The Tale of a Rare Genetic Disease – A Scientific Jaunt!

This essay was submitted by Shakunthala Natarajan for the 2019 Nxg Science Communicator Competition.

Prologue

Sometime ago, I went to a “science in café series” where the speaker was a molecular biologist working on finding a solution for a rare genetic disorder called, “Duchenne muscular dystrophy (DMD)”. This was my first-time hearing about it and I was shaken by how affected people live only up to their teens. Awareness about such rare diseases and research going on this front is very low among the general public. To bridge this gap, here is my narrative on this rare genetic disease.

What is DMD?

Duchenne’s muscular dystrophy is a type of severe muscular dystrophy, which affects 1 in 3500 boys. It is caused by mutation in the DMD gene, which codes for dystrophin, a protein made mainly by cardiac, skeletal muscles and also by few neurons in the brain. Dystrophin is responsible for stabilizing muscle fibres and when its functional form is not synthesized, it weakens muscle cells. This process starts from the pelvic muscles and progressively spreads, making the patient wheel-chair bound at a very early age. Most deaths occur due to damage of cardiac muscles leading to heart and respiratory complications. This is an X-linked recessive disease, usually passed on from carrier females to male progeny and rarely affects female progeny. Sometimes the disease can be caused due to de novo mutations, during germ cell formation or early embryo development. DMD can be diagnosed by molecular genetic testing and blood tests for creatine phosphokinase (enzyme present inside a healthy muscle cell) in the blood, due to leakage from damaged muscles.

Developments in DMD research

Although there is no cure for the disease, there have been some major breakthroughs. Some steroids like deflazacort, oxandrolone, which strengthen the muscle cells have shown to improve the ability of patients to walk. Next in line is a novel method called “Exon skipping”, which has been hailed as one of the most effective solutions found so far for DMD. Exons are regions of DNA, which code for proteins in the corresponding mRNA transcript. These exons are analogous to puzzle pieces. Only when all pieces of the correct shape are assembled without any loss do we get a complete picture. The same applies to the 79 exons forming the DMD gene, the largest human gene. But unfortunately in DMD, deletion of one or more exons occur. The exon puzzle is incomplete, thereby stalling genetic machinery. To skip the non-compatible exons, molecules called antisense oligonucleotides are injected and they bind to a non-compatible exon near the site of mutation, masking it from the transcription machinery. Remaining exons become compatible once again, producing a shortened but still functional dystrophin protein ameliorating the severity of the disease. This has been found to work in mouse models and several clinical trials are under process. An FDA approved injection based on Exon skipping called “Exondys 51”, which skips exon 51, has been approved for DMD caused by exon 52 deletion. The next milestone in DMD research has been the revolutionary genome editing technology,   CRISPR(Clustered regularly interspersed palindromic repeats) Cas 9 technology. Scientists have shown that, when gene editing was performed on target cells in dogs, the exon was cut near the deletion, thus stimulating DNA repair to seal the gap and produce functional dystrophin. But researchers opine that further animal studies are needed to test the safety and efficacy in humans. Novel drugs like Translarna, developed by PTC Therapeutics have been effective and have obtained conditional marketing authorization from European regulatory bodies. Premature stop codons in the exon sequences are the cause for 13% of DMD cases. Here Translarna intervenes and enables transcription to proceed through erroneous stop codons, helping produce functional dystrophin. But this exclusively works for DMD with premature stop codons.  A new approach to combat this disease has been to replace the dystrophin protein with its functional substitute utrophin protein. In line with this, clinical trials are ongoing in Oxford. Use of stem cells to replace damaged muscle cells is also being explored. To propel research in DMD, organizations around the world have established biobanks for DMD.

Towards the future

The march towards a cure is fraught not only with uncertainties, but also hope and effort. Moving forward I envision the progress of research in DMD in the following ways- The main reason for Duchenne’s muscular dystrophy being feared as fatal is due to permanent muscle damage affecting cardiac and lung functions. Finding biological shields to protect the cardiac and muscle cells can offer a way out.  Strengthening the muscle cells by increasing the blood flow to them and preventing replacement of damaged muscles with fat and connective tissues can help in efficient repair and delay disease progression. Late diagnosis of this condition in affected boys is another major road block. Early diagnosis of Duchenne’s can help a lot through molecular genetic testing for newborns, especially preterm babies. Currently no country has made such genetic tests mandatory. So, policy changes must be enforced to implement these tests at the neonatal stage. Monetary aspects are also major impediments in DMD research. This is mainly true in case of developing countries, where there is lack of awareness and dearth of funds for medical research. This can be changed through Government support and increase in awareness. Family members of DMD affected children play a central role in this battle, and this has been true in the case of Dystrophy Annihilation Research Trust (DART), Bangalore, India, which is a private research organization started by the parents of a kid affected by Duchenne’s in India. These efforts must be lauded and supported financially.

Epilogue

From the aforementioned developments and instances one can realize that the battle for tackling this fatal disease has gained momentum. The day where the sun will rise in a dystrophy-free world is not far off…

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References:

  1. Henderson.W, 2019 , “9 Areas of Research for Duchenne Muscular Dystrophy”, musculardystrophynews.com, , accessed on January 24, 2020.
  2. Luxner.L, 2019, “CureDuchenne Develops Biobank to Aid Duchenne Lab Research”,musculardystrophynews.com, accessed on January 27, 2020.
  3. Sample.I, 2018, “Doctors hail breakthrough in muscular dystrophy treatment”, The Guardian, accessed on January 27, 2020.
  4. Genetic and rare diseases information centre, <www.rarediseases.info.nih.gov > , accessed on January 28, 2020
  5. Wikipedia,“Duchenne muscular dystrophy”, <www.wikipedia.org >, accessed on January 23, 2020.
  6. Muscular Dystrophy UK, “Research progress in Duchenne muscular dystrophy” <www.musculardystrophyuk.org >, accessed on January 28, 2020.
  7. Dystrophy annihilation research trust, <www.dartindia.in> , accessed on January 23, 2020.
  8. Sugita.H et.al., 2010, “Progress in muscular dystrophy research with special emphasis on gene therapy”, Proc. Jpn. Acad., Ser; Vol 86, p:748-756

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