T-max: maximising insights from severe combined immunodeficiency and related disorders
Lead Research Organisation:
Newcastle University
Department Name: Translational and Clinical Res Institute
Abstract
T lymphocytes (T cells) are a special type of white blood cell that is crucial to the human immune system. We know this partly because babies who are unlucky enough to be born without T cells get terribly sick with infections that barely affect healthy children. This very rare condition, called severe combined immunodeficiency ("SCID"), used to be a death sentence until the development of bone marrow transplantation from the late 1960s onwards. Nowadays, stem cell transplantation can save most of these children, as long as their condition is recognised before infection takes hold. For this reason, we now are starting to screen newborn babies for SCID using a test carried out alongside other screens on the dried blood spot already collected at a week of age. If T cell numbers are low, babies undergo further testing and treatment to protect them from infection until the immune system can be put right.
Usually, being born with low levels of T cells happens because of spelling mistakes in one of our genes. Genes, which are made of DNA, provide the instructions to make individual proteins. In SCID, mistakes in a single gene mean that T cells are missing a protein they can't do without. As a result, the T cells can't develop properly, leaving the immune system depleted. Scientists have worked out a lot about how healthy T cells develop from studying the many ways this process can go wrong. It turns out that spelling mistakes in many different genes can prevent T cells from developing. This is partly because T cells develop in such a remarkable way!
It can be very helpful to know exactly which gene has gone wrong to cause a new case of SCID. It guides the way a patient is treated and furthermore, makes it possible to predict the risk to future pregnancies within the family. Sometimes scientists have been able to design ways of replacing the missing part without a stem cell transplant, for instance by gene therapy or enzyme replacement in some cases. These types of clever treatment rely on knowing exactly which gene has gone wrong, since that is the one that needs to be replaced.
It's frustrating then that around 1 in 10 cases of SCID can't be explained genetically, even using the very modern technique of genome sequencing. In this research project, we will try to get to the bottom of why T cell development fails there and what we might be able to do about it.
Some of these patients might have new sorts of spelling mistakes in "old" SCID genes, perhaps hidden in parts of the DNA that have the power to turn off neighbouring genes. To give us a better chance of finding these we will look more widely around each SCID gene using new and powerful ways of reading along DNA molecules, and check whether genes are turned on or off in patient's bone marrow cells.
Other patients will have spelling mistakes in new genes that haven't been linked to SCID before - they aren't on any textbook list. We have already found some strong candidates by screening for spelling mistakes in past patients with SCID. We have more work to do to understand why the affected genes are so important for T cells, because they are active in lots of other tissues too. To help, we will study each spelling mistake in cells in the test tube, and find out how it disturbs the structure and function of the related protein. We also will study whether the same spelling mistakes in the same genes can cause the mouse version of SCID. If we can be sure of these things, we will have learned something new and important about how T cells work. We should be in a better position to diagnose the same sort of SCID in future babies and provide answers to their mums and dads. We and others will be working hard to find new and better ways to rescue T cell development without a stem cell transplant.
Usually, being born with low levels of T cells happens because of spelling mistakes in one of our genes. Genes, which are made of DNA, provide the instructions to make individual proteins. In SCID, mistakes in a single gene mean that T cells are missing a protein they can't do without. As a result, the T cells can't develop properly, leaving the immune system depleted. Scientists have worked out a lot about how healthy T cells develop from studying the many ways this process can go wrong. It turns out that spelling mistakes in many different genes can prevent T cells from developing. This is partly because T cells develop in such a remarkable way!
It can be very helpful to know exactly which gene has gone wrong to cause a new case of SCID. It guides the way a patient is treated and furthermore, makes it possible to predict the risk to future pregnancies within the family. Sometimes scientists have been able to design ways of replacing the missing part without a stem cell transplant, for instance by gene therapy or enzyme replacement in some cases. These types of clever treatment rely on knowing exactly which gene has gone wrong, since that is the one that needs to be replaced.
It's frustrating then that around 1 in 10 cases of SCID can't be explained genetically, even using the very modern technique of genome sequencing. In this research project, we will try to get to the bottom of why T cell development fails there and what we might be able to do about it.
Some of these patients might have new sorts of spelling mistakes in "old" SCID genes, perhaps hidden in parts of the DNA that have the power to turn off neighbouring genes. To give us a better chance of finding these we will look more widely around each SCID gene using new and powerful ways of reading along DNA molecules, and check whether genes are turned on or off in patient's bone marrow cells.
Other patients will have spelling mistakes in new genes that haven't been linked to SCID before - they aren't on any textbook list. We have already found some strong candidates by screening for spelling mistakes in past patients with SCID. We have more work to do to understand why the affected genes are so important for T cells, because they are active in lots of other tissues too. To help, we will study each spelling mistake in cells in the test tube, and find out how it disturbs the structure and function of the related protein. We also will study whether the same spelling mistakes in the same genes can cause the mouse version of SCID. If we can be sure of these things, we will have learned something new and important about how T cells work. We should be in a better position to diagnose the same sort of SCID in future babies and provide answers to their mums and dads. We and others will be working hard to find new and better ways to rescue T cell development without a stem cell transplant.
Technical Summary
Primary failure of T cell production causes a severe combined immunodeficiency (SCID) that is incompatible with human life beyond infancy. Painstaking forward genetic work in babies with this extreme and rare (1:50000) phenotype has illuminated key aspects of T cell development, led to precision therapies including pegylated ADA and gene therapy, and informed the development of immunosuppressive agents such as JAK inhibitors. The recent implementation of newborn screening for SCID recognises both the life-threatening nature of this condition and the potential for curative treatment. However, the failure to reach a genetic diagnosis in a stubborn 10% of cases hinders clinical care and connotes a missed scientific opportunity for improved understanding of T cell biology.
The aim of this programme is to pursue the molecular origins of SCID in these remaining hard-to-diagnose patients. By definition, this group will be enriched for novel genetic aetiologies including variants in yet-to-be-discovered disease genes and pathogenic non-coding variants affecting known disease genes. To identify and prioritise candidate variants, we will combine contemporary genomic methods including short and long read sequencing with multi-omic analysis of precious patient samples (blood and marrow). We will investigate the effects of putative deleterious variants on proteins, cells and systems in a variety of models, including knock-in mice.
As a result of previous diagnostic discovery in our SCID cohort, we bring to this programme 4 novel candidate disease genes at various stages of enquiry into pathomechanism. Each is a ubiquitously expressed and essential gene for which no knock-out mouse model exists; all genes bear rare, predicted deleterious missense variants in infants with SCID. Understanding the contribution of the encoded proteins to adaptive immunity will uncover new biology and may identify potential to rescue the function of hypomorphic alleles in affected patients.
The aim of this programme is to pursue the molecular origins of SCID in these remaining hard-to-diagnose patients. By definition, this group will be enriched for novel genetic aetiologies including variants in yet-to-be-discovered disease genes and pathogenic non-coding variants affecting known disease genes. To identify and prioritise candidate variants, we will combine contemporary genomic methods including short and long read sequencing with multi-omic analysis of precious patient samples (blood and marrow). We will investigate the effects of putative deleterious variants on proteins, cells and systems in a variety of models, including knock-in mice.
As a result of previous diagnostic discovery in our SCID cohort, we bring to this programme 4 novel candidate disease genes at various stages of enquiry into pathomechanism. Each is a ubiquitously expressed and essential gene for which no knock-out mouse model exists; all genes bear rare, predicted deleterious missense variants in infants with SCID. Understanding the contribution of the encoded proteins to adaptive immunity will uncover new biology and may identify potential to rescue the function of hypomorphic alleles in affected patients.
