Genome Editing as a Clinical Treatment for Duchenne Muscular Dystrophy

Inquiry Question:

Should funding be allocated towards further research into genome editing as a clinical treatment for Duchenne Muscular Dystrophy?

Introduction:

Duchenne Muscular Dystrophy is a form of inherited neuromuscular disease found in children, causing progressive degeneration of muscle stability. It is as a result of a mutation in the DMD gene coding for the protein called dystrophin. A mutation is defined as the change in the base sequence of an organism. This mutation is inherited as it is passed on through germline cells to then be inherited in offspring. Approximately 1 in 3500 male births worldwide are affected by this recessive trait, making it the most prominent form of childhood muscular dystrophy. The prevalence of this condition sparked research in the scientific community into a cure for those affected. With the evolution of technology, genome editing has become an innovative tool that has the potential to cure a currently permanent disease. The groundbreaking technology called Crispr was created in 2015, that allows for the deletion, insertion or modification of DNA sequences. The discovery into the capability of gene editing through Crispr to act as a potential cure for the disease led to the development of this investigation. This report will research the potential of Crispr to be used as a treatment, taking into account the benefits and risks of the technology with the aim of evaluating the inquiry of ‘Should funding be allocated towards further research into genome editing as a clinical treatment for Duchenne Muscular Dystrophy?’

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Duchenne Muscular Dystrophy:

Duchenne Muscular Dystrophy, or Pseudohypertrophic Muscular Dystrophy, is an inheritable muscular disease that begins to affect individuals from early childhood. Symptoms can appear as early as infancy, typically presenting themselves between the ages of 1 and 6. A delayed development for milestones such as sitting, standing and walking independently are all considered initial symptoms of the disease. Between the ages of 6 -11 there is a continual progressive weakness of muscles, with most affected individuals being wheelchair restricted by adolescence. The condition can result in breathing difficulty, and its presence on cardiac muscles induces Cardiomyopathy, a condition where the heart becomes enlarged, by the age of 18. In most cases, ventilators become a 24 hours necessity to ensure breathing. The disease is life-threatening and it is rare to see survival past the age of 30. Duchenne Muscular Dystrophy originated from a mutation in the DMD gene. There are multiple possible mutations of the DMD gene that can result in the disease, with the most prominent cause being a large scale deletion which removes one or more exons from the gene. This would remove numerous amino acids from the polypeptide chain drastically changing the composition, structure and function of the protein. The other notable type of mutation is a large duplication which produces extra copies of the nucleotide sequence in the gene that distorts the resulting protein by interfering with the correct and ordered sequence of amino acids that should in the polypeptide chain. The other possible types of mutations occur less frequently but include deletions or substitutions to bases that then change the protein that eventuates. As a result of any of these mutations, the subsequent effect is a defective DMD gene which consequentially impairs the dystrophin protein that was originally intended. The dystrophin protein is found in skeletal and cardiac muscle and its role is to strengthen, stabilise and protect muscle fibres. A mutation in the DMD gene has severe consequences on dystrophin and hence, the muscles in the body. A dysfunctional or incompetent protein deprives muscles of required protection. when coupled with the repeated contraction and relaxation of muscles through use over time, this damages the muscle, leading to the death of these fibres. The DMD gene which codes for dystrophin is found on the X chromosome, therefore making Duchenne Muscular Dystrophy an X-linked trait. The mutated gene is also recessive with the original being dominant over it. This means that if there is one mutated gene in either paternal or maternal X chromosomes and an unmutated gene in the other, the original DMD gene will be expressed and the individual’s phenotype will show no characteristics of muscular dystrophy., they will just be a carrier. Both alleles are required to be altered in order for the disease to be expressed. This requirement for expression is true for women as they possess two X chromosomes, but as males only have one X chromosome they are at an increased risk of the disease. If a male’s mother has or is a carrier of the disease and they inherit the mutated gene, they will express phenotype of muscular dystrophy as there is no alternative allele to fall back on. As a result of this, the prevalence of Duchenne muscular Dystrophy is significantly larger in males than females. Currently, there are no approved clinical treatments for curing the disease but diagnostic testing is available. The most common method of diagnosis is a genetic test, generally performed through a blood test that is able to detect the presence and type of mutation there is in the dystrophin gene. Muscle biopsies are also conducted to examine the amount and location of dystrophin in muscle tissue. Once confirmed, assistive therapy is provided to affected individuals through medication, physiotherapy and electric muscle stimulation to prolong muscle use. [LINK]

Genome Editing:

Genome editing is an emerging, innovative and contemporary technology recently developed that is showing significant potential to cure multiple diseases, in particular, Duchenne Muscular Dystrophy. Genome editing is defined as the insertion, deletion, modification or replacement of DNA in the genome of an organism. Recent studies have utilised the relatively new biotechnology called Crispr-Cas9 which enables permanent gene therapy, otherwise known as genome editing. Crispr has been depicted as a cut and paste tool for editing the human genome that is able to identify and modify DNA through the use of proteins and RNA molecules. A recent experiment conducted by the Technical University of Munich highlighted the potential of Crispr gene scissor to act as a treatment for Duchenne Muscular Dystrophy by correcting the mutated dystrophin gene in pigs. This is the most promising experiment conducted to date as pigs are biologically similar to humans in many ways which leaves the potential for clinical trials to begin eventually to cure the disease. Researchers modified the Crispr-Cas9 gene scissors to remove the mutated section of the gene sequence creating a shorter dystrophin protein. In Figure 1, the gene therapy process is displayed on a mouse. It shows an adeno-associated virus being used to deliver the Cas9 protein that then excised exons 21 to 23 of the DMD which was the mutated section. The Cas9 protein removes the exons after being guided by a molecule known as guide RNA which can identify the DNA sequence being targeted. The result of this process is a shorter, deficient but functional dystrophin protein that can restore partial muscle function. The result of this process is the mutations that were previously missense or nonsense become viable, thus creating a partially accurate sequence that can be used in protein synthesis to create functional dystrophin that can restore limited muscle function. The original experiment highlighted that a permanent therapy for muscular dystrophy could be achieved due to the fact muscle and cardiac cell life is prolonged. According to Professor Christian Kupatt, “One half of myocardial cells remain functional from birth throughout the entire lifecycle of a human being.” Therefore, through editing the genome of cells such as myocardial cells, longer, permanent correction becomes a reality, as it was for the pig. This technology is promising for those affected with the condition as clinical trials look to be a logical step in the near future. Trials using Crispr have already commenced for cancer and cystic fibrosis patients further enforcing the exciting prospect that it could be used for muscular dystrophy to permanently treat more than 80% of Duchenne patients. As a result of Crispr-Cas9 and recent scientific studies, the introduction of genome editing into medical care as clinical treatment is a viable and tangible thought.

Evaluation:

The research and development of Crispr-Cas9 has sparked curiosity in the scientific community for its potential application towards Duchenne Muscular Dystrophy, but with every new technology there are essential questions that need to be asked to evaluate the benefits, risks and ethical implications. Genome editing has an undeniable benefit for those affected with Duchenne’s as it holds the potential to treat what was previously untreatable. Through correcting the mutated DMD gene individuals will be relieved of symptoms, possess basic muscle function and have a better quality of life that will last longer. Although this technology does have numerous benefits, it does have limitations that have been discovered during testing. Crispr-Cas9 is able to edit the genome correcting mutations but within experiments conducted for Duchenne Muscular Dystrophy, only certain sections of the gene were removed. Consequently, full muscle function would be impossible to restore with this level of current technology, which is used as a valid argument against the proposals for further funding. Taking into account the profound potential this technology possesses to save and improve lives, its value and need to be apart of clinical application is irrefutable. This statement holds especially true after considering the lack of alternative approved clinical treatments available for individuals. Currently, there is only the ability to diagnose the disease and the type of underlying mutation, with assistive therapy being the only pathway after a diagnosis has been made. Although there are studies using drugs being experimented with, this type of treatment is not permanent, potentially dangerous to the chemistry of the body and expensive to sustain the purchase of medication. Treatment using drugs is not as beneficial to patients as Crispr is, due to the fact that it doesn't personalise the treatment to each type of mutation, only catering for those with a specific mutation that the drug is applicable to. This is opposed to treatment through Crispr which takes into account each individual’s mutation by specifically coding the Guide RNA to their DNA. Despite the clinical benefits of the technology, the use of Crispr to treat disease distorts and divides society as to whether it should be done. From a legal aspect, there is contention on how laws should be formulated to determine when Crispr is deemed a valid medical response and when it becomes a way to edit the human race. Also taken into consideration is the regulation and construction of patents from corporations who may be able to control and heavily profit from development of the technology. Others completely disapprove of the use of Crispr because of possible personal or religious reasons with common arguments that humanity and the body is a product of nature and/or God, and therefore it should not be tampered with. Many are against the use of animal testing, protesting that it is unethical to make the decision and tamper with an innocent organism who is unable to express their willingness to be experimented on. As well as this, the issues of economic factors and accessibility have been called to attention with use of a new, experimental technology. Fortunately, Crispr is an accessible and cost effective treatment especially when compared to other technologies. Previously only 13% of Duchenne Muscular Dystrophy patients had access to experimental treatments due to cost. This is dramatically different with Crispr and with the ongoing development of the technology, the cost will likely decrease. Furthermore, genome editing is a permanent therapy reducing costs further by making it a single payment as opposed to alternative treatments. In an article by Stanford Medicine, it was also highlighted that there could be serious health risks associated with gene editing because the human immune system can be unpredictable in its reaction towards substances injection into the body. This is a major concern for Duchenne patients as the studied form of treatment relies on the injection of a virus into their system. Despite portraying the danger, they are aware and express that Crispr should be employed provided it is done with caution. This evaluation that Crispr has an overall benefit to society as a whole, in particular, patients with muscular dystrophy holds true regardless of the ethical and social considerations as it can have a significant positive impact on countless lives. Additionally, a study headed by the David Heart and Lung Research Institute of treatment displayed date of treatment in mice encapsulating the value and clinical utility of genome editing. As can be seen in Figure 2, four mice were treated and all four showed levels of dystrophin in their muscular cells. This is true testament to the potential of Crispr and act as effective reasoning to outweigh all social and ethical concerns.

Conclusion:

From this study, it can be clearly determined that genome editing is an innovative and powerful tool capable of making a significant difference in the lives of individuals affected by Duchenne Muscular Dystrophy. Thus, funding should be allocated towards further research into genome editing as a clinical treatment for Duchenne Muscular Dystrophy. As detailed, its impact on patients far outweighs the social and ethical implications with those concerns a cause for further funding. The funds would allow for the technology to be developed in a level of detail and caution that increases benefit through eliminating many of the physical concerns. The future of gene therapy through Crispr is unpredictable with the only guarantee being that it will become a successful technology capable of being an influential factor in modern medicine. In regards, to Duchenne Muscular Dystrophy, animal testing has yielded positive results and the next step looks to be human clinical trials where the effectiveness of the technology will be tested as a treatment. There is a genuine possibility that with further funding and research, Duchenne Muscular Dystrophy will be cured, becoming a treatable disease.

Figure 2 (https://www.sciencedirect.com/science/article/pii/S1525001616309741)

Reference:

1. https://www.technologynetworks.com/biopharma/news/gene-therapy-for-duchenne-muscular-dystrophy-successful-in-pigs-329888
2. https://newatlas.com/medical/crispr-gene-editing-muscular-dystrophy-pigs/
3. https://www.biospace.com/article/experimental-gene-therapy-for-duchenne-muscular-dystrophy-shows-promise/
4. https://www.tum.de/nc/en/about-tum/news/press-releases/details/35877/
5. https://stanmed.stanford.edu/2018winter/CRISPR-for-gene-editing-is-revolutionary-but-it-comes-with-risks.html
6. https://www.youtube.com/watch?v=8xNh1qr43oo
7. https://www.youtube.com/watch?v=UKbrwPL3wXE
8. https://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy#genes
9. https://www.genome.gov/
10. https://www.sciencedirect.com/science/article/pii/S1525001616309741
11. Eldra Pearl Solomon. P.William Davis - Human Anatomy and Physiology (Holt-Saunders International Editions)