Periodic Reporting for period 5 - RECOMB (Stem-cell based gene therapy for recombination deficient SCID (RECOMB))
Reporting period: 2023-07-01 to 2024-12-31
Severe combined immunodeficiency is a rare, life-threatening genetic disease in which the cells of the adaptive immune system fail to develop. To date, more than 20 genes have been identified to cause SCID phenotypes from which the third most common type is the recombination-deficient SCID (RAG-SCID). SCID affects 1:35,000 infants who may often seem healthy at birth but they typically experience a wide range of serious, life-threatening infections early in life and die within the first year without effective treatment. When it is diagnosed, the first aim is to treat active infections and prevent further infections. These treatments, however, are only temporary solutions, often partly effective, and they do not treat the underlying condition. The most common recombination defects are caused by mutations in RAG1, RAG2 and Artemis genes. Currently, the standard of care is allogeneic haematopoietic stem cell transplantation (allo-SCT). In allo-SCT, the deficient immune system is corrected by replacing the patient’s bone marrow with healthy, unmodified allogeneic donor stem cells from which all immune cells can properly develop. Despite the improvements, the transplant outcome and overall survival are still unsatisfactory in more than half of the patients lacking matched family or unrelated stem cell donor. Moreover, allo-SCT is intrinsically associated with the risk of graft-versus-host disease (GvHD), an immune reaction of donor T-cells directed against the recipient’s organs and tissues. This leads to a significantly inferior outcome in terms of morbidity, hospitalisation and transplant-related mortality. As allo-SCT is still facing limitations, there is an urgent need for new therapies based on the genetic correction of autologous stem cells where the patient’s own cells are modified and transplanted back. Recomb is a research consortium developing stem cell-based gene therapy (GT) as a life-saving alternative for RAG1-SCID patients. Recomb started in 2018 and is coordinated by Leiden University Medical Center (LUMC), Netherlands. It brings together world-renowned clinical and research professionals from 17 members who have expertise in primary immunodeficiencies, and some have recently conducted the first successful clinical trials using autologous stem cell-based GT for X-SCID and ADA-SCID in patients lacking a matched donor. These trials showed significant safety and efficacy in correcting immunodeficiency, allowing children to live normal lives. Recomb’s aim was to perform a first-in-human clinical study and provide treatment for RAG1-SCID patients. We aim to correct the deficiency by delivering the therapeutic gene into the target cells using a vector. after successful transduction, the introduced gene is passed to all newly formed immune cells, thus restoring the immune function and curing the patient for life after a single treatment. Using the patient’s own stem cells will exclude GvHD risk and increase survival. A unique aspect of the protocol is that the patient’s cells–not the patient–are transported to the transduction site at LUMC. After the cells are genetically modified, they are returned to the local centres for transplantation. Thus, the therapy is more comfortable and cost-effective for patients.
Previously a lentiviral-based approach was developed for transferring the therapeutic RAG1 gene into CD34+ HSCs to correct the deficiency, and proof-of-principle was obtained in preclinical mouse studies. It supported the feasibility of using gene-corrected stem cells to restore immune function by restoring B- and T-cell production. The vector batches were successfully produced and tested. When evaluating in vitro safety, the IVIM and SAGA assays showed that the vectors were not genotoxic and deemed safe for the trial. Moreover, we have been developing a novel, combined assay for preclinical risk assessment that provide more supportive data for regulatory evaluations. In vitro and in vivo preclinical evaluations have been performed in Rag1- Omenn syndrome models, Rag1-deficient mouse cells, and RAG1-SCID patient cells to help determine the full clinical spectrum of patients that can benefit from the therapy. Efficacy testing in hypomorphic Rag1 mouse models showed significant amelioration of the disease phenotype. The long-term efficacy and safety assessed in Rag1-deficient mice detected no signs of toxicity and normal survival. The vector also efficiently transduced RAG1-SCID patient cells and restored stable RAG1 expression with no toxicity. Altogether, these assessments confirmed efficacy and safety of gene therapy. After vector efficacy, safety and stability were confirmed, the trial opened in the Netherlands in Spain, Poland, UK, Italy, Turkey and Australia. So far, five patients have been enrolled and infused in this ongoing study, all of whom are clinically stable. Preliminary safety and efficacy data are promising. Long-term effects of gene therapy will continue to be monitored at both cellular and molecular levels using standardized protocols. This first-in-human real-world experience provides proof of concept that lentiviral RAG1-SCID gene therapy is effective and safe, and can be successfully conducted in a multinational trial design. Moreover, a separate study investigates the long-term outcome in transplanted SCID patients from a perspective of quality of life and health economics using validated questionnaires.
With the success of this project many advantageous impacts are envisaged on patients’ lives, society and economy, as well as on scientific and clinical practice. Most importantly, it is anticipated to provide treatment for RAG1-SCID patients with higher efficacy and safety. Moreover, it is expected to be more comfortable and cost-effective for the patients. Additionally, due to cryopreservation of the product, its distribution is facilitated to several centres, with the possibility to reach any affected child in the EU. This new model, including highly specialised centres with the expertise to receive, transduce and return cells to remote clinical units in the EU, will likely become a global standard. Besides, GT is expected to significantly reduce healthcare costs for the treatment of RAG-SCID in the long term and potentially many others. Given the success with X-SCID and ADA-SCID, GT will likely become the treatment of choice for the majority of SCID patients, offering an effective treatment option for over 70% of all genetically defined SCID patients in Europe and beyond. It is becoming more important to provide such therapy as the number of diagnosed RAG-SCID patients is expected to significantly increase due to newborn screening studies. Along with these ambitions, the consortium expects that the obtained knowledge can also be applied to other diseases that can be treated with autologous stem cell-based GT, i.e. SCIDs, immune and lysosomal storage diseases and haemoglobinopathies. The successful treatment of the first patients provides clinical proof of concept for RECOMB’s approach to treating RAG1-SCID and a promising perspective towards the above-mentioned expectations.