Introduction
Muscular dystrophy is a group of genetic disorders characterized by muscle weakness. Under normal conditions, muscle requires a precise equilibrium of strength and stability: strength for resistance to mechanical stress and internal tension caused by muscle contraction, and muscular stability for preserving shape, content, and function. Dystrophin, an intracellular protein, maintains muscle integrity. In skeletal muscle, the dystrophin-glycoprotein complex links the extracellular matrix to the cytoskeleton and coordinates the mechanical signaling necessary for muscle repair in response to injury. The most prevalent form of muscular dystrophy, Duchenne MD, and the less severe Becker MD are both primarily caused by the lack of functional dystrophin due to an internal or out-of-frame deletion within the gene. Both are associated with heart dysfunction, and sufferers are often wheelchair-bound by their early teens. The former often progress to death by respiratory or cardiac failure before their 30th birthday, while those diagnosed with Becker MD usually experience a slow progressive weakening with a variable lifespan.
Deletions in the dystrophin gene are responsible for the majority of patients. These defects may affect dystrophin mRNA processing and decrease its stability or activate nonsense-mediated decay pathways. The other less frequent mutations comprise single nucleotide changes at splice sites affecting the efficiency and creating other normal splicing patterns with the characteristics of a revertant phenotype, as well as cryptic splice sites causing out-of-frame skipping of exons and introducing a premature stop codon. Rare de novo mutations can be predicted to be less prevalent than germline mosaics, a result of double postzygotic mutations in different founder cells. The range of average percentages of de novo mutations was, for Duchenne MD, 30.7% and for Becker MD 12.1%. There are many affected multigenerational families with inherited muscular dystrophy due to residual dystrophin synthesis. De novo large rearrangements occur in 10%–15% of cases, and if duplications are only considered, they occur in one-third of all cases in the remaining cases. Deletions occur in 63.5% of cases up to 1.8 Mb in size. These findings are to some extent in both concordance and contradiction with previous data. Many parents at risk of having another affected child subsequently choose to undergo prenatal diagnostic tests that provide information about whether their child will have muscular dystrophy. A wide range of invasive diagnostic possibilities might also detect if a gestational carrier is a mosaic, and a germline mosaicism study might also be useful. There is no cure for Duchenne MD or Becker MD, but many promising lines of research are being implemented and developed, including animal models and cell transplantation. The most targeted goal of all these studies is the correction of the primary genetic defect, as dystrophin deficiency, created by mutations in the gene or by premature mRNA termination, results in muscular weakness.
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Current Treatments for Muscular Dystrophy
Since there is no cure available, the current treatment options for DMD are aimed at reducing the severity of symptoms, especially the consequences of reduced mobility. Physical therapy has been shown to provide positive benefits such as allowing mechanical recovery, promoting joint flexibility, and cardiovascular capacity. In contrast, corticosteroids have been shown to have preventive effects on the progression of the disease. In patients with heart problems, assist devices and pacemakers are also used when the heart's function decreases to under 30%, in addition to cardiac treatment. In many cases, individuals need to undergo surgery, usually to resolve orthopedic problems or to feed through a gastric tube. Unfortunately, all these therapies are only symptomatic and do not affect the disease. Only a few drugs are currently being developed that may delay the progression of DMD, such as tadalafil, a PDE5 inhibitor, or Eteplirsen and Ataluren - drugs capable of forcing the reading frame of genetic mutations. The first enzyme, tadalafil, was able to escape the consequences of the mutation on the dystrophin gene, and the second two stop codon inhibitors are currently clinically tested. For none of these drug categories, therapy based on the genetic cause of the disease, alternative treatments have been reported with prejudices. Indeed, all drugs must be classified as "orphan drugs - use allowed under strict control." Approval must be specifically requested for each individual country based on clinical evidence reported for each of these products. However, access to these therapies varies from country to country. Finally, all patients have different sensitivities and side effects induced by each drug. Therefore, research for these diseases, with the aim of finding increasingly effective therapies related to the molecular mechanisms underlying the disease, is important in countries such as Italy.
Gene Therapy Approaches Targeting Dystrophin
For muscular dystrophy, which is potentially fatal and has no cure yet, the unique underlying mutation in the dystrophin gene served as an ideal target for gene therapy. The concept of gene therapy is increasing dystrophin expression by delivering exogenous genetic material to muscle cells. The mechanisms for increasing dystrophin protein entail gene replacement, supplying artificial dystrophin genes, gene editing to restore the normal dystrophin reading frame, and exon skipping to splice out the mutated region. Gene therapy is the most promising avenue of research in the field, gaining traction due to the notable clinical benefits brought to preclinical and clinical trials. In preclinical animal models, enhanced performance, including increased muscle strength, prolonged ambulation, and decreased creatine levels in plasma and muscle, was observed when preventing myonecrosis. In clinical trials, improved muscle function was demonstrated in repeated measures, as well as improved muscle MRI and reduced myonecrosis compared with the sham arm. All four drugs are well-tolerated, with non-severe treatment-related adverse events.
One major obstacle for gene therapy is the delivery of the therapeutic gene to enough muscle fibers to create a clinical benefit. While the largely accepted approach to viral vectors has restricted ability to penetrate muscle that is fibrotic, immune-tolerant, or otherwise unhealthy, artificial vector strategies are being tested. One injection route applicable to a range of patients is a highly efficient means of transducing large amounts of muscle, which is opening gene therapy to a number of new therapeutic areas, such as diverse neuromuscular and other muscle disorders, and non-replacement therapies such as immune modulation. It is not toxic to most patients, perhaps because it is a non-nucleotide alternative, but antibodies can develop to the numerous components. After receiving the injection, the high volume of exon skipping induced results in a swift improvement in muscle strength; often this is combined with a reduction in serum creatine kinase, a common measure of myofiber damage. Because this is an artificial form of dystrophin that could lead to long-term complications, it is not yet clear how often each patient should get a booster dose or how long the benefit lasts. Nevertheless, improvement in dystrophin production and muscle strength has prevented progression to weakness, leading to ambulation and other improvements in function. Further work is being carried out to understand and refine the system so that side effects are truly minimized.
Small Molecule Therapies and Dystrophin Modulation
Small molecule therapies targeting dystrophin modulation are being developed to augment or alter the activity of specific biochemical pathways that influence dystrophin function or expression. In the dystrophin field, several pathways and proteins have been targeted with candidate therapies, including utrophin as a small but non-pathogenic scramble protein that binds the same membrane proteins as dystrophin. Most therapies in the small molecule pipeline intend to upregulate the level of this utrophin protein to act as a substitute for dystrophin. Strategies to reduce or prevent the degradation of the truncated but partially functional dystrophin epitopes are also being developed, as well as candidates that specifically restore the correct primary structure of the gene.
Damaging mutations in dystrophin typically result in the loss of protein arms in muscle fibers, leading to the subsequent breakdown and progressive weakness of the muscle. Some candidates work on specific genetic mutations and introduce a stop factor before the deletion to make an internal truncated protein. Small molecule agents can be taken for inactivation of the opposite dystrophin gene and thus provide a targeted mutation of the healthy gene dystrophin. Many further preclinical strategies for dystrophin modulation into different gene structures are being developed, as there is much excitement in the field that small molecules may provide a feasible edge and new horizon in dystrophin modulation, but no one is currently in the marketplace. In conclusion, personalized medicine may provide an approach with the most efficiency in an individual patient receiving the appropriate treatment based on genotype and dystrophin modulation molecule.
Conclusion and Future Directions
In this review, we have addressed dystrophin's normal functions, the molecular consequences of its loss, and analyzed the results of various therapeutic strategies that aim to induce the production of shorter, but functional, dystrophins, either through nonsense readthrough, exon skipping, gene editing, or therapy-induced alternative splicing. Despite the significant technological advancements of recent years, many factors conspire to prevent clear answers to the question of which strategy may be most effective and most clinically meaningful for physical health and morbidity in patients with DMD. Moreover, several issues remain unaddressed and require continuous work within the neuromuscular community.
The lack of a correlation between surrogate indicators of therapeutic efficacy in dystrophic animal models, such as increased muscle strength and reduced muscle damage, and the outcome of randomized therapeutic trials in patients should promote open and continuous discussions among clinicians, basic scientists, and patient advocacy groups. Most patient advocate parents are essentially interested in the preservation of psychomotor health in DMD boys: up-to-date multidisciplinary, integrative approaches that can deliver more efficient strategies for all patients are eagerly needed. Indeed, it is becoming increasingly clear that combining exon skipping with nonsense readthrough, gene editing, and molecular biology-based therapies in the future will ultimately prove to be the best, most comprehensive approach for the efficacy and well-being of the patients, and only highly collaborative efforts among different disciplines can yield synergy. Future directions, according to this approach, must contemplate the fast-moving fields of gene editing and molecular approaches to facilitate the approach to some of the established limitations of the available technologies; the need to test the overall multiplatform strategy in real-life Duchenne and Becker muscular dystrophy patients, likely additively or synergistically, in well-designed controlled trials; the need for a rigorous comparison between exon skipping and gene editing, in suitable animal models to strategize the regulatory path delineation; and the absolute need to follow appropriate regulatory criteria for the preclinical experiments of edited dogs in large-scale animal settings, to support the progression toward first-in-human studies, both in DMD and BMD with deletions and various deletions plus duplications, and to solidify the evidence for long-term safety and wide applicability of the mutation-independent genome-editing strategy.
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