Mesenchymal Stem Cells for Regenerative Medicine for Duchenne Muscular Dystrophy

Mesenchymal stem cells (MSCs) are multipotent stem cells that can be isolated from both foetal and adult tissues. Several groups demonstrated that transplantation of MSCs promoted the regeneration of skeletal muscle and ameliorated muscular dystrophy in animal models. Mesenchymal stem cells in skeletal muscle, also known as fibro-adipogenic progenitors (FAPs), are essential for the maintenance of skeletal muscle. Importantly, they contribute to fibrosis and fat accumulation in dystrophic muscle. Therefore, MSCs in muscle are a pharmacological target for the treatment of muscular dystrophies. In this chapter, we briefly update the knowledge on mesenchymal stem/progenitor cells and discuss their therapeutic potential as a regenerative medicine treatment of Duchenne muscular dystrophy.

miRNAs and Muscle Stem Cells

Skeletal muscle represents between 30 and 38% of the human body mass. Both the maintenance and repair of adult muscle tissue are directed by satellite cells (SCs). SCs are located beneath the basal lamina of the skeletal muscle myofiber. They are quiescent for most of their life but, in response to physiological stimuli or muscle trauma, they activate, proliferate, and enter the myogenic program via generating myogenic progenitors (myoblasts) that fuse to existing myofibers or de novo myofibers. MicroRNAs (miRNAs or miRs) play a critical role in regulating muscle regeneration and stem cell behavior. In this chapter, we review the pivotal role in the regulation of SC quiescence, activation, and differentiation in the context of muscular dystrophies.

The Impact of Payer and Reimbursement Authorities Evidence Requirements on Healthcare Solution Design for Muscular Dystrophies

For rare diseases that start early and are slowly degenerative, despite the desire to create solutions that benefit the patient, healthcare system realities can be prohibitive to generate an affordable and effective solution. The optimal care pathway for muscular dystrophy, similar to all degenerative diseases, would be a rapid and accurate diagnosis, pathophysiological confirmation and application of therapeutics that slowly replaces damaged tissue with healthy tissue, supported by adjuvant solutions that stimulate the tissue to repair and reduce inflammation and fibrosis. This would increase the lifespan and quality of life in an affordable way. For all diseases, two key stakeholders, the paying entity and the patient, fundamentally define whether revenue can be generated. Healthcare decision-making commissioners who agree to pay for the product and patient-reported outcomes jointly inform whether the intervention increases the quality of life related to existing standards of care and, therefore, if it should be paid for. This chapter explains why this has not yet happened and efforts initiated to correct this and addresses how the components and data used in this decision-making process could be updated, adapted and integrated into every stage of the development of solutions and how organisational innovation may enable the field.

Role of Growth Factors and Apoptosis Proteins in Cognitive Disorder Development in Patients with Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease; it occurs due to a mutation in the dystrophin protein gene; as a result, the protein is not synthesized and muscle tissue dies. On the one hand, we can say that this disease has been sufficiently studied; however, it is still incurable, and there are a number of issues remaining unclear in terms of the development of progressive dementia as a symptom in 30% of patients with Duchenne muscular dystrophy. We conducted a study at the intersection of molecular genetic, neurological, and enzyme-linked immunosorbent patients’ blood tests and experiments in organotypic culture, which allowed us to determine important points in the development of cognitive disorders in patients with Duchenne muscular dystrophy and identify a significant effect of growth factor concentration in patients. The chapter will present data on neurotrophic regulation in patients with Duchenne muscular dystrophy (by the best-studied neurotrophins), demonstrate special aspects of neuron-myocyte interaction, and broaden the understanding of the role of apoptosis and synthase proteins in the development of this disease. We would like to highlight the importance of prognostic criteria for the development of cognitive impairment and possible therapeutic measures to prevent progressive dementia

Duchenne Muscular Dystrophy (DMD) Treatment: Past and Present Perspectives

Duchenne muscular dystrophy (DMD) is one of the fatal X-linked disorders that are characterized by progressive muscle weakness and occur due to mutation in the largest human gene known as the DMD gene which encodes dystrophin protein that is mandatory for keeping the muscles structurally and functionally intact. The disease always affects boys (1 from every ~5000), and in some cases the female carriers are symptomatic. The disease usually leads to impairment in cardiac and pulmonary functions leading to the death of the patients in very young ages. Understanding DMD through precise molecular diagnosis will aid in determining the suitable therapeutic approach for the cases like designing exon-skipping antisense oligonucleotides (AOs) or stem cell-based therapies in conjunction with gene editing techniques (CRISPR/Cas9). Such therapies can correct the genetic defect in the DMD gene and ameliorate the symptoms. In this chapter, we will illustrate the past and current strategies for DMD disease treatment.

Facioscapulohumeral Muscular Dystrophy: Genetics and Trials

A complex combination of molecular pathways and cell interactions causes facioscapulohumeral muscular dystrophy (FSHD). Several new therapies pose a promising solution to this disease with no cure. This chapter aims to explain the genetics of facioscapulohumeral muscular dystrophy, and review the current clinical trials for the treatment of FSHD.