Microdystrophin: An Advent in Muscular Dystrophy Therapy
Muscular dystrophy is a term used to describe a group of hereditary illnesses that affect normal muscle formation in the body. It causes the muscles to gradually and progressively weaken over time. This is due to mutations in the genes that are responsible for the production of proteins needed for muscle development. As muscular dystrophy is a genetic condition, there is no cure, but there are available treatments and therapies to manage the symptoms.
There are several types of muscular dystrophy, but the most common and most severe is Duchenne muscular dystrophy (DMD). While females can be carriers of the disease, it mostly affects males early in their childhood. Men with Duchenne muscular dystrophy live up to 20 to 30 years on average. The disease has an estimated prevalence of 1 in 7,250 males according to data produced by the Centers for Disease Control and Prevention.
What Happens in the Body of a DMD patient?
Proteins are necessary for building muscles in the body. One of the most important of which is a structural protein called dystrophin, which is found mostly in skeletal and cardiac muscles and in small amounts in the brain. Dystrophin is part of a protein complex that promotes muscle strength and protection against injury.
This protein complex, also known as the dystrophin complex, anchors each muscle cell to its surrounding matrix, thus creating stability and plays a role in cell signaling by sending and receiving chemical signals produced by other surrounding proteins. The production of dystrophin is commanded by the DMD gene, the third-largest known gene in the human body.
In patients with DMD, mutations render this gene unable to give instructions for dystrophin production leading to progressive muscle weakness and atrophy and, in severe cases, dilated cardiomyopathy. Most mutations in the DMD gene that cause Duchenne muscular dystrophy are deletions while some are alterations and duplications, and the littlest mutations can lead to devastating outcomes. With the DMD gene unable to provide instructions for producing dystrophin, the skeletal and cardiac muscles waste with every movement and contraction resulting in irreversible damage.
Gene Therapy: The Only Road to a Concrete Solution
As Duchenne muscular dystrophy is a hereditary condition, the only possible way to address its underlying cause has always been gene therapy.
In gene therapy or gene transfer, genes are delivered as therapeutic agents usually through a virus. The virus then injects the genes into the body’s individual cells, allowing it to either replace, fix, or delete faulty genes and riding on the cell’s natural mitotic ability to take care of producing new cells containing the “fixed” gene.
For DMD patients, the goal is to replace the missing gene sequence deleted by the mutation. Scientists hope that this method would provide more permanent relief to DMD patients than other existing therapies but are fairly certain that it’s unlikely to halt or reverse the disease entirely.
While gene therapy proves to be promising in at least slowing down Duchenne muscular dystrophy, it is also faced with a number of challenges namely:
- The large size of the DMD gene, making it difficult to fit into the standard virus for delivery to muscle cells
- Sufficient quantity of new genes to be delivered without disrupting other tissues
- Evading unwanted immune response
As of late, a workaround for these potential problems has been created through the further study of an obscure case in the 1990s.
Microdystrophin: A Serendipitous Discovery
A case of a 61-year-old male with Duchenne muscular dystrophy had been documented in the 1990s by British muscular dystrophy researcher, Kay Davies. Given what was known about the disease during that time, the man was not supposed to be walking, let alone alive. Davies subsequently found out that the patient only had 46% of the DMD gene, opening the possibility of shortening the large gene to fit in a virus without destroying its ability to function properly. This serendipitous discovery inspired the creation of microdystrophin along with clinical efforts to provide a more enduring treatment for Duchenne muscular dystrophy.
In essence, microdystrophin is the shortened version of the original DMD gene, cut from around 14,000 letters down to 4,000. This was successfully done in 2002 by Associate Professor of Pediatrics Scott Harper at Ohio State University and scientist Jeff Chamberlain. With this successful endeavor, microdystrophin is now ready to be packaged and tested on selected Duchenne muscular dystrophy patients.
Putting Microdystrophin to the Test
Before human clinical trials can commence for any kind of promising treatment to any disease, scientists need to prove first its effectiveness on animals. In the case of Duchenne muscular dystrophy, microdystrophin should first be tested and proven effective on animals roughly the size of children. Genethon, a French gene therapy center, recently released videos of dogs that underwent the treatment and showed significant improvement by being able to jump low plastic hurdles to retrieve a toy. Dogs that did not get the treatment turned in circles and were unable to reach the toy. With this, studies aimed at young male patients with DMD started to arise.
Three research teams from the United States are reported to be ready to set the first clinical trials into motion as early as next month. One team is to begin the study at Nationwide Children’s Hospital in Columbus, Ohio with the aid of Sarepta Therapeutics and Parent Project Muscular Dystrophy. The other two teams— Solid Biosciences at Cambridge, Massachusetts, and pharmaceutical giant Pfizer— are to start towards the end of 2017 and into the first half of 2018. Pat Furlong, founding president and CEO of Parent Project Muscular Dystrophy, says her charity is prepared to supply $2.4 million to the Columbus project mainly for the production of viral particles that are grown in highly specialized clean rooms.
These upcoming studies sparked such raw hope in the parents of DMD patients that a lot of them are calling up to be put on the waitlist at Nationwide according to Furlong. The study is said to take in 12 children as subjects and to be led by Louise Rodino-Klapac, a pediatrics professor at Ohio State University, and gene therapy specialist Jerry Mendell.
CRISPR: A Better Alternative
Biotechnology companies Exonics and Editas Medicine think a gene-editing system called CRISPR is a more effective way of addressing the underlying cause of Duchenne muscular dystrophy. Eric Olson, UT Southwestern researcher and founder of Exonics, says CRISPR produced “mind-blowing” results on animals. CRISPR guides a protein called Cas9 to edit genes through an RNA guide molecule.
This RNA guide molecule is 105 letters long, 20 of which match the target faulty gene sequence. This allows Cas9 to locate the bad gene sequence and delete or alter it. Although proven to have worked successfully on mice, CRISPR is relatively new, and it would take some time before a timeline could be developed for human trials.
Genetic illnesses like Duchenne muscular dystrophy used to be a death sentence, but with recent developments in gene therapy and gene editing, there is a renewed hope for patients. Most of the upcoming treatments do not really promise a cure, but it would significantly impact the patient’s quality of living. At this juncture, microgene therapy is humanity’s best hope against muscular dystrophy.