Virus World

Ten children with the rare condition Artemis-deficient severe combined immunodeficiency had their immune systems either partially or fully restored with gene-replacement therapy. Children born without a working immune system due to a rare genetic disorder called Artemis-deficient severe combined immunodeficiency (Artemis-deficient SCID) may be able to lead normal lives thanks to a new gene-replacement therapy. A trial found that the therapy either partially or fully restored the immune systems of 10 infants with the condition. Each year, between 40 and 100 babies in the US are diagnosed with SCID. It is also known as bubble boy disease, after a 1970s documentary about a child with the condition who had to live inside a sterile, plastic bubble due to the lack of a functioning immune system. Most children with SCID will die before the age of 2 unless treated with a bone marrow transplant. However, infants with Artemis-deficient SCID – a rare subtype of the condition – are less likely to have a successful transplant due to unique genetic defects. Because gene-replacement therapy has shown promise in treating other types of SCID, Morton Cowan at the University of California, San Francisco, and his colleagues wanted to see if it could also treat Artemis-deficient SCID.

This subtype of SCID is caused by a defect in the gene that codes for the protein Artemis. Without Artemis, the body cannot produce important immune cells called T cells and B cells. The researchers extracted stem cells from the bone marrow of 10 infants with the condition and inserted corrected genetic information into the cells. The children then underwent a low dose of chemotherapy to kill cells in their bone marrow. This made space for the corrected stem cells, which were infused back into them using an IV. Follow-up blood tests found that all the children produced T cells and B cells between six and 16 weeks after treatment. Of the six infants who received the therapy two or more years ago, five now have fully functioning immune systems. With time, the other participants should also develop fully functional immune systems, says Jennifer Puck, also at the University of California, San Francisco. The next stage of the research is to conduct trials with more children. There were no serious side effects from the treatment itself, but researchers plan to follow the children for longer to be certain, says Cowan. The study may have also missed other potential side effects because of its small sample size, says Vincent Bonagura at the Feinstein Institutes for Medical Research in New York. But ultimately the treatment is a significant advancement in treating Artemis-deficient SCID, he says.

Research cited published in NEJM (Dec. 22, 2022):

https://doi.org/10.1056/NEJMoa2206575 

Scripps Research team finds that a nontoxic molecule closely related to resveratrol can overcome barriers to delivering gene therapy into stem cells. Gene therapy has broadened the treatment possibilities for those with immune system deficiencies and blood-based conditions, such as sickle cell anemia and leukemia. These diseases, which once would require a bone marrow transplant, can now be successfully treated by modifying patients’ own blood stem cells to correct the underlying genetic problem. But today’s standard process for administering gene therapy is expensive and time-consuming–a result of the many steps required to deliver the healthy genes into the patients’ blood stem cells to correct a genetic problem.

In a discovery that appears in the journal Blood, scientists at Scripps Research believe they have found a way to sidestep some of the current difficulties, resulting in a more efficient gene delivery method that would save money and improve 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,” says Bruce Torbett, PhD, associate professor in the Department of Immunology and Microbiology, who led the research. The new finding centers on caraphenol A, a small molecule closely related to resveratrol, which is a natural compound produced by grapes and other plants and found in red wine. Resveratrol is widely known as an antioxidant and anti-inflammatory agent. Similar to resveratrol, caraphenol A is anti-inflammatory, but in this study, it served a different role.

Torbett and his team became interested in the unique chemical properties of resveratrol and similar types of molecules and wondered if they could enable viral vectors, used in gene therapy to deliver genes, to enter blood stem cells more easily. This would be momentous because stem cells–and in particular, self-renewing hemopoietic stem cells–have many barriers of protection against viruses, making them challenging for gene therapy to infiltrate. “This is why gene therapy of hemopoietic stem cells has been hit-or-miss,” Torbett says. “We saw a way to potentially make the treatment process significantly more efficient.” The gene therapy treatment process currently requires isolating a very small population of hemopoietic stem cells from the blood of patients; these young cells can self-renew and give rise to all other types of blood cells. Therapeutic genes are then delivered to these cells via specially engineered viruses, called “lentiviral vectors,” which leverage viruses’ natural knack for inserting new genetic information into living cells.

However, hemopoietic stem cells are highly resilient to viral attacks. They protect themselves with structures known as interferon-induced transmembrane (IFITM) proteins, which intercept lentiviral vectors. Because of this, it can take many attempts–and a large quantity of expensive gene therapy vectors–to successfully delivery genes into hemopoietic stem cells, Torbett says. Torbett and his team found that by adding the resveratrol-like compound, caraphenol A, to human hemopoietic stem cells, along with the lentiviral vector mix, the cells let down their natural defenses and allowed vectors to enter more easily. Once the treated stem cells were placed into mice, they divided and produced blood cells containing the new genetic information.

Published in Blood on October 17, 2019: