) of these technologies is a very personal decision.  Perhaps such moral uncertainty is what caused Cooper’s doctors to be “reticent to discuss IVF head on” and “bashful about the idea of removing [t]his disease from [his] lineage.”

As Cooper says in the editorial “…we can, and we must be able to speak clearly about the best ways to prevent disease if we are serious about eliminating it.”  If every option were to be laid out on the table for consideration by the patient, then s/he would have the freedom to make a final decision in accordance with his/her own unique set of values.

What do you think?

RESET-HCM: Rethinking Exercise for HCM Patients – Interview with Dr. Sara Saberi and Dr. Sharlene Day

Editor’s note: This is our first interview feature on HCMBeat.  In the future, we hope to feature more interviews with other HCM researchers who have published articles of interest to the HCM community.  

By now, you have probably already heard the buzz about RESET- HCM – a study about the effects of exercise on HCM patients conducted by Dr. Sara Saberi and Dr. Sharlene Day at the Hypertrophic Cardiomyopathy Clinic of the University of Michigan’s Frankel Cardiovascular Center in collaboration with Dr. Matthew Wheeler and Dr. Euan Ashley of Stanford’s HCM Center. The findings were presented at the American College of Cardiology Conference on March 17, 2017 held in Washington D.C. and were the subject of this feature on HCMBeat. 

Recently, Cynthia Waldman of HCMBeat had the opportunity to sit down with Drs. Saberi and Day for a detailed conversation (over Skype) about the study.  What follows is a transcript of their conversation (which has been edited for readability).

Continue reading “RESET-HCM: Rethinking Exercise for HCM Patients – Interview with Dr. Sara Saberi and Dr. Sharlene Day”

End of the Road for Eleclazine and Liberty HCM Study

 Eleclazine:  The Liberty HCM Trial

It appears to be the end of the road for the Gilead drug eleclazine, a late sodium channel inhibitor previously known as GS-6615.  Eleclazine, with properties similar to the anti-angina drug ranolazine (which was approved by the FDA in 2006), was the subject of a recently terminated HCM clinical trial known as Liberty-HCM.  The HCM eleclazine study focused on whether the drug would improve symptoms and exercise capacity in patients with HCM by increasing their peak oxygen uptake, resulting in improved VO2 max readings on exercise testing.  The HCM study began enrolling patients in February 2015. Data collection had been scheduled to continue through June 2017. Continue reading “End of the Road for Eleclazine and Liberty HCM Study”

Depression: 10 Ways for Heart Patients to Cope Without Using Medication

This highly informative blog article from Carolyn Thomas of Heart Sisters , while targeted toward people with coronary artery disease, contains much useful information which can be applied to heart patients with other conditions as well.  This particular article offers many useful suggestions of ways to help combat depression which could just as easily be implemented by those with HCM.

An added bonus is that most of these suggestions do not involve ingesting anything at all!

One caveat she mentions, which bears repeating, is that you should ALWAYS discuss any type of dietary supplement with your cardiologist before you begin taking it.

Cincinnati Children’s Blog Answers Questions About Genetic Testing for Cardiomyopathies

This informative blog article about genetic testing features practical advice about genetic testing and is taken from answers provided in a live presentation by Drs. John Jefferies and Ivan Wilmot.

Issues addressed include: how the test is administered, insurance issues related to the test and the meaning of a positive genetic test.

 

 

Guest Blogger – The View from a HCM Center – by Dr. Steve Ommen of Mayo Clinic’s HCM Center

Good stories usually have a protagonist who is confronted with a challenge or conflict.  The story then follows the protagonist’s journey to overcome that challenge.  Often, there are one or more attempts at conflict resolution which prove unsuccessful, or that even make things worse before the path to success is revealed. In the end, the best stories are those where that successful path was right in front of the protagonist the entire time.

The Challenge for HCM Patients: Local Cardiologist vs. Center of Excellence

For a good story related to the world of hypertrophic cardiomyopathy, you need look no further than Jill Celeste’s HCMBeat blog post entitled “Myectomy:  A Twice in a Lifetime Experience.” The protagonist in this story is obviously Jill.  The conflict is the impact of her HCM symptoms on her quality of life.  Her journey included unsuccessful forays into different therapies before finally, Jill arrived at the resolution of her conflict by seeking care at a medical center with dedicated expertise in the treatment of HCM.

In the sake of full disclosure, that center happens to be Mayo Clinic where I work.  Jill’s great storytelling reminded me how some really clever books and movies tell the same story from a different point of view. In this blog post, I would like to give you my point of view as a physician who directs a HCM specialty center of the best way that you can navigate your own HCM.  I will share how care by a “center of excellence” can fit into the bigger picture of your HCM care and give you some suggestions for ways to balance so you can work well with both your local care team as well as a specialty center that may be a long way from your home. Continue reading “Guest Blogger – The View from a HCM Center – by Dr. Steve Ommen of Mayo Clinic’s HCM Center”