A Promising Future for Stem-Cell-Based Therapies in Muscular Dystrophies—In Vitro and In Vivo Treatments to Boost Cellular Engraftment

Muscular dystrophies (MD) are a group of genetic diseases that lead to skeletal muscle wasting and may affect many organs (multisystem). Unfortunately, no curative therapies are available at present for MD patients, and current treatments mainly address the symptoms. Thus, stem-cell-based therapies may present hope for improvement of life quality and expectancy. Different stem cell types lead to skeletal muscle regeneration and they have potential to be used for cellular therapies, although with several limitations. In this review, we propose a combination of genetic, biochemical, and cell culture treatments to correct pathogenic genetic alterations and to increase proliferation, dispersion, fusion, and differentiation into new or hybrid myotubes. These boosted stem cells can also be injected into pretreate recipient muscles to improve engraftment. We believe that this combination of treatments targeting the limitations of stem-cell-based therapies may result in safer and more efficient therapies for MD patients. Matricryptins have also discussed.

.Summary of muscular dystrophies, pathology and treatments.

Myotonic dystrophy protein kinase
A dominant disorder associated with clinical myotonia, progressive muscular weakness, and extra muscular manifestations such as cardiac arrhythmia and endocrine dysfunction.
No treatments are currently available that fundamentally alter the course of MMD1 or MMD2. The management of MMD patients is based on genetic counseling and the preservation of social independence and cardiopulmonary complications by providing symptomatic treatment for myotonia, hypersomnolence, and pain. Moreover, some experimental therapeutic approaches are under investigation, as antisense oligonucleotides (ASOs), gene therapy vectors, and small molecules.

Facioscapulohumeral dystrophy (FSHD)
Deletions within the D4Z4 repeat region located on chromosome 4q35 for type 1; mutations of SMCHD1 on chromosome 18p11 in association with a permission chromosome 4 allele account for the majority of type 2 disease. The epigenetic derepression of the a toxic-gain-offunction DUX4 protein' Facioscapulohumeral muscular dystrophy has a characteristic descending pattern of weakness, first affecting the face and shoulder followed by the distal lower extremity and the proximal hip girdle muscles, but many variations in the presentation can occur.
There are no registered therapies approved for FSHD. Although many drugs have been tested in clinical trials (prednisone diltiazem, albuterol, and a myostatin inhibitor), none showed a clear benefit. Stretching and range of motion exercises are also recommended (43,44,47) anormally silenced gene DUX4 (double homeobox 4).

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD)
X-linked recessive allelic disorders caused by mutations in the dystrophin gene

Dystrophin
The absence of dystrophin leads to progressive muscle necrosis, loss of independent ambulation by early adolescence, cardiomyopathy, respiratory insufficiency, and premature death in DMD individuals. BMD is caused by mutations in the same gene, leading to the production of an altered protein and the late onset of symptoms. BMD patients also have skeletal muscle weakness, but cardiac dysfunction in more pronounced So far, therapy aimed at a complete recovery has not been developed for these diseases. The most appropriate therapy would be complementation or restoration of dystrophin expression, such as gene therapy using viral vectors, read through therapy, or exon skipping therapy.

Emery-Dreifuss Muscular Dystrophy (EDMD)
Associated with mutations in the emerin gene (EMD) located in the X chromosome and other genes, such as FHL1, LMNA, SYNE1, SYNE2 cardiac deficiency, contracture prophylaxis, and surgery for scoliosis and short tendons. Other ongoing treatments in LGMD patients include a clinical trial of coenzyme Q10 and lisinopril in LGMD 2C-2F.

Oculopharyngeal muscular dystrophy (OPMD)
Repeat expansion in the PABPN1 gene that results in an N-terminal expanded polyalanine tract in polyA-binding protein nuclear 1 (PABPN1) polyadenylate binding protein (PABPN1) OPMD is mainly characterized by progressive eyelid drooping, swallowing difficulties (as the pharyngeal muscles are mostly affected) and proximal limb weakness.
No cure is currently available to arrest the disease. Surgical pharyngeal myotomy is the only treatment available to improve swallowing in these patients. Pharmacological therapies, currently under pre-clinical investigation, include antiprion drugs like 6-aminophenanthridine and guanabenz, and targeting the expPABPN1 using intracellular antibodies. However, none of these strategies directly correct the genetic defect of OPMD patients. (21-23)

Congenital muscular dystrophy (CMD)
There are more than 13 genes associated with CMD. Among them are: