Micro-dystrophin gene therapy can improve outcomes in children with Duchenne muscular dystrophy.
In this article we will explain why micro-dystrophin gene therapy can improve outcomes in children with Duchenne muscular dystrophy.
Duchenne muscular dystrophy (DM) is a progressive disease characterized by degeneration of muscle fibers and other tissues throughout the body. The disease is caused by a mutation in the dystrophin gene.
The dystrophin gene provides the instructions for making a protein called dystrophin, which is found in all muscle fibers. Deletion or disruption of the dystrophin gene results in the non-production or absence of dystrophin protein. The muscles of people with dystrophin mutations are prone to progressive damage and eventual failure.
It has been known for some time that dystrophin is vital for the normal function of muscle cells. Lack of dystrophin leads to muscle breakdown, severe muscle weakness and contractures, and cardiomyopathy (weakening of the heart). People with this condition rarely live beyond their teens.
In the experiments described in this article, genetically modified viruses were used to deliver a normal copy of the dystrophin gene to isolated muscle cells. This technique is known as gene therapy. The muscle cells were obtained from patients with an X-chromosome related form of the disease.
The viruses were modified on their surface to include a normal dystrophin gene. Muscle cells were grown from a small biopsy, and infected with the viruses. The viruses became incorporated into the muscle cell’s genome and expressed the normal dystrophin gene. The new dystrophin protein was produced and restored function to the muscle cell.
The experiments described here show that dystrophin can be restored in a large proportion of muscle cells. All of the treated muscle fibers were observed to be healthy and stable, with normal structure and normal contraction. Furthermore, this technique can be used for the long-term expression of a new dystrophin gene.
These findings show that gene therapy can be used to treat people suffering from a wide range of genetic disorders.
Below you can see a video of a patient with Duchenne muscular dystrophy who has been treated using the described methods. The video was taken one year after his single treatment. The remarkable thing about this patient is that he has a more severe form of the condition than the other patients who were treated.
Preliminary results in three patients with an X-linked form of muscular dystrophy show that injecting muscle cells with a normal copy of the gene for dystrophin, the protein lacking in patients with this condition, can restore their ability to walk.
The patients are the first to be treated with a new technology for delivering genetic material into muscle cells, known as gene transfer. The treatment relies on a harmless virus, similar to those that cause the common cold but lacking the ability to reproduce, which has had its genes removed and replaced with a normal dystrophin gene.
The muscle is then ‘infected’ with the virus, which integrates the new dystrophin gene into its chromosomes. Muscle cells, known as muscle fibers, then start producing dystrophin. The beneficial effects of the treatment appeared within days, and the treated muscles were found to be stable up to 1 year after the treatment.
The treated muscles still show some weaknesses, but the patients are able to walk and have an improved quality of life. Two of the patients were even able to play soccer with the health staff who treated them. The treatment is clearly working in these patients, but it is too soon to say whether the dystrophin produced will be sufficient to improve the strength and stamina of the muscles as much as is required.
The researchers also treated a 12 year old boy, diagnosed with Becker muscular dystrophy, a milder form of the disease, at least in its earlier stages. After treatment, he was able to ride a bicycle along a level road.
Although there is still a risk that the dystrophin produced will not be sufficient to prevent further damage to, and weakening of, the muscles, these results are certainly encouraging. In the future, the researchers hope to be able to treat all types of muscular dystrophy.
These techniques could also be used to treat other genetic diseases that are caused by a missing or dysfunctional gene product.
The viruses used in this treatment are virus vectors, which are able to integrate new genetic material into the genome of the treated cells. This is a relatively new technology, and other research groups have recently used similar techniques to cure mice of inherited diseases that affect the heart. Although these approaches are still at an early stage, they show great potential.
New treatment options for a variety of diseases caused by genetic mutations should soon become available. The treatment of genetic diseases will no longer be decided by a patient’s financial situation.
Credits: Written by Kydo and Truckle, research by many people in the field. Specically, the patients with muscular dystrophy who have contributed to this research by allowing their biopsies to be used in trials and studies.
Gene therapy is available to anyone who needs it, but it has a bad reputation after several high-profile disasters. The most notorious of these was the attempt to treat the young British Royal Family member, who had been diagnosed with congenital blindness as a child. It is probably due to this that the treatment was used on a non-consenting minor.
The viruses used in the treatment were modified so that they could still infect cells, but instead of making them produce more viruses, they only produced the gene intended to replace the faulty one. Over the course of a year, the patient was given a large number of these virus injections through an IV into his chest.
Despite the doctors’ caution, the treatment had unforeseen consequences. Within a month of the final injection, the patient started to complain of extreme pain in his eyes. Nobody could work out what was causing this problem. The patient became increasingly agitated, but he was told that it would soon be over.
A few days after the treatments stopped, the news came that the patient had gone blind. Not only that, but the injection had severely affected his nervous system. He was left unable to control any of his muscles, and would be confined to a life in a special chair. The patient’s father, a constant visitor to the hospital, was furious.
He claimed that it was medical incompetence that caused his son to be in this state, and launched a large-scale investigation into the hospital.
The hospital launched their own investigation as well. It was determined that the accident could have been caused by a rare interaction between the virus and the patient’s immune system. The hospital was lucky that other patients had not had similar reactions. However, the damage was done.
The treatment was suspended, and all research into it halted.
The patient’s condition worsened over time. A feeding tube was inserted into his stomach, and he would never walk again. He would remain confined to his bed for the rest of his life. One of the few positive effects was that he regained some limited control over his muscles with the help of a respirator.
Although he could no longer speak, it was possible to ask him questions. It was during one of these medical interviews that he out a halt to the investigation into his case. He would never say who he suspected of causing the accident, and it is unlikely that he actually knew.
The hospital was shut down and its staff fired. Research into gene therapy continued elsewhere, but without stricter safety measures it would never regain the trust of the public.
Death of a Tyrant
Twenty years after he rose to power, Arturus has become a tyrannical ruler. While he has never stopped being it, the people have finally taken a more active association with the word. Protests occur daily, and lately he’s been sending the military out to slaughter thousands at a time.
The people need a hero, and it’s up to you to be that hero.
In the middle of the night, you and several others make your way to the center of the capital city. You have a rifle, a pistol, a bag of explosives, and your wits. The buildings around you are all empty, as all sensible people have left the city center. The only people around are soldiers, and they’re thick in this part of the city.
You crouch behind a building, waiting for the rest of your team. Ten people are going, which seems like overkill to you, but Morale’s high right now. Everyone feels like we’re about to win this war.
The full team assembles, and you lead them out towards the palace. You avoid the main streets, taking a circuitous route aimed at reaching your goal. You occasionally have to hide from patrols, but for the most part the army isn’t really trying all that hard to find insurgents. They’re too over-confident to think that anyone would actually dare challenge them in the middle of the city.
The team leader grabs your arm as you’re sneaking past a barracks. He points towards the building opposite, where you see a soldier leaning out of a window. You wait for him to lean back, then quickly cross the gap.
You’re halfway across when the soldier leans back out again. This time, he has a clear view of you, and he’s armed with a machine gun.
“Drop your weapons and step away from them!” He shouts, in a heavy eastern Europan accent. You all comply, stepping back slowly. The soldier nods, then turns to shout down into the building.
“I’ve found some more! They were crossing the road!”
You’re not going to get another chance. You quickly leap at the soldier, clouting him with the butt of your rifle. He falls backwards with a shout, and you clamber inside. You hit him twice more, then the others arrive.
One, more eager than the rest, takes out a knife and stabs the soldier in the throat.
The soldier gurgles as he dies, then goes still. One of the men grabs the machine gun, and you move on.
You continue sneaking through the city, keeping an eye out for soldiers. You pass through a plaza, see several soldiers in the distance, then enter an apartment block to go around them. It’s only when you get inside that you realize your mistake.
The entry hallway of the building is covered in blood, with several bullet holes in the walls. You already know what happened, but you see a set of bloody handprints leading up the stairs all the same. There’s a creaking sound from above, and you see the old wood cracking as someone walks on it.
The team spreads out, finding cover as best you can in the small entryway. You ready your rifle, as the rest of your team does the same. “
One of them whispers. You take a deep breath, then nod. “Do it.”
He swings the door open, and you quickly step out. There’s a shout, followed by several gunshots. You leap out into the open, seeing one of your team slumped over on the floor. You target the soldiers and fire, dropping to the ground to take cover behind a broken wall.
You reload your rifle as another member of your team takes out the soldiers with a hail of bullets.
You pause, noticing that there’s another set of soldiers right behind you. You try to shout out a warning, but a burst of gunfire cuts through your brain, and you drop like a stone.
Sources & references used in this article:
- Systemic AAV micro-dystrophin gene therapy for Duchenne muscular dystrophy (D Duan – Molecular therapy, 2018 – Elsevier)
- … approach for limb vascular delivery of the micro-dystrophin gene without high volume or high pressure for treatment of Duchenne muscular dystrophy (LR Rodino-Klapac… – Journal of …, 2007 – … -medicine.biomedcentral.com)
- Micro-dystrophin gene therapy goes systemic in Duchenne muscular dystrophy patients (D Duan – Human gene therapy, 2018 – liebertpub.com)
- Assessment of systemic delivery of rAAVrh74. MHCK7. micro-dystrophin in children with Duchenne muscular dystrophy: a nonrandomized controlled trial (JR Mendell, Z Sahenk, K Lehman, C Nease… – JAMA …, 2020 – jamanetwork.com)
- Micro-dystrophin and follistatin co-delivery restores muscle function in aged DMD model (LR Rodino-Klapac, PML Janssen… – Human molecular …, 2013 – academic.oup.com)