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.
The Latest on: Duchenne Muscular Dystrophy
- CRISPR’d Stem Cells Could Provide Enduring Therapy for Muscular Dystrophyon September 18, 2019 at 5:42 am
In the past several years, we have seen some major advancements in the study of Duchenne muscular dystrophy (DMD), a rare but devastating genetic disorder that causes muscle loss and physical ...
- Texas university will no longer bred dogs with a muscular wasting diseaseon September 18, 2019 at 3:10 am
Texas A&M University (TAMU) will stop breeding canines onsite to have the genetic disease duchenne muscular dystrophy (DMD), which eventually leaves sufferers unable to walk. This follows years of ...
- Study: Gene editing may correct genetic mutation responsible for Duchenne muscular dystrophyon September 17, 2019 at 10:03 pm
Duchenne muscular dystrophy (DMD) is a rare but devastating genetic disorder that causes muscle loss and physical impairments. Researchers at the University of Missouri School of Medicine have shown ...
- Positive preliminary results from ATL1102 for DMD Phase II trialon September 17, 2019 at 7:23 pm
It has been great to be able to include the boys with Duchenne Muscular Dystrophy who are no longer ambulant in a clinical trial and the participants have enjoyed being able to take part." ...
- Texas A&M researchers bred sick dogs in hopes of finding human muscular dystrophy cureon September 17, 2019 at 4:08 pm
The sick dogs are quiet. In this Sept. 11, 2019, photo, Texas A&M graduate student Kyle Cox, who has Duchenne muscular dystrophy, shakes Amber's paw before heading to symphonic band rehearsal at the ...
- PPMD Awards University of Florida $1 Million for Novel Gene Therapy Approach Targeting the Hearton September 17, 2019 at 10:12 am
HACKENSACK, N.J., Sept. 17, 2019 /PRNewswire/ -- Parent Project Muscular Dystrophy (PPMD), a nonprofit organization leading the fight to end Duchenne muscular dystrophy (Duchenne), announced plans to ...
- Santhera to Present Long-Term Data with Puldysa® (Idebenone) in Duchenne Muscular Dystrophy at Upcoming Medical Congresseson September 16, 2019 at 10:00 pm
Pratteln, Switzerland, September 17, 2019 – Santhera Pharmaceuticals (SIX: SANN) will present data on the therapeutic effects of long-term treatment with Puldysa® (idebenone) in Duchenne ...
- Texas A&M researchers quietly bred sick dogs in hopes of finding human muscular dystrophy cureon September 13, 2019 at 3:11 pm
The dogs live on campus because researchers at Texas A&M use them to study Duchenne muscular dystrophy — a degenerative disease that’s terminal for mostly young boys. University scientists are seeking ...
- The global Duchenne muscular dystrophy (DMD) therapeutics market at a CAGR of over 37% during the forecast periodon September 11, 2019 at 7:59 am
Global Duchenne Muscular Dystrophy (DMD) Therapeutics Market: About this market Download the full report: https://www.reportbuyer.com/product/5813494/?utm_source=PRN This Duchenne muscular ...
- Reclaim the Day raises awareness of Duchenne Muscular Dystrophyon September 7, 2019 at 5:27 pm
Nine-year-old James Allen celebrated World Duchenne Awareness Day with a little help from his friends … and a Beatles tribute band. The Beatles-themed bash for the Beatles-mad Petawawa boy and ...
via Google News and Bing News