07 March 2013

Treatment of Duchenne myodystrophy: the next stage

Duchenne myodystrophy is one of the most common hereditary diseases, manifested by progressive degeneration of muscles and leading to the death of patients aged 20-40 years. The cause of the development of this disease is a mutation in the gene located on the female sex X chromosome encoding the protein dystrophin, necessary for the normal functioning of muscle fibers.

As an experimental model, scientists working under the guidance of Dr. Rita C. R. Perlingeiro used mice with mutations in the genes encoding dystrophin and utropin (a protein similar to dystrophin and expressed mainly by vascular muscle cells). The utropin gene is localized on the 6th chromosome. Such animals develop a severe form of muscular dystrophy, the symptoms of which are comparable to the symptoms of Duchenne myodystrophy. (For the results of the previous experiment of the Perlingeiro group, see the article "Muscular dystrophy in mice was cured with the help of human stem cells.")

This time, at the first stage of the study, the authors isolated fibroblasts of the skin of such animals and reprogrammed them into induced pluripotent stem cells (iPSCs) capable of differentiating into various types of cells in the body.

The second technology involved was a tool for genetic correction developed by specialists of the University of Minnesota – the so–called "Sleeping Beauty Transposon" (Sleeping Beauty Transposon) - a fragment of DNA that can be embedded in the human genome and used as a carrier of therapeutic genes. The researchers used it to embed a gene encoding the protein microutropin into the genome of differentiating iPSCs.

Being a derivative of utrophin, microutropin is able to maintain the viability of muscle fibers devoid of dystrophin. The main difference between microutropin and dystrophin is the immune system's response to these proteins. There is no dystrophin in the body of patients with Duchenne myodystrophy, so its appearance can cause the development of serious immune reactions. At the same time, they have a fully functioning uropin, which makes microutropin "invisible" to the immune system.

The last of the revolutionary technologies used by the authors was the method of obtaining muscle stem cells from induced pluripotent stem cells, also developed by specialists from the University of Minnesota.

This technology consists in a single pulse action on pluripotent cells by the Pax3 protein, which triggers their differentiation into muscle stem cells.

The resulting cells were transplanted into the muscle tissue of animals of the same line that was used to isolate skin cells at the first stage of the work. After transplantation, many muscle fibers expressing microutropin appeared in the muscles of animals. These fibers not only demonstrated good contractility, but also recovered after intentional damage.

The achieved results demonstrate the feasibility of using a combined technology implying the production of induced pluripotent stem cells and their genetic correction for the treatment of hereditary myodystrophy.

According to Dr. Perlingeiro, testing experimental treatments on animal models is a mandatory stage in the development of effective therapeutic approaches. However, she and the researchers working under her leadership are focused on transferring their proposed technology to human cells and preparing the ground for clinical trials.

Article by Antonio Filareto et al. An ex vivo gene therapy approach to treat muscular dystrophy using inducible pluripotent stem cells is published in the journal Nature Communications.

Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of the University of Minnesota:
U of M researchers utilize genetically corrected stem cells to spark muscle regeneration.

07.03.2013

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