Preface

Muscular dystrophy (MD) is an encompassing term that pertains to a cluster of hereditary neuromuscular disorders. These disorders are distinguished by the gradual deterioration of muscle strength, which arises from diverse mutations in different genes responsible for standard muscle structure and function.

Despite significant advancements in the molecular characterization and diagnosis of MD in recent years, most forms still lack effective treatment. Consequently, the management and rehabilitation of patients remains crucial in maintaining an acceptable level of functional ability. Therefore, research priorities have been and continue to be the development of various efficacious therapeutic options aimed at decelerating the progression of the disease and enhancing the quality of life and lifespan of individuals affected by it.

The present publication offers a comprehensive examination of recent progress in muscle illnesses, encompassing various topics about the genetic underpinnings of multiple forms of MD, potential therapeutic interventions, and the advantages associated with repurposing drugs for treating these conditions.

Also, this book analyzes the impact of different types of exercise training as adjunct therapies in mitigating problems, decelerating pathophysiological progression, and enhancing overall quality of life. It should be mentioned that the effects of exercise on the condition have yet to be comprehensively elucidated. However, recent studies have demonstrated that engaging in appropriate forms of physical activity can enhance the muscular strength of those with MD.

The knowledge and ideas presented within its pages will serve as a source of inspiration for both young and experienced researchers, enabling them to address the numerous inquiries that arise in the field of muscle pathology.

I want to thank all the authors who contributed to this book. I also want to thank Publishing Process Manager Ms. Kristina Kardum Cvitan at IntechOpen for her patience and valuable advice throughout the preparation of this book.

> **Gisela Gaina** Cell Biology, Neurosciences and Experimental Myology Laboratory, Victor Babes Institute of Pathology, Bucharest, Romania

**1**

**Chapter 1**

*Gisela Gaina*

**1. Introduction**

Introductory Chapter: Muscular

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.

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

**2. Potential therapeutic alternatives for muscular dystrophies**

Dystrophy and Potential

Therapeutic Alternatives

## **Chapter 1**

## Introductory Chapter: Muscular Dystrophy and Potential Therapeutic Alternatives

*Gisela Gaina*

## **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, exonskipping 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.

## **Author details**

Gisela Gaina

Cell Biology, Neurosciences and Experimental Myology Laboratory, Victor Babes Institute of Pathology, Bucharest, Romania

\*Address all correspondence to: gisela.gaina@ivb.ro

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Introductory Chapter: Muscular Dystrophy and Potential Therapeutic Alternatives DOI: http://dx.doi.org/10.5772/intechopen.111522*

## **References**

[1] Emery AE. The muscular dystrophies. Lancet. 2002;**359**(9307):687-695 [Internet] Available from: https:// linkinghub.elsevier.com/retrieve/pii/ S0140673602078157

[2] Gianola S, Castellini G, Pecoraro V, Monticone M, Banfi G, Moja L. Effect of Muscular Exercise on Patients with Muscular Dystrophy: A Systematic Review and Meta-Analysis of the Literature. Front Neurol. Nov 12 2020;**11**:958. DOI: 10.3389/ fneur.2020.00958

[3] Guiraud S, Davies KE. Pharmacological advances for treatment in Duchenne muscular dystrophy. Current Opinion in Pharmacology. 2017;**34**:36-48 [Internet] Available from: https:// linkinghub.elsevier.com/retrieve/pii/ S147148921630100X

[4] Aartsma-Rus A, Fokkema I, Verschuuren J, Ginjaar I, van Deutekom J, van Ommen G-J, et al. Theoretic applicability of antisensemediated exon skipping for Duchenne muscular dystrophy mutations. Human Mutation. 2009;**30**(3):293-299 [Internet] Available from: https://onlinelibrary. wiley.com/doi/10.1002/humu.20918

[5] Mercuri E, Bönnemann CG, Muntoni F. Muscular dystrophies. Lancet. 2019;**394**(10213):2025-2038 [Internet] Available from: https:// linkinghub.elsevier.com/retrieve/pii/ S0140673619329101

[6] Aartsma-Rus A, Singh KHK, Fokkema IFAC, Ginjaar IB, van Ommen G-J, den Dunnen JT, et al. Therapeutic exon skipping for dysferlinopathies? European Journal of Human Genetics. 2010;**18**(8):889-894 [Internet] Available from: http://www.nature.com/articles/ ejhg20104

[7] Aartsma-Rus A. Overview on AON Design. 2012. pp. 117-29. Available from: https://link.springer. com/10.1007/978-1-61779-767-5\_8

[8] Scharner J, Figeac N, Ellis JA, Zammit PS. Ameliorating pathogenesis by removing an exon containing a missense mutation: A potential exonskipping therapy for laminopathies. Gene Therapy. 2015;**22**(6):503-515 [Internet] Available from: https://www.nature.com/ articles/gt20158

[9] Luna Velez MV, da Silva P, Filho O, Verhaegh GW, Hooij O, El Boujnouni N, et al. Delivery of antisense oligonucleotides for splice-correction of androgen receptor pre-mRNA in castration-resistant prostate cancer models using cell-penetrating peptides. The Prostate. 2022;**82**(6):657-665 [Internet] Available from: https://onlinelibrary.wiley. com/doi/10.1002/pros.24309

[10] Dewaele M, Tabaglio T, Willekens K, Bezzi M, Teo SX, Low DHP, et al. Antisense oligonucleotide– mediated MDM4 exon 6 skipping impairs tumor growth. The Journal of Clinical Investigation. 2015;**126**(1):68-84 [Internet] Available from: https://www. jci.org/articles/view/82534

[11] Cole TA, Zhao H, Collier TJ, Sandoval I, Sortwell CE, Steece-Collier K, et al. α-Synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson's disease. JCI Insight. 2021 Mar 8;**6**(5):e135633. DOI: 10.1172/jci.insight.135633

[12] Yilmaz-Elis S, Aartsma-Rus A, Vroon A, van Deutekom J, de Kimpe S, tHoen PAC, et al. Antisense oligonucleotide mediated exon skipping as a potential strategy for the treatment

of a variety of inflammatory diseases such as rheumatoid arthritis. Annals of the Rheumatic Diseases. 2012;**71** (Suppl. 2):i75-i77 [Internet] Available from: https://ard.bmj.com/lookup/ doi/10.1136/annrheumdis-2011-200971

[13] Mali P, Yang L, Esvelt KM, Aach J, Guell M, DiCarlo JE, et al. RNA-guided human genome engineering via Cas9. Science (80-). 2013;**339**(6121):823-826 [Internet] Available from: https://www. sciencemag.org/lookup/doi/10.1126/ science.1232033

[14] Vitiello L, Marabita M, Sorato E, Nogara L, Forestan G, Mouly V, et al. Drug Repurposing for Duchenne Muscular Dystrophy: The Monoamine Oxidase B Inhibitor Safinamide Ameliorates the Pathological Phenotype in mdx Mice and in Myogenic Cultures from DMD Patients. Front Physiol. Aug 14 2018;**9**:1087. DOI: 10.3389/ fphys.2018.01087

## **Chapter 2**
