A Way Out

A majority of our life is defined by our choices. For the most part, we have the power to decide everything from what we want to eat today to what we want to spend the rest of our lives doing. But what about those life-altering decisions that have already been made for us, sometimes even before we are born? Is it just the luck of the draw? Should we just accept the cards we were dealt with or is there something we can do to  change the course of our lives?

        For years, many have succumbed to incurable diseases because the therapies used to treat the disease were anything but sufficient. People worldwide suffer from inherited disorders that can cost them later in life and even impact the future of generations to come. One such disease is hypertrophic cardiomyopathy (HCM). HCM is a genetic disorder that displays an autosomal dominant inheritance pattern¹. According to the National Human Genome Research Institute, autosomal dominant explains how certain traits are inherited. Autosomal signifies that the trait acquired is from a non-sex chromosome; thus, for humans, autosomal diseases are derived from chromosomes 1 through 22. Furthermore, dominant explains how many copies of the mutated gene are required for the disease phenotype. If it is dominant disorder, then only one copy of the mutated gene will display the disease phenotype. Other examples of autosomal dominant diseases are Huntington disease and Marfan Syndrome².

        Therefore, in cases of familial hypertrophic cardiomyopathy, it only takes one mutated

gene to dictate what the rest of your life will look like. HCM is depicted by the thickening of the left ventricle of the heart, lowered chamber capacity, and an enlarged heart¹. The muscle walls of heart thicken which restricts blood flow causing the ventricle to work harder to pump blood to the rest of the body⁴. The prevalence of HCM is estimated to occur in around 1 out of 625 people to 1 in 344 people¹. The European Society of Cardiology suggests that a heart wall thickness greater than or equal to 15 mm is indicative of HCM³.  HCM is a hereditary disorder which affects approximately 0.2% of the population worldwide¹. Common symptoms of HCM include dizziness, fainting, fatigue, chest pain, shortness of breath, and arrhythmias which can lead to death⁷.

        While a number of different mutational events can occur, the most prevalent, accounting for up to 40% of HCM cases involve mutations in a gene called MYBPC3.  This gene is responsible for creating the cardiac myosin binding protein C, a cardiac protein, and is typically inherited from at least one parent⁸. Treatment of patients who have MYBPC3 mutations involve regular monitoring and medications and to open heart surgery or an implantable cardioverter-defibrillator (ICD)⁵. While these treatments options will only alleviate symptoms and are temporary solutions, there is no cure presently. The survival rate of people with HCM is 98% after 1 year, 94.3% after 3, and 82.2% after 5⁶. While HCM is not necessarily a death sentence, a person’s mortality is always looming over their shoulder. People should not have to live in fear, wondering which day will be their last. Perhaps with genome editing, they won’t have to anymore.

        In a 2017 study conducted by Ma et al, the effects of genome editing to correct germline mutations that cause HCM were explored. Here, healthy gamete donors who had homozygous and heterozygous heritable MYBPC3 mutations were used. They used CRISPR-Cas9 to specifically target the heterozygous MYBPC3 mutation in embryos prior to implantation⁸. CRISPR-Cas9 is a genome editing technology that allows for an organism’s DNA to be altered. The technology involves creation of a small piece of RNA which contains a guide sequence that attaches to a specific portion of the DNA. That RNA piece will also bind to an enzyme called Cas9. Essentially, the RNA recognizes the portion of DNA which needs to be removed from the genome and Cas9 will cut that DNA at the specific location. After the DNA is cut, a customized DNA sequence will replace the sequence that was removed from the genome⁹. Therefore, this technology is especially promising for individuals with mutations that cause incurable diseases. 

        Ma et al. explains that homologous direct repair (HDR) is necessary for gene correction. They found that the double strand breaks in the human gametes and zygotes were fixed by using an internal HDR mechanism by using a wild-type allele as a template. However, in induced pluripotent stem cells, the rate of HDR was much lower indicating that DNA damage response system behaved differently in gametes and embryos. One problem, though, is that , there are still off target effects like non-homologous end joining induced indels that need to be controlled for and understood⁸. We are not close to where we need to be, but this is one step to finding the answer. Undoubtedly, there are many challenges to using gene therapy. The first of which is limited sample size and the difficulty in setting clear boundaries¹⁰. Furthermore, editing the germline can cause intended consequences to future generations. Although there is heavy criticism and controversy surrounding this study, I am hopeful for the future. Right now, CRISPR-Cas9 has only been tested on animal models and embryos, but in the future, I expect to see this technology being used in humans who discover their diseases later in life.  After more testing, the goal is to help those who are victims to genetic mutations and allow them to live disease free. If this expands to humans and is successful, individuals will no longer have to succumb to the whimsy of their genes.

By Rachel Crasta, Master of Medical Sciences Student, University of Kentucky

References:

1.      Marian, Ali J., and Eugene Braunwald. “Hypertrophic Cardiomyopathy.” Circulation Research, vol. 121, no. 7, 2017, pp. 749–770., doi:10.1161/circresaha.117.311059.

2.      “Autosomal Dominant.” Genome.gov, NIH, www.genome.gov/genetics-glossary/Autosomal-Dominant.

3.      Authors/Task Force Members, Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, Hagege AA, Lafont A, Limongelli G, Mahrholdt H, McKenna WJ, Mogensen J, Nihoyannopoulos P, Nistri S, Pieper PG, Pieske B, Rapezzi C, Rutten FH, Tillmanns C, Watkins H. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy: the task force for the diagnosis and management of hypertrophic cardiomyopathy of the european society of cardiology (ESC). Eur Heart J. 2014;35:2733–2779. doi: 10.1093/eurheartj/ehu284.

4.      “Hypertrophic Cardiomyopathy.” Www.heart.org, www.heart.org/en/health-topics/cardiomyopathy/what-is-cardiomyopathy-in-adults/hypertrophic-cardiomyopathy.

5.      Mcnamara, James W., et al. “MYBPC3 Mutations Are Associated with a Reduced Super-Relaxed State in Patients with Hypertrophic Cardiomyopathy.” Plos One, vol. 12, no. 6, 2017, doi:10.1371/journal.pone.0180064.

            6.    Liu, Qun, et al. “Survival and Prognostic Factors in Hypertrophic Cardiomyopathy: a Meta-  

                  Analysis.” Nature News, Nature Publishing Group, 20 Sept. 2017,                          

                  https://www.nature.com/articles/s41598-017-12289-4.

7.      “Hypertrophic Cardiomyopathy.” HIE Multimedia - Hypertrophic Cardiomyopathy, slu.adam.com/content.aspx?productId=117&isArticleLink=false&pid=1&gid=000192.

8.      Ma, Hong, et al. “Correction of a Pathogenic Gene Mutation in Human Embryos.” Nature, vol. 548, no. 7668, 2017, pp. 413–419.,doi:10.1038/nature23305.

9.      “What Are Genome Editing and CRISPR-Cas9? - Genetics Home Reference - NIH.” U.S. National Library of Medicine, National Institutes of Health, ghr.nlm.nih.gov/primer/genomicresearch/genomeediting.

10.  Papasavva, Panayiota, et al. “Rare Opportunities: CRISPR/Cas-Based Therapy Development for Rare Genetic Diseases.” Molecular Diagnosis & Therapy, vol. 23, no. 2, 2019, pp. 201–222., doi:10.1007/s40291-019-00392-3.