Max Delbruck Center for Molecular Medicine Research Findings Open New Direction for Muscle Gene Therapy Targets

Dec 23, 2019 | Cell Therapy, Muscle Stem Cell, Regenerative Medicine, Stem Cell

Max Delbruck Center for Molecular Medicine Research Findings Open New Direction for Muscle Gene Therapy Targets

Researchers at Germany’s Max Delbruck Center for Molecular Medicine in the Helmholtz Association have uncovered a new subtype of muscle stem cells. The researchers report that these cells have the ability to build and regenerate new muscles, making them potential targets for the gene therapy drug development.

Muscles are Regenerative

As muscles are used for work or exercise upon strain, which involves tiny tears in the muscle fibers, the body acts regeneratively, to repair them. For example, upon muscle injury, the muscle triggers an endogenous regenerative program—a reserve supply of muscle stem cells that are called satellite cells. These cells reside around the muscle fibers and are essential in the regenerative process. Satellite cells produce new muscle fibers in the process called muscle regeneration and people maintain this ability well into old age. The German team centers on these cells as they offer potential targets for new therapeutic approaches for people with muscle diseases.

The Researchers and New Hypothesis

Professor Simone Spuler, a research group leader at the Experimental and Clinical Research Center (ECRC), a joint institution of the Max Delbruck Center for Molecular Medicine in the Helmholtz Association (MDC) and Charité—Universitätsmedizin Berlin, heads the Myology Group at the MDC. Their team have reported that what researchers previously assumed about a certain protein—the transcription factor PAX7—was incorrect. Apparently, researchers have operated under the assumption that transcription factor PAX7 is the key player in muscle regeneration. According to Professor Spuler, “Cells from which new muscles arise have enormous potential for developing gene therapies to treat muscle atrophy. And PAX7 is actually considered a characteristic property of muscle-building satellite cells.”

MDC Findings Take Research down a New Path

But according to their recent study findings, reported in the journal Nature Communications, it is possible for muscles to grow and regenerate without PAX7. According to their most recent findings, they have characterized a previously unknown subtype of satellite cells that may play an important rule in the future development of gene therapies from muscle cells.

Dr. Andreas Marg, a senior scientists in the Spuler lab and the study’s lead author, reports, “The findings will certainly surprise many researchers in the field.” He commented, “I previously focused my research on PAX7-positive cells. Our findings lead us down a new path.”

The Study Centered on a Young Girl Battling Muscular Dystrophy

The research findings were made possible to a young girl named Lavin. Suffering from a genetic form of muscular dystrophy since birth she was the protagonist for the study. With all of the muscles of a healthy person each one of her muscles is very small. The disease has particularly impacted the musculature along the spine. She also suffers breathing problems and struggles to bend forward or keep her head up. 

Lavin’s Cells Regenerate without PAX7

A gene analysis revealed that the PAX7 gene is damaged in Lavin—her cells can’t produce this protein (this was discovered by the University of Munich in 2017). However, shortly thereafter Spuler and Marg learned of this extremely rare mutation—one not described by researchers prior. The researchers took samples of Lavin’s muscle tissue and used a novel procedure to filter out her satellite cells. They then implanted them in mice. The MDC researchers observed that new muscles grew in the mice from Lavin’s cells—despite the absence of PAX7.

How to Repair Defective Genes in Muscle Cells

Lavin can walk and climb relatively well but barely has strength in her diaphragm—leading to breathing problems. What if the researchers could develop a gene therapy for Lavin using the CRISPR/Cas9 gene-editing tool? This could be possible but, as Spuler notes, to accomplish this, “CRISPRR/Cas9 would have to specifically target the cells of the axial musculature, and that is not yet possible.” This mission drives the Spuler unit within MDC. And for Lavin and her family, although a tough existence, have a small glimmer of hope that a tailored therapy could be found.

The Study: An Intensive Collaboration and the CLEC14A Observation

This study involved not only MDC but also with scientists from other institutions as well as Professor Nikolaus Rajewsky’s research unit at the Berlin Institute of Medical Systems Biology (BIMSB). There they compared Lavin’s cells with those of healthy donated cells. After conducting a single-cell analysis (looking at activity of each cell individually), they found a previously unknown cell population. In fact, based on this rigorous effort the scientists uncovered, in around 20% of the healthy donors, the majority of the activated satellite cells don’t produce any PAX7, despite the fact that the genetic information is present in the cells.

The team found that CLEC14A, a protein that is found in many blood vessel cells, was also highly expressed in Lavin’s muscle stem cells.

Summary

This study observes previously unknown subtype of satellite cells and includes 1) researchers identified thee cells in the stem cell niche, where the satellite cells reside, 2) PAX7 is not present in the cells, 3) other characteristic proteins such as CLEC14A are present instead, and 4) new muscle fibers can be derived from this cell population. This opens up a whole new pathway of research as up till now it was thought that only cells with PAX7 are considered targets for gene therapy research involving satellite cells. This new study reveals that the subtype discovered should also play a role in therapeutic development.

Max Delbruck Center for Molecular Medicine in the Helmholtz Association

MDC is an internationally renowned biomedical research center in Berlin. Named after Max Delbruck (one of the founders of modern genetics and molecular biology), it is one of sixteen research centers of the Helmholtz Association of German Research Centers. An elite institution, MDC has been nominated as 14th top research institute worldwide according to a Thompson Reuters ranking, based on research in molecular biology and genetics. It was founded in 1992 as the successor to the Zentralinstitut fur Molekularbiologie, which depended on the German Academy of Sciences Berlin till 1990. The institute combines research in Molecular Biology with clinical research with a focus on multi-organ diseases such as heart failure. Its general research areas include 1) cardiovascular and metabolic disease 2) cancer research 3) nervous system and 4) molecular systems biology.

Helmholtz Association of German Research Centers

This is the largest scientific organization in Germany—a union of 18 scientific-technical and biological-medical research centers. The annual budget of this network totals nearly 5 billion Euros, of which 72% are primarily raised from public funds. The remaining amounts are acquired via the individual centers in the form of contract funding.  Its public funds derive from the federal government (90%) and the rest from individual states in Germany

Lead Research/Investigator

Professor Simone Spuler, MDC

Dr. Andreas Marg, MDC

Nikolaus Rajewsky, MDC

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