Therapies for recombination-deficient severe combined immunodeficiency

Therapies for recombination-deficient severe combined immunodeficiency
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Leiden University Medical Center, Netherlands, is developing stem cell-based gene therapy for recombination-deficient severe combined immunodeficiency.

Leiden University Medical Center is the co-ordinating partner for the Recomb research consortium, which aims to develop a novel autologous haematopoietic stem cell-based gene therapy to fill the unmet medical need for treating recombination-deficient severe combined immunodeficiency (RAG-SCID)

Severe combined immunodeficiency (SCID) is a rare, life-threatening genetic disease. Affected infants are born without a functional immune system. If not diagnosed and treated in time, it leads to death in the first year of life. Currently, the standard of care for SCID is allogeneic haematopoietic stem cell transplantation (allo-SCT). Although the results with allo-SCT have significantly improved in the last decades, outcome is still unsatisfactory if a matched stem cell donor is not available. Moreover, allo-SCT is intrinsically associated with the risk of graft-versus-host disease (GvHD). Gene therapy offers a life-saving alternative for SCID patients and may increase their chance of survival with less risk of complications.

Recomb is a research consortium, funded by the European Union Horizon 2020 programme, aiming to develop new stem cell-based gene therapy treatment for the third most common type of SCID called recombination-deficient SCID or RAG-SCID. Here, we introduce our aims to fill the unmet medical need for treating RAG-SCID.

What is severe combined immunodeficiency?

Primary immunodeficiencies (PID) are a heterogeneous group of over 350 rare genetic disorders that affect either the development or the function of the immune system. The most severe form of PIDs is SCID, which comprises a group of diseases in which the cells of the adaptive immune system fail to develop properly due to an underlying genetic defect.

While T lymphocyte development is affected in all forms of SCID, concomitant deficiencies in B lymphocytes and natural killer cells are present depending on the genetic subgroup. To date more than 20 genes have been identified to cause SCID phenotypes within three major categories:

  1. Signalling defects (X-SCID)
  2. Metabolic defects (ADA-SCID)
  3. Recombination defects.

The latter is represented by genetic defects in the recombination machinery that drives V(D)J recombination of T-cell receptor (TCR) and immunoglobulin (Ig) genes. The most common defects are found in RAG1, RAG2 and Artemis genes.1-5

SCID affects around 1:35,000 infants, with approximately 145 babies born with the disease each year in the EU.6-7 SCID babies may often seem healthy at birth but, as they are born without a functional immune system, they typically experience a wide range of serious, eventually life-threatening infections early in their life, including pneumonia, meningitis and sepsis, and die within the first year unless effective treatment is given. When the SCID diagnosis is confirmed, 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.

Allogeneic haematopoietic stem cell transplantation

Currently, the standard of care is allo-SCT where the deficient/dysfunctional 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. Allo-SCT is most successful when performed with a human leukocyte antigen (HLA) matched family or unrelated donor. However, in more than half of the patients, a matched donor is not available. When allo-SCT treatment is performed with a mismatched donor, the transplant outcome and overall survival are significantly less successful. Moreover, any allo-SCT, particularly when a mismatched donor is used, bears the risk of 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. Thus, despite major improvements in haemopoietic stem cell transplantation (HSCT) outcome in SCID, allo-SCT is still facing major limitations with respect to both curative potential and survival chance.

Therefore, there is an urgent need for new and improved strategies based on the genetic correction of autologous stem cells where the patient’s own cells are modified and transplanted back. Advanced therapy medicinal products (ATMPs), involving gene therapies, are innovative therapies that offer groundbreaking new opportunities for more specific and targeted treatment.

The Recomb consortium

Recomb is a research consortium that has been set up to develop such an ATMP. Its overall aim is to provide an autologous stem cell-based gene therapy for treating the most common form of recombination-deficient SCID category, RAG1-SCID. Gene therapy is designed to correct deficiencies by delivering the therapeutic gene into the target cells using vectors, thus restoring the production and function of wild-type protein.

It is possible to replace faulty genes in the patient’s own, autologous haematopoietic stem cells…

Want to learn more about the Recomb consortium? Intrigued about the first-in-human clinical study and treatment for RAG1-SCID? Curious about the expected outcomes and benefits of this research?

Stay tuned for more, as the rest of this article will appear in issue 8 of Health Europa Quarterly, which will be published in February 2019.


  1. Oettinger MA et al. (1990). RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science 248(4962): 1517-23
  2. Oettinger MA et al. (1992). The recombination activating genes, RAG 1 and RAG 2, are on chromosome 11p in humans and chromosome 2p in mice. Immunogenetics 35(2): 97-101
  3. Cavazzana-Calvo M et al. (1996). RAG1 mediates signal sequence recognition and recruitment of RAG2 in V(D)J recombination. Cell 87(2): 253-62
  4. Buckley RH et al. (1997). Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants. J Pediatr 130(3): 378-87
  5. Al-Herz W et al. (2012). Classification of primary immunodeficiency disorders: one-fits-all does not help anymore. Clin Immunol 144(1): 24-5
  6. Kwan A et al. (2014). Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States.’ JAMA 2014 Aug 20;312(7):729-38
  7. Rechavi E et al. (2017). ‘First Year of Israeli Newborn Screening for Severe Combined Immunodeficiency-Clinical Achievements and Insights.’’ Front Immunol 2017 Nov 6;8:1448.

Professor Dr Frank JT Staal, PhD
Professor of Molecular Stem
Cell Biology
Co-ordinator of Recomb
Leiden University Medical Center
+31 71 526 4657

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