Substituting the next-best protein

April 24, 2020

When an actor is unable to perform in the theatre, an understudy--ideally one with some practice in the role--can take her place on stage. A study from Dr. Bernard Jasmin's laboratory at the University of Ottawa and published today in Nature Communications shows that the same is true of proteins. Its results point the way toward novel therapies for Duchenne muscular dystrophy.

Children born with Duchenne muscular dystrophy (DMD) have a mutation in the X-chromosome gene that would normally code for dystrophin, a protein that provides structural integrity to skeletal muscles. The loss of this protein causes severe symptoms, including deteriorating muscle strength beginning around the age of four. The average life expectancy of a child with this condition currently stands at 26 years.

While there is no cure, a promising area of research has developed around the protein utrophin, which is ~ 80% identical to dystrophin and even takes its place early during muscle development. Utrophin is produced from a gene on Chromosome 6 and can be expected to be intact in a DMD patient.

"Utrophin-based therapy is actually applicable to all DMD patients, regardless of their dystrophin mutation" says Dr. Christine Péladeau, the lead post-doctoral fellow on this project. "And this is not something we see with most other therapeutic approaches."

This study looked at a specific "IRES-dependent translation" pathway, which induces a cell's ribosome to trigger utrophin's production. The team tested 262 FDA-approved drugs to see which ones could most effectively activate IRES-mediated translation to boost utrophin expression in muscle. Two drugs that are currently on the market stood out as the strongest contenders--the beta receptor blocker Betaxolol and the cholesterol-lowering drug Pravastatin. When administered in a mouse model of DMD, these drugs each promoted increases in muscle strength close to that of healthy mice.

A number of advantages support targeting utrophin as a DMD therapy above more difficult approaches including dystrophin gene replacement using viral vectors. The repurposing of FDA-approved drugs can also speed the clinical trial process. The doses required are expected to be quite low, improving the chances of low toxicity.

What's more, utrophin seems to be involved in the body's own efforts to fight the disease.

"There is a tendency for DMD muscles to try to naturally upregulate the levels of utrophin, knowing that it doesn't have dystrophin," says Dr. Bernard Jasmin, who leads the lab where the work was conducted. "Obviously it's not enough, but in the absence of this endogenous upregulation, DMD would be a lot worse."

Further stimulation of that natural response via the identified pathway works with the body to strengthen muscles, without the danger of an adverse immune response to the therapy. It also demonstrates the promise of using IRES-mediated translation for therapeutic purposes. It serves as a proof of principle to bolster the idea that this method could be used in other diseases like cancer and neurodegenerative diseases.
-end-


University of Ottawa

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.