Chronic Inflammation May Enhance Sustained Delivery of New Muscular Dystrophy Therapy

The Duchenne Muscular Dystrophy is a genetic disorder that is accompanied by symptoms of progressive muscle weakness and degeneration. Duchenne muscular dystrophy is caused by the absence of dystrophin, a protein that is responsible for keeping muscles cells intact, and accounts for one of the nine types of muscular dystrophy conditions.

Duchenne muscular dystrophy is usually severe and manifests at very early stages with its symptoms becoming visible in boys as early as the ages of 4 years old and follows a rapid succession of changes that causes the conditions to worsen. DMD primarily affects boys but can be seen in female counterparts in rare cases and will typically manifest with loss of muscles first in the hips, upper leg region and pelvis, before spreading to the thighs and shoulders then the skeletal muscles of the upper arms, the trunk and the legs.

Children challenged with DMD usually have significant challenges in movement including troubles standing up, moving and walking. Characteristically, the progression of DMD means that kids with the condition are mostly unable to walk by the time they clock the ages of 12. For children with DMD, the physical symptoms are manifest in a number of ways but will primarily take form in the affected muscles looking larger than other unaffected parts due to the presence of higher fat content.

Scoliosis, a sideways curvature of the spinal cord, may be common in cases of DMD while other children may show some type of intellectual disability and cognitive impairment. For children in early teens, the symptoms of DMD may manifest in the cardiovascular and respiratory systems, leaving the muscles therein affected. There may be a case of Becker muscular dystrophy (BMD), which has been found to be a milder type of DMD and will begin to appear in the teen years or early years of adulthood. The course of the BMD is however slower and less predictable than the course of the DMD.

The Duchenne muscular dystrophy disorder is X-linked recessive. This mode of inheritance is such that the mutation in a gene lying on the X chromosome causes the phenotype (for physical characteristic) to be expressed in males. The disease is believed to be most dominant in male due to their necessary hemizygous state for the gene mutation as they have one Y and one X chromosome, unlike the case with females who are homozygous for gene mutation, carrying the XX chromosomes.

DMD is strongly hereditary and genetic-related as research has shown that over 67 percent of the cases of DMD in children occur as a result of inheritance from the parents. The other one third (33 percent) of the cases is linked to new mutation in the gene that is responsible for the dystrophin protein.

Dystrophin remains highly important in the body for maintaining the cell membranes of the muscle fibers and the lack of the protein in the muscle cells lead to fragility in the cells and leaves cells prone to easy damages. Genetic testing has been used to make the diagnosis in children at birth, and children with the condition have been shown to have high levels of creatine kinase in their blood content. Statistics have revealed that the DMD affects around 5,000 male children at birth with the average life expectancy slated for 26 years. The age may however be extended to 30 or 40 with excellent health care for patients. 

As of now, there is no cure Duchenne muscular dystrophy, but physical therapy, corrective surgeries and braces may be highly beneficial to managing the symptoms. A recent research has also revealed that macrophages may enhance the treatment of Duchenne muscular dystrophy.

The recent study involving macrophages

Macrophages are important cells of the immune system that are developed as a response agent to battle infections or accumulating dead or damaged cells. They are large, specialized cells of the immune system that serve the primary function of identifying, engulfing and destroying target cells. Macrophages, are involved in inflammations and have been shown to actively uptake a newly approved medication for the Duchenne muscular dystrophy, promoting the sustained delivery of the medication to the regenerating muscle fibers even long after the medication itself has left the blood stream and circulation.

The experimental study led by the Children’s national health system researchers was published on the October 16th, 2017, and it shares vivid details on the cellular mechanisms of the morpholino antisense drug delivery to muscles. The study also enhances the understanding of how these drugs target the affected muscle tissues while suggesting an avenue to improve the treatment procedures for Duchenne muscular dystrophy. 

Not until recently, arguably all the pharmaceutical therapies existing for the treatment of the DMD disease focused and lay emphasis on targeting the symptoms of the devastating condition rather than tending to its root and genetic causes. The FDA, in September 2016, however approved the first exon-skipping treatment for the Duchenne muscular dystrophy, which seeks to restore the dystrophin protein expression in affected muscles. Some promise has also been shown in preclinic studies with the application of Eteplirsen, antisense phosphonodiamidite morpholino oligomer.

The clinical results have shown sporadic and variable dystrophin production in the muscles of people who were administered the treatment. The medication has been shown to vanish from the blood circulation in a matter of hours after administration and research efforts are emphasizing on the mechanism of delivery of the medication to the muscle in order to disocover new ways to increase cellular uptake and effectiveness.

The current challenge lies in the little understanding available as to how the medication is delivered to the muscle fibers and how the pathology of the disease impacts the process. The knowledge in this regard is believed to offer new ways of boosting both delivery and effectiveness according to Dr. Terrence Partridge, a study co-leader and principal investigator in the Children’s center for Genetic medicine research.

In a bid to resolve the challenges, Novak, Partridge and Colleagues have adopted an experimental model of DMD that embodies a version of the faulty Duchenne muscular dystrophy gene, which likes the original manifestation in human cells destroys the dystrophin expression in muscles. The phosphonodiamidite morpholino oligomer (PMO) was labeled with a fluorescent tag to track the route of the medicine into the muscle fibers.

The research showed that the medication entered the muscles but only localized to the patches of regenerating muscles. This is where it accumulated within the infiltrating macrophages and immune cells that are involved in part of the inflammatory responses that is encompassed with the medication, delivery and efficacy.

The PMO medication as earlier noted, remained rapidly dispersed and cleared from the blood stream, but the medication remained in the immune cells and macrophages for up to 7 days and subsequently entered the muscle stem cells, permitting direct transport into the regenerating muscle fibers.

The report also showed that the coadmistration of the PMO with a traceable DNA nucleotide analog allowed the researchers to define the stage of the regeneration process that promoted heightened uptake in the muscle stem cells and efficient expression of the dystrophin in the muscle fibers.

The macrophages were shown to extend the period of availability of the medication to the satellite cells and muscle fibers and could possibly be a panacea to improving the uptake and delivery of the medicine to the muscle. While further research will be needed, positive discoveries such as these will significantly influence the development of a feasible cure for the fatal DMD disease.