Muscle Wasting: Mutations can be repaired with gene scissors
Muscle wasting can have a variety of causes. Those affected find it more difficult to perform movements smoothly – or, in the worst case, not at all. Often the disease is one muscle weakness ahead. Researchers are now reporting on a new treatment with mRNA.
Like the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) in a recent Message writes, mutations that lead to muscle atrophy can be repaired with the CRISPR/Cas9 gene scissors. A research team has now introduced the tool with mRNA into human muscle stem cells for the first time. A method was found that can be used therapeutically.
Disease can be fatal
It’s just a tiny change in the genome, but it has fatal effects: Muscular dystrophies are almost always triggered by a single faulty gene. As different as the mutations in the fifty or so known forms of these diseases are, they all ultimately lead to a very similar result.
“Due to the gene error, the structure and function of the muscles change, so that the patients suffer from progressive muscle atrophy”explains Professor Simone Coiler, head of the Myology working group at the Experimental and Clinical Research Center (ECRC), a joint facility of the MDC and the Charité – Universitätsmedizin Berlin.
If, for example, the respiratory or heart muscles are affected, the disease can be fatal.
So far not curable
Muscular dystrophies are not yet curable. That is exactly what Coiler and her team are trying to change. Her most recent publication, which was published in the journal “Molecular Therapy Nucleic Acids“ was published, clears the way for a study in which a therapy developed at the ECRC is to be tested for the first time on patients with hereditary muscle wasting.
“For years we have been pursuing the idea of taking muscle stem cells from sick people, repairing the altered genes using CRISPR/Cas9 gene scissors, and injecting the treated cells back into the muscles so that they multiply there and form new muscle tissue.”, explains Dr. Helena Escobar, postdoctoral researcher in Coiler’s group.
Some time ago, the researchers were able to show that the method works in mice suffering from muscle wasting. “So far, however, our method has had a catch”under Escobar: “We introduced the blueprint for the gene scissors into the stem cells using plasmids – circular, double-stranded DNA molecules from bacteria.”
However, plasmids could unintentionally integrate into the double-stranded genome of human cells and then lead to undesired effects that are difficult to predict. “Therefore, we could not have treated patients like this”explains Escobar.
Targeted repair of genetic defects
The team therefore went in search of a better alternative: they found it in the form of mRNA, the single-stranded genetic material molecules that have recently made a name for themselves as an essential component of two COVID-19 vaccines.
“In the vaccines, the mRNA molecules contain the genetic information for the construction of the spike protein of the virus, with which the pathogen penetrates human cells”says Christian Stadelmann, a doctoral student in Coiler’s group. “For our purposes, we use mRNA molecules that contain the instructions for building the gene scissors.”
In order to smuggle the mRNA into the stem cells, the scientists used a process called electroporation, in which the cell membranes temporarily become permeable to larger molecules.
“Using mRNA, which contained the genetic information for a green fluorescent dye, we were initially able to demonstrate that almost all stem cells absorb the mRNA molecules.”according to Stadelmann.
In a next step, the researchers used an intentionally modified molecule on the surface of human muscle stem cells to show that the method can be used to repair genetic defects in a targeted manner.
Don’t expect miracles
Finally, the research team tried out a tool similar to the CRISPR/Cas9 gene scissors, which, however, does not cut the DNA, but only changes it precisely at one point. “We can work even more finely with it. However, this tool is not suitable for every mutation that causes muscular dystrophy”explains Stadelmann.
With experiments in the Petri dish, the experts have now been able to show that the repaired muscle stem cells, like healthy cells, are able to fuse with one another and form young muscle fibers.
“We are now planning to start a first clinical study with five to seven patients suffering from muscular dystrophy towards the end of the year”, so Coiler. However, she points out that no miracles are to be expected. “Sick people who are in a wheelchair will not simply get up and start walking even after our therapy.”
But for many of those affected, it is a big step forward when a small muscle that is important for gripping or swallowing, for example, works better again. According to Coiler, the idea of also repairing larger muscles, such as those needed for standing and walking, is already in the air.
However, the molecular tools would have to become so reliable that they could be safely introduced not only into isolated muscle stem cells, but directly into the degenerated muscle. (ad)
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This text corresponds to the specifications of medical specialist literature, medical guidelines and current studies and has been checked by medical professionals.
Important NOTE:
This article contains general advice only and should not be used for self-diagnosis or treatment. He can not substitute a visit at the doctor.