Advancements in stem cell-based gene therapies for immune disorders

The group of reNEW Leiden PI Prof. Frank Staal, has published two papers on the development of hematopoietic stem cell-based lentiviral gene therapies. The first paper, published in Biomedicines, shows pre-clinical data that demonstrates safety and efficacy of a lentiviral gene therapy to treat the severe immunodeficiency RAG1-SCID. These data substantiate the Phase I/IIa clinical trial that’s currently ongoing in the EU, UK, Turkey and Australia. The second paper, published in Blood Advances, highlights the potential of epigenetic regulators to advance HSC-based gene correction further in the future. 

Hematopoietic stem cell (HSC) transplants from healthy donors can effectively treat patients with severe hematological and immunological diseases. However, these transplants are severely hindered by mismatch related complications, which means not all patients can be successfully treated. Staal: “Over the last decades, the genetic correction and transplantation of the patient’s own hematopoietic stem cells – called autologous stem cell gene therapy – has emerged as a compelling alternative. We are working on future therapies that employ this approach and thereby aim to cure inherited immune disorders.” Two articles on advancements related to this development were recently published by Staal’s group.

Data to support ongoing RAG1-SCID clinical trial
RAG1-SCID is one of the inherited immune disorders that Staal’s team is working to treat. Due to genetic flaws in the RAG1 gene, young patients with this hereditary disorder lack B and T cells – the cells that make up our adaptive immune system. These patients are therefore very vulnerable to infections. Recently, Staal’s group created a lentiviral gene therapy in which the patient’s HSCs are transplanted back into the patient after a functional RAG1 gene is integrated into the DNA of the cells. The therapy has recently entered a Phase I/IIa clinical trial and is currently recruiting patients in among others reNEW Leiden and Melbourne. The pre-clinical data that substantiate this trial are now published in Biomedicines.

In the study, Staal and his group studied the efficacy and safety of the HSC-based lentiviral gene therapy. “To prove the efficacy of the therapy we transduced HSCs of RAG1-SCID patients with our lentiviral vector, thereby restoring RAG1 levels in these cells. We then transplanted these stem cells into a immunocompromised mouse model,” says Staal. By doing so, the researchers were able to restore the development of functional  human T and B cells and functionality of the adaptive immune system. Additionally, and equally important, the researchers successfully demonstrated safety of the novel therapy. Staal: “For this we investigated if the RAG1 gene was integrated at safe locations of the DNA, meaning far away from locations that could cause cancer, and were excited to see that this was not the case.” Altogether, the results from this pre-clinical study show the efficacy and safety of the therapy and pave the way for the ongoing Phase I/IIa clinical trial.

Refining current protocols
Bringing gene therapies, such as the therapy for RAG1-SCID, to the clinic can be challenging due to high costs. “The production of viruses that can be used for gene therapies in a clinical setting is an expensive process, in some cases costing millions of euros to treat a small number of patients. These costs raise a barrier for clinical translation of therapies currently under development and are a critical concern within the field. It is therefore important to develop optimized protocols that help alleviate this financial burden,” says Staal.

In order to overcome this challenge, Staal’s team now developed an optimized protocol for the culture, expansion and viral transduction of hematopoietic stem cells in the lab. They discovered that the addition of epigenetic regulators had a positive impact on these processes. “We added two epigenetic regulators to our culture conditions and observed that both increased expansion of HSCs in the lab,” says Staal. He continues: “In addition, one of these compounds improved the efficiency of viral transductions, providing a major benefit for the gene therapy field as it ensures long-term correction of HSCs and reduces the costs associated with viral vectors.” The study thereby highlights the potential therapeutic effect of epigenetic regulators to advance HSC-based gene therapies in the future and emphasizes the importance of refining current culture protocols for successful clinical application.