Duchenne Muscular Dystrophy
Steroids (corticosteroids) are the only medications approved to treat Duchenne patients regardless of mutation. They may act to slow down the progression of muscle deterioration. They are different from the anabolic steroids that are sometimes misused by athletes who want to become stronger. Recent studies confirm the benefits of starting glucocorticoids in younger children, before significant physical decline.
Taking steroids may cause many side effects. Side effects should be monitored and addressed at each visit with your neuromuscular provider. A child who is taking steroids may be more likely to get sick. Make sure your child gets a ﬂu and pneumonia shot to avoid these common illnesses.
Duchenne is a complex, multi-system disorder, caused by a mutation (or flaw), in one of the largest genes in the human body, the dystrophin gene.
Treating Duchenne will require a two-prong approach:
- Restoring or replacing dystrophin, the underlying cause of Duchenne; and
- Treating Duchenne symptoms that arise from the absence of dystrophin.
RESTORING OR REPLACING DYSTROPHIN
Dystrophin restoration or replacement aims to treat the underlying cause of the disease which is the lack of dystrophin, the protein that provides stability to the muscles. Exon skipping, nonsense mutation readthrough, and gene therapy are all ways that dystrophin restoration/replacement is being explored.
One of the most common types of mutations in the dystrophin gene occurs when a piece of the code in the middle of the gene is missing or deleted. If the edges of this deleted piece of code are neat, the muscle cell can usually stitch the genetic message back together to make a shorter, but still functional dystrophin protein. This type of tidy-edged deletion, also known as an in-frame deletion, often results in Becker muscular dystrophy. However, when the edges of the deletion are ragged, or an out-of-frame deletion, the cell can’t use the mismatched edges to make any kind of dystrophin, resulting in Duchenne.
Researchers have been able to use short pieces of stabilized DNA called antisense oligonucleotides (“AONs”) to encourage the muscle cells to trim up those untidy edges in out-of-frame deletions. By skipping additional segments of the dystrophin code called exons in the muscle cell’s working copy of the gene, the ragged edges of the deletion can be pulled back together to make a smaller, but still functional, dystrophin protein.
Deletions in different areas of the dystrophin gene will require different sets of these AONs to trim up the ragged edges. There are approved therapies for skipping exons 51, 53, and 45, with additional therapies in clinical trials. There are also ongoing studies to test second generation AONs.
Nonsense Mutation Readthrough
In Duchenne, sometimes the dystrophin gene mutation causes a premature stop in the reading of the gene. This results in no full-length functional dystrophin at all. Strategies involving small molecules that enable the production of full-length dystrophin by “reading through” or reading over this premature stop are being developed and are in clinical trials.
As of 2021, gene therapy is in clinical trials for Duchenne. Researchers are using microdystrophins housed within viral vectors for these trials and they are showing promise. Viral delivery harnesses the virus’s natural ability to deposit genetic material right to the muscle cell nucleus. The result of this viral “infection” would be the successful recoding of each muscle cell in the patient’s body.
TREATING DUCHENNE SYMPTOMS
Several other therapeutic approaches are also in clinical trials for Duchenne, including many that are not mutation-specific so they would benefit all patients regardless of their mutation.
When there is no dystrophin in the body, the muscle is damaged and the body naturally tries to repair this damage through muscle regeneration. This continual state of muscle degeneration and regeneration produces other effects such as fibrosis, inflammation, calcium imbalance, muscle wasting, cellular energy depletion, and cardiac dysfunction. These are called downstream effects because they happen due to the lack of dystrophin. There are many therapeutic strategies aimed at addressing these downstream effects.
Please visit the Parent Project Muscular Dystrophy website to learn more about the various therapeutic approaches for treating Duchenne, the robust pipeline for Duchenne and to view a comprehensive list of clinical trials.
Spinal Muscular Atrophy
Spinal muscular atrophy (SMA) is an autosomal recessive, neuromuscular disease characterized by progressive muscle weakness and atrophy. SMA is caused by a homozygous deletion of the survival motor neuron 1 (SMN1) gene, which is associated with reduction of functional SMN protein. This protein is required for the survival and function of motor neurons, which are responsible for maintaining muscle health. The survival motor neuron 2 (SMN2) gene, often termed the “back-up” gene is a paralog of SMN1, which produces insufficient amounts of the fully functional SMN protein, necessary for motor neuron survival. Variance in SMN2 copy number has been inversely correlated with disease severity, with more copies of this back-up gene associated with a milder phenotype.
SMA is the number one genetic cause of death for infants. Traditionally, it has been classified into five clinical phenotypes, (SMA type 0-4) based on severity and age of symptoms’ onset. Type I, the most severe and common form, presents early in infancy, before the age of 6 months. Despite the early onset of SMA, in SMA type I (~2.5 months) diagnostic delays are common and may put a significant financial, logistical, and emotional strain on families.[i], [ii] In infants with SMA type I, the onset of irreversible denervation occurs within the first three months with loss of 90% of motor units occurring within six months of age.[iii]
Despite persistent diagnostic delays, the data from SMA clinical trials demonstrate that early treatment dramatically increases benefit to the patient. Nusinersen (Spinraza)TM, marketed by Biogen and currently the only FDA-approved drug for all types of SMA, is an antisense oligonucleotide (ASO) designed to increase production of fully functional SMN protein in the SMN2 gene. Both clinical and preclinical studies indicate that early treatment exposure is critical to modifying the rapid and irreversible loss of motor neurons. Data from ENDEAR, a phase 3 sham-controlled trial that assessed the safety and efficacy of nusinersen in SMA type I infants with 2 copies of SMN2, showed that infants treated with nusinersen, with a disease duration of ≤12 weeks showed greater improvements in motor function and motor milestones than untreated patients (75% vs. 0%; p< 0.0001).[iv] In infants with disease duration greater than 12 weeks, the response rate still greatly favored the nusinersen treated group (32% vs. 0%; p=0.0026) but at a much lower rate.[v] Nusinersen also had an impact on survival rate, showing a treatment benefit in event-free survival (p=0.0004).iii Additionally, a few nusinersen-treated infants in the ENDEAR trial achieved milestones previously unseen in infants with SMA type I including supine to prone rolling and sitting without support.[iii]
Although all infants with SMA type I showed significant response to treatment with nusinersen, the administration of nusinersen prior to 6 weeks of age had even more substantial impact. Interim analysis of the data from the NURTURE trial, which enrolled pre-symptomatic infants (median age at first dose was 19 days), reports milestone achievements much aligned with normal development .[vi]
All infants in the NURTURE trial have thus far achieved the motor milestone of independent sitting and none have required permanent ventilation. The most recent interim analysis, reported in October 2018, evaluated survival and respiratory intervention rates in infants (n=25) who were genetically diagnosed with SMA and began treatment in the presymptomatic stage of the disease.[vii] As of May 2018, all patients in the study were alive and none required tracheostomy or permanent ventilation.vii Additionally, 22 of the 25 participants were able to walk either with assistance or independently according to the motor milestone standard of the World Health Organization and all 25 were able to sit without support.vii As we compare the data from the NURTURE and ENDEAR studies, it is evident that early administration of treatment vastly alters the SMA phenotype and encourages normal development.[viii]
Gene therapy, also called gene transfer, uses a vector to replace the faulty SMN1 gene at the cellular level. The vector may be delivered intravenously or potentially, intrathecally. This potential treatment modality may offer the opportunity for a single dose treatment of the disease.[ix] In a phase 1, open-label, dose escalation trial, 15 patients with SMA Type 1 were treated with a single dose of AVXS-101, an intravenous adeno-associated virus serotype 9 which carried non-replicating SMN complementary DNA that encoded SMA protein.ix The patients were enrolled into two cohorts that received different doses; cohort 1 received a low dose while cohort 2 received a high dose.ix Upon completion of the study, and two years post treatment, all 15 patients reached the age of 20 months without requiring permanent mechanical ventilation.[ix]
In December 2018, Novartis announced that the FDA accepted the Biologics License Application (BLA) for AVXS-101 or Zolgensma; a decision by regulators is expected in mid-2019.[x]
For a description of SMA therapeutic approaches on the horizon, please visit http://www.curesma.org/research/our-strategy/drug-discovery/therapeutic-approaches/#SMN1. You may also visit Cure SMA’s SMA Diagnostic Toolkit at www.SMArtMoves.CureSMA.org for additional information on the impact of early diagnosis and treatment in SMA, and to learn more about the early hallmark symptoms of SMA,. A comprehensive list of educational resources related to SMA treatment may also be accessed at Cure SMA’s For Healthcare Providers: Educational Resources page located at http://www.curesma.org/support-care/for-healthcare-providers/educational-resources/.
Additional resources can be found at ChildMuscleWeakness.org.
[i] Qian, Y., McGraw, S., Henne, J., Jarecki, J., Hobby, K., & Yeh, W.-S. (2015). Understanding the experiences and needs of individuals with Spinal Muscular Atrophy and their parents: a qualitative study. BMC Neurology (2015) 15:217, 15. doi:10.1186/s12883-015-0473-3.
[ii] Belter, L., Cook, S., Crawford, T., Jarecki, J., Jones, C., Kissel, J., . . . Hobby, K. (2018). An overview of the Cure SMA membership database: Highlights of key demographic and clinical characteristics of SMA members. Journal of Neuromuscular Diseases. Journal of Neuromuscular Diseases. doi:10.3233/JND-170292
[iii] Swoboda, K., Prior, T., Scott, C., McNaught, T., Wride, M., Reyna, S., & al., e. (2005). Natural history of denervation in SMA: Relation to age, SMN2 copy number, and function. American Neurological Association, 57(5), 704-712. doi:10.1002/ana.20473
[iv] Finkel, R., Chiriboga, C., Vajsar, J., Day, J., Montes, J., De Vivo, D., . . . Bishop, K. (2015). Treatment of infantile-onset spinal muscular atrophy with nusinersen: A phase 2, open-label, dose-escalation study. Lancet, 388, 3017-3026. doi:https://doi.org/10.1016/S0140-6736(16)31408-8
[v] Finkel, RS; Kirschner, J; Mercuri, E; De Vivo, DC; Bertini, E; Foster, R; Reyna, SP; Farwell, W. (2017, January). Primary Efficacy and Safety Results from the Phase 3 ENDEAR Study of Nusinersen in Infants Diagnosed with Spinal Muscular Atrophy (SMA). Poster session presented at the 43rd Annual Congress of the British Paediatric Neurology Association 11-13, Cambridge, UK.
[vi] De Vivo, DC; Bertini, E; Hwu, W-L; Foster, R; Bhan, I; Gheuens, S; Farwell, W; Reyna, SP. (2018, March). Nusinersen in Infants Who Initiate Treatment in a Presymptomatic Stage of Spinal Muscular Atrophy (SMA): Interim Efficacy and Safety Results from the Phase 2 NURTURE Study. Poster session presented at the Muscular Dystrophy Association Clinical Conference, Arlington, VA.
[vii] Biogen. (2018, October 6). New Spinraza (Nusinersen) Data Presented at Annual Congress of the World Muscle Society Demonstrate Benefits in Treating Presymptomatic Infants with Spinal Muscular Atrophy [Press Release]. Retrieved from http://investors.biogen.com/news-releases/news-release-details/new-spinrazar-nusinersen-data-presented-annual-congress-world
[viii] Finkel, RS; Kirschner, J; Mercuri, E; De Vivo, DC; Bertini, E; Foster, R; Reyna, SP; Farwell, W. (2018, March). Benefits of Earlier Treatment with Nusinersen in Infants and Children with Spinal Muscular Atrophy (SMA). Poster session presented at the Muscular Dystrophy Association Clinical Conference, Arlington, VA. Chia-Wei Lin MS, Stephanie J. Kalb PhD, Wei-Shi Yeh PhD. for Delay in Diagnosis of Spinal Muscular Atrophy: A Systematic Literature Review, Pediatric Neurology, Volume 53, Issue 4, October 2015, Pages 293-300.
[ix] Mendell, J., Al Zaidy, S., Shell, R., Arnold, W., Rodino Klapac, L., Prior, T., . . . Braun. (2017). Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. New England Journal of Medicine, 377(18), 1713-1722. doi:10.1056/NEJMoa1706198.
[x] Novartis. (2018, December 3). Novartis announces FDA filing acceptance and Priority Review of AVXS-101, a one-time treatment designed to address the genetic root cause of SMA Type 1 [Press Release]. Retrieved from http://investors.avexis.com/phoenix.zhtml?c=254285&p=irol-newsArticle&ID=2378942.