Using nature’s scaffolding to coax cells to develop into muscle

by Fred Thys, Weymouth, Massachusetts

Neil Camarta, who has FSHD and founded the FSHD Canada Foundation, discovered that there is something called muscle regeneration when he partnered with Lululemon founder Chip Wilson to create Solve FSHD, a venture philanthropic association committed to putting $100 million into therapies for FSHD.

Camarta said he and Wilson learned that the Spinal Muscular Atrophy (SMA) Foundation was working on muscle regeneration for patients with that condition. Camarta said the SMA Foundation offered to work with Solve FSHD on research on rebuilding muscle.

Camarta learned that Stephen Badylak, DVM PhD MD, at the University of Pittsburgh’s McGowan Institute for Regenerative Medicine was looking into skeletal muscle regeneration in soldiers who had lost muscle due to war wounds. Of 13 patients with traumatic loss of huge amounts of muscle, called volumetric muscle loss in which the muscle’s regenerative capacity is overwhelmed, Badylak explained, “The reason that skeletal muscle regenerative capacity is overwhelmed is not known with certainty. It is unlikely due to an insufficient number of stem cells, but rather more likely that the genetic pathways that promote fibrosis suppress the innate regenerative pathways with this severe type of injury. Our current efforts involve trying to identify the promoters of this fibrotic pathway and figure out ways to block them.”

Badylak’s team was able to replace an average of 38% of the missing muscle mass.

“And [we saw] a huge increase in function, so these patients were all extremely happy with the outcomes,” he said. His team is now conducting a second clinical trial with a similar set of patients.

 

Secret sauce: Extracellular matrix

The key to the recovery was a material Badylak and his team have been studying for 25 years called the extracellular matrix, one of the signaling mechanisms with mammalian tissue responsible for regeneration. “We identified methods for removing the cells from tissues to harvest the extracellular matrix which remains,” he explained, “and we identified the favorable biologic properties of the matrix, including the signaling molecules that promote a regenerative response.

 

“When you put this material into the site of a muscle injury, it degrades and it releases signaling molecules that recruit your body’s own stem cells to that site,” Badylak continued. “It increases blood vessel formation at that site. It increases nerve growth at that site, and it increases muscle growth at that particular site. It makes sense that the body would build into our tissue mechanisms for repair following injury.”

 Badylak said the extracellular matrix, or ECM, is present in every tissue.

“I wondered if it would work for me,” said Camarta. He called Badylak, who agreed to see if muscle regeneration could work on patients with FSHD.

Camarta donated muscle tissue. Badylak found that the energy in muscle cells affected with FSHD increased, and the cells grew and divided.

The next step was to see if the therapy worked in mice affected with FSHD. Badylak provided ECM to work with mice at Myologica, in Baltimore, that are a model for slow progression FSHD, as well as mice with SMA and Duchenne muscular dystrophy, he said.

“We’re finding that, indeed, these same positive effects on skeletal muscle appear to work in these different animal models of disease,” Badylak said. “We’ve found that we can markedly decrease the amount of inflammation that’s there. We can increase the activity of what are called satellite cells or muscle progenitor cells, and we can show that this is associated with better function of the muscles than in the control group.”

 It doesn’t cure the disease, Badylak emphasized, but does increase the formation of new muscle tissue.

 

Next steps: Testing in larger animals

The question now, he said, is whether there is a potential therapeutic role for human patients with these diseases.

Before that question can be answered, Badylak said, studies in bigger animals are in progress with the material his team has supplied. If the results are positive, he said, he can approach the Food and Drug Administration to request either a pilot or a Phase 1 clinical trial to establish safety and dosage.

Badylak said his team’s role is to provide the material that is then used by other researchers in different animal models. The material being used is nano-sized lipid-bound vessels embedded in the extracellular matrix of every tissue, Badylak said. His team have been able to isolate these vessels and have found that they get the same results when they use these matrix-bound nanovesicles, or MBV, alone as they get by using the entire extracellular matrix.

“It looks like they’re one of the major bioactive components of the extracellular matrix,” Badylak explained. “And so in some of the studies being done, we are just injecting the MBV component of the ECM, and in some of our preliminary studies we’ve gotten some very, very good results.”

Camarta, who is 70, said regardless of when therapies for FSHD are found to halt the progression of the disease, he wants to be able to get some of his muscles back. “If I can regain my muscles back faster than I’m losing them, that’s a win.”

 

Courtesy of FSHD Society

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