Inherited Immunological Diseases

Inborn errors of immunity (IEI) are a group of rare inherited diseases that result in immunodeficiency and/or autoimmunity, inflammation and malignancy. Around 500 individual genes have been identified to cause different IEI and this number continues to increase with wider application of next generation genetic sequencing. We aim to determine the molecular and cellular mechanisms by which specific gene mutations in IEI cause immunological diseases and to use this knowledge to develop new therapies.

Cell and gene therapies, once limited to research studies, are now used widely in clinical medicine for a broad range of indications from ultra-rare, inherited diseases to autoimmunity and transplantation to solid malignancies and blood cancers. Many forms of cellular immunotherapy are based on the infusion of patient-derived immune cells which have been genetically engineered ex vivo to enhance their function (e.g., to improve their ability to recognise and kill cancer cells). Other forms of gene therapy are designed to specifically correct inherited mutations in various cell types.

Our portfolio of research in the field of cell and gene therapy includes engineering of T cells (effector and regulatory) and stem cells, spanning the translational pipeline from animal models to phase I/II First in Human clinical trials.

Projects

Understanding the pathogenesis of inborn errors of immunity (inherited immunodeficiency disorders)

As clinical academics we provide clinical care for one of the largest cohort of adult patients with inborn errors of immunity (IEI) in Europe. Our research group aims to understand the molecular and cellular pathogenesis of these diseases, both to identify new causative genes and to understand how specific genetic mutations or variants of unknown significance impact immune cell function. For this we use a combination of bioinformatic approaches, in-vitro cell line models and primary cells. We aim to improve genetic diagnosis of IEI, understand how different mutations in specific IEI genes contribute to variation in disease phenotype and test whether targeted IEI drug therapies correct immune cell function.

Lead Investigators

• Professor Siobhan Burns
• Professor Emma Morris

Developing novel cell and gene therapy approaches to treat inborn errors of immunity

We are using gene editing approaches (eg CRISPR/Cas9, Base and Prime Editing) to correct monogenic defects identified in our patient population. In vitro and in vivo experiments are performed to demonstrate functional correction of affected immune cells and therefore the potential to reverse the clinical phenotype observed in patients.

Lead Investigators

• Professor Emma Morris (Institute of Immunity & Transplantation, UCL)
• Professor Siobhan Burns (Institute of Immunity & Transplantation, UCL)

Clinical research in patients with immunodeficiency

We undertake a range of clinical studies to investigate immunodeficiency conditions and their consequences, with a particular focus on chronic infection. Recent work has included analyses of Campylobacter infections in common variable immunodeficiency, SARS-CoV-2 neutralisation capacity of therapeutic immunoglobulin products, investigation of chronic COVID-19 and chronic norovirus infection and the gut mucosal microbiome in chronic granulomatous disorder.

Lead Investigators

• Dr David Lowe (Institute of Immunity & Transplantation, UCL)
• Professor Siobhan Burns (Institute of Immunity & Transplantation, UCL)

Exploring antibiotic resistance in the respiratory tract of patients with antibody deficiency

We are investigating phenotypic and molecular indicators of antibiotic resistance in respiratory samples from antibody-deficient patients. This includes the use of metagenomics to define the resistome and assess possible transmission between patients in the clinical service.

Lead Investigator

• Dr David Lowe (Institute of Immunity & Transplantation, UCL)

Clinical research relating to novel stem cell and gene therapies for inborn errors of immunity

We have transplanted the largest number of adults with primary immunodeficiency in the world and perform translational clinical research on these cohorts to improve clinical outcomes, identify optimal transplant protocols and to describe late complications. We recruit patients to first in human clinical trials exploring the safety, feasibility and efficacy of novel gene therapy approaches for monogenic immunodeficiencies. As these diseases are rare or ultra-rare, we work with many collaborators worldwide.

Lead Investigator

• Professor Emma Morris (Institute of Immunity & Transplantation, UCL)

Development of next generation of T cell therapies using advanced gene editing techniques

We are using gene editing approaches to develop novel T cell therapy approaches for inherited and acquired diseases. Our research focuses on developing platform technologies applicable to a wide variety of T cell therapies which we hope will reduce the need for chemotherapy and pave the way for in vivo T cell engineering. 

Lead Investigator

• Dr Tom Fox (Institute of Immunity & Transplantation, UCL)

Our experts

Selected publications

1. Fink DL, Idilli O, Shields A, Richter A, Burns SO (2024). Prevalence of Anti-Interferon α Auto-Antibodies in Patients with Antibody Deficiency. J Clin Immunol. 2024 Jul 11;44(7): 161.
2. Degirmencay A, Thomas S, Holler A, Burgess S, Morris EC, Stauss HJ (2024). Exploitation of CD3ζ to enhance TCR expression levels and antigen-specific T cell function. Front Immunol. 2024 May 30;15: 1386132.
3. Anantharachagan A, Loh SY, Burns SO ... Morris EC (2024). Allogeneic hematopoietic stem cell transplantation outcome in oldest known surviving patients with Wiskott-Aldrich syndrome. J Allergy Clin Immunol Glob. 2023 Nov 22;3(1): 100191.
4. Roa-Bautista A, Brown LK, Tadros S, Burns SO, Godbole G*, Lowe DM* (2023). Clinical Features, Immunological Characteristics, and Treatment Outcomes of Campylobacter spp. Infections in Patients With Common Variable Immunodeficiency. J Allergy Clin Immunol Pract 2023; 11: 3493-3501.e4.
5. Minskaia E, Maimaris J ... Morris EC, Burns SO (2023). Autosomal Dominant STAT6 Gain of Function Causes Severe Atopy Associated with Lymphoma. J Clin Immunol. 2023 Oct;43(7): 1611-1622.
6. Albuquerque AS, Maimaris J, McKenna AJ ... Morris EC, Burns SO (2023). Practical challenges for functional validation of STAT1 gain of function genetic variants. Clin Exp Immunol. 2023 Apr 25;212(2): 166-169.
7. Fox TA, Houghton BC, Petersone L ... Burns SO, Sansom DM, Booth C, Morris EC (2022). Therapeutic gene editing of T cells to correct CTLA-4 insufficiency. Sci Transl Med. 2022 Oct 26;14(668).
8. Brown LK, Moran E, Goodman A, Baxendale H ... Lowe DM (2022). Treatment of chronic or relapsing COVID-19 in immunodeficiency. J Allergy Clin Immunol 2022; 149: 557-561.
9. Brown LK, Ruis C, Clark I, Roy S ... Burns SO, Breuer J*, Lowe DM* (2019). A comprehensive characterisation of chronic norovirus infection in immune deficient hosts. J Allergy Clin Immunol 2019; 44:1450-1453.
10. Ruis C, Brown LK, Roy S, Atkinson C, Burns SO ... Breuer J*, Lowe DM* (2018). Mutagenesis in Norovirus in Response to Favipiravir Treatment. N Engl J Med 2018 379: 2173-2176.

Gene & stem cell therapies: Correcting nature's spelling mistakes

Emma Morris, Professor of Clinical Cell and Gene Therapy, explains how doctors and scientists can use new gene therapy and gene editing methods to treat rare inherited diseases for the Medical Sciences Public Lecture Series.