Advances in Muscular Dystrophy Muscular

Advances in Muscular Dystrophy Muscular Dystrophy Muscular dystrophy (MD) is a genetic disorder that results in progressive muscular degeneration particularly those of the skeletal system (Dalkilic and Kunkel, 2003). MD impacts both skeletal and cardiac muscles which can result in progressive loss of ambulation as well as respiratory and cardiac functioning (Trollet et al., 2009). Today there are over thirty genes that are known to contribute to the various forms of musclular dystrophy which result in symptoms of varying degrees.

The most common form of MD is Duchenne MD which is caused by a mutation in the dystrophin gene and impacts 1 in 3500 males born (Trollet et al., 2009). There are also several other forms of MD including limb-girdle congenital, facioscapulohumeral, myotonic, oculopharyngeal, distal and Emery -- Dreifuss muscular dystrophy (Trollet et al., 2009). Each type of MD has been categorized by clinical presentation, method of inheritance, age of onset, and progression of illness (Lovering et al., 2005).

Research into the field of MD regularly uncovers new genes that contribute to the manifestation of this illness as well as providing insight into the complexity of this illness. In order for any treatment to impact the progression of the illness or better yet cure the disease, we must have a thorough understanding of the pathogenesis of the disorder (Mhashilkar et al., 2001).

Although the pathogenesis of MD is fairly well understood the ability to provide adequate treatment is confounded by the fact that the skeletal muscle is the largest body tissue, comprising 30% of the total body mass and is widely distributed (Clemens and Duncan, 2001). Further concern is the fact that this tissue is composed of fibers that have lost the ability to divide (Cossu and Sampaolesi, 2004). Any attempts at correcting this issue must restore the proper functioning of millions of fibers which are embedded in the basal lamina (Cossu and Sampaolesi, 2004).

While there are many treatments geared toward stalling the devastating progression of this disorder, few can specifically target the primary pathology in a manner that has been proven effective. Nevertheless, the last decade has brought about advances in the treatment of this disorder including new perspectives and approaches that did not exist years ago.

While there are no present corrective therapies for MD many of the current therapies geared at supportive and preventative care include surgery, corticosteroid administration for muscle weakness, cardiovascular medication to treat cardiomyopathy, ventilation for respiratory issues, and physiotherapy (Trollet et al., 2009). While these treatments focus on the disease progression and attempt to alleviate symptoms, they are unable to address the pathogenesis of the disease itself. However, recent advances in genetics, molecular biology and muscle physiology have resulted in new strategies to treat the disease phenotype.

The most common treatments include gene therapy, cell replacement therapy, psychopharmacological approaches, exon, as well Gene therapy has been aimed at mitigating the genetic deficiencies that have led to symptoms in patients with MD. Trollet et al. (2009) describe gene therapy as the introduction of a therapeutic nucleic acid into targeted cells in order to alter the physiology of the cells.

Gene therapies have emphasized the restoration of a functional dystrophin gene through the use of whole cells, plasmid and viral vectors, gene correction strategies, and upregulation of homologous genes (McClorey et al., 2005). One of the major challenges in the development of gene therapy for muscular dystrophy includes the need to target specific muscles for each manifestation of MD (Trollet et al., 2009). This can be challenging since muscle tissue makes up such a significant portion of total body mass.

Despite the significant potential that gene therapy has for patients with MD, it still remains in the preclinical and clinical trial stages of intervention. Still one should be cautiously optimistic about the potential of full implementation of gene therapy in MD patients while being mindful of the many hurdles that researchers face when translating successes with animals to human subjects. In order to achieve successful gene therapy to muscle will require a regional or systemic intravascular route of delivery to efficiently transducer skeletal muscle (Clemens and Duncan, 2001).

There are concerns about the manner in which the body's immune defense mechanisms will react to the gene transfer and whether or not the innate responses will lead the body to attack the transplanted cells. These concerns have only been found in high doses of virus that was administered intravascularly, however, this still deserves attention (Cossu and Sampaolesi, 2007). Another alternative strategy to gene therapy is exon skipping which differs from gene therapy in that it focuses on the gene transcript rather than the gene itself (McClorey et al., 2005).

Exon skipping prevents the transcription of the exon containing the mutation. Exon skipping is a process by which synthetic DNA molecules, antisense, are utilized to create a bridge by which the dysfunctional parts of the gene can be skipped over (Partridge, 2010). This intervention has been found to be particularly useful when treating Duchenne MD in laboratory animals and experts are hoping that this will correlate to human subjects as well. Cell therapy has also shown promise in the treatment of MD.

In this approach cells can be taken either from a donor that has healthy formations of the mutated gene or by utilizing repaired cells of the individual with MD (Cossu and Sampaolesi, 2004). The use of the individuals own genes has been made possible through the cloning process and these genes can then be introduced into the system of the MD patient. Recent studies have shown an 11% improvement in the positive muscle fibers surrounding the area of injection (Cossu and Sampaolesi, 2004).

This approach is not without its challenges as well including the availability of donor cells as well as the failure of the donor cells to disperse throughout the muscle resulting in a concentration of cells in a particular area. Attempts to overcome this barrier have utilized stem cells and cells taken from bone marrow which have been proven to have regenerating factors in skeletal muscles (Cossu and Sampaolesi, 2004).

Pharmacological interventions have also shown promise in the treatment of MD these medications have primarily been utilized to stop the progression of the dystrophic process and have taken the form of protease inhibitors, anti-inflammatory drugs, calcium blockers and drugs that impact the metabolism of proteins and lipids (Cossu and Sampaolesi, 2004). Despite ongoing research, pharmacological interventions have not proven to be particularly effective in the reduction of symptomolgy producing only modest results in clinical trials (Cossu and Sampaolesi, 2004).

However, there is data to suggest that the use of corticosteroid treatments can reduce the loss of ambulation by 2 to 4 years and will decrease the risk of the development of skeletal defects as well as slowing the onset of respiratory and cardiac issues (Cossu and Sampaolesi, 2004). Yet one must also pay attention to the potential negative side effects of these drugs and weigh this against the benefits. Over the last decade, ongoing research and.