DEC 29, 2019 2:35 PM PST

A Molecular Switch for Modulating Gene Therapy Doses

WRITTEN BY: Carmen Leitch

Genetic errors cause many different kinds of diseases, and gene therapy has aimed to relieve those symptoms by addressing the root cause; if the genetic error can be fixed, the symptoms of the illness will stop. But a major drawback to gene therapy is that once it's given to a patient, its effects can't be dialed down or controlled. Scientists have now created a kind of switch that can be added to gene therapies, so that doctors can have some control over how they are dosed. The work has been reported in Nature Biotechnology.

Scripps Research Immunology Professor Michael Farzan, PhD, developed a gene therapy switch with postdoctoral researcher Guocai Zhong, PhD and research assistant Haimin Wang. / Credit: Scripps Research

"I think that our approach offers the only practical way at present to regulate the dose of a gene therapy in an animal or a human," said the research leader, Michael Farzan, Ph.D., of Scripps Research in Jupiter.

The researchers incorporated a molecule called a morpholino that's already been approved by the Food and Drug Administration (for other uses) into gene therapy. They tested it by suppressing a gene for a hormone called erythropoietin (EPO), which is an anemia treatment. The scientists were able to control the expression of the gene over a wide range by using the morpholino.

When people are born with genetic mutations that cause disease, gene therapy could potentially cure the disease if it's successfully delivered to enough of the right cells, but it might have to be steadily administered since injections and drugs only stick around in the body for so long.

In this work, the researchers used a mouse model of anemia that's linked to kidney disease. They injected a modified EPO gene into the muscle tissue of the mice, and the EPO production was effectively reduced. When the morpholino was also applied, EPO levels went up dramatically, and remained there for a week.

"We got what I would have said before was an impossible range of in vivo regulation from this system," Farzan says.

In their system, the researchers used a kind of biological switch from a group of molecules called hammerhead ribozymes. These ribozymes cleave themselves in half when they are transcribed from DNA into an RNA molecule. The researchers used this switch as part of a therapeutic transgene; when it's copied into RNA, it will get cut in half before it can be translated into a protein. The morpholino stops the cutting of the RNA by blocking the ribozyme action, theoretically allowing more of the therapeutic RNA to be copied into protein. Thus, the ribozyme is a kind of off switch, while the morpholino turns the activity of the transgene on again.

The researchers want to also turn the ribozyme switch into a failsafe mechanism for gene therapies, allowing for errant transgenes to be permanently disabled.


Sources: AAAS/Eurekalert! via Scripps Research Institute, Nature Biotechnology

About the Author
  • Experienced research scientist and technical expert with authorships on 28 peer-reviewed publications, traveler to over 60 countries, published photographer and internationally-exhibited painter, volunteer trained in disaster-response, CPR and DV counseling.
You May Also Like
DEC 08, 2019
Cell & Molecular Biology
DEC 08, 2019
Time-Restricted Eating Improves Symptoms of Metabolic Syndrome
Occasional fasting has been linked to a variety of health benefits....
DEC 23, 2019
Genetics & Genomics
DEC 23, 2019
A New Type of Muscle Cell That Could be a Target for Gene Therapy is ID'ed
Muscles have a supply of restorative stem cells called satellite cells, and now they have identified a new type....
DEC 25, 2019
Drug Discovery & Development
DEC 25, 2019
New Drug to Make Breast Cancer Treatment More Affordable
The US Food and Drug Administration has granted accelerated approval to new breast cancer drug, trastuzumab deruxtecan. The drug’s increasing recogni...
JAN 20, 2020
Cell & Molecular Biology
JAN 20, 2020
Using Modified Red Blood Cells As a Drug Delivery System
For a drug to be effective, it has to get to the right place to exert its impact....
FEB 09, 2020
Cell & Molecular Biology
FEB 09, 2020
Switching Inflammation Off at the Molecular Level
While chronic inflammation is a natural result of getting old, experiencing stress, and toxin exposure, it's been theorized to be the basis for many chronic diseases....
FEB 10, 2020
Cell & Molecular Biology
FEB 10, 2020
Lighting a Path to an Alzheimer's Disease Treatment
Alzheimer's impacts millions of people around the world; globally, it is thought to cost $605 billion a year, and there is still no way to treat it....
Loading Comments...