Skeletal muscle cells isolated using the ERBB3 and NGFR surface markers (right) restore human dystrophin (green) after transplantation significantly greater than previous methods (left).
Discovery is major step towards a stem cell replacement therapy for Duchenne Muscular Dystrophy
UCLA scientists have developed a new strategy to efficiently isolate, mature and transplant skeletal muscle cells created from human pluripotent stem cells, which can produce all cell types of the body. The findings are a major step towards developing a stem cell replacement therapy for muscle diseases including Duchenne Muscular Dystrophy, which affects approximately 1 in 5,000 boys in the U.S. and is the most common fatal childhood genetic disease.
The study was published in the journal Nature Cell Biology by senior author April Pyle, associate professor of microbiology, immunology and molecular genetics and member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. Using the natural human development process as a guide, the researchers developed ways to mature muscle cells in the laboratory to create muscle fibers that restore dystrophin, the protein that is missing in the muscles of boys with Duchenne.
Without dystrophin, muscles degenerate and become progressively weaker. Duchenne symptoms usually begin in early childhood; patients gradually lose mobility and typically die from heart or respiratory failure around age 20. There is currently no way to reverse or cure the disease.
For years, scientists have been trying different methods that direct human pluripotent stem cells to generate skeletal muscle stem cells that can function appropriately in living muscle and regenerate dystrophin-producing muscle fibers. However, the study led by Pyle found that the current methods are inefficient; they produce immature cells that are not appropriate for modeling Duchenne in the laboratory or creating a cell replacement therapy for the disease.
“We have found that just because a skeletal muscle cell produced in the lab expresses muscle markers, doesn’t mean it is fully functional,” said Pyle. “For a stem cell therapy for Duchenne to move forward, we must have a better understanding of the cells we are generating from human pluripotent stem cells compared to the muscle stem cells found naturally in the human body and during the development process.”
By analyzing human development, the researchers found a fetal skeletal muscle cell that is extraordinarily regenerative. Upon further analysis of these fetal muscle cells two new cell surface markers called ERBB3 and NGFR were discovered; this enabled the reserchers to precisely isolate muscle cells from human tissue and separate them from various cell types created using human pluripotent stem cells.
Once they were able to isolate skeletal muscle cells using the newly identified surface markers, the research team matured those cells in the lab to create dystrophin-producing muscle fibers. The muscle fibers they created were uniformily muscle cells, but the fibers were still smaller than those found in real human muscle.
“We were missing another key component,” said Michael Hicks, lead author of the study. The skeletal muscle cells were not maturing properly, he explained. “We needed bigger, stronger muscle that also had the ability to contract.”
Once again, the team looked to the natural stages of human development for answers. Hicks discovered that a specific cell signaling pathway called TGF Beta needs to be turned off to enable generation of skeletal muscle fibers that contain the proteins that help muscles contract. Finally, the team tested their new method in a mouse model of Duchenne.
“Our long term goal is to develop a personalized cell replacement therapy using a patient’s own cells to treat boys with Duchenne,” said Hicks. “So, for this study we followed the same steps, from start to finish, that we’d follow when creating these cells for a human patient.”
First, the Duchenne patient cells were reprogrammed to become pluripotent stem cells. The researchers then removed the genetic mutation that causes Duchenne using the gene editing technology CRISPR-Cas9. Using the ERBB3 and NGFR surface markers, the skeletal muscle cells were isolated and then injected into mice at the same time a TGF Beta inhibitor was administered.
“The results were exactly what we’d hoped for,” said Pyle. “This is the first study to demonstrate that functional muscle cells can be created in a laboratory and restore dystrophin in animal models of Duchenne using the human development process as a guide.”
Further research will focus on generating skeletal muscle stem cells that can respond to continuous injury and regenerate new muscle long-term using the team’s new isolation and maturation strategy.
Learn more: UCLA researchers create skeletal muscle from stem cells
The Latest on: Duchenne Muscular Dystrophy
- Muscular dystrophy drug wins approvalon December 13, 2019 at 6:09 pm
The FDA said late Thursday it approved Sarepta Therapeutics' Vyondys 53 for patients with a form of Duchenne's muscular dystrophy. Duchenne's affects about 1 in every 3,600 boys in the U.S., causing ...
- FDA gives nod to first newborn screening test for Duchenne muscular dystrophyon December 13, 2019 at 6:00 pm
has won a thumbs up from the U.S. FDA for its GSP Neonatal Creatine Kinase-MM kit. The assay is the first test approved in the U.S. for help in screening newborns for Duchenne muscular dystrophy (DMD) ...
- FDA allows new test for newborn screenings of muscular dystrophyon December 13, 2019 at 2:22 pm
(KXAN) — The U.S. Food and Drug Administration has authorized testing to aid in newborn screenings of Duchenne Muscular Dystrophy, a rare genetic disorder that causes progressive muscle deterioration ...
- Police K9 handlers surprise Derry boy struggling with muscular dystrophy with a wheelchair accessible vanon December 13, 2019 at 2:01 pm
Groce struck up a relationship over a year ago with Aiden Moore of Derry and his mother over social media. While Aiden underwent treatments at the hospital for Duchenne muscular dystrophy, he would ...
- FDA Approves Previously Rejected Muscular Dystrophy Treatmenton December 13, 2019 at 12:42 pm
The US Food and Drug Administration approved a Duchenne muscular dystrophy drug yesterday (December 13) that it had originally rejected in August, reports STAT. The approval is based on the results of ...
- Sarepta Catches a Big Break With Duchenne Muscular Dystrophy Drugon December 13, 2019 at 12:10 pm
Sarepta Therapeutics Inc. (NASDAQ: SRPT) shares jumped on Friday after the firm announced that the U.S. Food and Drug Administration (FDA) has approved Vyondys 53 (golodirsen) for the treatment of ...
- In Surprise Decision, US Approves Muscular Dystrophy Drugon December 13, 2019 at 11:42 am
The FDA said late Thursday it approved Sarepta Therapeutics' Vyondys 53 for patients with a form of Duchenne's muscular dystrophy. Duchenne's affects about 1 in every 3,600 boys in the U.S., causing ...
- Sarepta wins surprise approval for second Duchenne muscular dystrophy drugon December 13, 2019 at 7:49 am
The agency announced the accelerated approval of Cambridge, Massachusetts-based Sarepta Therapeutics’ Vyondys 53 (golodirsen) for Duchenne muscular dystrophy, or DMD, in patients who carry a ...
- PerkinElmer Launches First FDA-Approved Assay Kit to Screen for Duchenne Muscular Dystrophy in Newbornson December 13, 2019 at 5:20 am
This solution is the first commercially available assay for screening newborns affected by Duchenne muscular dystrophy (DMD). DMD is an X-linked recessive disease and the most prevalent type of ...
- FDA authorizes first test to aid in newborn screening for Duchenne Muscular Dystrophyon December 12, 2019 at 4:17 pm
SILVER SPRING, Md., Dec. 12, 2019 /PRNewswire/ -- Today, the U.S. Food and Drug Administration authorized marketing of the first test to aid in newborn screening for Duchenne Muscular Dystrophy (DMD), ...
via Google News and Bing News