Congratulations to Allara Zlyberberg, postdoctoral researcher in the Little Lab at the Melbourne node of the Novo Nordisk Foundation Centre for Stem Cell Medicine, reNEW, for winning first prize in the fourth ARTxSCIENCE competition.
Researchers from the group of reNEW PI Frank Staal employed a new platform to gain insights into T-cell development in patients with the severe inborn error of immunity RAG1-SCID. They also used the platform to test the effect of a proprietary stem cell gene therapy for this condition. The study, published in Blood Advances, highlights the potential of the platform to study T-cell development in immunodeficiencies in detail and assess the potency of novel gene therapies for these conditions.
In 2022, a patient with RAG1-SCID was treated for the first time at LUMC with a new stem cell gene therapy developed in the lab of reNEW PI Frank Staal. Patients with this condition lack a functioning immune system due to a defect in their DNA. The therapy repairs this defect in the patient’s blood stem cells outside the body. Once returned to the patient, the corrected stem cells can produce healthy immune cells.
“The trial is still ongoing, but the first patients treated are showing very promising results. The immune cells in their blood are recovering,” says pediatric immunologist and reNEW AI Lisa Ott de BruinThe clinical study has now been expanded to other European countries and to reNEW Melbourne.
Peeking
Peeking inside the ‘black box’ of T-cell development
T-cells are one of the immune cells derived from blood stem cells. Yet it remains challenging to learn more about how T-cells develop, both in healthy people and in patients with severe immune deficiencies such as RAG1-SCID.
Researcher Kirsten Canté-Barrett explains: “To mature into T-cells, blood stem cells travel to the thymus. Studying this in patients is challenging, as thymus biopsies are highly invasive and therefore generally not feasible. In this study, we therefore used artificial thymuses (ATOs) to study T-cell development in the lab.”
Blockade
ATOs are miniature 3D models of the thymus grown in the lab. These models have previously been used to study T-cell development in various forms of SCID. The researchers have now used them for the first time to gain more insight into RAG1-SCID and the effects of their stem cell gene therapy, while the same patients were undergoing treatment in a real-world clinical setting.
They found that blood stem cells from healthy donors successfully developed into T-cells in the ATOs, whereas this was not the case for blood stem cells from RAG1-SCID patients. “The diseased cells run into a blockade during their development, preventing them from maturing into fully functional T-cells. Thanks to the ATOs we were able to pinpoint exactly where this blockade occurs, something that would otherwise have been very difficult,” says Canté-Barrett.
Staal’s team then used the ATOs for the first time to study the effect of a lentiviral stem cell gene therapy on T-cell development. Lisa Ott de Bruin: “We examined how our proprietary stem cell therapy influences the development of T-cells in the diseased stem cells. We concluded that our therapy lifts the developmental blockade, allowing the stem cells to once again mature into functional T-cells. This corresponds with what we see in treated patients.”
Faster insights, faster treatments
According to the researchers, ATOs could become a powerful tool for developing new therapies. Staal: “ATOs allow us to study T-cell development much faster — in just six weeks instead of several months — and with far more precision. This means we can better understand rare immune disorders like SCID and speed up the testing of new therapies.”
To this end, the team are now actively exploiting ATOs as a diagnostic tool for SCID patients without a known genetic cause. These studies help distinguishing between thymic defects and hematopoietic stem cell defects which is key for their treatment plan. In parallel, the team assess T-cell development of iPS-derived hematopoietic stem cells – with patient-specific mutations – in ATOs to model hypomorphic RAG1 deficiencies and test the potential of novel gene therapies for these conditions. The latter is part of a Targeted Disease Team with collaborators Ng, Stanley and Elefanty from reNEW Melbourne.
Staal concludes: “Our hope is that these and other studies with ATOs will eventually lead to more treatment options for patients who currently have none.”
