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
AUG 27, 2020
Cardiology
Are Dry Mouth and Hypertension Connected?
AUG 27, 2020
Are Dry Mouth and Hypertension Connected?
Dry mouth is one of those things you sort of ignore until you can refill your water bottle. Maybe you should take a seco ...
SEP 06, 2020
Cell & Molecular Biology
The Beginnings of a Protein Are Captured in 3D
SEP 06, 2020
The Beginnings of a Protein Are Captured in 3D
There are many genes in the DNA that gives rise to an organism, and genes that code for protein are a critical part of t ...
SEP 14, 2020
Health & Medicine
Direct Amplification: Rapid, Extraction-Free RT-qPCR Results
SEP 14, 2020
Direct Amplification: Rapid, Extraction-Free RT-qPCR Results
As the SARS-CoV-2 pandemic continues to rage across the United States and around the globe, the demand for COVID-19 test ...
SEP 13, 2020
Cell & Molecular Biology
RNA Found on the Surface of Human Cells
SEP 13, 2020
RNA Found on the Surface of Human Cells
The surface of a cell carries many features to help it carry out its functions, communicate with other cells, gather inf ...
SEP 19, 2020
Cell & Molecular Biology
Reward and Punishment Take Similar Paths in the Mouse Brain
SEP 19, 2020
Reward and Punishment Take Similar Paths in the Mouse Brain
Scientists have determined that mice have brain cells that can help them learn to avoid bad experiences.
OCT 13, 2020
Immunology
Why Halloween Is Extra Scary for Kids With Peanut Allergies
OCT 13, 2020
Why Halloween Is Extra Scary for Kids With Peanut Allergies
A recent study showed that there is an 85 percent spike in peanut allergy anaphylaxis cases on Halloween. The study, per ...
Loading Comments...