Introductory Chapter: Muscular Dystrophy and Potential Therapeutic Alternatives

1. Introduction

Muscle disorders, known as myopathies, are rare or extremely rare diseases that may be classified into two categories: inherited and acquired. The inherited ones include illnesses caused by X-linked, autosomal-recessive, or autosomal-dominant inheritance patterns in distinct genes-encoding proteins that play critical roles in muscle form and function. Different mutations that can occur in these genes alter the function of the proteins responsible for muscle structural support and homeostasis and lead to diseases with different degrees of severity. Duchenne muscular dystrophy (DMD), with the allelic form Becker muscular dystrophy (BMD), is the most frequent and severe form of muscular dystrophy (MD) that affects children, followed by myotonic dystrophy (DM1) and facioscapulohumeral muscular dystrophy (FSHD). Despite advances in understanding MD mechanisms and the development of molecular investigative techniques, no effective treatment is currently available. Over the past two decades, research efforts have focused on characterizing disease mechanisms and developing various diagnostic tools for muscular dystrophy and inherited disorders that affect skeletal and cardiac muscle tissues and are characterized by progressive muscle weakness, wasting, and muscle degeneration. At the same time, research was also directed toward improving the quality of life and life expectancy of patients affected by these diseases by developing promising experimental strategies.

2. Potential therapeutic alternatives for muscular dystrophies

Despite differences in causation and symptoms, nearly all types of muscular dystrophy induce muscle weakness and loss, leading to limits in everyday activities and fatigue [1]. Thus, the researches were oriented to slow the progression of symptoms and ameliorate various kinds of muscular dystrophy through exercise-based therapies [2], pharmacological approaches oriented both targeting the primary defect and the downstream pathological changes [3], cell-based therapy and gene therapy treatments aimed to correct the genetic mutations. Among therapies targeting the primary genetic defect, exon-skipping is one the most promising therapeutic strategies. The most research and the most valuable results were obtained in the studies on DMD [4], the most common form of muscular dystrophy with fatal outcomes. In DMD patients, some mutations in the DMD gene change the reading frame and lead to the production of a nonfunctional protein—dystrophin. Exon skipping approaches use antisense oligonucleotides (ASOs) to alter transcript splicing to modulate protein expression. Thus, an out-of-frame mutation becomes an in-frame mutation, the reading frame is restored, and a partially functional dystrophin protein can be produced. A severe DMD phenotype is thus transformed into a milder BMD phenotype, which results in a later onset of symptoms, a slower rate of disease progression [5], and implicitly, a higher life expectancy.

With progress in ASO chemistry, reduced toxicity, and increased potency, exon-skipping approaches have also been developed for other muscular conditions such as dysferlinopathy [6], sarcoglycanopathies [7], laminopathies [8] as well as for other diseases like cancer [9, 10], Parkinson disease [11], and rheumatoid arthritis [12]. However, this approach is estimated to be costly and needs lifelong administration.

In the last period, gene editing with CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/Cas9) has rapidly become the most widely used tool for editing allowing more precise gene editing [13] and is a promising therapeutic that can permanently correct a mutation. Despite recent developments, restrictions such as delivery efficiency remain. Nevertheless, additional research is needed to ensure the CRISPR system’s safety and precision before it can be used in clinical trials.

Another interesting approach for muscular dystrophy, known as repurposing, uses existing drugs that are already approved for use and have been tested in humans for various other diseases [14]. Prior knowledge of information about their pharmacology, pharmacokinetics, and potential toxicity is particularly important for people with life-threatening illnesses, such as MDs, who cannot wait for a traditional medicine development cycle. This urgent need for new therapeutic options for these severe diseases means that drug repositioning could be a possible answer.

In conclusion, this book covers some distinctive aspects of these pathologies and potential therapies and palliative care to improve muscle function.