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Teaser, summary, work performed and final results

Periodic Reporting for period 1 - RECOMB (Stem-cell based gene therapy for recombination deficient SCID (RECOMB))

Teaser

Severe combined immunodeficiency (SCID) 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...

Summary

Severe combined immunodeficiency (SCID) 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 around 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 their life, and die within the first year without effective treatment. When SCID is diagnosed, the first aim is to treat active infections and to prevent further infections. These treatments, however, are only temporary solutions, often partly effective, and they do not treat the underlying condition. The most common defects are found in RAG1, RAG2 and Artemis genes.
Currently, the standard of care for SCID 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 in allo-SCT, the transplant outcome and overall survival are still unsatisfactory in more than half of the patients who lack 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 major 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 such stem cell-based gene therapy as a life-saving alternative for RAG1- SCID patients. Recomb received funding from the EU Horizon 2020 programme and started its activities in 2018. It is coordinated by Leiden University Medical Center (LUMC) in the Netherlands and brings together world-renowned clinical and research professionals from one Israeli and 15 European institutes and the International Patient Organisation for Primary Immunodeficiencies. The members have expertise in primary immunodeficiencies, and some have recently conducted the first successful clinical trials using autologous stem cell-based gene therapy for X-linked SCID and ADA-SCID in patients lacking a matched donor. These trials showed significant safety and efficacy in correcting the immunodeficiency, allowing children to live normal lives.
Recomb aims to perform first-in-human clinical study and provide treatment for RAG1-SCID patients recruited at the participating centres. The therapy is designed to correct the deficiency by delivering the therapeutic gene into the target cells using a vector. If the transduction of these cells is successful, 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. The use of the patient’s own stem cells will exclude the risk of GvHD and thereby increases survival. In addition, a unique aspect of the protocol is that the patient’s cells – not the patient – will be transported to the transduction site at LUMC, and after the cells are genetically modified, they will be returned to the local centres for transplantation. Thus, the therapy is expected to be more comfortable and cost-effective for the patients and their families.

Work performed

Previously the members of the Recomb consortium successfully developed a lentiviral-based approach for transferring the therapeutic RAG1 gene into CD34+ hematopoietic stem cells 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 the immune function by restoring B-cell and T-cell production.
During the first period of the project, a lentiviral vector batch was successfully produced to support the planned clinical trial. The in vitro safety of the batch has been evaluated. In vitro immortalization assay and the new surrogate assay for genotoxicity assessment proved a beneficial safety profile and a non-transforming nature of the vector. In vitro and in vivo efficacy tests have been initiated in Rag1-deficient mouse cells, Rag1- Omenn syndrome models, and RAG1-SCID patient cells to help determine the full clinical spectrum of patients that can benefit from the therapy. Furthermore, preclinical validation studies of the vector have confirmed the feasibility of gene therapy using human CD34+ stem cells. Upon regulatory approval, ten patients will be recruited at the participating centres to conduct the trial. These patients will be monitored at both cellular and molecular levels to assess short and long-term effects of gene therapy. For cellular analyses, the optimization of highly standardized immune monitoring protocols and tools have been accomplished in this period. Also, knowledge is currently being acquired of the normal immune system development in the first years of life as reference for the interpretation of immune reconstitution upon gene therapy. As molecular characterization is also important, protocols have been set up for state-of-the-art vector safety analyses, and functional readout of the RAG1 gene-corrected cells to measure immune reconstitution in detail. Moreover, questionnaires and individual interviews have been developed for ethical, clinical and economic evaluations. All collected parameters (clinical, cellular, molecular) are expected to improve future cellular and gene therapy‒based treatments.

Final results

If Recomb is indeed as successful as expected, many advantageous impacts are envisaged on patients’ lives, society and economy, as well as on the scientific and clinical practice.
Most importantly, it is anticipated to provide treatment for RAG1-SCID patients with higher efficacy and safety. Moreover, the therapy is expected to be more comfortable and cost-effective for the patients. Additionally, due to cryopreservation of the product, its distribution will be 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, gene therapy 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, gene therapy 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 the current 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 gene therapy, i.e. other SCIDs, immune disorders, lysosomal storage diseases and haemoglobinopathies.

Website & more info

More info: http://www.recomb.eu.