New Gene Therapy Approach Reduces Cost and Improves Efficiency

A more efficient approach to gene therapy that could lower costs and improve patient outcomes has recently been developed by a team from Scripps Research. This work, published on October 17 in the journal Blood, offers a potential alternative to the standard process of delivering gene therapy, which is expensive, time-consuming, and requires many steps to administer healthy genes to the patients’ stem cells.

“If you can repair blood stem cells with a single gene delivery treatment, rather than multiple treatments over the course of many days, you can reduce the clinical time and expense, which removes some of the limitations of this type of approach,” explained research leader Bruce Torbett, PhD, associate professor in the Department of Immunology and Microbiology.

What is Gene Therapy?

The goal of gene therapy is to introduce a healthy version of a gene to a patient’s stem cells to replace a defective copy of this gene. This approach is designed to treat inherited conditions caused by genetic mutations, such as sickle cell anemia. Patients with sickle cell have a mutation in a gene that codes for a protein in blood cells, leading to misshaped cells that cause a myriad of clinical issues. The goal of gene therapy is to replace this mutated gene with a healthy copy to restore normal protein synthesis and eliminate the disease symptoms. This is often done by implanting the healthy gene into a modified virus, known as a viral vector, and having this virus use its innate ability to infiltrate host cells and inject this healthy gene into them.

The Current Approach

Gene therapy treatments typically require the harvesting of a small population of hemopoietic stem cells, the cells that serve as precursors for all types of blood cells, from the patient’s blood. Viral vectors containing therapeutic genes are then introduced to these cells with the goal being for them to insert this genetic information into the stem cells.

The hemopoietic stem cells defend themselves from viral penetrance using interferon-induced transmembrane (IFITM) proteins that block the viral vectors. For this reason, many gene therapies require a large number of vectors and many attempts for success, which is an expensive process.

A More Efficient Approach

In their work, the Scripps team focused on caraphenol A, a molecular relative of resveratrol, a natural compound made by grapes and other plants present in wine. Resveratrol is known to have antioxidant and anti-inflammatory properties. Although caraphenol A shares these anti-inflammatory properties, it served a much different purpose in this work.

Observing the chemical properties of resveratrol and associated molecules such as caraphenol A, Torbett and colleagues wanted to investigate whether they could be used in gene therapy to improve the viral vector’s ability to enter blood stem cells. Enhancing viral vector penetrance into host cells would be advantageous, being that the cells natural defense mechanisms against viral attacks present a challenge in gene therapy.

“This is why gene therapy of hemopoietic stem cells has been hit-or-miss,” explained Torbett. “We saw a way to potentially make the treatment process significantly more efficient.”

The researchers found that by adding caraphenol A to human hemopoietic stem cells with the viral vector present, the stem cell’s defense was weakened, and the viral penetrance increased. When these treated stem cells were implanted into mice in this study, they were observed to produce blood cells that contained the new genetic information.

In addition to saving costs, this approach also cuts down the time required for a patient to receive a gene therapy treatment. Reducing treatment time is not only convenient for the patient, but it lowers the chance that the stem cells lose their self-renewing properties as well. The more time the stem cells spend being outside of the body and being manipulated, the higher the likelihood of them losing their proliferative ability is.

Torbett’s team is continuing to research how stem cells combat viral attacks, hoping to lower the cost of gene therapy while improving efficiency.