Gene therapy against spinal cord muscular atrophy
American scientists working under the guidance of Professor Arthur Burghs from Ohio State University managed to correct motor functions with the help of gene therapy, restore the transmission of nerve impulses and increase the survival rate of mice with simulated spinal cord muscular atrophy (Werdnig-Hoffmann disease). The results of the work were published on February 28 in the preliminary on-line version of the journal Nature Biotechnology in the article "Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN".
Spinal cord muscular atrophy is a hereditary disease based on mutations of the motor neuron survival gene (SMN), which reduce the synthesis of the protein product of this gene in the motor neurons of the anterior horns of the spinal cord. In the USA, this disease occurs with a frequency of 1 case per 6000 newborns and leads to the death of children before they reach 2-4 years of age. (Exceptions occur, but very rarely.) The life expectancy of patients depends on how the specific mutation that caused the disease affects the work of the respiratory muscles. To date, there are no effective methods of treating spinal cord muscular atrophy, and physiotherapy methods are usually used to alleviate its symptoms.
In their work, the researchers used a modified adenovirus that can infect cells and penetrate the blood-brain barrier, but has lost the ability to cause disease in humans and mice.
Newborn mice (under the age of 10 days), in which the SMN gene was disrupted by genetic engineering methods, were injected intravenously with a virus whose genome contained a DNA fragment encoding the functional form of the gene. To visualize the spread of the therapeutic virus in the body of some animals, a viral vector was introduced, which also contains a gene for a green fluorescent protein.
As a result, it turned out that the effectiveness of the procedure depends very much on the time of the start of treatment. The viral vector injected into mice no older than five days over the next 10 days delivered the therapeutic gene to almost half (42%) of motor neurons. This significantly improved the transmission of electrical signals from the spinal cord to the muscles and the coordination of muscle work, as well as increased the life expectancy of mice compared to animals in the control group. The introduction of a therapeutic virus to 10-day-old animals had practically no effect on their condition.
13 days after the procedure, testing of the physical condition of the animals showed that 90% of the mice of the experimental group practically did not differ from normal animals in terms of the development of the muscular and nervous systems, whereas the mice of the control group already showed symptoms of the disease, expressed in disorders of muscle functioning. Animals of the experimental group normally gained weight and lived much longer than untreated mice. Some of them were alive 250 years after treatment – at the time of sending the article to the editor.
Gene therapy did not increase the production of SMN protein in the motor neurons of animals to normal values, however, the protein level provided by it was sufficient to effectively eliminate the symptoms of the disease, which to date has not been achieved by drug developers. Medications for the treatment of spinal cord muscular atrophy, currently under development, increase the level of SMN, however, to ensure a stable therapeutic effect, they must be taken throughout life.
It is not yet known at what age the therapy developed by the researchers will be most effective for humans. It can be either a month or a week after birth. The situation is further complicated by the fact that the symptoms of spinal cord muscular atrophy usually do not appear in newborns, and screening for the detection of this disease is not carried out due to its high cost.
The authors hope to begin clinical studies of the approach they have developed after conducting the necessary toxicological tests and obtaining official permission. To speed up the process, they conducted an experiment in which they injected a one-day-old macaque cub with a viral vector containing a green fluorescent protein gene. The results showed that the vector in this case successfully overcomes the blood-brain barrier and penetrates into motor neurons.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru Based on ScienceDaily: Gene Therapy Reverses Effects of Lethal Childhood Muscle Disorder in Mice.
15.03.2010