Scientists have discovered a compound, similar to resveratrol, that can penetrate the natural defenses of stem cells to aid gene therapy.
Gene therapy has revolutionized treatment possibilities in recent years, particularly for patients suffering from immune system deficiencies and blood-based conditions. For example, diseases such as sickle cell anemia and leukemia, which would have previously required a bone marrow transplant for any hope of treatment, can now be managed by modifying the blood stem cells of patients, correcting the genetics at the root of the problem.
Although gene therapy is undeniably successful, the process for administering healthy genes into the patients’ blood stem cells to correct the genetic problem is costly and time consuming.
Scientists from the Scripps Research Institute (CA, USA) have found a way to streamline the process, hopefully making the gene delivery method more efficient and therefore improving treatment outcomes.
“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 Bruce Torbett, Associate Professor in the Department of Immunology and Microbiology, who led the research team.
The research is published in the journal Blood. It focuses on caraphenol A, which is a natural compound produced by plants and grapes, commonly found in red wine and is closely related to resveratrol. Resveratrol is a well-known antioxidant and anti-inflammatory agent and caraphenol A also has anti-inflammatory properties — although in this setting it has served a different purpose.
Resveratrol and similar molecules have specific chemical properties that triggered the scientists to consider whether they could be used to enable viral vectors to deliver genes into the blood stem cells more easily as part of gene therapy. Stem cells, in particular hemopoietic still cells such as those in the blood, are very well protected against viruses, making this process all the more challenging.
“This is why gene therapy of hemopoietic stem cells has been hit-or-miss,” Torbett stated. “We saw a way to potentially make the treatment process significantly more efficient.”
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The current gene therapy process entails isolating a few hemopoietic stem cells from the blood of patients, which can self-renew and differentiate into different types of blood cells, and into which therapeutically designed genes can be delivered via engineered viruses — lentiviral vectors — taking advantage of viruses’ ability to insert altered genetic information into existing cells.
Hemopoietic stem cells are particularly resistant to attack, using structures called interferon-induced transmembrane (IFITM) proteins as the first line of defense against such lentiviral vectors. This is what makes conventions gene therapy so time consuming and expensive as it can take many attempts before the vector is successfully implanted into the hemopoietic stem cells.
What Torbett and his team discovered was that if you added caraphenol A to the lentiviral vector mix, the stem cells let down these defenses, therefore, allowing easier access into the stem cells. The researchers tested the treated stem cells by placing them in mice where they divided and successfully produced new blood cells containing the corrected genes.
Not only is this new method give a more effective way of inserting the correct genetic information, but it also is more time efficient, which in itself gives many benefits for patients. The faster transfection of cells means that the new stem cells can be re-administered to the patient much sooner, which is better for them and also the stem cells are less likely to lose their self-renewing properties, which can be affected the longer they are outside of the body.
The team are continuing to work to discover more about why stem cells are so resistant to genetic manipulation in the hopes of further improving treatment efficacy and cost. They emphasize that they hope to be able to translate their work from the lab into the clinic as soon as possible so as to help the patients of these diseases, which are predominately children, as soon as possible.
Sources: Ozog S, Timberlake ND, Hermann K et al. Resveratrol trimer enhances gene delivery to hematopoietic stem cells by reducing antiviral restriction at endosomes. Blood. 134 (16), 1298—1311 (2019); https://scripps.edu/news-and-events/press-room/2019/20191017-torbett-genetherapy.html