Improved Gene Editing Tools Provide Hope for Duchenne Muscular Dystrophy Patients

The year 2017 has witnessed researchers making great strides in the direction of finding better methods that can lead to the cure of various muscular dystrophies, particularly for Duchenne muscular dystrophy. Scientists at UT Southwestern Medical Center reported in Science Translational Medicine that they had developed a much better gene editing technique using CRISPR-Cas9, raising hopes and bringing the medical world closer to the liquidation of these debilitating morbidities of young children.

To understand these innovations, we need to first understand some basics about DMD, and the way that new genetic research/genetic repair is carried out.

Duchenne Muscular Dystrophy (DMD) is one of the most common forms of muscular dystrophy. It is mostly inherited, though it could also be due to a mutation during the time of contraception (which is also rare). DMD is also more common and severe in males, as compared to females. It can also show its first signs before boys turn 5 years old, and the majority of patients become wheelchair ridden before their 12^th birthday. Extreme muscular weakness leads not only to physical disability, but to a decreased lifespan, which is often the result of respiratory and cardiac failure.

In DMD, muscles are not able to produce a protein called dystrophin, which is essential for maintaining healthy muscular cells in the body. Thus, these muscular cells in a patient continue to die off, causing to be progressively weak over time. The body is not able to produce dystrophin due to a faulty gene. As most already know, genes provide the information necessary for the production of various proteins. Thus, one of the critical approaches being developed by researchers is finding a way to edit and correct the faulty code in the gene so that these patients could eventually regain the strength that they need within their muscles.

However, researchers cannot carry out these gene editing experiments in humans due to ethical issues. Moreover, these experiments were just not imaginable a couple of decades ago, due to the lack of any such technology. But, everything changed with the advent of a new and useful gene editing tool called CRISPR-Cas9.

How CRISPR changes the game with Duchenne muscular dystrophy

Central to all the modern gene editing experiments and studies is the tool set called CRISPR-Cas9, which is a set of proteins accidentally discovered in the mid-1980s. These sets of proteins are thought to be part of the immune system of early, primitive, singular cell organisms. When viruses attack these single-cell organisms, CRISPR-Cas9 helps to find out the alien gene code and delete it from the genome. With time, researchers learned how to use CRISPR-Cas9 to edit genes in a way they wanted. CRISPR is like a scissor that can unwind a DNA strand and cut and repair the part, but only the part directed by Cas9 protein.

We can actually call CRISPR-Cas9 a scissor that can cut and repair the defective genes in a way we like.

However, having such a versatile genetic repair tool is not enough. After all, we cannot start using it directly on humans, as we are still not sure about its accuracy, or unseen effects that such editing can cause. Hence, it is logical to carry out these experiments on animals. For this purpose, we need animals, that are closely related to a human's anatomy and that are quick and cheap to breed, which is where a lab mouse would typically come into the picture.

These lab mice are no ordinary mice. Modern labs use an unique mouse called a transgenic mouse. However, the mouse is still very different from humans, as we parted from each other during evolution a long time back, So, they typically have a different metabolism, set of diseases and so on. If we test CRISPR-Cas9 or other tools on the mouse, they can provide lots of information, but not exactly the kind of information we would like. For this purpose, humans have learned to modify their genetic code, so that they behave more like the human body.

CRISPR-Cas9 and transgenic mice together make a powerful research tool, providing information and solutions that are easier to replicate in humans.

So, the researcher at the UT Southwestern Medical Center has created a new and better mouse model. They have succeeded in creating a transgenic mouse with precisely the same genetic defect found in DMD that humans have. This means that we now have much more accurate animal models to work and experiment with.

Earlier, researchers were trying to cure the muscular dystrophy in ordinary mice with the help of CRISPR-Cas9, which was entirely different from DMD. Though the success of such experiments gave us lots of information, they could not be replicated in humans, as how DMD presents itself in humans is different.

So how would this new mouse model help? This new transgenic mouse would replace the models created decades back. Because the genetic defects leading to DMD in this transgenic mouse are very similar to humans, it means that any cure that is successful in them can be easily replicated in humans, thus cutting down the transition time between the lab and real-life conditions.

In fact, this new transgenic mouse has already started to help researchers find a cure for Duchenne muscular dystrophy. In some of the early experiments, researchers were able to restore 80-90% of muscular strength in transgenic mouse suffering from DMD. 

This is a definitely a milestone in research, and we can look forward to see what other developments can come out of this during the year 2018.

References

1. Chen S, Sun H, Miao K, Deng C-X. CRISPR-Cas9: from Genome Editing to Cancer Research. Int J Biol Sci. 2016;12(12):1427-1436. doi:10.7150/ijbs.17421.
2. Perlman RL. Mouse models of human disease. Evol Med Public Health. 2016;2016(1):170-176. doi:10.1093/emph/eow014.
3. UT Southwestern Medical Center. Researchers Devise Improved Gene-Editing Process for Duchenne Muscular Dystrophy. http://www.newswise.com/articles/researchers-devise-improved-gene-editing-process-for-duchenne-muscular-dystrophy. Published November 29, 2017. Accessed December 30, 2017.
4. Kumar TR, Larson M, Wang H, McDermott J, Bronshteyn I. Transgenic Mouse Technology: Principles and Methods. Methods Mol Biol. 2009;590:335-362. doi:10.1007/978-1-60327-378-7_22.