Duchenne Muscular Dystrophy (DMD), a disease that affects children now sees these children reaching and living longer into adulthood. One of the nine forms of MD, Duchenne, usually presents in early childhood between the ages of three and five, and although girls can be affected, it is more prevalent in boys. The disease affects 1 in 3,500 worldwide and most patients are in wheelchairs by the age of fifteen. Because of the way that the lack of dystrophin is believed to affect the neuron connection and message transmittal, those affected are likely to have neurological deficiencies that are wide ranging and include speech, memory, intelligence, attention, mental health and seizures.
The prognosis for children diagnosed with the disorder until recently did not extend beyond the teenage years, but recent improvements in cardiac and respiratory care have seen life expectancy extend for some patients into their thirties, with a few living well into their forties. This expanded adult population prompts the need for implementation of new care and treatment protocols as well as expansion of clinical trials.
Exon chains on the dystrophin gene in patients with DMD contain errors or mutations that manifest as large deletions in chain resulting in missing exons, duplication of the same exons in the chain or minor deletions and duplications, so the exons don’t fit together well and . Consequently it lacks the proper instructions to create the dystrophin protein that helps muscles work the way that they should. Over eighteen hundred different mutations of the exon chains have been identified but the only way of knowing which mutations affect a patient is through genetic testing, knowing the specific mutations and deletions on individual dystrophin genes helps in tailoring treatment plans and makes managing care easier.
Approximately two thirds of people that are affected by DMD have deletions and duplications of the exons on the dystrophin gene, the rest of the population are likely the result of not easily identifiable point mutations.
Current Treatment and Clinical Trials
Currently the best therapies for DMD involves exon skipping. In this therapy where section of exons are skipped to allow the creation of dystrophin that is at least partially functioning. Unlike other forms of muscular dystrophy where deletions of the exon chains are in frame deletions that still allow for a partially functioning dystrophin protein to be created, DMD’s out of frame deletions that disturbs the cells ability to read instructions and thus do not allow for this. Researchers by studying Beckers, a phenotypically similar yet milder form that manifests later and has a slower rate of declination, realized that if they applied the process that happens in Beckers organically to DMD, they may be able to create a partially functioning protein.
Two experimental drugs, eteplirsen which specifically targets exon 51, and drisapersen known as molecular patches are used in exon skipping by employing a molecule called antisense oligonucleotide. As this suggests this molecule is specifically created to ignore certain exons by “masking” them. In this case let’s say you have an exon chain 50 to 57, on that chain 52 has deletions or mutations so 51 can’t connect to 52, and 52 can’t connect to 53. Skipping exon 52 and 53 would restore some functionality to the chain because it would allow 51 and 54 to connect directly and would no longer be an out of frame chain. You would also need to skip 53 because it wouldn’t able to connect with 51 because the connector sites wouldn’t be able to communicate. The drug would allow the body to skip reading exons 52 and 53 as part of the chain, resulting in a shorter but readable in frame exon chain capable of producing a partial protein.
This methodology doesn’t work for all patients as the mutations and deletions are specific to each individual, but an estimated thirteen percent of boys can be benefited from skipping of exon 51. It’s estimated to work on about eighty-three percent of people and must be tailored for specificity. Injecting a molecular patch into the bloodstream or under the skin has been shown to start the creation of dystrophin, and although reasonably well tolerated kidney and skin related side effects are indicated and for it to be effective, treatment needs to be repeated often. Other drugs are currently being developed that targets other exons on the chain.
Stop Codon Readthrough
Around seven percent of DMD cases are caused by premature stop codons. When a ribosome reaches one of the three stop codons UAG, UAA and UGA on an mRNA strand it’s a signal that protein synthesis has been completed. In the seven percent of DMD patients affected this completion is signaled prematurely because of mutations of the stop codons, resulting in dystrophin not being synthesized or fully synthesized. What stop codon readthrough does is allows synthesis to happen even in the presence of codon mutations with the aid of the antibiotic Gentamicin suppressing the stop codon.
The treatment result in some DMD mice allowed for a dystrophin expression of about twenty percent of normal levels. In human trials employing two six day courses separated by seven weeks, three out of four trial subjects expressed an increase in dystrophin production with no displayed toxicity. Despite the success of this particular trial, the results when using Gentamicin have been spotty at best, currently new forms of small molecules that mimic the read through ability of Gentamicin but at lower concentrations such as PTC124 are in trial.
New Clinical Trials
Because of the newly expanded adult population with DMD, new trials with expanded objectives and standardized outcome measures will need to be put in place. One such trial, the North Star Network is currently be set up in the UK under the guidance of Dr. Ros Quinlivan of University College London. The aim of the program is start with studying the progression and treatment of DMD in children, collecting data on the most and using the data to provide outcome measures by which to structure adult treatment protocols. The network aims to set up treatment and training clinics and workshops across the UK where practitioners can not only be trained in treatment protocols, but trained to also collect the data and upload it to an electronic database where it can be accessed.
Gene Replacement Therapy
Another treatment in development at the moment is gene replacement therapy. Using viruses as a vector to deliver replacement copies of functional dystrophin genes. The issue with that is viruses will often trigger an immune response that will make the recipient sick. What researchers propose is to remove the genetic material of non immune system triggering viruses, and replacing them with the dystrophin gene, then inserting it into DMD patients with the aim of tricking the body into accepting the replacement so that it produces the dystrophin protein. The science behind this is not new, but clinical trials are scarce and there isn’t enough data to yet gauge the success of gene replacement therapies on DMD.
Moving Into the Future
Recent successes in identifying the specific genes that cause DMD in patients have allowed for clinical care to be more specific and individualized, because of these advances DMD patients are now living longer more fulfilling lives going on to university, getting married and starting families. However their access to information pertaining to how to continue to treat the disease well into adulthood is limited due to that population being relatively new. Treatments that work for still growing bodies may not work quite as well for adults and so it’s become necessary to find new, standardized yet effective therapies so that individuals with DMD continue to live well into old age while still leaving room for further improvement through additional trials.