Friday 25 February 2011
Gene therapy holds promise for spinal muscular atrophy
US scientists have reviewed the recent developments in gene therapy as a treatment for spinal muscular atrophy. The introduction of a virus containing the SMN1 gene into mice missing this gene has proven to be very successful in the laboratory. The lessons learned from testing in mice will hopefully allow researchers to successfully test it in larger animals, paving the way for human trials.
Spinal muscular atrophy is caused by a mutation in a gene called SMN1. This gene contains instructions for a protein; "survival of motor neuron 1" (SMN) which is crucial for the survival of motor neurons - the nerves which control muscle movement. In patients with spinal muscular atrophy, the absence of a healthy SMN1 gene causes a lack of SMN protein.
Gene therapy is a promising therapeutic approach for increasing the levels of SMN protein in people with spinal muscular atrophy. With gene therapy, a working version of the SMN1 gene is introduced into cells. The hope is that the working gene will produce SMN protein, reducing the symptoms of the disease.
Contents:
What are the most promising approaches?
Scientists in Massachusetts, Drs Passini and Cheng, have reviewed the recent advances in gene therapy. Spinal muscular atrophy is an ideal candidate for gene therapy because it is caused by just one gene, SMN1. Therefore, scientists hope that inserting a working version of this gene will be able to restore muscle function. However, delivering the gene to the nerves which are relatively inaccessible is a challenge.
A common strategy of introducing the SMN1 gene into the motor neurons where it is needed is to inject a virus containing the SMN1 gene into cells. A mouse model of spinal muscular atrophy, called an "SMA mouse" is often used by researchers because it has similar symptoms to patients. Researchers have experimented with different doses of the healthy gene, different types of virus, and different places to inject, and found that they each affected how successful the treatments were.
In 2004 it was reported that two-day-old SMA mice injected with a virus containing the SMA1 gene directly into muscle, had a 20% increased survival rate. However with this approach each muscle affected by spinal muscular atrophy would probably have to be injected individually which would be impractical. Another approach is to inject the virus into the central nervous system. This approach is desirable as it requires a smaller dosage and is associated with a smaller immune reaction. The results of a study reported in 2010 showed that while the treatment was successful in improving symptoms and survival, the mice still died prematurely. This may be because the treatment was unable to reach the heart which is thought to be affected in these severely affected mice.
A third way is to introduce the virus with the healthy SMN1 gene into the bloodstream. The virus passes from the blood into the nervous system and enters motor neurons. In a study published in 2010, two-day-old SMA mice were treated, and the healthy gene was found in a large proportion of motor neurons. These mice showed vast improvement in symptoms and a near normal lifespan. However, when ten-day-old SMA mice were treated in the same way, there was no improvement in survival rates. This is because a barrier forms when mice are about a week old which stops the virus passing from the blood to the central nervous system. More studies need to be conducted to determine when this barrier is fully formed in children so we know how early the treatment would need to be. Alternatively, drugs could be used at the same time as the treatment that would decrease the barrier's resistance.
What does this mean for patients?
This review shows that gene therapy is emerging as a promising potential treatment for spinal muscular atrophy. Scientists are confident that the success of gene therapy treatment of spinal muscular atrophy in animals makes it an ideal candidate to progress to clinical trials.
Deciding which patients should be recruited to the first clinical trials is a complicated process. People who have Type 1 spinal muscular atrophy are the most severely affected, so would benefit the most from a successful trial. However, due to the rapid progression of the disease, the trials would need to be done as quickly as possible after a patient has been diagnosed to increase the likelihood of a positive result. People with Types 2 and 3 spinal muscular atrophy have milder, more slowly progressing symptoms so trials may need to be several years long in order to see any effects of the treatment. This means that separate trials would have to be designed specifically for each type of spinal muscular atrophy.
Before the therapy can be tested on humans, studies need to prove that the healthy SMN1 gene can be safely delivered to motor neurons in large animals that have a central nervous system more similar to humans. By combining the knowledge gained from trials in SMA mice, scientists are optimistic for more positive results in future research.
Further information and links
More information about spinal muscular atrophy.
More information about spinal muscular atrophy gene therapy.
Read about gene therapy in Target Research magazine.
Current clinical trials for spinal muscular atrophy.
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