Treatment and Gene Therapy for DMD and BMD

Molecular Identification of the Dystrophin Gene:

Understanding the exact location of the genetic changes allows geneticists and genetic counselors to definitively diagnose a disorder and possibly identify the causes of symptoms and targeted treatments. As the largest human gene, DMD spans 2.4 MB and consists of 79 exons. Dystrophinopathies are caused specifically by variants located within DMD at Xp21 (13). The study of dystrophin led to the identification of a major complex of another muscular dystrophy–associated muscle membrane protein, the dystrophin-glycoprotein complex (DGC). The DGC is a multisubunit complex comprised of peripheral and integral membrane proteins forming a structural linkage between the F-actin cytoskeleton and the extracellular matrix (7). It provides mechanical support to the plasma membrane and is important for the stability and function of the muscles (7; 10). There have been new insights that indicate that if any of the three core components of the DGC are not present in the skeletal muscle, it may lead to the development of muscular dystrophy. DGC-associated variants have been found to cause forms of Limb-Girdle Muscular Dystrophy (LGMD) and Myoclonus-Dystonia Syndrome (7).

Once alterations to DMD were identified as pathogenic and widespread sequencing allowed for broad data collection, partial gene deletions were found to account for two-thirds of dystrophinopathies. Deletions commonly occur during the formation of maternal egg cells during meiosis. As in many genetic disorders, there are specific regions across DMD that have preferentially clustered areas most prone to abnormal genetic changes called “hotspots of mutation.” Two deletions hotspots exist, one involving the first 20 exons, and the other, in the center of the gene around exons 45-53 (10;11).

The reading frame is a way to describe the intended DNA sequence within a gene. It consists of a group of three nucleotide bases in a specific order, together called a codon, that encodes for one specific amino acid. Deletions that cause DMD usually disturb the translational reading frame, meaning that the group of three nucleotide bases are shifted and each codon is disrupted, causing it to either code for the wrong amino acid, or cease to function altogether. (11; 13). 60-70% of the changes in DMD and BMD patients occur due to deletions. (10). Duplications cause disease in about 5% of DMD and BMD patients. These changes vary in size but tend to cluster around duplication hotspots of mutation, which span exons 3–7 and 44–55. (12, 16). Point mutations, small deletions, and insertions account for the remaining cases, approximately 15-30% of DMD and 10-15% of BMD cases (10).

The clinical severity of the disease depends on the disruption of the gene’s reading frame. BMD is the result of in-frame mutations, meaning, the reading frame is preserved, whereas, DMD is caused due to out-frame mutations, where the reading frame is completely disrupted (6).  It is valuable to gain information on the specific genetic change that caused the presentation of each dystrophy to enable appropriate genetic testing for each family member. Outside of genetic testing, this knowledge can allow providers and researchers to establish accurate variant-specific treatments.

Treatment:

It is essential to detect cardiac conduction defects early, as cardiac muscle deterioration can be slowed if abnormalities are detected before symptoms occur (18). Treatment for cardiac symptoms may include beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARB) (5).

The chronic use of a group of medications called corticosteroids is one of the cornerstones of drug treatments found to effectively slow the progression of DMD. This treatment is most effective when children start these medications before substantial physical decline (4; 10). Prednisone and deflazacort are commonly prescribed corticosteroids for treating dystrophinopathies (15). Still, it is important to note that such treatments are associated with common side effects like weight gain, short stature, acne, behavioral changes, osteoporosis, and both long bone and vertebral compression fractures (15).

Genetic Counseling:

Individuals and families affected by DMD and BMD should be referred to genetic counseling and consider their options for testing, treatment, and support. Family members consistently receiving genetic counseling services would greatly improve the way the community understands the inheritance of the condition and determine if they would like to be screened, which can aid in the early detection of affected and unaffected carrier statuses.

Genetic Treatments and Gene Therapy:

Although there is not yet a cure for DMD or BMD, different types of genetic treatments and therapies provide the most promising approach to treating muscular dystrophies. As these techniques are dependent on gene alterations, the FDA must approve each of these therapies before use:

Exon
Skipping
Therapy

Exon skipping therapy is another genetic treatment that has the potential to treat almost 60% of DMD patients. Exon skipping restores some function to the dystrophin gene by adjusting the patient’s altered reading frame so the patient is able to produce a partially functioning dystrophin protein. These treatments are ongoing and administered via injection. Exon skipping therapies are only able to be used by patients with genetic changes in specific exons that can be improved when the person’s genes are instructed to skip the exon with the harmful alteration. This means genetic testing must be performed on a patient to confirm whether or not they are eligible for these treatments. Examples of exon skipping therapies approved by the FDA include (9): 

Casimersen (AMONDYS 45) - skips exon 45

Viltolarsen (VILTEPSO) - skips exon 53

Eteplirsen (EXONDYS 51) - skips exon 51: benefits 14% of all DMD patients and 20% of DMD patients with deletions (17).

Gene
Therapy

Gene Therapy is when genetic material is administered to the body with the intention of it permanently altering an individual’s current genetic expression. This is an irreversible process and therefore the most thoroughly reviewed by medical safety boards. Adeno-Associated Viruses (AAV) have been the principal tool involved in developing a targeted system to safely deliver genetic treatments for the majority of DMD patients, regardless of the type of genetic change that led to the dystrophy (2). This is important because many other gene therapies can only be used by patients that have the specific genetic change that the therapy was developed for, which can exclude patients of different populations who are in need of care. The pharmaceutical company, Sarepta, recently reached a roadblock in FDA approval for a first-of-its-kind gene therapy for DMD patients, SRP-9001, after the FDA reversed its decision to allow the treatment to move forward without further review from an independent panel (1). SRP-9001 utilizes an AAV vector to deliver genetic material to drive the production of dystrophin in skeletal and cardiac muscles and has demonstrated a consistent safety profile with study patients and shows promising results in current data (19, 20).

There are many free testing programs available to those with a family history or symptoms of dystrophinopathies

Clover Genetics can help you determine your risk: contact us today!

Researched by: Hiya Abrol; Rachel Baer, MSc

Co-Authored by: Rachel Baer, MSc

Edited and Reviewed for Accuracy by: Rachel Baer, MSc, Mark Schmertmann, MSW, LSW, and Andrew J. McCarty, MS, CGC

Published April 2023

Sources:

  1. Samal, A. Sarepta slides as FDA about-turn on panel clouds gene therapy approval path. (2023, March 17). Reuters. https://www.reuters.com/business/healthcare-pharmaceuticals/sarepta-slides-surprise-fda-panel-meeting-adds-uncertainty-gene-therapy-2023-03-17/ 

  2. Genethon gets the green light from the ANSM to start an innovative gene therapy trial for Duchenne muscular dystrophy. (2020, December 2). Généthon. https://www.genethon.com/genethon-gets-the-green-light-from-the-ansm-to-start-an-innovative-gene-therapy-trial-for-duchenne-muscular-dystrophy/

  3. Thada PK, Bhandari J, Umapathi KK. Becker Muscular Dystrophy. [Updated 2022 Aug 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan. https://www.ncbi.nlm.nih.gov/books/NBK556092/ 

  4. Duchenne Muscular Dystrophy (DMD) -diseases. Muscular Dystrophy Association. (2021, April 29). Retrieved from https://www.mda.org/disease/duchenne-muscular-dystrophy 

  5. Becker Muscular Dystrophy (BMD) - Diseases. Muscular Dystrophy Association. (2021, July 1). Retrieved from https://www.mda.org/disease/becker-muscular-dystrophy

  6. Juan-Mateu J, Gonzalez-Quereda L, Rodriguez MJ, Baena M, Verdura E, et al. (2015) DMD Mutations in 576 Dystrophinopathy Families: A Step Forward in Genotype-Phenotype Correlations. PLOS ONE 10(8): e0135189. https://doi.org/10.1371/journal.pone.0135189 

  7. Hakan Tarakci, Joachim Berger. The sarcoglycan complex in skeletal muscle. Front. Biosci. (Landmark Ed) 2016, 21(4), 744–756. https://doi.org/10.2741/4418 

  8. MedlinePlus. Bethesda (MD): National Library of Medicine (US); updated November 1, 2016. Duchenne and Becker Muscular Dystrophy; Accessed March 7, 2023 . Available from: https://medlineplus.gov/genetics/condition/duchenne-and-becker-muscular-dystrophy/ 

  9. Elangkovan, N., & Dickson, G. (2021). Gene Therapy for Duchenne Muscular Dystrophy. Journal of neuromuscular diseases, 8(s2), S303–S316. https://doi.org/10.3233/JND-210678

  10. Duan, D., Goemans, N., Takeda, S. et al. Duchenne muscular dystrophy. Nat Rev Dis Primers 7, 13 (2021). https://doi.org/10.1038/s41572-021-00248-3 

  11. Turnpenny, P. D., & Ellard, S. (2011). Emery’s Elements of Medical Genetics E-Book. In Google Books. Elsevier Health Sciences, 308. https://books.google.ie/books?id=K_E8DENm_GYC&lpg=PP1&pg=PP1#v=onepage&q&f=false 

  12. Nakamura, A., Fueki, N., Shiba, N. et al. Deletion of exons 3−9 encompassing a mutational hot spot in the DMD gene presents an asymptomatic phenotype, indicating a target region for multiexon skipping therapy. J Hum Genet 61, 663–667 (2016). https://doi.org/10.1038/jhg.2016.28 

  13. Bellayou, H., Hamzi, K., Rafai, M. A., Karkouri, M., Slassi, I., Azeddoug, H., & Nadifi, S. (2009). Duchenne and Becker Muscular Dystrophy: Contribution of a Molecular and Immunohistochemical Analysis in Diagnosis in Morocco. Journal of Biomedicine and Biotechnology, 2009. https://doi.org/10.1155/2009/325210

  14. Genetic Causes - Parent Project Muscular Dystrophy. (2017). Parent Project MuscularDystrophy.https://www.parentprojectmd.org/about-duchenne/what-is-duchenne/genetic-causes/

  15. Olivas, R. (2017, February 9). FDA Approves Emflaza for Treatment of Duchenne Muscular Dystrophy. Muscular Dystrophy Association. https://strongly.mda.org/fda-approves-emflaza-for-treatment-of-duchenne-muscular-dystrophy/?_gl=1 

  16. Nakamura, A., Shiba, N., Miyazaki, D. et al. Comparison of the phenotypes of patients harboring in-frame deletions starting at exon 45 in the Duchenne muscular dystrophy gene indicates potential for the development of exon skipping therapy. J Hum Genet 62, 459–463 (2017). https://doi.org/10.1038/jhg.2016.152

  17. Lim, K. R., Maruyama, R., & Yokota, T. (2017). Eteplirsen in the treatment of Duchenne muscular dystrophy. Drug Design, Development, and Therapy, Volume11, 533–545. https://doi.org/10.2147/dddt.s97635 

  18. Hermans, M. C. E. (2013). Getting a grip on myotonic dystrophy type 1. https://doi.org/10.26481/dis.20130621mh

  19. Sarepta Therapeutics, Inc. (2022). Sarepta Therapeutics Announces That U.S. FDA has Accepted the Filing and Granted Priority Review for the Biologics License Application for SRP-9001, Sarepta’s Gene Therapy for the Treatment of Ambulant Individuals with Duchenne Muscular Dystrophy.  Sarepta Therapeutics, Website. Published November 28, 2022. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-us-fda-has-accepted-filing-and#:~:text=SRP%2D9001%20is%20an%20investigational,for%20muscle%20at%20the%20membrane.

  20. Radke, J. (2023). Mechanism of Action of SRP-9001, A Gene Therapy for Duchenne Muscular Dystrophy. CheckRare. Published on web: January 5, 2023. https://checkrare.com/mechanism-of-action-of-srp-9001-a-gene-therapy-for-duchenne-muscular-dystrophy/